U.S. patent application number 09/916440 was filed with the patent office on 2002-05-09 for cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting b-amyloid peptide release and/or its synthesis by use of such compounds.
Invention is credited to Audia, James E., Britton, Thomas C., Cwi, Cynthia L., Dressman, Bruce A., Droste, James J., Freedman, Stephen, Henry, Steven S., John, Varghese, Latimer, Lee H., Mabry, Thomas E., McDaniel, Stacey L., Neitz, Jeffrey, Nissen, Jeffrey S., Pleiss, Michael A., Porter, Warren J., Reel, Jon K., Scott, William Leonard, Stucky, Russell D., Thorsett, Eugene D., Tung, Jay S., Wu, Jing.
Application Number | 20020055500 09/916440 |
Document ID | / |
Family ID | 26744963 |
Filed Date | 2002-05-09 |
United States Patent
Application |
20020055500 |
Kind Code |
A1 |
Wu, Jing ; et al. |
May 9, 2002 |
Cycloalkyl, lactam, lactone and related compounds, pharmaceutical
compositions comprising same, and methods for inhibiting B-amyloid
peptide release and/or its synthesis by use of such compounds
Abstract
Disclosed are compounds which inhibit .beta.-amyloid peptide
release and/or its synthesis, and, accordingly, have utility in
treating Alzheimer's disease. Also disclosed are pharmaceutical
compositions comprising a compound which inhibits .beta.-amyloid
peptide release and/or its synthesis as well as methods for
treating Alzheimer's disease both prophylactically and
therapeutically with such pharmaceutical compositions.
Inventors: |
Wu, Jing; (San Mateo,
CA) ; Tung, Jay S.; (Belmont, CA) ; Thorsett,
Eugene D.; (Moss Beach, CA) ; Pleiss, Michael A.;
(Sunnyvale, CA) ; Nissen, Jeffrey S.;
(Indianapolis, IN) ; Neitz, Jeffrey; (San
Francisco, CA) ; Latimer, Lee H.; (Oakland, CA)
; John, Varghese; (San Francisco, CA) ; Freedman,
Stephen; (Walnut Creek, CA) ; Britton, Thomas C.;
(Carmel, IN) ; Audia, James E.; (Indianapolis,
IN) ; Reel, Jon K.; (Carmel, IN) ; Mabry,
Thomas E.; (Indianapolis, IN) ; Dressman, Bruce
A.; (Indianapolis, IN) ; Cwi, Cynthia L.;
(Indianapolis, IN) ; Droste, James J.;
(Indianapolis, IN) ; Henry, Steven S.; (New
Palestine, IN) ; McDaniel, Stacey L.; (Bloomington,
IN) ; Scott, William Leonard; (Indianapolis, IN)
; Stucky, Russell D.; (Indianapolis, IN) ; Porter,
Warren J.; (Indianapolis, IN) |
Correspondence
Address: |
BURNS DOANE SWECKER & MATHIS L L P
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Family ID: |
26744963 |
Appl. No.: |
09/916440 |
Filed: |
July 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09916440 |
Jul 30, 2001 |
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08996422 |
Dec 22, 1997 |
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60064851 |
Dec 23, 1996 |
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Current U.S.
Class: |
514/212.03 ;
514/327; 514/424; 514/659 |
Current CPC
Class: |
A61P 25/28 20180101;
C07D 223/18 20130101; A61K 38/05 20130101; C07D 471/06 20130101;
A61K 31/5513 20130101; A61K 31/40 20130101; C07D 471/08 20130101;
C07D 307/33 20130101; C07C 237/22 20130101; C07D 471/04 20130101;
A61K 31/445 20130101; C07C 2603/32 20170501; C07D 311/76 20130101;
A61K 31/4015 20130101 |
Class at
Publication: |
514/212.03 ;
514/327; 514/424; 514/659 |
International
Class: |
A61K 031/55; A61K
031/45; A61K 031/4015; A61K 031/13 |
Claims
What is claimed is:
1. A method for inhibiting .beta.-amyloid peptide release and/or
its synthesis in a cell which method comprises administering to
such a cell an amount of a compound or a mixture of compounds
effective in inhibiting the cellular release and/or synthesis of
.beta.-amyloid peptide wherein said compounds are represented by
formula I: 111wherein R.sup.1 is selected from the group consisting
of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted
alkyl, substituted alkenyl, substituted alkynyl, substituted
cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and
heterocyclic; W, together with --C(H).sub.pC(.dbd.X)--, forms a
cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or
substituted cycloalkenyl group wherein each of said cycloalkyl,
cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted
cycloalkenyl group is optionally fused to form a bi- or multi-fused
ring system (preferably no more than 5 fused rings) with one or
more ring structures selected from the group consisting of
cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group
which, in turn, each of such ring structures are optionally
substituted with 1 to 4 substituents selected from the group
consisting of hydroxyl, halo, alkoxy, substituted alkoxy,
thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl,
carboxyl esters, alky, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,
N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted
alkylamino, N,N-disubstituted alkylamino, --NHC(O)R.sup.4,
--NHSO.sub.2R.sup.4, --C(O)NH.sub.2, --C(O)NHR.sup.4,
--C(O)NR.sup.4R.sup.4, --S(O)R.sup.4, --S(O).sub.2R.sup.4,
--S(O).sub.2NHR.sup.4 and --S(O).sub.2NR.sup.4R.sup.4 where each
R.sup.4 is independently selected from the group consisting of
alkyl, substituted alkyl, or aryl; X is selected from the group
consisting of oxo (.dbd.O), thiooxo (.dbd.S), hydroxyl (--H, --OH),
thiol (H,--SH) and hydro (H,H); Y is represented by the formula:
112wherein each R.sup.2 is independently selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl
and heterocyclic; Z is represented by the formula --T--CX'X"C(O)--
where T is selected from the group consisting of a bond covalently
linking R.sup.1 to --CX'X"--, oxygen, sulfur, --NR.sup.5 where
R.sup.5 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is
hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or
X' and X" together form an oxo group; m is an integer equal to 0 or
1; n is an integer equal to 0, 1 or 2; p is an integer equal to 0
or 1 such that when p is zero, the ring defined by W and
--C(H).sub.pC(.dbd.X)-- is unsaturated at the carbon atom of ring
attachment to Y and when p is one, the ring is saturated at the
carbon atom of ring attachment to Y, with the following provisos:
A. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a 2-(S)-indanol group; B.
when R.sup.1 is phenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
trans-2-hydroxy-cyclohex-1-yl group; C. when R.sup.1 is phenyl, Z
is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then W, together
with >CH and >C.dbd.X, does not form a gammabutyrolactone
group or a 5,5-dimethyl-gammabutyrolactone group; D. when R.sup.1
is phenyl, Z is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
.epsilon.-caprolactam group; E. when R.sup.1 is cyclopropyl,
R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p
is 1, then W, together with >CH and >C.dbd.X, does not form
an N-methylcaprolactam group; F. when R.sup.1 is
4-chlorobenzoyl-CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G. when
R.sup.1 is 2-phenylphenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R.sup.1 is
CH.sub.3OC(O)CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-(t-butylC(O)CH.sub-
.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; I. when R.sup.1 is
4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,
CH.sub.3OC(O)CH.sub.2--, 4-HOCH.sub.2-phenyl,
2,4,6-trifluorophenyl, 2-trifluoromethyl-4-fluorophenyl, or
CH.sub.3S--, R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1,
n is 1, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a 2,3-dihydro-1-(N,N-diethylamino-C-
H.sub.2CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; J. when
R.sup.1 is 2,6-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH(OH)C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2-
CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, K. when m is 1
and n is 1, then 113does not equal cycloalkyl of from 3 to 8 carbon
atoms optionally substituted with 1 to 3 alkyl groups.
2. A method for preventing the onset of AD in a human patient at
risk for developing AD which method comprises administering to said
patient a pharmaceutical composition comprising a pharmaceutically
inert carrier and an effective amount of a compound or a mixture of
compounds of formula I: 114wherein R.sup.1 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl,
heteroaryl and heterocyclic; W, together with
--C(H).sub.pC(.dbd.X)--, forms a cycloalkyl, cycloalkenyl,
heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl
group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic,
substituted cycloalkyl or substituted cycloalkenyl group is
optionally fused to form a bi- or multi-fused ring system
(preferably no more than 5 fused rings) with one or more ring
structures selected from the group consisting of cycloalkyl,
cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in
turn, each of such ring structures are optionally substituted with
1 to 4 substituents selected from the group consisting of hydroxyl,
halo, alkoxy, substituted alkoxy, thioalkoxy, substituted
thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino,
N-substituted alkylamino, N-alkyl N-substituted alkylamino,
N,N-disubstituted alkylamino, --NHC(O)R.sup.4, --NHSO.sub.2R.sup.4,
--C(O)NH.sub.2, --C(O)NHR.sup.4, --C(O)NR.sup.4R.sup.4,
--S(O)R.sup.4, --S(O).sub.2R.sup.4, --S(O).sub.2NHR.sup.4 and
--S(O).sub.2NR.sup.4R.sup.4 where each R.sup.4 is independently
selected from the group consisting of alkyl, substituted alkyl, or
aryl; X is selected from the group consisting of oxo (.dbd.O),
thiooxo (.dbd.S), hydroxyl (--H, --OH), thiol (H,--SH) and hydro
(H,H); Y is represented by the formula: 115wherein each R.sup.2 is
independently selected from the group consisting of alkyl
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula --T--CX'X"C(O)-- where T is
selected from the group consisting of a bond covalently linking
R.sup.1 to --CX'X"--, oxygen, sulfur, --NR.sup.5 where R.sup.5 is
hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen,
hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X"
together form an oxo group; m is an integer equal to 0 or 1; n is
an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such
that when p is zero, the ring defined by W and
--C(H).sub.pC(.dbd.X)-- is unsaturated at the carbon atom of ring
attachment to Y and when p is one, the ring is saturated at the
carbon atom of ring attachment to Y, with the following provisos:
A. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a 2-(S)-indanol group; B.
when R.sup.1 is phenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
trans-2-hydroxy-cyclohex-1-yl group; C. when R.sup.1 is phenyl, Z
is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then W, together
with >CH and >C.dbd.X, does not form a gammabutyrolactone
group or a 5,5-dimethyl-gammabutyrolactone group; D. when R.sup.1
is phenyl, Z is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
E-caprolactam group; E. when R.sup.1 is cyclopropyl, R.sup.2 is
--CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form an
N--methylcaprolactam group; F. when R.sup.1 is
4chlorobenzoyl-CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G. when
R.sup.1 is 2-phenylphenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>--CH and >C.dbd.X, does not form an
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R.sup.1 is
CH.sub.3OC(O)CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-(t-butylC(O)CH.sub-
.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; I. when R.sup.1 is
4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,
CH.sub.3OC(O)CH.sub.2--, 4-HOCH.sub.2-phenyl,
2,4,6-trifluorophenyl, 2-trifluoromethyl-4-fluorophenyl, or
CH.sub.3S--, R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1,
n is 1, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a 2,3-dihydro-1-(N,N-diethylamino-C-
H.sub.2CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; J. when
R.sup.1 is 2,6-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH(OH)C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2-
CH2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, K. when m is 1 and
n is 1, then 116 does not equal cycloalkyl of from 3 to 8 carbon
atoms optionally substituted with 1 to 3 alkyl groups.
3. A method for treating a human patient with AD in order to
inhibit further deterioration in the condition of that patient
which method comprises administering to said patient a
pharmaceutical composition comprising a pharmaceutically inert
carrier and an effective amount of a compound or a mixture of
compounds of formula I: 117wherein R.sup.1 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl,
heteroaryl and heterocyclic; W, together with
--C(H).sub.pC(.dbd.X)--, forms a cycloalkyl, cycloalkenyl,
heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl
group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic,
substituted cycloalkyl or substituted cycloalkenyl group is
optionally fused to form a bi- or multi-fused ring system
(preferably no more than 5 fused rings) with one or more ring
structures selected from the group consisting of cycloalkyl,
cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in
turn, each of such ring structures are optionally substituted with
1 to 4 substituents selected from the group consisting of hydroxyl,
halo, alkoxy, substituted alkoxy, thioalkoxy, substituted
thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino,
N-substituted alkylamino, N-alkyl N-substituted alkylamino,
N,N-disubstituted alkylamino, --NHC(O)R.sup.4, --NHSO.sub.2R.sup.4,
--C(O)NH.sub.2, --C(O)NHR.sup.4, --C(O)NR.sup.4R.sup.4,
--S(O)R.sup.4, --S(O).sub.2R.sup.4, --S(O).sub.2NHR.sup.4 and
--S(O).sub.2NR.sup.4R.sup.4 where each R.sup.4 is independently
selected from the group consisting of alky, substituted alkyl, or
aryl; X is selected from the group consisting of oxo (.dbd.O),
thiooxo (.dbd.S), hydroxyl (--H, --OH), thiol (H,--SH) and hydro
(H,H); Y is represented by the formula: 118wherein each R.sup.2 is
independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula --T--CX'X"C(O)-- where T is
selected from the group consisting of a bond covalently linking
R.sup.1 to --CX'X"--, oxygen, sulfur, --NR.sup.5 where R.sup.5 is
hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen,
hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X"
together form an oxo group; m is an integer equal to 0 or 1; n is
an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such
that when p is zero, the ring defined by W and
--C(H).sub.pC(.dbd.X)-- is unsaturated at the carbon atom of ring
attachment to Y and when p is one, the ring is saturated at the
carbon atom of ring attachment to Y, with the following provisos:
A. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a 2-(S)-indanol group; B.
when R.sup.1 is phenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
trans-2-hydroxy-cyclohex-1-yl group; C. when R.sup.1 is phenyl, Z
is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then W, together
with >CH and >C.dbd.X, does not form a gammabutyrolactone
group or a 5,5-dimethyl-gammabutyrolactone group; D. when R.sup.1
is phenyl, Z is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
.epsilon.-caprolactam group; E. when R.sup.1 is cyclopropyl,
R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p
is 1, then W, together with >CH and >C.dbd.X, does not form
an N-methylcaprolactam group; F. when R.sup.1 is
4-chlorobenzoyl-CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G. when
R.sup.1 is 2-phenylphenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R.sup.1 is
CH.sub.3OC(O)CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-(t-butylC(O)CH.sub-
.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; I. when R.sup.1 is
4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,
CH.sub.3OC(O)CH.sub.2--, 4-HOCH.sub.2-phenyl,
2,4,6-trifluorophenyl, 2-trifluoromethyl4-fluorophenyl, or
CH.sub.3S--, R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1,
n is 1, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a 2,3-dihydro-1-(N,N-diethylamino-C-
H.sub.2CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; J. when
R.sup.1 is 2,6-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH(OH)C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2-
CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, K. when m is 1
and n is 1, then 119 does not equal cycloalkyl of from 3 to 8
carbon atoms optionally substituted with 1 to 3 alkyl groups.
4. A method according to any of claims 1, 2 or 3 where, in formula
I, m is zero.
5. A method according to claim 4 wherein R.sup.1 is aryl or
heteroaryl.
6. A method according to claim 5 wherein R.sup.1 is selected from
the group consisting of (a) phenyl, (b) a substituted phenyl group
of the formula: 120wherein R.sup.c is selected from the group
consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo,
hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein R.sup.b and
R.sup.c are fused to form a heteroaryl or heterocyclic ring with
the phenyl ring wherein the heteroaryl or heterocyclic ring
contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms
independently selected from the group consisting of oxygen,
nitrogen and sulfur R.sup.b and R.sup.b' are independently selected
from the group consisting of hydrogen, halo, nitro, cyano,
trihalomethyl, alkoxy, and thioalkoxy with the proviso that when
R.sup.c is hydrogen, then R.sup.b and R.sup.b' are either both
hydrogen or both substituents other than hydrogen, (c) 2-naphthyl,
(d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions
with 1 to 5 substituents selected from the group consisting alkyl,
alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and
heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl
containing 1 to 3 substituents selected from the group consisting
of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl,
thioalkoxy, thioaryloxy provided that said substituents are not
ortho to the heteroaryl attachment to the --NH group.
7. The method according to claim 5 wherein R.sup.1 is selected from
the group consisting of mono-, di- and tri-substituted phenyl
groups.
8. The method according to claim 7 wherein R.sup.1 is a
disubstituted phenyl selected from the group consisting of
3,5-dichlorophenyl, 3,5-difluorophenyl,
3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3-(trifluoromethyl)4-chlorophenyl,
3-chloro4-cyanophenyl, 3-chloro-4-iodophenyl, and
3,4-methylenedioxypheny- l.
9. The method according to claim 7 wherein R.sup.1 is a
monosubstituted phenyl selected from the group consisting of
4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl,
4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.
10. The method according to claim 7 wherein R.sup.1 is a
trisubstituted phenyl selected from the group consisting of
3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.
11. The method according to claim 5 wherein R.sup.1 is selected
from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl,
benzothiazol-6-yl, 5-indolyl, and phenyl.
12. A method according to any of claims 1, 2 or 3 wherein m is
one.
13. A method according to claim 12 wherein R.sup.1 is selected from
the group consisting of phenyl, 1-naphthyl, 2-naphthyl,
2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl,
2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,
2-trifluoromethylphenyl- , 4-fluorophenyl, 4-chlorophenyl,
4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl,
4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl,
4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl,
4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl,
3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl,
3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl,
3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,
2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,
3,5-difluorophenyl, 3,5-dichlorophenyl,
3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,
3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,
2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,
2,3,4,5,6-pentafluoroph- enyl, 2,5-dimethylphenyl, 4-phenylphenyl,
2-fluoro-3-trifluoromethylphenyl- , adamantyl, benzyl,
2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,
iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl,
--CH.sub.2-cyclohexyl, --CH.sub.2-cyclopentyl,
--CH.sub.2CH.sub.2-cyclopropyl, --CH.sub.2CH.sub.2-cyclobutyl,
--CH.sub.2CH.sub.2-cyclohexyl, --CH.sub.2CH.sub.2-cyclopentyl,
pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including
5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl),
thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl,
furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,
thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,
2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-- yl,
3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,
1-phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl,
(CH.sub.3).sub.2CH.dbd.CHCH.sub.2CH.sub.2CH(CH.sub.3)--,
.phi.C(O)CH.sub.2-, thien-2-yl-methyl, 2-(thien-2-yl)ethyl,
3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,
2-(4-methoxyphenyl)ethyl- , norboran-2-yl, (4-methoxyphenyl)methyl,
(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,
(3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl- ,
(4-methoxyphenyl)methyl, (4-methylphenyl)methyl,
(4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,
(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,
(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,
(1-trifluoromethyl)ethyl, (4methoxyphenyl)ethyl,
CH.sub.3OC(O)CH.sub.2--, benzylthiomethyl,
5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl,
indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl,
CH.sub.3CH.dbd.CH--, CH.sub.3CH.sub.2CH.dbd.CH--,
(4-chlorophenyl)C(O)CH.sub.2--, (4-fluorophenyl)C(O)CH.sub.2--,
(4-methoxyphenyl)C(O)CH.sub.2--, 4-(fluorophenyl)-NHC(O)CH.sub.2--,
1-phenyl-n-butyl, (.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2NC(O)CH.sub.2--,
(.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2--, methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH.sub.2--, 4-methoxyphenyl-C(O)CH.sub.2--,
phenyl-C(O)CH.sub.2--, CH.sub.3C(O)N(.phi.)-, ethenyl,
methylthiomethyl, (CH.sub.3).sub.3CNHC(O)CH.sub.2--,
4fluorophenyl-C(O)CH.sub.2--, diphenylmethyl, phenoxymethyl,
3,4-methylenedioxyphenyl-CH.sub.2--, benzo[b]thiophen-3-yl,
(CH.sub.3).sub.3COC(O)NHCH.sub.2--, trans-styryl,
H.sub.2NC(O)CH.sub.2CH.sub.2--,
2-trifluoromethylphenyl-C(O)CH.sub.2,
.phi.C(O)NHCH(.phi.)CH.sub.2--, mesityl,
CH.sub.3CH(.dbd.NHOH)CH.sub.2--,
4-CH.sub.3-.phi.-NHC(O)CH.sub.2CH.sub.2--,
.phi.C(O)CH(.phi.)CH.sub.2--, (CH.sub.3).sub.2CHC(O)NHCH(.phi.)-,
CH.sub.3CH.sub.2OCH.sub.2--,
CH.sub.3OC(O)CH(CH.sub.3)(CH.sub.2).sub.3--, 2,2,2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH.sub.3-benzofuran-3-yl,
2-(2,4-dichlorophenoxy)ethyl, .phi.SO.sub.2CH.sub.2--,
3-cyclohexyl-n-propyl, CF.sub.3CH.sub.2CH.sub.2CH.sub.2- and
N-pyrrolidinyl.
14. A method according to any of claims 1, 2 or 3 where n is one or
two, and each R.sup.2 is independently selected from the group
consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl,
heteroaryl and heterocyclic.
15. The method according to claim 14 wherein R.sup.2 is selected
from the group consisting of methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, 2-methyl-n-butyl,
6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl,
cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclohexyl,
--CH.sub.2CH.sub.2-cyclopr- opyl, --CH.sub.2CH.sub.2-cyclohexyl,
--CH.sub.2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,
m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,
phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl,
p-(CH.sub.3).sub.2NCH.sub.2CH.sub.2CH.sub.2O-benzyl,
p-(CH.sub.3).sub.3COC(O)CH.sub.2O-benzyl, p-(HOOCCH.sub.2O)-benzyl,
2-aminopyrid-6-yl, p-(N-morpholino-CH.sub.2CH.sub.2O)-benzyl,
--CH.sub.2CH.sub.2C(O)NH.sub.2, --CH.sub.2-imidazol4-yl,
--CH.sub.2-(3-tetrahydrofuranyl), --CH.sub.2-thiophen-2-yl,
--CH.sub.2(1-methyl)cyclopropyl, --CH.sub.2-thiophen-3-yl,
thiophen-3-yl, thiophen-2-yl, --CH.sub.2--C(O)O-t-butyl,
--CH.sub.2--C(CH.sub.3).sub.3,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, 2-methylcyclopentyl,
cyclohex-2-enyl, --CH[CH(CH.sub.3).sub.2]COOCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).dbd.CH.sub.2, --CH.sub.2CH.dbd.CHCH.sub.3
(cis and trans), --CH.sub.2OH, --CH(OH)CH.sub.3,
--CH(O-t-butyl)CH.sub.3, --CH.sub.2OCH.sub.3, --(CH2)4NH-Boc,
--(CH2)4NH.sub.2, --CH.sub.2-pyridyl, pyridyl, --CH.sub.2-naphthyl,
--CH.sub.2-(N-morpholino), p-(N-morpholino-CH.sub.2C-
H.sub.2O)-benzyl, benzo[b]thiophen-2-yl,
5-chlorobenzo[b]thiophen-2-yl,
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,
5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,
6-methoxynaphth-2-yl, --CH.sub.2CH.sub.2SCH.sub.3, thien-2-yl,
thien-3-yl, and the like.
16. A method according to any of claims 1, 2 or 3 wherein the
cyclic groups defined by W and --C(H).sub.pC(.dbd.X)-- is selected
from the group consisting of lactones, lactams, thiolactones,
thiolactams, heterocyclic and cycloalkyl groups.
17. The method according to claim 16 wherein the cyclic group
defined by W and --C(H).sub.pC(.dbd.X)--, forms a lactam or
thiolactam ring of the formula: 121wherein p is zero or one, T is
selected from the group consisting of alkylene, substituted
alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
18. The method according to claim 17 wherein the lactam ring is
selected from the group consisting of 122wherein A-B is selected
from the group consisting of alkylene, alkenylene, substituted
alkylene, substituted alkenylene and --N.dbd.CH--; Q' is oxygen or
sulfur; each V is independently selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; R.sup.b is selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl,
heterocyclic, and the like; R.sup.c is selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and
substituted cycloalkyl; t is an integer from 0 to 4; t' is an
integer from 0 to 3; and w is an integer from 0 to 3.
19. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)-- is a ring of
the formula: 123wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
20. The method according to claim 19 wherein the alcohol or thiol
substituted groups is selected from the group consisting of
124wherein each V is independently selected from the group
consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkly,
alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an
integer from 0 to 3.
21. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 125wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
22. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 126wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
23. The method according to claim 22 wherein the compound of
formula I is selected from the group consisting of 127wherein each
V is independently selected from the group consisting of hydroxy,
acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted
alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl,
cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,
trihalomethyl and the like; R.sup.a is selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an
integer from 0 to 4; and w is an integer from 0 to 3.
24. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 128wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alknyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
25. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 129wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl,. cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
26. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 130wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
27. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 131wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
28. The method according to claim 27 wherein the compound of
formula I is selected from the group consisting of: 132
29. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 133wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
30. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 134wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
31. The method according to claim 16 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 135wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
32. A pharmaceutical composition comprising a pharmaceutically
inert carrier and a pharmaceutically effective amount of a compound
of formula I: 136wherein R.sup.1 is selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
substituted alkyl, substituted alkenyl, substituted alkynyl,
substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl
and heterocyclic; W, together with --C(H).sub.pC(.dbd.X)--, forms a
cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or
substituted cycloalkenyl group wherein each of said cycloalkyl,
cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted
cycloalkenyl group is optionally fused to form a bi- or multi-fused
ring system (preferably no more than 5 fused rings) with one or
more ring structures selected from the group consisting of
cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group
which, in turn, each of such ring structures are optionally
substituted with 1 to 4 substituents selected from the group
consisting of hydroxyl, halo, alkoxy, substituted alkoxy,
thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl,
carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,
N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted
alkylamino, N,N-disubstituted alkylamino, --NHC(O)R.sup.4,
--NHSO.sub.2R.sup.4, --C(O)NH.sub.2, --C(O)NHR.sup.4,
--C(O)NR.sup.4R.sup.4, --S(O)R.sup.4, --S(O).sub.2R.sup.4,
--S(O).sub.2NHR.sup.4 and --S(O).sub.2NR.sup.4R.sup.4 where each
R.sup.4 is independently selected from the group consisting of
alkyl, substituted alkyl, or aryl; X is selected from the group
consisting of oxo (.dbd.O), thiooxo (.dbd.S), hydroxyl (--H, --OH),
thiol (H,--SH) and hydro (H,H); Y is represented by the formula:
137wherein each R.sup.2 is independently selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl
and heterocyclic; Z is represented by the formula --T--CX'X"C(O)--
where T is selected from the group consisting of a bond covalently
linking R.sup.1 to --CX'X"--, oxygen, sulfur, --NR.sup.5 where
R.sup.5 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is
hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or
X' and X" together form an oxo group; m is an integer equal to 0 or
1; n is an integer equal to 0, 1 or 2; p is an integer equal to 0
or 1 such that when p is zero, the ring defined by W and
--C(H).sub.pC(.dbd.X)-- is unsaturated at the carbon atom of ring
attachment to Y and when p is one, the ring is saturated at the
carbon atom of ring attachment to Y, with the following provisos:
A. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a 2-(S)-indanol group; B.
when R.sup.1 is phenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
trans-2-hydroxy-cyclohex-1-yl group; C. when R.sup.1 is phenyl, Z
is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then W, together
with >CH and >C.dbd.X, does not form a gammabutyrolactone
group or a 5,5-dimethyl-gammabutyrolactone group; D. when R.sup.1
is phenyl, Z is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
.epsilon.-caprolactam group; E. when R.sup.1 is cyclopropyl,
R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p
is 1, then W, together with >CH and >C.dbd.X, does not form
an N-methylcaprolactam group; F. when R.sup.1 is
4-chlorobenzoyl-CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G. when
R.sup.1 is 2-phenylphenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R.sup.1 is
CH.sub.3OC(O)CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-(t-butylC(O)CH.sub-
.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; I. when R.sup.1 is
4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,
CH.sub.3OC(O)CH.sub.2--, 4-HOCH.sub.2-phenyl,
2,4,6-trifluorophenyl, 2-trifluoromethyl-4-fluorophenyl, or
CH.sub.3S--, R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1,
n is 1, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a 2,3-dihydro-1-(N,N-diethylamino-C-
H.sub.2CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; J. when
R.sup.1 is 2,6-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH(OH)C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2-
CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, K. when m is 1
and n is 1, then 138 does not equal cycloalkyl of from 3 to 8
carbon atoms optionally substituted with 1 to 3 alkyl groups.
33. The pharmaceutical composition according to claim 32 where, in
formula I, m is zero.
34. The pharmaceutical composition according to claim 33 wherein
R.sup.1 is aryl or heteroaryl.
35. The pharmaceutical composition according to claim 34 wherein
R.sup.1 is selected from the group consisting of (a) phenyl, (b) a
substituted phenyl group of the formula: 139wherein R.sup.c is
selected from the group consisting of acyl, alkyl, alkoxy,
alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl,
thioalkoxy, and wherein R.sup.b and R.sup.c are fused to form a
heteroaryl or heterocyclic ring with the phenyl ring wherein the
heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which
from 1 to 3 are heteroatoms independently selected from the group
consisting of oxygen, nitrogen and sulfur R.sup.b and R.sup.b' are
independently selected from the group consisting of hydrogen, halo,
nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the
proviso that when R.sup.c is hydrogen, then R.sup.b and R.sup.b'
are either both hydrogen or both substituents other than hydrogen,
(c) 2-naphthyl, (d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or
8 positions with 1 to 5 substituents selected from the group
consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl,
thioalkoxy, aryl, and heteroaryl, (e) heteroaryl, and (f)
substituted heteroaryl containing 1 to 3 substituents selected from
the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo,
nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said
substituents are not ortho to the heteroaryl attachment to the --NH
group.
36. The pharmaceutical composition according to claim 32 wherein
R.sup.1 is selected from the group consisting of mono-, di- and
tri-substituted phenyl groups.
37. The pharmaceutical composition according to claim 36 wherein
R.sup.1 is a disubstituted phenyl selected from the group
consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl,
3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3-(trifluoromethyl)4chlorophenyl,
3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and
3,4-methylenedioxyphenyl.
38. The pharmaceutical composition according to claim 36 wherein
R.sup.1 is a monosubstituted phenyl selected from the group
consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl,
4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl,
4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.
39. The pharmaceutical composition according to claim 36 wherein
R.sup.1 is a trisubstituted phenyl selected from the group
consisting of 3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.
40. The pharmaceutical composition according to claim 32 wherein
R.sup.1 is selected from 2-naphthyl, quinolin-3-yl,
2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and
phenyl.
41. The pharmaceutical composition according to any of claim 32
wherein m is one.
42. The pharmaceutical composition according to claim 41 wherein
R.sup.1 is selected from the group consisting of phenyl,
1-naphthyl, 2-naphthyl, 2-chlorophenyl, 2-fluorophenyl,
2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl,
2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl,
4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl,
4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,
4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,
3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,
3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl,
3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl,
2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl,
3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl,
3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,
3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,
3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro4-trifluoromethylphenyl, 4-benzyloxyphenyl,
2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,
2,3,4,5,6-pentafluoroph- enyl, 2,5-dimethylphenyl, 4-phenylphenyl,
2-fluoro-3-trifluoromethylphenyl- , adamantyl, benzyl,
2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,
iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl,
--CH.sub.2-cyclohexyl, --CH.sub.2-cyclopentyl,
--CH.sub.2CH.sub.2-cyclopropyl, --CH.sub.2CH.sub.2-cyclobutyl,
--CH.sub.2CH.sub.2-cyclohexyl, --CH.sub.2CH.sub.2-cyclopentyl,
pyrid-2-yl, pyrid-3-yl, pyrid-4yl, fluoropyridyls, chloropyridyls,
thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl,
furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,
thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,
2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl,
3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,
1-phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl,
(CH.sub.3).sub.2CH.dbd.CHCH.sub.2CH.sub.2CH(CH.sub.3- )--,
.phi.C(O)CH.sub.2--, thien-2-yl-methyl, 2-(thien-2-yl)ethyl,
3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,
2-(4-methoxyphenyl)ethyl- , norboran-2-yl, (4-methoxyphenyl)methyl,
(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,
(3-hydroxyphenyl)methyl, (4hydroxyphenyl)methyl,
(4-methoxyphenyl)methyl, (4-methylphenyl)methyl,
(4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,
(2,4dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,
(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-p-chlorophenyl)ethyl,
(1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl,
CH.sub.3OC(O)CH.sub.2--, benzylthiomethyl,
5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl,
indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl,
CH.sub.3CH.dbd.CH--, CH.sub.3CH.sub.2CH.dbd.CH--,
(4-chlorophenyl)C(O)CH.sub.2--, (4-fluorophenyl)C(O)CH.sub.2--,
(4-methoxyphenyl)C(O)CH.sub.2--, 4-(fluorophenyl)-NHC(O)CH.sub.2--,
1-phenyl-n-butyl, (.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2NC(O)CH.sub.2--,
(.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2--, methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH.sub.2--, 4-methoxyphenyl-C(O)CH.sub.2--,
phenyl-C(O)CH.sub.2--, CH.sub.3C(O)N(.phi.)-, ethenyl,
methylthiomethyl, (CH.sub.3).sub.3CNHC(O)CH.sub.2--,
4-fluorophenyl-C(O)CH.sub.2--, diphenylmethyl, phenoxymethyl,
3,4-methylenedioxyphenyl-CH.sub.2--, benzo[b]thiophen-3-yl,
(CH.sub.3).sub.3COC(O)NHCH.sub.2--, trans-styryl,
H.sub.2NC(O)CH.sub.2CH.sub.2--,
2-trifluoromethylphenyl-C(O)CH.sub.2,
.phi.C(O)NHCH(.phi.)CH.sub.2--, mesityl,
CH.sub.3CH(.dbd.NHOH)CH.sub.2--,
4-CH.sub.3-.phi.-NHC(O)CH.sub.2CH.sub.2--,
.phi.C(O)CH(.phi.)CH.sub.2--, (CH.sub.3).sub.2CHC(O)NHCH(.phi.)-,
CH.sub.3CH.sub.2OCH.sub.2--,
CH.sub.3OC(O)CH(CH.sub.3)(CH.sub.2).sub.3--, 2,2,2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH.sub.3-benzofuran-3-yl,
2-(2,4-dichlorophenoxy)ethyl, .phi.SO.sub.2CH.sub.2--,
3-cyclohexyl-n-propyl, CF.sub.3CH.sub.2CH.sub.2CH.sub.2-- and
N-pyrrolidinyl.
43. The pharmaceutical composition according to claim 32 where n is
one or two, and each R.sup.2 is independently selected from the
group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl,
aryl, heteroaryl and heterocyclic.
44. The pharmaceutical composition according to claim 43 wherein
R.sup.2 is selected from the group consisting of methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, 2-methyl-n-butyl,
6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl,
cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclohexyl,
--CH.sub.2CH.sub.2-cyclopropyl, --CH.sub.2CH.sub.2-cyclohexyl,
--CH.sub.2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,
m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,
phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl, p-(CH.sub.3).sub.2NCH.sub.2CH.sub-
.2CH.sub.2O-benzyl, p-(CH.sub.3).sub.3COC(O)CH.sub.2O-benzyl,
p-(HOOCCH.sub.2O)-benzyl, 2-aminopyrid-6-yl,
p-(N-morpholino-CH.sub.2CH.s- ub.2O)-benzyl,
--CH.sub.2CH.sub.2C(O)NH.sub.2, --CH.sub.2-imidazol4-yl,
--CH.sub.2-(3-tetrahydrofuranyl), --CH.sub.2-thiophen-2-yl,
--CH.sub.2( 1-methyl)cyclopropyl, --CH.sub.2-thiophen-3-yl,
thiophen-3-yl, thiophen-2-yl, --CH.sub.2-C(O)O-t-butyl,
--CH.sub.2-C(CH.sub.3).sub.3, --CH.sub.2CH(CH.sub.2CH.sub.3).sub.2,
2-methylcyclopentyl, cyclohex-2-enyl,
--CH[CH(CH.sub.3).sub.2]COOCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).dbd.CH.sub.2, --CH.sub.2CH.dbd.CHCH.sub.3
(cis and trans), --CH.sub.2OH, --CH(OH)CH.sub.3,
--CH(O-t-butyl)CH.sub.3, --CH.sub.2OCH.sub.3,
--(CH.sub.2).sub.4NH-Boc, --(CH.sub.2).sub.4NH.sub.2,
--CH.sub.2-pyridyl, pyridyl, --CH.sub.2-naphthyl,
--CH.sub.2-(N-morpholino),
p-(N-morpholino-CH.sub.2CH.sub.2O)-benzyl, benzo[b]thiophen-2-yl,
5-chlorobenzo[b]thiophen-2-yl,
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,
5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,
6-methoxynaphth-2-yl, --CH.sub.2CH.sub.2SCH.sub.3, thien-2-yl,
thien-3-yl, and the like.
45. The pharmaceutical composition according to claim 32 wherein
the cyclic groups defined by W and --C(H).sub.pC(.dbd.X)-- is
selected from the group consisting of lactones, lactams,
thiolactones, thiolactams, heterocyclic and cycloalkyl groups.
46. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W and --C(H).sub.pC(.dbd.X)--, forms a
lactam or thiolactam ring of the formula: 140wherein p is zero or
one, T is selected from the group consisting of alkylene,
substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
47. The method according to claim 46 wherein the lactam ring is
selected from the group consisting of 141wherein A-B is selected
from the group consisting of alkylene, alkenylene, substituted
alkylene, substituted alkenylene and --N.dbd.CH--; Q' is oxygen or
sulfur; each V is independently selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; R.sup.b is selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl,
heterocyclic, and the like; R.sup.e is selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and
substituted cycloalkyl; t is an integer from 0 to 4; t' is an
integer from 0 to 3; and w is an integer from 0 to 3.
48. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--C(H).sub.pC(.dbd.X)-- is a ring of the formula: 142wherein p is
zero or one, T is selected from the group consisting of alkylene,
substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
49. The pharmaceutical composition according to claim 48 wherein
the alcohol or thiol substituted groups is selected from the group
consisting of 143wherein each V is independently selected from the
group consisting of hydroxy, acyl, acyloxy, alky, substituted
alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl,
aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an
integer from 0 to 3.
50. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--C(H).sub.pC(.dbd.X)--, forms a ring of the formula: 144wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
51. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--C(H).sub.pC(.dbd.X)--, forms a ring of the formula: 145wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alky, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
52. The pharmaceutical composition according to claim 51 wherein
the compound of formula I is selected from the group consisting of
146wherein each V is independently selected from the group
consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an
integer from 0 to 3.
53. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--C(H).sub.pC(.dbd.X)--, forms a ring of the formula: 147wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
54. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--C(H).sub.pC(.dbd.X)--, forms a ring of the formula: 148wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
55. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--C(H).sub.pC(.dbd.X)--, forms a ring of the formula: 149wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
56. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--C(H).sub.pC(.dbd.X)--, forms a ring of the formula: 150wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
57. The pharmaceutical composition according to claim 56 wherein
the compound of formula I is selected from the group consisting of:
151
58. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--CH).sub.pC(.dbd.X)--, forms a ring of the formula: 152wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S--and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
59. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--CH).sub.pC(.dbd.X)--, forms a ring of the formula: 153wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
60. The pharmaceutical composition according to claim 45 wherein
the cyclic group defined by W, together with
--CH).sub.pC(.dbd.X)--, forms a ring of the formula: 154wherein p
is zero or one, T is selected from the group consisting of
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
61. A compound of formula I: 155wherein R.sup.1 is selected from
the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl,
heteroaryl and heterocyclic; W, together with
--CH).sub.pC(.dbd.X)--, forms a cycloalkyl, cycloalkenyl,
heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl
group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic,
substituted cycloalkyl or substituted cycloalkenyl group is
optionally fused to form a bi- or multi-fused ring system
(preferably no more than 5 fused rings) with one or more ring
structures selected from the group consisting of cycloalkyl,
cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in
turn, each of such ring structures are optionally substituted with
1 to 4 substituents selected from the group consisting of hydroxyl,
halo, alkoxy, substituted alkoxy, thioalkoxy, substituted
thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino,
N-substituted alkylamino, N-alkyl N-substituted alkylamino,
N,N-disubstituted alkylamino, --NHC(O)R.sup.4, --NHSO.sub.2R.sup.4,
--CO)NH.sub.2, --C(O)NHR.sup.4, --C(O)NR.sup.4R.sup.4,
--S(O)R.sup.4, --S(O).sub.2R.sup.4, --S(O).sub.2NHR.sup.4 and
--S(O).sub.2NR.sup.4R.sup.4 where each R.sup.4 is independently
selected from the group consisting of alkyl, substituted alkyl, or
aryl; X is selected from the group consisting of oxo (.dbd.O),
thiooxo (.dbd.S), hydroxyl (--H, --OH), thiol (H,--SH) and hydro
(H,H); Y is represented by the formula: 156wherein each R.sup.2 is
independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
Z is represented by the formula --T--CX'X"C(O)-- where T is
selected from the group consisting of a bond covalently linking
R.sup.1 to --CX'X"--, oxygen, Sulfur, --NR.sup.5 where R.sup.5 is
hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen,
hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X"
together form an oxo group; m is an integer equal to 0 or 1; n is
an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such
that when p is zero, the ring defined by W and
--CH).sub.pC(.dbd.X)-- is unsaturated at the carbon atom of ring
attachment to Y and when p is one, the ring is saturated at the
carbon atom of ring attachment to Y, with the following provisos:
A. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, M is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a 2-(S)-indanol group; B.
when R.sup.1 is phenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
trans-2-hydroxy-cyclohex-1-yl group; C. when R.sup.1 is phenyl, Z
is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then W, together
with >CH and >C.dbd.X, does not form a gammabutyrolactone
group or a 5,5-dimethyl-gammabutyrolactone group; D. when R.sup.1
is phenyl, Z is --CH.sub.2C(O)--, m is 1, n is 0, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
.epsilon.-caprolactam group; E. when R.sup.1 is cyclopropyl,
R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p
is 1, then W, together with >CH and >C.dbd.X, does not form
an N-methylcaprolactam group; F. when R.sup.1 is
4-chlorobenzoyl-CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G. when
R.sup.1 is 2-phenylphenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R.sup.1 is
CH.sub.3OC(O)CH.sub.2--, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an
2,3-dihydro-1-(t-butylC(O)CH.sub-
.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; I. when R.sup.1 is
4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,
CH.sub.3OC(O)CH.sub.2--, 4-HOCH.sub.2-phenyl,
2,4,6-trifluorophenyl, 2-trifluoromethyl-4-fluorophenyl, or
CH.sub.3S--, R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1,
n is 1, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a 2,3-dihydro-1-(N,N-diethylamino-C-
H.sub.2CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one; J. when
R.sup.1 is 2,6-difluorophenyl, R.sup.2 is --CH.sub.3, Z is
--CH(OH)C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2-
CH.sup.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, K. when m is 1
and n is 1, then 157 does not equal cycloalkyl of from 3 to 8
carbon atoms optionally substituted with 1 to 3 alkyl groups.
62. The compound according to claim 61 where, in formula I, m is
zero.
63. The compound according to claim 62 wherein R.sup.1 is aryl or
heteroaryl.
64. The compound according to claim 63 wherein R.sup.1 is selected
from the group consisting of (a) phenyl, (b) a substituted phenyl
group of the formula: 158wherein R.sup.c is selected from the group
consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo,
hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein R.sup.b and
R.sup.c are fused to form a heteroaryl or heterocyclic ring with
the phenyl ring wherein the heteroaryl or heterocyclic ring
contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms
independently selected from the group consisting of oxygen,
nitrogen and sulfur R.sup.b and R.sup.b' are independently selected
from the group consisting of hydrogen, halo, nitro, cyano,
trihalomethyl, alkoxy, and thioalkoxy with the proviso that when
R.sup.c is hydrogen, then R.sup.b and R.sup.b' are either both
hydrogen or both substituents other than hydrogen, (c) 2-naphthyl,
(d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions
with 1 to 5 substituents selected from the group consisting alkyl,
alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and
heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl
containing 1 to 3 substituents selected from the group consisting
of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl,
thioalkoxy, thioaryloxy provided that said substituents are not
ortho to the heteroaryl attachment to the --NH group.
65. The compound according to claim 61 wherein R.sup.1 is selected
from the group consisting of mono-, di- and tri-substituted phenyl
groups.
66. The compound according to claim 65 wherein R.sup.1 is a
disubstituted phenyl selected from the group consisting of
3,5-dichlorophenyl, 3,5-difluorophenyl,
3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3-(trifluoromethyl)4-chlorophenyl,
3-chloro4-cyanophenyl, 3-chloro4-iodophenyl, and
3,4-methylenedioxyphenyl- .
67. The compound according to claim 65 wherein R.sup.1 is a
monosubstituted phenyl selected from the group consisting of
4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl,
4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.
68. The compound according to claim 65 wherein R.sup.1 is a
trisubstituted phenyl selected from the group consisting of
3,4,5-trifluorophenyl and 3,4,5-trichlorophenyl.
69. The compound according to claim 61 wherein R.sup.1 is selected
from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl,
benzothiazol-6-yl, 5-indolyl, and phenyl.
70. The compound according to any of claim 61 wherein m is one.
71. The compound according to claim 70 wherein R.sup.1 is selected
from the group consisting of phenyl, 1-naphthyl, 2-naphthyl,
2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl,
2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,
2-trifluoromethylphenyl- , 4-fluorophenyl, 4-chlorophenyl,
4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl,
4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl,
4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl,
4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl,
3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl,
3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl,
3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,
2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,
3,5-difluorophenyl, 3,5-dichlorophenyl,
3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,
3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,
2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,
2,3,4,5,6-pentafluoroph- enyl, 2,5-dimethylphenyl, 4-phenylphenyl,
2-fluoro-3-trifluoromethylphenyl- , adamantyl, benzyl,
2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,
n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,
iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl,
--CH.sub.2-cyclohexyl, --CH.sub.2-cyclopentyl,
--CH.sub.2CH.sub.2-cyclopropyl, --CH.sub.2CH.sub.2-cyclobutyl,
--CH.sub.2CH.sub.2-cyclohexyl, --CH.sub.2CH.sub.2-cyclopentyl,
pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls,
thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl,
furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,
thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,
2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl,
3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,
1-phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl,
(CH.sub.3).sub.2CH.dbd.CHCH.sub.2CH.sub.2CH(CH.sub.3- )--,
.phi.C(O)CH.sub.2--, thien-2 -yl-methyl, 2-(thien-2-yl)ethyl,
3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,
2-(4-methoxyphenyl)ethyl- , norboran-2-yl, (4-methoxyphenyl)methyl,
(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,
(3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl- ,
(4-methoxyphenyl)methyl, (4-methylphenyl)methyl,
(4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,
(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,
(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,
(1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl,
CH.sub.3OC(O)CH.sub.2--, benzylthiomethyl,
5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl,
indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl,
CH.sub.3CH.dbd.CH--, CH.sub.3CH.sub.2CH.dbd.CH--,
(4-chlorophenyl)C(O)CH.sub.2--, (4-fluorophenyl)C(O)CH.sub.2--,
(4-methoxyphenyl)C(O)CH.sub.2--, 4-(fluorophenyl)-NHC(O)CH.sub.2--,
1-phenyl-n-butyl, (.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2NC(O)CH.sub.2--,
(.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2--, methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH.sub.2--, 4-methoxyphenyl-C(O)CH.sub.2--,
phenyl-C(O)CH.sub.2--, CH.sub.3C(O)N(.phi.)--, ethenyl,
methylthiomethyl, (CH.sub.3).sub.3CNHC(O)CH.sub.2--,
4-fluorophenyl-C(O)CH.sub.2--, diphenylmethyl, phenoxymethyl,
3,4-methylenedioxyphenyl-CH.sub.2--, benzo[b]thiophen-3-yl,
(CH.sub.3).sub.3COC(O)NHCH.sub.2--, trans-styryl,
H.sub.2NC(O)CH.sub.2CH.sub.2--,
2-trifluoromethylphenyl-C(O)CH.sub.2,
.phi.C(O)NHCH(.phi.)CH.sub.2--, mesityl,
CH.sub.3CH(.dbd.NHOH)CH.sub.2--,
4--CH.sub.3-.phi.-NHC(O)CH.sub.2CH.sub.2--,
.phi.C(O)CH(.phi.)CH.sub.2--, (CH.sub.3).sub.2CHC(O)NHCH(.phi.)--,
CH.sub.3CH.sub.2OCH.sub.2--,
CH.sub.3OC(O)CH(CH.sub.3)(CH.sub.2).sub.3--, 2,2,2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH.sub.3-benzofuran-3-yl,
2-(2,4-dichlorophenoxy)ethyl, .phi.SO.sub.2CH.sub.2--,
3-cyclohexyl-n-propyl, CF.sub.3CH.sub.2CH.sub.2CH.sub.2-- and
N-pyrrolidinyl.
72. The compound according to claim 61 where n is one or two, and
each R.sup.2 is independently selected from the group consisting of
alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and
heterocyclic.
73. The compound according to claim 61 wherein R.sup.2 is selected
from the group consisting of methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, 2-methyl-n-butyl,
6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl,
cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclohexyl,
--CH.sub.2CH.sub.2-cyclopr- opyl, --CH.sub.2CH.sub.2-cyclohexyl,
--CH.sub.2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,
m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,
phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl,
p-(CH.sub.3).sub.2NCH.sub.2CH.sub.2CH.sub.2O-benzyl,
p-(CH.sub.3).sub.3COC(O)CH.sub.2O-benzyl, p-(HOOCCH.sub.2O)-benzyl,
2-aminopyrid-6-yl, p-(N-morpholino-CH.sub.2CH.sub.2O)-benzyl,
--CH.sub.2CH.sub.2C(O)NH.sub.2, --CH.sub.2-imidazol-4-yl,
--CH.sub.2-(3-tetrahydrofuranyl), --CH.sub.2-thiophen-2-yl,
--CH.sub.2( 1-methyl)cyclopropyl, --CH.sub.2-thiophen-3-yl,
thiophen-3-yl, thiophen-2-yl, --CH.sub.2--CO)O-t-butyl,
--CH.sub.2--CCH.sub.3).sub.3, --CH.sub.2CH(CH.sub.2CH.sub.3).sub.2,
2-methylcyclopentyl, cyclohex-2-enyl,
--CH[CH(CH.sub.3).sub.2]COOCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).dbd.CH.sub.2, --CH.sub.2CH.dbd.CHCH.sub.3
(cis and trans), --CH.sub.2OH, --CH(OH)CH.sub.3,
--CH(O-t-butyl)CH.sub.3, --CH.sub.2OCH.sub.3,
--(CH.sub.2).sub.4NH-Boc, --(CH.sub.2).sub.4NH.sub.2,
--CH.sub.2-pyridyl, pyridyl, --CH.sub.2-naphthyl,
--CH.sub.2-(N-morpholino),
p-(N-morpholino-CH.sub.2CH.sub.2O)-benzyl, benzo[b]thiophen-2-yl,
5-chlorobenzo[b]thiophen-2-yl,
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,
5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,
6-methoxynaphth-2-yl, --CH.sub.2CH.sub.2SCH.sub.3, thien-2-yl,
thien-3-yl, and the like.
74. The compound according to claim 61 wherein the cyclic groups
defined by W and --C(H).sub.pC(.dbd.X)-- is selected from the group
consisting of lactones, lactams, thiolactones, thiolactams,
heterocyclic and cycloalkyl groups.
75. The compound according to claim 74 wherein the cyclic group
defined by W and --C(H).sub.pC(.dbd.X)--, forms a lactam or
thiolactam ring of the formula: 159wherein p is zero or one, T is
selected from the group consisting of alkylene, substituted
alkylene, alkenylene, substituted alkenylene,
--(R.sup.21Z).sub.qR.sub.21-- and --ZR.sup.21-- where Z is a
substituent selected from the group consisting of --O--, --S-- and
>NR.sup.20, each R.sup.20 is independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkenyl, substituted
alkynyl, aryl, heteroaryl and heterocyclic, each R.sup.21 is
independently alkylene, substituted alkylene, alkenylene and
substituted alkenylene with the proviso that when Z is --O-- or
--S--, any unsaturation in the alkenylene and substituted
alkenylene does not involve participation of the --O-- or --S--,
and q is an integer of from 1 to 3.
76. The method according to claim 75 wherein the lactam ring is
selected from the group consisting of 160wherein A-B is selected
from the group consisting of alkylene, alkenylene, substituted
alkylene, substituted alkenylene and --N.dbd.CH--; Q' is oxygen or
sulfur; each V is independently selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; R.sup.b is selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl,
heterocyclic, and the like; R.sup.c is selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and
substituted cycloalkyl; t is an integer from 0 to 4; t' is an
integer from 0 to 3; and w is an integer from 0 to 3.
77. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)-- is a ring of
the formula: 161wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
78. The compound according to claim 77 wherein the alcohol or thiol
substituted groups is selected from the group consisting of
162wherein each V is independently selected from the group
consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an
integer from 0 to 3.
79. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 163wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
80. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 164wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
81. The compound according to claim 80 wherein the compound of
formula I is selected from the group consisting of 165wherein each
V is independently selected from the group consisting of hydroxy,
acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted
alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl,
cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,
trihalomethyl and the like; R.sup.a is selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an
integer from 0 to 4; and w is an integer from 0 to 3.
82. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 166wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
83. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 167wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
84. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 168wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
85. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 169wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
86. The compound according to claim 85 wherein the compound of
formula I is selected from the group consisting of: 170
87. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H).sub.pC(.dbd.X)--, forms a ring
of the formula: 171wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
88. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H)).sub.pC(.dbd.X)--, forms a ring
of the formula: 172wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
89. The compound according to claim 74 wherein the cyclic group
defined by W, together with --C(H)).sub.pC(.dbd.X)--, forms a ring
of the formula: 173wherein p is zero or one, T is selected from the
group consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
90. A compound selected from the group consisting of:
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-aminodibenzosuberane
1-(R)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-(S)-indanol
1-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-(R)-indanol
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-indanol
2-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1-cyclohexanol
1-(R,S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1,2,3,4-tetrahyd-
ro-2-naphthol
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-aminobenz[f]cyc-
loheptan-2-ol
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydr-
o-6H-dibenzo[a,c]cyclohepten-6-ol
1-(S)-(N'-(3,5-difluorophenylacetyl)-L-a- laninyl)-aminoindan-2-one
2-(N'-(phenylacetyl)-L-alaninyl)aminocyclohexan-- 1-one
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-dib-
enzo[a,c]cyclohepten-6-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-am-
ino-.gamma.-butyrolactone
3-(N'-(3,4-dichlorophenyl)-L-alaninyl)amino-.gam- ma.-butyrolactone
4-(N'-(cyclopentylacetyl)-L-alaninyl)amino-1,1-dimethyl--
3-isochromanone
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,1-dime-
thyl-3-isochromanone
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-.ga-
mma.-butyrolactam
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-.delta-
.-valerolactam
1-benzyl-3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-a-
mino-.delta.-valerolactam
3-N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-
-4-methyl-.epsilon.-caprolactam
3-(N'-(3,5-difluorophenylacetyl)-L-alaniny-
l)amino-1,2,3,4-tetrahydroquinolin-2-one
1-benzyl-3-(N'-(3,5-difluoropheny-
lacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroquinolin-2-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroisoqu-
inolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-benzyl-1,-
2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alani-
nyl)amino-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-phenyl-1,2,3,4-tetrah-
ydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-6--
fluoro-1,2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl-
)-L-alaninyl)amino-7-fluoro-1,2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-phenethyl-1,2,3,4-tet-
rahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-
-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylace-
tyl)-L-alaninyl)amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-phenyl-1,2,3,4-tetrah-
ydroisoquinolin-3-one
(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-(9-aminof-
luroren-1-yl)glycine .delta.-lactam
3-(N'-(phenylacetyl)-L-alaninyl)amino-- .epsilon.-caprolactam
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-ami-
no-.epsilon.-caprolactam
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)a-
mino-1-benzyl-.epsilon.caprolactam
3-(S)-N'-(3,5-difluorophenylacetyl)-L-a-
laninyl)amino-1-(2-methoxyethyl)-.epsilon.-caprolactam
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-.epsilon.-c-
aprolactam
3-N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-.epsil-
on.-caprolactam
3-N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-.-
epsilon.-caprolactam
3-N'-(3,5-difluorophenylacetyl)-L-alaninyl-amino)-7-b-
enzyl-.epsilon.-caprolactam
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaniny-
l)amino-1-benzyl-4,7-methano-.epsilon.-caprolactam
3-(S)-N'-(cyclopentylac-
etyl)-L-alaninyl)amino-1-benzyl-.epsilon.-caprolactam
3-(S)-(N'-(cyclopentylacetyl)-L-phenylglycinyl)amino-1-benzyl-.epsilon.-c-
aprolactam
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-phen-
ethyl)-.epsilon.-caprolactam
3(S)-N'-(cyclopentylacetyl)-L-phenylglycinyl)-
amino-1-(2-phenethyl)-.epsilon.-caprolactam
3-(N'-(3,4-dichlorophenyl)-D,L-
-alaninyl)amino-.epsilon.-caprolactam
3-(S)-(N'-(cyclopropylacetyl)-L-phen-
ylglycinyl)amino-1-methyl-.epsilon.-caprolactam
3-(N'-(3,5-difluorophenyla- cetyl)-L-alaninyl)amino-8-octanelactam
4-(N'-(3,5-difluorophenylacetyl)-L--
alaninyl)amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,2,3,4-tetrah-
ydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2--
methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-2-yl)-1,2,3,4--
tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)am-
ino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-4-yl)-1,2,3,4--
tetrahydroisoquinolin-3-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-a-
mino-1-methyl-2-indolinone
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]ami-
no-1-methyl4-phenyl-3,4-trans-dihydrocarbostyril
3-[N'-(3,5-difluorophenyl-
acetyl)-L-alaninyl]amino-1-methyl4-phenyl-3,4-cis-dihydrocarbostyril
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino4-phenyl-3,4-trans-dihyd-
rocarbostyril
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-3-methyl-1-
,3,4,5-tetrahydro-2H-3-benzazepin-2-one
1-(S)-(N'-(3,5-difluorophenylacety-
l)-L-alaninyl)amino-3-ethyl4'-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2--
one
3-(3,5-difluorophenylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahy-
dro-2H-1-benzazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amin-
o-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
3-(N'-(3,5-difluorophenylacetyl-
)-L-alaninyl)amino-1-benzyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
3-(N'-(cyclopentylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-
-1-benzazepin-2-one
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino--
1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
3-(N'-(3,5-difluoropheny-
lacetyl)-L-alaninyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin--
2-one
3-(3,5-difluorophenylacetyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-
-1-benzazepin-2-one
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino--
1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5-oxa-1,3,4-
,5-tetrahydro-2H-1-benzazepin-2-one
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-
-alaninyl)amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}-amino-3,3-dimethyl-5,7-dihyd-
ro-6H-benz[b]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amin-
o-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-3,3,7-trimethyl-5,7-dih-
ydro-6H-benz[b]azepin-6-one
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)am-
ino-5-phenyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5,5-dimethyl-1,-
3,4,5-tetrahydro-2H-1-benzazepin-2-one
5-(S)-[N'-(3,5-difluorophenylacetyl-
)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-((S) and
(R)-3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alanin-
yl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(3,5-difluorophenyl-.alpha.-ketoacetyl)-L-alaninyl]amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(3,5-difluorophenylace-
tyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-((S)-3,5-difluorophenyl-.alpha-
.-hydroxyacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-
-6-one
5-(S)-[N'-((S)-3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-tert-leu-
cinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methoxyacetyl)-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-(3,5-difluorophenylacetyl)-L-alani-
nyl]amino-7-(methylcarboxylate)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(3,3-dimethyl-2-butan-
oyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-(3,5-difluorophenylacety-
l)-L-alaninyl]amino-7-(morpholinylacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-
-6-one
5-(S)-(N'-((S)-(+)-2-Hydroxy-3-methylbutyryl)-L-alaninyl)amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-cyclopentyl-.alpha.-hydr-
oxyacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-(N'-((S) and
(R)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-cyclopentyl-.alpha.-hy-
droxyacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azep-
in-6-one
5-[N'-cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-(3,5-difluorophenylacetyl)--
L-alaninyl]amino-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(2-methylpropyl)-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-(2-hydroxy-3-methylbutyryl)-L-val-
inyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(S)-[N'-((S and
R)-2-hydroxy-3,3-dimethylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-phenyl-furazan-3-yl)alaninyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenyla-
cetyl)-L-alaninyl-}amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,-
d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-phenbut-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-
-L-alaninyl}amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-(2',2',2'-trifluoroe-
thyl)-5,7-dihydro-H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacety-
l)-L-alaninyl}amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-9-fluoro-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-alani-
nyl}-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-10-fluoro-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-alan-
inyl}amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-7-phenbutyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}ami-
no-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-phenbutyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amin-
o-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoroma-
ndelyl]-L-valinyl}amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepi-
n-6-one
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-13-fluoro-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-[(S)-3,5-difluoromandelyl]--
L-valinyl}amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
3-(N'-(3,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2-methoxyphenoxyacetyl)-L-a-
laninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-isopropylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(ethoxyacetyl)-L-alaninyl)amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-ethoxyphenylacetyl)-L-alaninyl)ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorobenzoyl)-L-alaninyl)-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(o-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-
,4-benzodiazepin-2-one
3-(N'-(3,3-diphenylpropionyl)-L-alaninyl)amino-2,3--
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-phenoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
3-(N'-(indole-3-acetyl)-L-alaninyl)amino-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-((4-methylphenoxy)acetyl)-L-
-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2-phenoxyphenylacetyl)-L-al-
aninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,4-dichlorophenoxyacetyl)-L-alaniny-
l)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
3-(N'-(methylthio)acetyl)-L-alaninyl)amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(methoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-
,4-benzodiazepin-2-one
(S)-3-(N'-(phenoxyacetyl)-L-alaninyl)amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(phenylacetyl)--
L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-phenoxybutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-methoxyphenoxyacetyl)-L-alaniny-
l)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-(trifluoromethyl)phenylacetyl)glycinyl)-L-alaninyl)amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-butoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(2-methoxyphenyl)propionyl)-
-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(isopropoxylacetyl)-L-alaninyl-
)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(1-phenyl-1H-tetrazole-5-acetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(3,4-methylenedio-
xyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4--
benzodiazepin-2-one
(S)-3-(N'-(3-cyclopentylpropionyl)-L-alaninyl)amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-cyclopentene-1-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-chloro-6-fluorophenylace-
tyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-
-one
(S)-3-(N'-(cyclohexylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,5-difluorophenylacetyl)-L-a-
laninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(pentafluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,5-dimethylphenoxyacetyl-
)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-on-
e
(S)-3-(N'-(4-chlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-chlorophenoxyacetyl)-L-ala-
ninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(benzoylformyl)-L-alanin-
yl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,5-dimethylphenylacetyl-
)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-on-
e
(S)-3-(N'-(2,6-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,4-difluorophenylacetyl-
)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-on-
e
(S)-3-(N'-(mesitylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-biphenylacetyl)-L-alaninyl)amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,4-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(trans-styrylacetyl)-L-ala-
ninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-benzoylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(trans-3-hexenoyl)-L-alaninyl)am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(heptanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-
,4-benzodiazepin-2-one
(S)-3-(N'-(3-(4-methylphenyl)propionyl)-L-alaninyl)-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(4-chlorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-phenylbutyryl)-L-ala-
ninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-(4-methoxyphenyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-methoxycarbonylpropio-
nyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-
-one
(S)-3-(N'-(4-phenylbutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(benzylthio)propionyl)-L-ala-
ninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-methylpentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(6-methoxycarbonylheptanoyl)-L-al-
aninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-indanylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-methoxyphenylacetyl)-L-alaninyl)-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-thiopheneacetyl)-L-alaniny-
l)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-tolylacetyl)-L-a-
laninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,6-difluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(-(4-methoxyphenyl)propionyl)--
L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(m-tolylacetyl)-L-alaninyl-
)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-chlorophenoxyacetyl)-L-alan-
inyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-naphthylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-chlorophenylacetyl)-L-alaninyl)-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-methylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,4-methylenedioxyphenylacet-
yl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2--
one
(S)-3-(N'-(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-isopropylphenoxyacetyl-
)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-on-
e
(S)-3-(N'-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(phenylmercaptoacetyl)-L-ala-
ninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,5-dimethoxyphenylacetyl)-L--
alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(o-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,3-diphenylpropionyl)-L-alaninyl)am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-phenoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(indole-3-acetyl)-L-alaninyl)ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,5-bis(trifluorom-
ethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4--
benzodiazepin-2-one
(S)-3-(N'-(2-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-fluorophenoxyacetyl)-L-ala-
ninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,4-dichlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-((methylthio)acetyl)-L-ala-
ninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-fluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-thionaphthenacetyl)-L-alaninyl)-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(methoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(ethoxyacetyl)-L-alaninyl)amino-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-indolepropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(2-chlorophenyl)propionyl)-L-a-
laninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
-benzodiazepin-2-one
(S)-3-(N'-(hexanoyl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(5-phenylpentanoyl)-L--
alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-nitrophenoxyacetyl)-L-alani-
nyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(3-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(5-methylhexanoyl)-L-a-
laninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(hydrocinnamyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(octanoyl)-L-alaninyl)amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(3-hydroxyphe-
nyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one
(S)-3-(N'-(3-(4-hydroxyphenyl)propionyl)-L-alaninyl)amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(5-hydantoinacetyl)-L-a-
laninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(trifluoromethyl)butyryl)-L-al-
aninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-methyl-3-Benzofuranacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(propionyl)-L-alaninyl)-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(cyclopropylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-methoxypropionyl)-L-alaninyl)a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(5-(thienyl)pentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(4-fluorophenyl)propionyl)--
L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(4-fluorophenoxy)propionyl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-norbornaneacetyl)-L-
-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,3-difluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-pentenoyl)-L-alaninyl)amino-
-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-(2,4-dichlorophenoxy)butyryl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,3-dichlorophenoxy-
acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepi-
n-2-one
(S)-3-(N'-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl)amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-fluorophenyl-
acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepi-
n-2-one (S)-3-(N'-(2-(4-cyanophenoxy)-2-methyl
propionyl)-L-alaninyl)amino-
-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-nitrophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-(hydroxymethyl)phenoxyacetyl-
)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-on-
e
(S)-3-(N'-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-fluoro-2-(trifluorom-
ethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4--
benzodiazepin-2-one
(S)-3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-fluoro-4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(4-fluorobenzoyl)propionyl)--
L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-((2-methylphenoxy)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-methoxyphenoxyacetyl)-L--
alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(phenylsulfonyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-methoxyphenylacetyl)-
-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one (S)-3-(N'-(p-isopropyl
phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one
(S)-3-(N'-(4-pentenoyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-hydroxyphenoxyacetyl)--
L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-oxopentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-hydroxyphenylacetyl)-L-alaninyl)a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,4-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(4-methoxybenzoyl)prop-
ionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-
-2-one
(S)-3-(N'-(thiophene-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(6-phenylhexanoyl)-L-alani-
nyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(isovaleryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H--
1,4-benzodiazepin-2-one
(S)-3-(N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl-
)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(1-adamantaneacetyl)-L--
alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(cyclohexanepentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2-thiopheneacetyl)-L-phenylgl-
ycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-(trifluoromethyl)phenylacetyl)-L-phenylglycinyl)amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,5-difluoro-
phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4--
benzodiazepin-2-one
(S)-3-(N'-(3-tolylacetyl)-L-phenylglycinyl)amino-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-fluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3-bromophenylacetyl)-L--
phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2--
one
(S)-3-(N'-(3-chlorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,4-methylenedioxyph-
enylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-be-
nzodiazepin-2-one
(S)-3-(N'-(phenylmercaptoacetyl)-L-phenylglycinyl)amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1-
H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,5-bis(trifluoromethyl)phenylacetyl)-
-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-
-2-one
(S)-3-(N'-((methylthio)acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(phenoxyacetyl)-L-ph-
enylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-on-
e
(S)-3-(N'-(phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(cyclohexylacetyl)-L-phenylglyc-
inyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(benzo[b]thiophene-3-
-acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one
(S)-3-(N'-(benzoylformyl)-L-phenylglycinyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(2,6-difluorophen-
ylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benz-
odiazepin-2-one
(S)-3-(N'-(2,4-difluorophenylacetyl)-L-phenylglycinyl)amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,4-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(butyryl)-L-phenylgl-
ycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(heptanoyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-(2-thienyl)butyryl)-L-phenylglyc-
inyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(5-methylhexanoyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(hydrocinnamyl)-L-phenylglyc-
inyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(cyclopentylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(propionyl)-L-phenylglyciny-
l)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(3,4,5-trifluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
(S)-3-(N'-(4-phenylbutyryl)-
-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-
-2-one
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(-
4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(2-thiopheneacetyl)-
-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benz-
odiazepin-2-one
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-1-methyl-2,3-di-
hydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(2-thiopheneacetyl)-
-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorop-
henyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-me-
thyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-
-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-
-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2-thiopheneacetyl)-L-a-
laninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-
-1H-1,5-benzodiazepine
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-
,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-
-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenyl-
acetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzo-
diazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophe-
nyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihyd-
ro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L--
alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-on-
e
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophe-
nyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2-
,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4-
,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3-fluorophenylacetyl)-
-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benz-
odiazepin-2-one
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-1-methyl-2,3-
-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-fluorophenylacetyl)-L-alan-
inyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodi-
azepin-2-one
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2-
,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-fluorophenylacetyl-
)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin--
2-one
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophe-
nyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-d-
imethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4--
trifluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(methylthio)acetyl)-L-ala-
ninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiaze-
pin-2-one
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro--
5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(methylthio)acetyl)-L-ala-
ninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2--
one
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-
-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(methylthio)acetyl)-
-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin--
2-one
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro--
1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(methylthio)acetyl)-L-alaninyl)a-
mino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin--
2-one
3-(N'-(methylthio)acetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-
-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(phenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifl-
uorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(phenylacetyl)-L-alaninyl)amin-
o-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(phenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl-
)-1H-1,4-benzodiazepin-2-one
3-(N'-(phenylacetyl)-L-alaninyl)amino-7-chlor-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(phenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dih-
ydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(phenylacetyl)-L-alaninyl)a-
mino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(phenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1-
H-1,4-benzodiazepin-2-one
3-(N'-(phenylacetyl)-L-alaninyl)amino-7-bromo-5--
(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(phenylacetyl)-L-alaninyl)-amino-)2,4-dioxo-1,5-bis-(2,2-dimethylpr-
opyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(benzoylformyl)-L-ala-
ninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiaz-
epin-2-one
3-(N'-(benzoylformyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)--
2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(benzoylformyl)-L-al-
aninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-o-
ne
3-(N'-(benzoylformyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(benzoylformyl)-L-alaninyl)amino-7-
-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(benzoylformyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-
-1H-1,4-benzodiazepin-2-one
3-(N'-(benzoylformyl)-L-alaninyl)amino-5-cyclo-
hexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(benzoylformyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dih-
ydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(benzoylformyl)-L-alaninyl)-
-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5--
benzodiazepine
3-(N'-(butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,-
4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(butyryl)-L-alaninyl)-
amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2--
one
3-(N'-(butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)--
1H-1,4-benzodiazepin-2-one
3-(N'-(butyryl)-L-alaninyl)amino-7-chloro-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro--
1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(butyryl)-L-alaninyl)amino-5-(2--
thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-
-benzodiazepin-2-one
3-(N'-(butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorop-
henyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(butyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl-
)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(4-(2-thienyl)butyryl)-L--
alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzod-
iazepin-2-one
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-1-(2-oxo-2-phe-
nylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-t-
hiazolyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4-(2-thienyl)butyryl)-L-alanin-
yl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-
-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-(2-thienyl)butyr-
yl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazep-
in-2-one
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-di-
hydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-(2-thienyl)butyryl)-L-a-
laninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzo-
diazepin-2-one
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)-amino-)-2,4-dioxo--
1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4--
trifluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-ala-
ninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiaze-
pin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro--
5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-ala-
ninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2--
one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-
-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-
-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin--
2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro--
1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)a-
mino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin--
2-one 3-(
N'-(cyclopentylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,-
2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl--
1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethy-
l)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-(trifluorometh-
yl)butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-b-
enzodiazepin-2-one
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-c-
hloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorop-
henyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dih-
ydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-(trifluoromethyl)butyryl-
)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin--
2-one
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-bromo-5-(2-flu-
orophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)-amino-)2,4-dioxo-1,5-bis-(-
2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4-
,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobuty-
ryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4--
benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-1-meth-
yl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L--
alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-ben-
zodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-(2-thie-
nyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro--
1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alani-
nyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiaz-
epin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,-
5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(isovaleryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluo-
robutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(isovaleryl)-L-alaninyl)amino-1--
(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(isovaleryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)--
1H-1,4-benzodiazepin-2-one
3-(N'-(isovaleryl)-L-alaninyl)amino-7-chloro-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(isovaleryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihyd-
ro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(isovaleryl)-L-alaninyl)amino-
-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(isovaleryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H--
1,4-benzodiazepin-2-one
3-(N'-(isovaleryl)-L-alaninyl)amino-7-bromo-5-(2-f-
luorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(isovaleryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpro-
pyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(L-alpha-hydroxyisocap-
royl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,-
4-benzodiazepin-2-one
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-1-
-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-
-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(L-alpha-hydroxyisocaproyl-
)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaz-
epin-2-one
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-chloro-5-(-
2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihy-
dro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(L-alpha-hydroxyisocaproyl)--
L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2--
one
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-bromo-5-(2-fluoro-
phenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(-
2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-tri-
fluorobutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(L-(+)-mandelyl)-L-alaninyl)-
amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2--
one
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thia-
zolyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino--
7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-d-
ihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(L-(+)-mandelyl)-L-alanin-
yl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-
-1H-1,4-benzodiazepin-2-one
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-7-brom-
o-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(3-fluorobenzyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacety-
l)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-
-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylac-
etyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4-b-
enzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phe-
nyl-2,3-dihydro-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin--
2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihyd-
ro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylac-
etyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-be-
nzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phen-
yl-2,3-dihydro-1-(2-phenylethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacety-
l)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-(N-phthalimidyl)ethyl)-1H-1,-
4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5--
phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
((2-tetrahydrofuranyl)methyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(2-(1,4-benzodioxanyl)methyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(3,3-dimethyl-2-oxo-propyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacet-
yl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(6-(2-trifluoromethylquinoliny-
l)methyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-al-
aninyl)amino-5-phenyl-2,3-dihydro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-
-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(ethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L--
alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-pyridylmethyl)-1H-1,4-benzodiazep-
in-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-di-
hydro-1-(2-oxo-2-(N-indolinyl)ethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-al-
aninyl)amino-5-phenyl-2,3-dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-tert-
-butylbenzyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alani-
nyl)amino-5-phenyl-2,3-dihydro-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin--
2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-
,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-a-
laninyl)amino-5-phenyl-2,3-dihydro-1-(isopropyl)-1H-1,4-benzodiazepin-2-on-
e
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(1-met-
hoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-ethy-
lbutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)am-
ino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-phen-
ylethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)a-
mino-5-phenyl-2,3-dihydro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-(N-p-
hthalimidyl)ethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L--
alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4-benzodiaze-
pin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro--
1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-di-
methyl-2-oxo-butyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-
-alaninyl)amino-5-phenyl-2,3-dihydro-1-(5-benzofurazanylmethyl)-1H-1,4-ben-
zodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-d-
ihydro-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(6-(2-t-
rifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclop-
ropylmethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alanin-
yl)amino-5-phenyl-2,3-dihydro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(ethyl)-
-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-p-
henyl-2,3-dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepi-
n-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1--
(propyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(cyclopentylacetyl)-L-alaninyl)a-
mino-5-phenyl-2,3-dihydro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(b-
enzyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaniny-
l)amino-5-phenyl-2,3-dihydro-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-
-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro--
1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobut-
yryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4-b-
enzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-pheny-
l-2,3-dihydro-1-(isopropyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(1-
-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-
-ethylbutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-a-
laninyl)amino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-benzodiazep-
in-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobu-
tyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4-b-
enzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-pheny-
l-2,3-dihydro-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-
-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro--
1-(3,3-dimethyl-2-oxo-butyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(5-
-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobu-
tyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenoxypropyl)-1H-1,4-be-
nzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-
-2,3-dihydro-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepi-
n-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihyd-
ro-1-(cyclopropylmethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-
-methylbutyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L--
alaninyl)amino-5-phenyl-2,3-dihydro-1-(ethyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-
-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(p-
ropyl)-1H-1,4-benzodiazepin-2-one
3-(N'-(4,4,4-trifluorobutyryl)-L-alaniny-
l)amino-5-phenyl-2,3-dihydro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one
3-(
N'-(L-(+)-mandelyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimeth-
ylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
(S)-3-(N'-(N-pyrrolidin-
ylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one
3-(N'-(2-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2-thiopheneacetyl)-L-alanin-
yl)amino-2,3-dihydro-1-methyl-5-phenyl -1H-1,4-benzodiazepin-2-one
3-(N'-(3-(trifluoromethyl)phenylacetic)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(4-tolylacetyl)-L-alaninyl)-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L-a-
laninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(m-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-
,4-benzodiazepin-2-one
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
3-(N'-(4-chlorophenoxyacetyl)-L-alaninyl)amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(2-naphthylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1-
H-1,4-benzodiazepin-2-one
3-(N'-(3-methylphenoxyacetyl)-L-alaninyl)amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-methoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(-
2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2-thiopheneacetyl)-L-alaniny-
l)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl--
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-bromophenylacetyl)-L-al-
aninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-on-
e
3-[(N'-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(-
2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-ethoxyphenylacetyl)-L-alan-
inyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1--
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,5-bis(trifluorom-
ethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1-
H-1,4-benzodiazepin-2-one
3-[(N'-((methylthio)acetyl)-L-alaninyl)amino]-2,-
3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyr-
idyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(pentafluorophenoxyacetyl)-L-alani-
nyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-methy-
l-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,4,6-trimethylphenylac-
etyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodia-
zepin-2-one
3-[(N'-(4-biphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-meth-
yl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,4-difluorophenylacet-
yl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiaze-
pin-2-one
3-[(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino]-2,3-dihydro-1-me-
thyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(5-methylhexanoyl)-L--
alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2--
one
3-[(N'-(3-methoxycarbonylpropionyl)-L-alaninyl)amino]-2,3-dihydro-1-me-
thyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,6-difluoromandelyl-
)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
3-[(N'-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-
-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,5-difluoromandelyl)-L-al-
aninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-on-
e
3-[(N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-met-
hyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-fluoro-2-(trifluoro-
methyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)--
1H-1,4-benzodiazepin-2-one
3-[(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amin-
o]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-
-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 3-[(N'-(beta-phenyll
actyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzod-
iazepin-2-one
3-[(N'-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(-
2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-chloromandelyl)-L-alaninyl-
)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)--
1H-1,4-benzodiazepin-2-one
3-[(N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl-
)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(-
2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(L-alpha-hydroxyisocaproyl)-L-
-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-
-one
3-[(N'-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-
-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(D-3-phenyl]actyl)-L-alanin-
yl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-methocyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimet-
hyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl--
2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-di-
methyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethy-
l-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimeth-
yl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-ethoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimeth-
yl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1--
(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihyd-
ro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-((methylthio)acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-
-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-
-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-di-
methyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3--
dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-
-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-biphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-
-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-di-
methyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-(2-thienyl)butyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-
-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-
-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,6-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimeth-
yl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-
-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimeth-
yl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-
-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-d-
ihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-on-
e
3-[(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dim-
ethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dim-
ethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(beta-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl--
2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobuty-
l)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-chloromandelyl)-L-al-
aninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-
-benzodiazepin-2-one
3-[(N'-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-(-
3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-
-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimet-
hyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-d-
imethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethy-
l-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-
-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-methoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-die-
thyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl-
aminoethyl)-5-(2-pyridyl)-1\ H-1,4-benzodiazepin-2-one
3-[(N'-(N"-acetyl-N"-phenylglycinyl)L-alaninyl)amino]-2,3-dihydro-1-(2-N,-
N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N--
diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-dieth-
yl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diet-
hyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1--
(2-N,N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihyd-
ro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N--
diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,-
N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(benzoylformyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N--
diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diet-
hyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diet-
hyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-di-
ethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-d-
iethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(beta-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N-
,N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-die-
thyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-
-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-dieth-
yl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[(N'-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyla-
minoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-me-
thylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(meth-
yl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacety-
l)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahy-
dro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-
-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepi-
ne
3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(met-
hyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacet-
yl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahy-
dro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-am-
ino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiaz-
epine
3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bi-
s-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cy-
clopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2-
-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(m-
ethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylac-
etyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-t-
etrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-phenylal-
aninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-
-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,-
4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-
-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-
-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-
-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluoropheny-
lacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3-
,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-(2-t-
hienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydr-
o-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine-
]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-
e
3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5--
bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-b-
is-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-b-
is-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-b-
is-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2--
methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(me-
thyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylace-
tyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tet-
rahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-
-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzod-
iazepine
3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5--
bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(cyc-
lopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpro-
pyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-a-
laninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzod-
iazepine
3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyc-
lopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-methylprop-
yl)-2,3,4,5-tetrahydro-1H-1.5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-va-
linyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodia-
zepine
3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclop-
ropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-methylp-
ropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-
-norvalinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-be-
nzodiazepine
3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bi-
s-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2-methyl-
propyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)--
L-methioninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5--
benzodiazepine
3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-
-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(2-met-
hylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(methy-
l)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-phe-
nylalaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydr-
o-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2-
,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(methy-
l)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-phe-
nylglycinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydr-
o-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-
-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepi-
ne
3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(m-
ethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-(-
2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tet-
rahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-
-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzod-
iazepine
3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5--
bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyc-
lopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-serinyl]-amino-2,4-dioxo-1,5-bis-(2-methylprop-
yl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-th-
reoninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1-
,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1-
,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cycloprop-
ylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl-
)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-
-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dio-
xo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropy-
lmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobut-
ryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahyd-
ro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,-
4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopr-
opylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-methyl-
propyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutr-
yl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5--
benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-
-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-met-
hylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(methy-
l)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-
-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydr-
o-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino--
2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-
e
3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(met-
hyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-
-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrah-
ydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]--
amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodi-
azepine
3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-
-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(c-
yclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-m-
ethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(m-
ethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutry-
l)-L-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5--
tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl-
)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepine
3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dio-
xo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bi-
s-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bi-
s-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bi-
s-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2-met-
hylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-threoninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-
-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N-(4,4,4-trifluorobutryl)-L-t-
hreoninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro--
1H-1,5-benzodiazepine
3-(3,5-difluorophenylacetyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-(N'-(3,5-difluorophenylacetyl)-L--
alaninyl)amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-5-phenyl-1-
H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-ami-
no-2,3-dihydro-1-methyl-5-(1-piperidinyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacety-
l)-L-alaninyl]-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,-
4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-N'-methyl-L-alaniny-
l]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dihydro-1-
-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-5-cyclohexyl-2,3-dihyd-
ro-1-methyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L--
alaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-
-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-me-
thyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophen-
yl-.alpha.-hydroxyacetyl)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1-
H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-
-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-
-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-me-
thyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophen-
ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4--
benzodiazepin-2-one
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]--
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-valinyl]-amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl-
)-L-alaninyl]amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-isobutyl--
5-phenyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenyl-.alpha.-hyd-
roxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodia-
zepin-2-one
3-[N'-(3,5-difluorophenyl-.alpha.-oxoacetyl)-L-alaninyl]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-valinyl]ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L--
alaninyl]amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-cycloprop-
ylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenyl-.al-
pha.-fluoroacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-b-
enzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-d-
ihydro-1-n-propyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3-methylbutyryl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-phenylgl-
ycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
3-[N'-(3-methylbutyryl)-L-alaninyl]amino-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(2-phenylthioacetyl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3-(4-methoxyphenyl)propionyl)-L-a-
laninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
3-[N'-(4-cyclohexylbutyryl)-L-alaninyl]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2--
pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-methyl-2-hydroxylbutyryl)-L-a-
laninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(3,3-dimethylbutryl)-L-alaninyl]-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3-[N'-(thien-2-yl-acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyri-
dyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenylacetyl)-L-alaniny-
l]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-py-
ridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-phenylthioacetyl)-L-alaninyl]am-
ino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-p-
yridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-trifluoromethylphenylacetyl)-L-
-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2--
one
3-[N'-(3,5-di(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-dihyd-
ro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyr-
idyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-cyclohexylacetyl)-L-alaninyl]ami-
no-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(thionaphth-3-yla-
cetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodia-
zepin-2-one
3-[N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihyd-
ro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-
-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,4-difluorophenylacetyl)-L-al-
aninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2--
pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(5-methylhexanoyl)-L-alaninyl]am-
ino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(-
2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,6-difluorophenyl)-.alpha.-h-
ydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-b-
enzodiazepin-2-one
3-[N'-(4-fluorophenyl)-.alpha.-hydroxyacetyl)-L-alaniny-
l]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,5-difluorophenyl)-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-di-
hydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,4,6-trifluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-methy-
l-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-trifluoromethyl-4-fluo-
rophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,-
4-benzodiazepin-2-one
3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3--
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-phenyl-2-hydroxypropionyl)-
-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin--
2-one
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1--
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-chlorophenyl-.alp-
ha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H--
1,4-benzodiazepin-2-one
3-[N'-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihyd-
ro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-methylthiopropionyl)-L--
alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-o-
ne
3-[N'-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-nitrophenylacetyl)-L-al-
aninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylc-
arbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbony-
lmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluoropheny-
lacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-py-
ridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-bromophenylacetyl)-L-alaninyl]a-
mino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodi-
azepin-2-one
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(te-
rt-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylca-
rbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(ter-
t-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-di-(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarb-
onylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-cyclomethylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcar-
bonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylc-
arbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert--
butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butyl-
carbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-but-
ylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-(2-thienyl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylca-
rbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbon-
ylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-methoxycarbony-
lacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-py-
ridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,6-difluorophenyl-.alpha.-hydrox-
yacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-py-
ridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-fluorophenyl-.alpha.-hydroxyace-
tyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridy-
l)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,5-difluorophenyl-.alpha.-hydroxyace-
tyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridy-
l)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,4,6-trifluorophenylacetyl)-L-alanin-
yl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-ben-
zodiazepin-2-one
3-[N'-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl-
]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzo-
diazepin-2-one
3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-
-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-but-
ylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro
1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-
-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-chlorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylca-
rbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbony-
lmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,3,5-trifluoroph-
enylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-
-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-methylthiopropionyl)-L-alani-
nyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-be-
nzodiazepin-2-one
3-[N'-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-d-
ihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-o-
ne
3-[N'-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylc-
arbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diet-
hylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylami-
no)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophen-
ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2--
pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-bromophenylacetyl)-L-alaninyl-
]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benz-
odiazepin-2-one
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1--
(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-dieth-
ylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethyl-
amino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethyl-
amino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-di-
ethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-phenyl-2-oxoacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-dieth-
ylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,-
N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-die-
thylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-((3,4-difluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-
-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-((4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-die-
thylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylam-
ino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-di-
ethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,6-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dih-
ydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-on-
e
3-[N'-(4-fluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydr-
o-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dih-
ydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-on-
e
3-[N'-(4-hydroxymethylphenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-
-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,-
N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl]amino-2,3-dihyd-
ro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-die-
thylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-d-
iethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,-
N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N-
,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(4-chlorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-3-thienylglycinyl]amin-
o-2,4-dioxo-1,5-bis(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodia-
zepine
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-oxo-1-
-methyl-5-phenyl-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amini-L-1H-imidazole[1,2-a]-6-
-phenyl-1,4-benzodiazepine
4-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]ami-
no-L-1H-imidazole[1,2-a]-2,4-dihydro-6-phenyl-1,4-benzodiazepine
4-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-L-4H[1,2,4]triazole[4,3-
-a]-6-phenyl-1,4-benzodiazepine
3-[N'-(3,5-difluorophenylacetyl)-L-alaniny-
l]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzod-
iazepine
3-[N'-(3,5-difluorophenylacetyl)-(R)-2-thienylglycinyl]amino-2,4--
dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(cyclopropylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1--
methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(cyclopentylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(
1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methy-
l-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenyl-.alph-
a.-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrah-
ydro-1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]ami-
no-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiaze-
pine
3-[N'-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-methy-
lpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(cyclopropylacetyl-
)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro--
1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenylacetyl)-5-5,2-phenylglyciny-
l]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benz-
odiazepine
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,-
5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(cyclopentylacetyl)-L-alaninyl]-amino-2,
4-dioxo-1,5-bis-(cycloprop-
ylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(cyclopentyl-.alp-
ha.-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-
-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenylacetyl)-
-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahyd-
ro-1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)--
L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydr-
o-1H-1,5-benzodiazepine
3-[N'-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dio-
xo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1,5--
bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phen-
yl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-[N'-(cyclopentylacetyl)-L-al-
aninyl]amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiaze-
pine
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-
-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
5-{N'-(cyclopentylacetyl)-L-alaninyl}-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-cyclopentylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
5-{N'-(cyclohexylacetyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(t-butylacetyl)-L-alaninyl}-
-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d-
]azepin-6-one
5-{N'-(3-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-fluorophenylacetyl)-L-alaninyl}-
-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
5-{N'-(3-(trifluoromethyl)phenylacetyl)-L-alaninyl}--
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
5-{N'-(hexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
5-{N'-(heptanoyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{3,4-difluorophenylacetyl)-L-al-
aninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopropylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one
5-{N'-(2-cyclopentene-1-acetyl)-L-alaninyl}-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-cyclohexylpropionyl)-L-
-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]a-
zepin-6-one
5-{N'-(citronellyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
5-{N'-(3-benzoylpropionyl)-L-alaninyl}-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-chlorophenylacetyl)-L--
alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-pentenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]-
azepin-6-one
5-{N'-(valeryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
5-{N'-(2-thiophenecetyl)-L-alaninyl}-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-(2-thienyl)butyryl)-L-alani-
nyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-(4-nitrophenyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
5-{N'-(2,4-difluorophenylacetyl)-L-alaninyl}-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,6-difluorophen-
ylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e
5-{N'-(4-isopropylphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
5-{N'-(1-adamantaneacetyl)-L-alaninyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclohexanepentanoyl)--
L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-((methylthio)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
5-{N'-(2-thiophenepentanoyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-norbornaneacetyl)-L-alan-
inyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-4-methy-
lnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-3-cyclopropylalaninyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)4-cyc-
lohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-4-meth-
ylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclohexylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopropylacetyl)-4-ethylnorleucinyl}-am-
ino-7-methyl-5,7-dihydro-(6H-dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
5-{N'-(3-(trifluoromethyl)phenylacetyl)-4-ethylnorleuc-
inyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4-difluorophenylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,4-difluorophenylacetyl)-4-ethyl-
norleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-fluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopentylacetyl)-4-methylnorleucin-
yl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclohexylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopropylacetyl)-4-methylnorleucinyl}--
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-thiopheneacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-4-methylnorleucinyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(trifluoromethyl)-
phenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,-
d]azepin-6-one
5-{N'-(4-fluorophenylacetyl)-4-methylnorleucinyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4-difluorophenylacet-
yl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one
5-{N'-(2,4-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-fluorophenylacetyl)-4-cycl-
ohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopentylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclohexylacetyl)-4-cyclohexylhomo-
alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopropylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-4-cyclohexylhomoalanin-
yl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-fluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4-difluorophenylacetyl)-4-cyc-
lohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,4-difluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-fluorophenylacetyl)-6-flu-
oronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopentylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclohexylacetyl)-6-fluoronorleucinyl}--
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclopropylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-6-fluoronorleucinyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(trifluoromethyl)-
phenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,-
d]azepin-6-one
5-{N'-(4-fluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4-difluorophenylacet-
yl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one
5-{N'-(2,4-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-methoxyphenylacetyl)-L-ala-
ninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
5-{N'-(1-naphthylacetyl)-L-alaninyl}-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4-methylenedioxyph-
enylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6--
one
5-{N'-(hydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz-
[b,d]azepin-6-one
5-{N'-(octanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl-
}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-methylphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-chlorophenyl)propionyl)-L-alaniny-
l}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one
5-{N'-(3-(4-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4,5-trifluorophenyl-
acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-(4-methoxyphenyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(methoxycarbonyl)propionyl)-L-alaniny-
l}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one
5-{N'-(3-(benzylthio)-propionyl)-L-alaninyl}-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-methylpentanoyl)-L-alan-
inyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(7-carbomethoxyheptanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
5-{N'-(2-indanylacetyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(5-carbomethoxypentanoyl)-L-
-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-methyl-3-Benzofuranacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
5-{N'-(propionyl)-L-alaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-methoxypropionyl)-L-alanin-
yl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-fluorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-fluorophenoxy)propionyl)-L-alanin-
yl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-pentenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]-
azepin-6-one
5-{N'-(4-(2,4-dichlorophenoxy)butyryl)-L-alaninyl}-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,3-dichlorophenoxyacet-
yl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4'-fluorosuccinanilyl)-L-alaninyl}-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(n-(diphenylmethyl)glutaramyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz [b,d]azepin-6-one
5-{N'-(2-fluorophenylacetyl)-L-alaninyl}-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyanoacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]-
azepin-6-one
5-{N'-(succinanilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
5-{N'-(2,4-dichlorophenoxyaceyl)-L-alaninyl}-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-nitrophenylace-
tyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(beta-propylhydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
5-{N'-(3-(2,4-dimethylbenzoyl)propionyl)-L-alani-
nyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,4,6-trifluorophenylacet-
yl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-fluoro-4-(trifluorometh-
yl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azep-
in-6-one
5-{N'-(4-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-methoxyphenoxyacetyl)-L-alaninyl}--
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
5-{N'-(2-bromophenylacetyl)-L-alaninyl}-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-benzyloxyphenoxyacetyl-
)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-hydroxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
5-{N'-(levulinyl)-L-alaninyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-hydroxyphenylacetyl)-L-alaninyl-
}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-methoxybenzoyl)propionyl)-L-alaniny-
l}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-phenylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-hydroxyphenylacetyl)-L-alaninyl}-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-(thiophene-3-acetyl)-L-alaninyl}-amino-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(6-phenylhexanoyl)-L-a-
laninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(cyclohexanebutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
5-{N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,4,5-trifluorophen-
ylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e
5-{N'-(vinylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d-
]azepin-6-one
5-{N'-(3-methylthiopropionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-nitrophenylacetyl)-L-alaninyl-
}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(n-tert-butylsuccinamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
5-{N'-(4-bromophenylacetyl)-L-alaninyl}-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(4-fluorobenzoyl)prop-
ionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(o-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
5-{N'-(p-tolylaceyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(m-tolylacetyl)-L-alaninyl}-amin-
o-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4-dichloropheny-
lacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
5-{N'-(3-methylphenoxyacetyl)-L-alaninyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-isopropylphenoxyacet-
yl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
5-{N'-(phenylmercaptoacetyl)-L-alaninyl}-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-ethoxyphenylacetyl)-L-
-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,5-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-(o-tolylacetyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,3-diphenylpropionyl)-L-a-
laninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-(3-phenoxypropionyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
5-{N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl}-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-((4-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
5-{N'-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-phenoxyphenylacety-
l)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4-dichlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-(4-fluorophenoxyacetyl)-L-alaninyl}-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,4,5-trimethoxyph-
enylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6--
one
5-{N'-(2,4-dichlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-thianaphthenacetyl)-L-alaninyl}-amin-
o-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-[N'-(methoxyacetyl)-L--
alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(ethoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d-
]azepin-6-one
5-{N'-(phenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-methoxyphenoxyacetyl)-L-alaninyl}-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-butoxyphenylac-
etyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(2-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
5-{N'-(N,N-dimethylsuccinamyl)-L-alaninyl}-a-
mino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(3,4-methylenedioxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-chloro-6-fluorophenylacety-
l)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,5-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
5-{N'-(pentafluorophenoxyacetyl)-L-alaninyl}-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-bis(trifluor-
omethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d-
]azepin-6-one
5-{N'-(3,5-dimethylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-chlorophenylacetyl)-L-ala-
ninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
5-{N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl}-amin-
o-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-dimethoxyphen-
ylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e
5-{N'-(2,5-dimethylphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-(mesitylacetyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-biphenylacetyl)-L-alanin-
yl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(N-(tert-butoxycarbonyl)-3-aminopropionyl)-L-alaninyl}-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(trans-styrylacetyl)-L-ala-
ninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-acetamidobutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
5-{N'-(3-(2-chlorophenyl)propionyl)-L-alaninyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(butyryl)-L-alaninyl-
}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(trans-3-hexenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz-
[b,d]azepin-6-one
5-{N'-(5-phenylvaleryl)-L-alaninyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(3-methoxyphenyl)propionyl)-L-a-
laninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-chloro-beta-methylhydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-(trifluoromethyl)butyryl)-L-al-
aninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(alpha-naphthoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
5-{N'-(3-(4-phenoxybenzoyl)propionyl)-L-alaninyl}-a-
mino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5{N'-(3-(2-trifluoromethylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3-benzoylamino-3-phenyl-propi-
onyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-(hydroxyimino)pentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
5-{N'-(4'-methylglutaranilyl)-L-alaninyl}-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-((4-(4-ethyl-phenox-
y)-phenoxy)-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]a-
zepin-6-one
5-{N'-(3-Benzoyl-3-phenylpropionyl)-L-alaninyl}-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-(hydroxymethyl)phenoxyace-
tyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4,4,4-trifluorobutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
5-{N'-(3-isobutyrylamino-3-phenyl-propionyl)-L-ala-
ninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-((2-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
5-{N'-(3-(phenylsulfonyl)propionyl)-L-alaninyl}-a-
mino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
5-{N'-(3-ethoxypropionyl)-L-alaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,3-difluoromandelyl)-L-alan-
inyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,6-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
5-{N'-(4-fluoromandelyl)-L-alaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2,5-difluoromandelyl)-L-alan-
inyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(dl-beta-phenyllactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
5-{N'-(dl-mandelyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
5-{N'-(p-chloromandelyl)-L-alaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(1-alpha-hydroxyisocaproyl)-L-
-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-bromomandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one
5-{N'-(1-(+)-lactyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
5-{N'-(d-3-phenylacetyl)-L-alaninyl}-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(5-methylhexanoyl)-L--
alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-L-2-phenylgl-
ycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-L-2-cyclohexylg-
lycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
5-{N'-(3,5-difluorophenylacetyl)-L-alpha-(2-th-
ienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-thiopheneacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
5-{N'-(2-thiopheneacetyl)-L-2-phenylglycinyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-thiopheneacetyl)--
L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-thiopheneacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-thiopheneacetyl)-L-threoninyl}-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(2-thiopheneacety-
l)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]a-
zepin-6-one
5-{N'-(isovaleryl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-L-2-phenylglycinyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(isovaletyl)-L-leucinyl-
}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-L-threoninyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(isovaleryl)-L-alpha-(2-thienyl-
)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(phenylacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one
5-{N'-(phenylacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(phenylacetyl)-L-leucinyl}-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-{N'-(phenylacetyl)-L--
2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e
5-{N'-(phenylacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one
5-{N'-(phenylacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; and
pharmaceutically acceptable salts thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/064,851 which was converted pursuant to 37
C.F.R. .sctn.1.53(b)(2)(ii) from U.S. patent application Ser. No.
08/780,025, filed Dec. 23, 1996.
FIELD OF THE INVENTION
[0002] This invention relates to compounds which inhibit
.beta.-amyloid peptide release and/or its synthesis, and,
accordingly, have utility in treating Alzheimer's disease.
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(1996)
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(1995)
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(1995)
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(1995)
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[0101] All of the above publications, patents and patent
applications are herein incorporated by reference in their entirety
to the same extent as if each individual publication, patent or
patent application was specifically and individually indicated to
be incorporated by reference in its entirety.
State of the Art
[0102] Alzheimer's Disease (AD) is a degenerative brain disorder
characterized clinically by progressive loss of memory, cognition,
reasoning, judgment and emotional stability that gradually leads to
profound mental deterioration and ultimately death. AD is a very
common cause of progressive mental failure (dementia) in aged
humans and is believed to represent the fourth most common medical
cause of death in the United States. AD has been observed in races
and ethnic groups worldwide and presents a major present and future
public health problem. The disease is currently estimated to affect
about two to three million individuals in the United States alone.
AD is at present incurable. No treatment that effectively prevents
AD or reverses its symptoms and course is currently known.
[0103] The brains of individuals with AD exhibit characteristic
lesions termed senile (or amyloid) plaques, amyloid angiopathy
(amyloid deposits in blood vessels) and neurofibrillary tangles.
Large numbers of these lesions, particularly amyloid plaques and
neurofibrillary tangles, are generally found in several areas of
the human brain important for memory and cognitive function in
patients with AD. Smaller numbers of these lesions in a more
restrictive anatomical distribution are also found in the brains of
most aged humans who do not have clinical AD. Amyloid plaques and
amyloid angiopathy also characterize the brains of individuals with
Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage
with Amyloidosis of the Dutch Type (HCHWA-D). At present, a
definitive diagnosis of AD usually requires observing the
aforementioned lesions in the brain tissue of patients who have
died with the disease or, rarely, in small biopsied samples of
brain tissue taken during an invasive neurosurgical procedure.
[0104] The principal chemical constituent of the amyloid plaques
and vascular amyloid deposits (amyloid angiopathy) characteristic
of AD and the other disorders mentioned above is an approximately
4.2 kilodalton (kD) protein of about 39-43 amino acids designated
the .beta.-amyloid peptide (.beta.AP) or sometimes A.beta.,
A.beta.P or .beta./A4. .beta.-Amyloid peptide was first purified
and a partial amino acid sequence was provided by Glenner, et
al..sup.1 The isolation procedure and the sequence data for the
first 28 amino acids are described in U.S. Pat. No.
4,666,829.sup.2.
[0105] Molecular biological and protein chemical analyses have
shown that the .beta.-amyloid peptide is a small fragment of a much
larger precursor protein termed the amyloid precursor protein
(APP), that is normally produced by cells in many tissues of
various animals, including humans. Knowledge of the structure of
the gene encoding APP has demonstrated that .beta.-amyloid peptide
arises as a peptide fragment that is cleaved from APP by protease
enzyme(s). The precise biochemical mechanism by which the
.beta.-amyloid peptide fragment is cleaved from APP and
subsequently deposited as amyloid plaques in the cerebral tissue
and in the walls of the cerebral and meningeal blood vessels is
currently unknown.
[0106] Several lines of evidence indicate that progressive cerebral
deposition of .beta.-amyloid peptide plays a seminal role in the
pathogenesis of AD and can precede cognitive symptoms by years or
decades. See, for example, Selkoe.sup.3. The most important line of
evidence is the discovery that missense DNA mutations at amino acid
717 of the 770-amino acid isoform of APP can be found in affected
members but not unaffected members of several families with a
genetically determined (familial) form of AD (Goate, et al..sup.4;
Chartier Harlan, et al..sup.5; and Murrell, et al..sup.6) and is
referred to as the Swedish variant. A double mutation changing
lysine.sup.595-methionine.sup.596 to
asparagine.sup.595-leucine.sup.596 (with reference to the 695
isoform) found in a Swedish family was reported in 1992 (Mullan, et
al..sup.7). Genetic linkage analyses have demonstrated that these
mutations, as well as certain other mutations in the APP gene, are
the specific molecular cause of AD in the affected members of such
families. In addition, a mutation at amino acid 693 of the
770-amino acid isoform of APP has been identified as the cause of
the .beta.-amyloid peptide deposition disease, HCHWA-D, and a
change from alanine to glycine at amino acid 692 appears to cause a
phenotype that resembles AD is some patients but HCHWA-D in others.
The discovery of these and other mutations in APP in genetically
based cases of AD prove that alteration of APP and subsequent
deposition of its .beta.-amyloid peptide fragment can cause AD.
[0107] Despite the progress which has been made in understanding
the underlying mechanisms of AD and other .beta.-amyloid peptide
related diseases, there remains a need to develop methods and
compositions for treatment of the disease(s). Ideally, the
treatment methods would advantageously be based on drugs which are
capable of inhibiting .beta.-amyloid peptide release and/or its
synthesis in vivo.
SUMMARY OF THE INVENTION
[0108] This invention is directed to the discovery of a class of
compounds which inhibit .beta.-amyloid peptide release and/or its
synthesis and, therefore, are useful in the prevention of AD in
patients susceptible to AD and/or in the treatment of patients with
AD in order to inhibit further deterioration in their condition.
The class of compounds having the described properties are defined
by formula I below: 1
[0109] wherein R.sup.1 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted
alkyl, substituted alkenyl, substituted alkynyl, substituted
cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and
heterocyclic;
[0110] W, together with --C(H).sub.pC(.dbd.X)--, forms a
cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or
substituted cycloalkenyl group wherein each of said cycloalkyl,
cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted
cycloalkenyl group is optionally fused to form a bi- or multi-fused
ring system (preferably no more than 5 fused rings) with one or
more ring structures selected from the group consisting of
cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group
which, in turn, each of such ring structures are optionally
substituted with 1 to 4 substituents selected from the group
consisting of hydroxyl, halo, alkoxy, substituted alkoxy,
thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl,
carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,
N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted
alkylamino, N,N-disubstituted alkylamino, --NHC(O)R.sup.4,
--NHSO.sub.2R.sup.4, --C(O)NH.sub.2, --C)NHR.sup.4,
--(O)NR.sup.4R.sup.4, --S(O)R.sup.4, --S(O).sub.2R.sup.4,
--S(O).sub.2NHR.sup.4 and --S(O).sub.2NR.sup.4R.sup.4 where each
R.sup.4 is independently selected from the group consisting of
alkyl, substituted alkyl, or aryl;
[0111] X is selected from the group consisting of oxo (.dbd.O),
thiooxo (.dbd.S), hydroxyl (--H, --OH), thiol (H,--SH) and hydro
(H,H);
[0112] Y is represented by the formula: 2
[0113] wherein each R.sup.2 is independently selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl
and heterocyclic;
[0114] Z is represented by the formula --T--CX'X"C(O)-- where T is
selected from the group consisting of a bond covalently linking
R.sup.1 to --CX'X"--, oxygen, sulfur, --NR.sup.5 where R.sup.5 is
hydrogen, acyl, alkyl, aryl or heteroaryl group;
[0115] X' is hydrogen, hydroxy or fluoro,
[0116] X" is hydrogen, hydroxy or fluoro, or X' and X" together
form an oxo group;
[0117] m is an integer equal to 0 or 1;
[0118] n is an integer equal to 0, 1 or 2;
[0119] p is an integer equal to 0 or 1 such that when p is zero,
the ring defined by W and --C(H).sub.pC(.dbd.X)-- is unsaturated at
the carbon atom of ring attachment to Y and when p is one, the ring
is saturated at the carbon atom of ring attachment to Y,
[0120] with the following provisos:
[0121] A. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is
--CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
2-(S)-indanol group;
[0122] B. when R.sup.1 is phenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
trans-2-hydroxy-cyclohex-1-yl group;
[0123] C. when R.sup.1 is phenyl, Z is --CH.sub.2C(O)--, m is 1, n
is 0, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a gamma-butyrolactone group or a
5,5-dimethyl-gamma-butyrolactone group;
[0124] D. when R.sup.1 is phenyl, Z is --CH.sub.2C(O)--, m is 1, n
is 0, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a E-caprolactam group;
[0125] E. when R.sup.1 is cyclopropyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an N-methylcaprolactam
group;
[0126] F. when R.sup.1 is 4-chlorobenzoyl-CH.sub.2--, R.sup.2 is
--CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form an
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one;
[0127] G. when R.sup.1 is 2-phenylphenyl, R.sup.2 is --CH.sub.3, Z
is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together
with >CH and >C.dbd.X, does not form an
7-methyl-5,7-dihydro-6H-dibenz[b- ,d]azepin-6-one;
[0128] H. when R.sup.1 is CH.sub.3OC(O)CH.sub.2--, R.sup.2 is
--CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form an
2,3-dihydro-1-(t-butylC(O)CH.sub-
.2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;
[0129] I. when R.sup.1 is 4-ethoxyphenyl, 2,4,6-trimethylphenyl,
4-phenylphenyl, CH.sub.3OC(O)CH.sub.2--, 4-HOCH.sub.2-phenyl,
2,4,6-trifluorophenyl, 2-trifluoromethyl-4-fluorophenyl, or
CH.sub.3S--, R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1,
n is 1, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2CH.sup.2--)-5-(2-pyridyl)-1H-1,4--
benzodiazepin-2-one;
[0130] J. when R.sup.1 is 2,6-difluorophenyl, R.sup.2 is
--CH.sub.3, Z is --CH(OH)C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2-
CH.sup.2--)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,
[0131] K. when m is 1 and n is 1, then 3
[0132] does not equal cycloalkyl of from 3 to 8 carbon atoms
optionally substituted with 1 to 3 alkyl groups.
[0133] Accordingly, in one of its method aspects, this invention is
directed to a method for inhibiting .beta.-amyloid peptide release
and/or its synthesis in a cell which method comprises administering
to such a cell an amount of a compound or a mixture of compounds of
formula I above effective in inhibiting the cellular release and/or
synthesis of .beta.-amyloid peptide.
[0134] Because the in vivo generation of .beta.-amyloid peptide is
associated with the pathogenesis of AD.sup.8.9, the compounds of
formula I can also be employed in conjunction with a pharmaceutical
composition to prophylactically and/or therapeutically prevent
and/or treat AD. Accordingly, in another of its method aspects,
this invention is directed to a prophylactic method for preventing
the onset of AD in a patient at risk for developing AD which method
comprises administering to said patient a pharmaceutical
composition comprising a pharmaceutically inert carrier and an
effective amount of a compound or a mixture of compounds of formula
I above.
[0135] In yet another of its method aspects, this invention is
directed to a therapeutic method for treating a patient with AD in
order to inhibit further deterioration in the condition of that
patient which method comprises administering to said patient a
pharmaceutical composition comprising a pharmaceutically inert
carrier and an effective amount of a compound or a mixture of
compounds of formula I above.
[0136] In formula I above, when m is zero (i.e., there is a
covalent bond from R.sup.1 to NH), R.sup.1 is preferably aryl
(including substituted aryl) or heteroaryl (including substituted
heteroaryl). In this embodiment, further preferred R.sup.1 groups
include
[0137] (a) phenyl,
[0138] (b) a substituted phenyl group of the formula: 4
[0139] wherein R.sup.c is selected from the group consisting of
acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen,
nitro, trihalomethyl, thioalkoxy, and wherein R.sup.b and R.sup.c
are fused to form a heteroaryl or heterocyclic ring with the phenyl
ring wherein the heteroaryl or heterocyclic ring contains from 3 to
8 atoms of which from 1 to 3 are heteroatoms independently selected
from the group consisting of oxygen, nitrogen and sulfur
[0140] R.sup.b and R.sup.b' are independently selected from the
group consisting of hydrogen, halo, nitro, cyano, trihalomethyl,
alkoxy, and thioalkoxy with the proviso that when R.sup.c is
hydrogen, then R.sup.b and R.sup.b' are either both hydrogen or
both substituents other than hydrogen,
[0141] (c) 2-naphthyl,
[0142] (d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8
positions with 1 to 5 substituents selected from the group
consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl,
thioalkoxy, aryl, and heteroaryl,
[0143] (e) heteroaryl, and
[0144] (f) substituted heteroaryl containing 1 to 3 substituents
selected from the group consisting of alkyl, alkoxy, aryl, aryloxy,
cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided
that said substituents are not ortho to the heteroaryl attachment
to the --NH group.
[0145] When m is zero, particularly preferred substituted phenyl
R.sup.1 groups include mono-, di- and tri-substituted phenyl groups
including 3,5-disubstituted phenyls such as 3,5-dichlorophenyl,
3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl, etc.;
3,4-disubstituted phenyls such as 3,4-dichlorophenyl,
3,4-difluorophenyl, 3-(trifluoromethyl)4-chlorophenyl- ,
3-chloro4-cyanophenyl, 3-chloro4-iodophenyl,
3,4-methylenedioxyphenyl, etc.; 4-substituted phenyls such as
4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl,
4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl,
4-(phenylcarbonyl)phenyl, 4-(1-ethoxy)ethylphenyl, etc.,
3,4,5-trisubsituted phenyls such as 3,4,5-trifluorophenyl,
3,4,5-trichlorophenyl, etc.
[0146] Specific R.sup.1 groups for when m is zero include
3,4-dichlorophenyl, 4-phenylfurazan-3-yl, and the like.
[0147] When m is zero, other preferred R.sup.1 substituents
include, by way of example, 2-naphthyl, quinolin-3-yl,
2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, phenyl, and
the like.
[0148] When m is one, preferred R.sup.1 groups include
unsubstituted aryl groups such as phenyl, 1-naphthyl, 2-naphthyl,
etc.; substituted aryl groups such as monosubstituted phenyls
(preferably substituents at 3 or 5 positions); disubstituted
phenyls (preferably substituents at 3 and 5 positions); and
trisubstituted phenyls (preferably substituents at the 3,4,5
positions). Preferably, the substituted phenyl groups do not
include more than 3 substituents. Examples of substituted phenyls
include, for instance, 2-chlorophenyl, 2-fluorophenyl,
2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl,
2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl,
4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl,
4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,
4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,
3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,
3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl,
3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl,
2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl,
3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl,
3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,
3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,
3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,
3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)- phenyl,
2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,
2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,
2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,
2,3,4,5,6-pentafluoroph- enyl, 2,5-dimethylphenyl, 4-phenylphenyl,
2-fluoro-3-trifluoromethylphenyl- ,
[0149] When m is one, other preferred R.sup.1 groups include, by
way of example, adamantyl, benzyl, 2-phenylethyl,
3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,
iso-propyl, iso-butyl, sec-butyl, tell-butyl, n-pentyl,
iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl,
--CH.sub.2-cyclohexyl, --CH.sub.2-cyclopentyl,
--CH.sub.2CH.sub.2-cyclopr- opyl, --CH.sub.2CH.sub.2-cyclobutyl,
--CH2CH.sub.2-cyclohexyl, --CH.sub.2CH.sub.2-cyclopentyl,
pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including
5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl),
thien-2-yl, thien-3-yl, benzothiazol4-yl, 2-phenylbenzoxazol-5-yl,
furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,
thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,
2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-- yl,
3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,
1-phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl,
(CH.sub.3).sub.2CH.dbd.CHCH.sub.2CH.sub.2CH(CH.sub.3)--,
.phi.C(O)CH.sub.2--, thien-2-yl-methyl, 2-(thien-2-yl)ethyl,
3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,
2-(4-methoxyphenyl)ethyl- , norboran-2-yl, (4-methoxyphenyl)methyl,
(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,
(3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl- ,
(4-methoxyphenyl)methyl, (4-methylphenyl)methyl,
(4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,
(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,
(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,
(1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl,
CH.sub.3OC(O)CH.sub.2--, benzylthiomethyl,
5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl,
indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl,
CH.sub.3CH.dbd.CH--, CH.sub.3CH.sub.2CH.dbd.CH--,
(4-chlorophenyl)C(O)CH.sub.2--, (4-fluorophenyl)C(O)CH.sub.2--,
(4-methoxyphenyl)C(O)CH.sub.2--,
4-(fluorophenyl)--NHC(O)CH.sub.2--, 1-phenyl-n-butyl,
(.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2NC(O)CH.sub.2--,
(.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2--, methylcarbonylmethyl,
(2,4-dimethylphenyl)C(O)CH.sub.2--, 4-methoxyphenyl-C(O)CH.sub.2--,
phenyl-C(O)CH.sub.2--, CH.sub.3C(O)N(.phi.)--, ethenyl,
methylthiomethyl, (CH.sub.3).sub.3CNHC(O)CH.sub.2--,
4-fluorophenyl-C(O)CH.sub.2--, diphenylmethyl, phenoxymethyl,
3,4-methylenedioxyphenyl-CH.sub.2--, benzo[b]thiophen-3-yl,
(CH.sub.3).sub.3COC(O)NHCH.sub.2--, trans-styryl,
H.sub.2NC(O)CH.sub.2CH.sub.2--,
2-trifluoromethylphenyl-C(O)CH.sub.2,
.phi.C(O)NHCH(.phi.)CH.sub.2--, mesityl,
CH.sub.3CH(.dbd.NHOH)CH.sub.2--,
4--CH.sub.3-.phi.-NHC(O)CH.sub.2CH.sub.2--,
.phi.C(O)CH(.phi.)CH.sub.2--, (CH.sub.3).sub.2CHC(O)NHCH(.phi.)--,
CH.sub.3CH.sub.2OCH.sub.2--,
CH.sub.3OC(O)CH(CH.sub.3)(CH.sub.2).sub.3--, 2,2,2-trifluoroethyl,
1-(trifluoromethyl)ethyl, 2-CH.sub.3-benzofuran-3-yl,
2-(2,4-dichlorophenoxy)ethyl, .phi.SO.sub.2CH.sub.2--,
3-cyclohexyl-n-propyl, CF.sub.3CH.sub.2CH.sub.2CH.sub.2-- and
N-pyrrolidinyl.
[0150] Still other preferred R.sup.1 groups include those set forth
in the Tables below.
[0151] When n is one or two, each R.sup.2 is preferably (and
independently for n=2) selected from the group consisting of alkyl,
substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and
heterocyclic.
[0152] Particularly preferred R.sup.2 substituents include, by way
of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, 2-methyl-n-butyl,
6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl,
cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclohexyl,
--CH.sub.2CH.sub.2-cyclopr- opyl, --CH.sub.2CH.sub.2-cyclohexyl,
--CH.sub.2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,
m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,
phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,
m-trifluoromethylphenyl,
p-(CH.sub.3).sub.2NCH.sub.2CH.sub.2CH.sub.2O-benzyl,
p-(CH.sub.3).sub.3COC(O)CH.sub.2O-benzyl, p-(HOOCCH.sub.2O)-benzyl,
2-aminopyrid-6-yl, p-(N-morpholino-CH.sub.2CH.sub.2O)-benzyl,
--CH.sub.2CH.sub.2C(O)NH.sub.2, --CH.sub.2-imidazol-4-yl,
--CH.sub.2-(3-tetrahydrofuranyl), --CH.sub.2-thiophen-2-yl,
--CH.sub.2(1-methyl)cyclopropyl, --CH.sub.2-thiophen-3-yl,
thiophen-3-yl, thiophen-2-yl, --CH.sub.2--C(O)O-t-butyl,
--CH.sub.2--C(CH.sub.3).sub.3,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, -2-methylcyclopentyl,
-cyclohex-2-enyl, --CH[CH(CH.sub.3).sub.2]COOCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).dbd.CH.sub.2, --CH.sub.2CH.dbd.CHCH.sub.3
(cis and trans), --CH.sub.2OH, --CH(OH)CH.sub.3,
--CH(O-t-butyl)CH.sub.3, --CH.sub.2OCH.sub.3,
--(CH.sub.2).sub.4NH-Boc, --(CH.sub.2).sub.4NH.sub.2,
--CH.sub.2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl),
pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), --CH.sub.2-naphthyl
(e.g., 1-naphthyl and 2-naphthyl), --CH.sub.2-(N-morpholino),
p-(N-morpholino-CH.sub.2CH.sub.2O)-benzyl, benzo[b]thiophen-2-yl,
5-chlorobenzo[b]thiophen-2-yl,
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,
5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,
6-methoxynaphth-2-yl, --CH.sub.2CH.sub.2SCH.sub.3, thien-2-yl,
thien-3-yl, and the like.
[0153] Compounds of this invention include, by way of example,
[0154]
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-aminodibenzosuberane
[0155]
1-(R)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-(S)-indano-
l
[0156]
1-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-(R)-indano-
l
[0157]
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-indanol
[0158]
2-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1-cyclohexanol
[0159]
1-(R,S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1,2,3,4-te-
trahydro-2-naphthol
[0160]
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-aminobenz[f]cyclohepta-
n-2-ol
[0161]
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-di-
benzo[a,c]cyclohepten-6-ol
[0162]
1-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-aminoindan-2-one
[0163] 2-(N'-(phenylacetyl)-L-alaninyl)aminocyclohexan-1-one
[0164]
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-di-
benzo[a,c]cyclohepten-6-one
[0165]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-.gamma.-butyrola-
ctone
[0166]
3-(N'-(3,4-dichlorophenyl)-L-alaninyl)amino-.gamma.-butyrolactone
[0167]
4-(N'-(cyclopentylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-isochroma-
none
[0168]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-is-
ochromanone
[0169]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-.gamma.-butyrolac-
tam
[0170]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-.delta.-valerolac-
tam
[0171]
1-benzyl-3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-.de-
lta.-valerolactam
[0172]
3-N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-4-methyl-.epsilon.-
-caprolactam
[0173]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydr-
oquinolin-2-one
[0174]
1-benzyl-3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4--
tetrahydroquinolin-2-one
[0175]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydr-
oisoquinolin-3-one
[0176]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-benzyl-1,2,3,4--
tetrahydroisoquinolin-3-one
[0177]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,2,3,4--
tetrahydroisoquinolin-3-one
[0178]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-phenyl-1,2,3,4--
tetrahydroisoquinolin-3-one
[0179]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-6-fluoro-1,2,3,4--
tetrahydroisoquinolin-3-one
[0180]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-fluoro-1,2,3,4--
tetrahydroisoquinolin-3-one
[0181]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-phenethyl-1,2,3-
,4-tetrahydroisoquinolin-3-one
[0182]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1,2,3,4--
tetrahydroisoquinolin-3-one
[0183]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-6-phenyl-1,2,3,4--
tetrahydroisoquinolin-3-one
[0184]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-phenyl-1,2,3,4--
tetrahydroisoquinolin-3-one
[0185]
(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-(9-aminofluroren-1-yl)gl-
ycine .delta.-lactam
[0186]
3-(N'-(phenylacetyl)-L-alaninyl)amino-.epsilon.-caprolactam
[0187]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-.epsilon.-ca-
prolactam
[0188]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-.eps-
ilon.-caprolactam
[0189]
3-(S)-N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-methoxyet-
hyl)-.epsilon.-caprolactam
[0190]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-.epsi-
lon.-caprolactam
[0191]
3-N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-.epsilon.--
caprolactam
[0192]
3-N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-.epsilon.--
caprolactam
[0193]
3-N'-(3,5-difluorophenylacetyl)-L-alaninyl-amino)-7-benzyl-.epsilon-
.-caprolactam
[0194]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-4,7--
methano-.epsilon.-caprolactam
[0195]
3-(S)-(N'-(cyclopentylacetyl)-L-alaninyl)amino-1-benzyl-.epsilon.-c-
aprolactam
[0196]
3-(S)-(N'-(cyclopentylacetyl)-L-phenylglycinyl)amino-1-benzyl-.epsi-
lon.-caprolactam
[0197]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-phenethy-
l)-.epsilon.-caprolactam
[0198]
3-(S)-(N'-(cyclopentylacetyl)-L-phenylglycinyl)amino-1-(2-phenethyl-
)-.epsilon.-caprolactam
[0199]
3-(N'-(3,4-dichlorophenyl)-D,L-alaninyl)amino-.epsilon.-caprolactam
[0200]
3-(S)-(N'-(cyclopropylacetyl)-L-phenylglycinyl)amino-1-methyl-.epsi-
lon.-caprolactam
[0201]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-8-octanelactam
[0202]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-benzyl-1,2,3,4--
tetrahydroisoquinolin-3-one
[0203]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,2,3,4--
tetrahydroisoquinolin-3-one
[0204]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1-phenyl-
-1,2,3,4-tetrahydroisoquinolin-3-one
[0205]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-2-yl)-1,-
2,3,4-tetrahydroisoquinolin-3-one
[0206]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-3-yl)-1,-
2,3,4-tetrahydroisoquinolin-3-one
[0207]
4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-4-yl)-1,-
2,3,4-tetrahydroisoquinolin-3-one
[0208]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-1-methyl-2-indol-
inone
[0209]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-methyl-4-phenyl-
-3,4-trans-dihydrocarbostyril
[0210]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-methyl-4-phenyl-
-3,4-cis-dihydrocarbostyril
[0211]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-4-phenyl-3,4-tran-
s-dihydrocarbostyril
[0212]
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-3-methyl-1,3,4,5--
tetrahydro-2H-3-benzazepin-2-one
[0213]
1-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-3-ethyl-4'-fl-
uoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
[0214]
3-(3,5-difluorophenylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetr-
ahydro-2H-1-benzazepin-2-one
[0215]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,3,4,5-tetrahydr-
o-2H-1-benzazepin-2-one
[0216]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,3,4,5--
tetrahydro-2H-3-benzazepin-2-one
[0217]
3-(N'-(cyclopentylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahy-
dro-2H-1-benzazepin-2-one
[0218]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,3,-
4,5-tetrahydro-2H-1-benzazepin-2-one
[0219]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,5-dimethyl-1,3,-
4,5-tetrahydro-2H-1-benzazepin-2-one
[0220]
3-(3,5-difluorophenylacetyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2-
H-1-benzazepin-2-one
[0221]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-5-ox-
a-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[0222]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5-oxa-
-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[0223]
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-5-th-
ia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[0224]
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}-amino-3,3-dimethyl-5,7-
-dihydro-6H-benz[b]azepin-6-one
[0225]
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amino-3,3,7-trimethyl-5-
,7-dihydro-6H-benz[b]azepin-6-one
[0226]
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-3,3,7-trimethyl-5-
,7-dihydro-6H-benz[b]azepin-6-one
[0227]
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-1,3,4,5--
tetrahydro-2H-3-benzazepin-2-one
[0228]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5,5-dimet-
hyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[0229]
5-(S)-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[0230] 5-(S)-[N'-((S) and
(R)-3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L--
alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0231]
5-(S)-[N'-(3,5-difluorophenyl-c-ketoacetyl)-L-alaninyl]amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0232]
5-(S)-[N'-(3,5-difluorophenylacetyl)-L-valinyl]amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[0233]
5-(S)-[N'-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0234]
5-(S)-[N'-((S)-3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-valinyl]-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0235]
5-(S)-[N'-((S)-3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-tert-leu-
cinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0236]
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methoxyacetyl)-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0237]
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methylcarboxyl-
ate)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0238]
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(3,3-dimethyl-2-
-butanoyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0239]
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(morpholinylace-
tyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0240]
5-(S)-(N'-((S)-(+)-2-Hydroxy-3-methylbutyryl)-L-alaninyl)amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0241]
5-[N'-cyclopentyl-.alpha.-hydroxyacetyl)-L-valinyl]amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0242] 5-(S)-(N'-((S) and
(R)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0243]
5-[N'-cyclopentyl-.alpha.-hydroxyacetyl)-L-tert-leucinyl]amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0244]
5-[N'-cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0245]
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H,7H-
-dibenz[b,d]azepin-6-one
[0246]
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(2-methylpropyl-
)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0247]
5-[N'-(2-hydroxy-3-methylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[0248] 5-(S)-[N'-((S and
R)-2-hydroxy-3,3-dimethylbutyryl)-L-valinyl]amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0249]
5-{N'-(.sup.4-phenyl-furazan-3-yl)alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[0250]
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-methyl-1,2,3,4,-
5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6-one
[0251]
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-phenbutyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[0252]
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-cyclopropymethy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0253]
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-(2',2',2'-trifl-
uoroethyl)-5,7-dihydro-H-dibenz[b,d]azepin-6-one
[0254]
5-{N'-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-cyclohexyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[0255]
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-9-fluoro-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0256]
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}-amino-13-fluoro-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0257]
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-10-fluoro-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0258]
5-{N'-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-7-cyclopropylmeth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0259]
5-{N'-[(S)-3,5difluoromandelyl]-L-alaninyl}amino-7-phenbutyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[0260]
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-cyclopropylmethy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0261]
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-phenbutyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[0262]
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-hexyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[0263]
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-10-fluoro-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0264]
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-13-fluoro-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0265]
5-{N'-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-9-fluoro-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0266]
3-(N'-(3,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0267]
3-(N'-(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0268]
3-(N'-(.sup.4-isopropylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0269]
3-(N'-(ethoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
[0270]
3-(N'-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0271]
3-(N'-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0272]
3-(N'-(2,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0273]
3-(N'-(3,5-difluorobenzoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0274]
3-(N'-(o-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
[0275]
3-(N'-(3,3-diphenylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0276]
3-(N'-(3-phenoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
[0277]
3-(N'-(indole-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
[0278]
3-(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydr-
o-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0279]
3-(N'-((4-methylphenoxy)acetyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0280]
3-(N'-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0281]
3-(N'-(2-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0282]
3-(N'-(3-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0283]
3-(N'-(3,4-dichlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0284]
3-(N'-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0285]
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0286]
3-(N'-(methoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
[0287]
(S)-3-(N'-(phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0288]
(S)-3-(N'-(phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
[0289]
(S)-3-(N'-(2-phenoxybutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0290]
(S)-3-(N'-(3-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0291]
(S)-3-(N'-(4-(trifluoromethyl)phenylacetyl)glycinyl)-L-alaninyl)ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0292]
(S)-3-(N'-(4-butoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0293]
(S)-3-(N'-(3-(2-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0294]
(S)-3-(N'-(4-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0295]
(S)-3-(N'-(isopropoxylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0296]
(S)-3-(N'-(1-phenyl-1H-tetrazole-5-acetyl)-L-alaninyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0297]
(S)-3-(N'-(3-(3,4-methylenedioxyphenyl)propionyl)-L-alaninyl)amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0298]
(S)-3-(N'-(3-cyclopentylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0299]
(S)-3-(N'-(2-cyclopentene-1-acetyl)-L-alaninyl)amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0300]
(S)-3-(N'-(2-chloro-6-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0301]
(S)-3-(N'-(cyclohexylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0302]
(S)-3-(N'-(2,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0303]
(S)-3-(N'-(pentafluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0304]
(S)-3-(N'-(3,5-dimethylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0305]
(S)-3-(N'-(4-chlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0306]
(S)-3-(N'-(3-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0307]
(S)-3-(N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0308]
(S)-3-(N'-(benzoylformyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0309]
(S)-3-(N'-(3,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0310]
(S)-3-(N'-(2,5-dimethylphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0311]
(S)-3-(N'-(2,6-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0312]
(S)-3-(N'-(2,4-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0313]
(S)-3-(N'-(mesitylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0314]
(S)-3-(N'-(4-biphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0315]
(S)-3-(N'-(3,4-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0316]
(S)-3-(N'-(trans-styrylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0317]
(S)-3-(N'-(3-benzoylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0318]
(S)-3-(N'-(trans-3-hexenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0319]
(S)-3-(N'-(heptanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
[0320]
(S)-3-(N'-(3-(4-methylphenyl)propionyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0321]
(S)-3-(N'-(3-(4-chlorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0322]
(S)-3-(N'-(3-phenylbutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0323]
(S)-3-(N'-(4-(4-methoxyphenyl)butyryl)-L-alaninyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0324]
(S)-3-(N'-(3-methoxycarbonylpropionyl)-L-alaninyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0325]
(S)-3-(N'-(4-phenylbutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0326]
(S)-3-(N'-(3-(benzylthio)propionyl)-L-alaninyl)amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0327]
(S)-3-(N'-(3-methylpentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0328]
(S)-3-(N'-(6-methoxycarbonylheptanoyl)-L-alaninyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0329]
(S)-3-(N'-(2-indanylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0330]
(S)-3-(N'-(4-methoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0331]
(S)-3-(N'-(2-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0332]
(S)-3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0333]
(S)-3-(N'-(3-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-di-
hydro-1-methyl-5-phenyl-1H- L,4-benzodiazepin-2-one
[0334]
(S)-3-(N'-(4-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0335]
(S)-3-(N'-(2,6-difluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0336]
(S)-3-(N'-(-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0337]
(S)-3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0338]
(S)-3-(N'-(m-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0339]
(S)-3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0340]
(S)-3-(N'-(4-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0341]
(S)-3-(N'-(2-naphthylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0342]
(S)-3-(N'-(3-chlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0343]
(S)-3-(N'-(3-methylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0344]
(S)-3-(N'-(3,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0345]
(S)-3-(N'-(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0346]
(S)-3-(N'-(4-isopropylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0347]
(S)-3-(N'-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0348]
(S)-3-(N'-(phenylmercaptoacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0349]
(S)-3-(N'-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0350]
(S)-3-(N'-(2,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0351]
(S)-3-(N'-(o-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0352]
(S)-3-(N'-(3,3-diphenylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0353]
(S)-3-(N'-(3-phenoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0354]
(S)-3-(N'-(indole-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0355]
(S)-3-(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0356]
(S)-3-(N'-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0357]
(S)-3-(N'-(2-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-l1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0358]
(S)-3-(N'-(3-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0359]
(S)-3-(N'-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0360]
(S)-3-(N'-(2,4-dichlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0361] (S)-3-(N'-((methylthio)acetyl)-L-alaninyl)am
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0362]
(S)-3-(N'-(4-fluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0363]
(S)-3-(N'-(4-thionaphthenacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0364] (S)-3-(N'-(methoxyacetyl)-
L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-H-1,4-benzodiazepin-2-one
[0365]
(S)-3-(N'-(ethoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
[0366]
(S)-3-(N'-(3-indolepropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0367]
(S)-3-(N'-(3-(2-chlorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0368]
(S)-3-(N'-(butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one
[0369]
(S)-3-(N'-(hexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
[0370]
(S)-3-(N'-(5-phenylpentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0371]
(S)-3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0372]
(S)-3-(N'-(4-nitrophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0373]
(S)-3-(N'-(3-(3-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0374]
(S)-3-(N'-(5-methylhexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0375]
(S)-3-(N'-(hydrocinnamyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0376]
(S)-3-(N'-(octanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
[0377]
(S)-3-(N'-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0378]
(S)-3-(N'-(3-(4-hydroxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0379]
(S)-3-(N'-(3,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0380]
(S)-3-(N'-(5-hydantoinacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0381]
(S)-3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0382]
(S)-3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0383]
(S)-3-(N'-(2-methyl-3-Benzofuranacetyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0384]
(S)-3-(N'-(propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
[0385]
(S)-3-(N'-(cyclopropylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0386]
(S)-3-(N'-(3-methoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0387]
(S)-3-(N'-(5-(thienyl)pentanoyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0388]
(S)-3-(N'-(3-(4-fluorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0389]
(S)-3-(N'-(3-(4-fluorophenoxy)propionyl)-L-alaninyl)amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4benzodiazepin-2-one
[0390]
(S)-3-(N'-(2-norbornaneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0391]
(S)-3-(N'-(2,3-difluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0392]
(S)-3-(N'-(3-pentenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
[0393]
(S)-3-(N'-(4-(2,4-dichlorophenoxy)butyryl)-L-alaninyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0394]
(S)-3-(N'-(2,3-dichlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0395]
(S)-3-(N'-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl)amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0396]
(S)-3-(N'-(2-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0397] (S)-3-(N'-(2-(4-cyanophenoxy)-2-methyl
propionyl)-L-alaninyl)amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0398]
(S)-3-(N'-(2-nitrophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0399]
(S)-3-(N'-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0400]
(S)-3-(N'-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl)ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0401]
(S)-3-(N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0402]
(S)-3-(N'-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0403]
(S)-3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0404]
(S)-3-(N'-(2-fluoro4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0405]
(S)-3-(N'-(4-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0406]
(S)-3-(N'-(3-(4-fluorobenzoyl)propionyl)-L-alaninyl)amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0407]
(S)-3-(N'-((2-methylphenoxy)acetyl)-L-alaninyl)amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0408]
(S)-3-(N'-(4-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0409]
(S)-3-(N'-(3-(phenylsulfonyl)propionyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0410]
(S)-3-(N'-(2-methoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0411]
(S)-3-(N'-(2-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0412]
(S)-3-(N'-(p-isopropylphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0413]
(S)-3-(N'-(4-pentenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
[0414]
(S)-3-(N'-(4-hydroxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0415]
(S)-3-(N'-(4-oxopentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
[0416]
(S)-3-(N'-(2-hydroxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0417]
(S)-3-(N'-(3,4-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0418]
(S)-3-(N'-(3-(4-methoxybenzoyl)propionyl)-L-alaninyl)amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0419]
(S)-3-(N'-(thien-3-ylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0420]
(S)-3-(N'-(6-phenylhexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0421]
(S)-3-(N'-(isovaleryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one
[0422]
(S)-3-(N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0423]
(S)-3-(N'-(2,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0424]
(S)-3-(N'-(1-adamantaneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0425]
(S)-3-(N'-(cyclohexanepentanoyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0426]
(S)-3-(N'-(2-thiopheneacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0427]
(S)-3-(N'-(3-(trifluoromethyl)phenylacetyl)-L-phenylglycinyl)amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0428]
(S)-3-(N'-(3,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0429]
(S)-3-(N'-(3-tolylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0430]
(S)-3-(N'-(3-fluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0431]
(S)-3-(N'-(3-bromophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0432]
(S)-3-(N'-(3-chlorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0433]
(S)-3-(N'-(3,4-methylenedioxyphenylacetyl)-L-phenylglycinyl)amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0434]
(S)-3-(N'-(phenylmercaptoacetyl)-L-phenylglycinyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0435]
(S)-3-(N'-(acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
[0436]
(S)-3-(N'-(3,5-bis(trifluoromethyl)phenylacetyl)-L-phenylglycinyl)a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0437]
(S)-3-(N'-((methylthio)acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0438]
(S)-3-(N'-(phenoxyacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0439]
(S)-3-(N'-(phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0440]
(S)-3-(N'-(cyclohexylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0441]
(S)-3-(N'-(2,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0442]
(S)-3-(N'-(benzo[b]thiophene-3-acetyl)-L-phenylglycinyl)amino-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0443]
(S)-3-(N'-(benzoylformyl)-L-phenylglycinyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0444]
(S)-3-(N'-(2,6-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0445]
(S)-3-(N'-(2,4-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0446]
(S)-3-(N'-(3,4-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0447]
(S)-3-(N'-(butyryl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0448]
(S)-3-(N'-(heptanoyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0449]
(S)-3-(N'-(4-(2-thienyl)butyryl)-L-phenylglycinyl)amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0450]
(S)-3-(N'-(5-methylhexanoyl)-L-phenylglycinyl)amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0451]
(S)-3-(N'-(hydrocinnamyl)-L-phenylglycinyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0452]
(S)-3-(N'-(cyclopentylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0453]
(S)-3-(N'-(propionyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0454]
(S)-3-(N'-(3,4,5-trifluorophenylacetyl)-L-phenylglycinyl)amino-2,3--
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0455]
(S)-3-(N'-(4-phenylbutyryl)-L-phenylglycinyl)amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0456]
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(-
4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0457]
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)--
2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0458]
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(-
2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0459]
3-(N'-(.sup.2-thiopheneacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0460]
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophen-
yl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0461]
3-(N'-(.sup.2-thiopheneacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-d-
ihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0462]
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-
-1-methyl-1H-1,4-benzodiazepin-2-one
[0463]
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluoropheny-
l)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0464]
3-(N'-(2-thiopheneacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,-
2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0465]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phe-
nyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0466]
3-(N'-(3,5difluorophenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenyle-
thyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0467]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihy-
dro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0468]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0469]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chl-
orophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0470]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-
-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0471]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3--
dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0472]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluo-
rophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0473]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5--
bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0474]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl--
1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0475]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethy-
l)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0476]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro--
5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0477]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0478]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorop-
henyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0479]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dih-
ydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0480]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihy-
dro-1-methyl-1H-1,4-benzodiazepin-2-one
[0481]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluoroph-
enyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0482]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis--
(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0483]
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(-
4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0484]
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)--
2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0485]
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(-
2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0486]
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0487]
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophen-
yl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0488]
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydr-
o-1-methyl-1H-1,4-benzodiazepin-2-one
[0489]
3-(N.'-(methylthio)acetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydr-
o-1-methyl-1H-1,4-benzodiazepin-2-one
[0490]
3-(N'-(methylthio)acetyl)-L-alaninyl)amino-7-bromo-5-(2-fluoropheny-
l)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0491]
3-(N'-(methylthio)acetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,-
2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0492]
3-(N'-(phenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-
-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0493]
3-(N'-(phenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-d-
ihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0494]
3-(N'-(phenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thi-
azolyl)-1H-1,4-benzodiazepin-2-one
[0495]
3-(N'-(phenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0496]
3-(N'-(phenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2-
,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0497]
3-(N'-(phenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-m-
ethyl-1H-1,4-benzodiazepin-2-one
[0498]
3-(N'-(phenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-me-
thyl-1H-1,4-benzodiazepin-2-one
[0499]
3-(N'-(phenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,-
3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0500]
3-(N'-(phenylacetyl)-L-alaninyl)-amino-)2,4-dioxo-1,5-bis-(2,2-dime-
thylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0501]
3-(N'-(benzoylformyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,-
4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0502]
3-(N'-(benzoylformyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3--
dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0503]
3-(N'-(benzoylformyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-th-
iazolyl)-1H-1,4-benzodiazepin-2-one
[0504]
3-(N'-(benzoylformyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0505]
3-(N'-(benzoylformyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)--
2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0506]
3-(N'-(benzoylformyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1--
methyl-1H-1,4-benzodiazepin-2-one
[0507]
3-(N'-(benzoylformyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-m-
ethyl-1H-1,4-benzodiazepin-2-one
[0508]
3-(N'-(benzoylformyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2-
,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0509]
3-(N'-(benzoylformyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-di-
methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0510]
3-(N'-(butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trif-
luorobutyl)-1H-1,4-benzodiazepin-2-one
[0511]
3-(N'-(butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydr-
o-5phenyl-1H-1,4-benzodiazepin-2-one
[0512]
3-(N'-(butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazoly-
l)-1H-1,4-benzodiazepin-2-one
[0513]
3-(N'-(butyryl)-L-alaninyl)amino-7chloro-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
[0514]
3-(N'-(butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-di-
hydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0515]
3-(N'-(butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-
-1H-1,4-benzodiazepin-2-one
[0516]
3-(N'-(butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl--
1H-1,4-benzodiazepin-2-one
[0517]
3-(N'-(butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dih-
ydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0518]
3-(N'-(butyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethyl-
propyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0519]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl1-
-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0520]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethy-
l)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0521]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro--
5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0522]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro--
1-methyl-5-phenyl-H-1,4-benzodiazepin-2-one
[0523]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorop-
henyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0524]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dih-
ydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0525]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihy-
dro-1-methyl-1H-1,4-benzodiazepin-2-one
[0526]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluoroph-
enyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0527]
3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis--
(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0528]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(-
4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0529]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)--
2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0530] 3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-l
-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0531]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0532]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophen-
yl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0533]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydr-
o-1-methyl-1H-1,4-benzodiazepin-2-one
[0534]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-
-1-methyl-1H-1,4-benzodiazepin-2-one
[0535]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluoropheny-
l)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0536]
3-(N'-(cyclopentylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,-
2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0537]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2,3-dihydro-5-p-
henyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0538]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-1-(2-oxo-2-phen-
ylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0539]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-1-methyl-2,3-di-
hydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0540]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0541]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2-c-
hlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0542]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-(2-thienyl)-2-
,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0543]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-cyclohexyl-2,-
3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0544]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-bromo-5-(2-fl-
uorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0545]
3-(N'-(3-(trifluoromethyl)butyryl)-L-alaninyl)-amino-)2,4-dioxo-1,5-
-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0546]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-2,3-dihydro-5-pheny-
l-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0547] 3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-
-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0548]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-1-methyl-2,3-dihydr-
o-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0549]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0550]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-5-(2-chlor-
ophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0551]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-d-
ihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0552]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-di-
hydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0553]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-bromo-5-(2-fluoro-
phenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0554]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bi-
s-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0555]
3-(N'-(isovaleryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-t-
rifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0556]
3-(N'-(isovaleryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dih-
ydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0557]
3-(N'-(isovaleryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiaz-
olyl)-1H-1,4-benzodiazepin-2-one
[0558]
3-(N'-(isovaleryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0559]
3-(N'-(isovaleryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-
-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0560]
3-(N'-(isovaleryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-met-
hyl-1H-1,4-benzodiazepin-2-one
[0561]
3-(N'-(isovaleryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-meth-
yl-1H-1,4-benzodiazepin-2-one
[0562]
3-(N'-(isovaleryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3--
dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0563]
3-(N'-(isovaleryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimet-
hylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0564]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-2,3-dihydro-5-ph-
enyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0565]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-1-(2-oxo-2-pheny-
lethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0566]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-1-methyl-2,3-dih-
ydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one
[0567]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-chloro-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0568]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-chloro-5-(2-ch-
lorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0569]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-(2-thienyl)-2,-
3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0570]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-cyclohexyl-2,3-
-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0571]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-bromo-5-(2-flu-
orophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0572]
3-(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-
-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0573]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4-
,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one
[0574]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-
-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0575]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-t-
hiazolyl)-1H-1,4-benzodiazepin-2-one
[0576]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0577]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-
-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0578]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-
-methyl-1H-1,4-benzodiazepin-2-one
[0579]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1--
methyl-1H-1,4-benzodiazepin-2-one
[0580]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)--
2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0581]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(3-fluorobenzyl)-1H-1,4-benzodiazepin-2-one
[0582]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(benzyl)-1H-1,4-benzodiazepin-2-one
[0583]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one
[0584]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one
[0585]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one
[0586]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one
[0587]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one
[0588]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one
[0589]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-phenylethyl)-1H-1,4-benzodiazepin-2-one
[0590]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one
[0591]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-(N-phthalimnidyl)ethyl)-1H-1,4-benzodiazepin-2-one
[0592]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-biphenylmethyl)-1H- l,4-benzodiazepin-2-one
[0593]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-((2-tetrahydrofuranyl)methyl)-1H-1,4-benzodiazepin-2-one
[0594]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-(1,4-benzodioxanyl)methyl)-1H-1,4-benzodiazepin-2-one
[0595]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one
[0596]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(3,3-dimethyl-2-oxo-propyl)-1H-1,4-benzodiazepin-2-one
[0597]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one
[0598]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one
[0599]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one
[0600]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one
[0601]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-ethyl-1H-1,4-benzodiazepin-2-one
[0602]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(3-pyridylmethyl)-1H-1,4-benzodiazepin-2-one
[0603]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-oxo-2-(N-indolinyl)ethyl)-1H-1,4-benzodiazepin-2-one
[0604]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one
[0605]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihy-
dro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one
[0606]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
benzyl)-1H-1,4-benzodiazepin-2-one
[0607]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one
[0608]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one
[0609]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one
[0610]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
isopropyl)-1H-1,4-benzodiazepin-2-one
[0611]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one
[0612]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
2-ethylbutyl)-1H-1,4-benzodiazepin-2-one
[0613]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one
[0614]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
2-phenylethyl)-1H-1,4-benzodiazepin-2-one
[0615]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
3-phenylpropyl)-1H-1,4-benzodiazepin-2-one
[0616]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
2-(N-phthalimidyl)ethyl)-1H-1,4-benzodiazepin-2-one
[0617]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
2-biphenylmethyl)-1H-1,4-benzodiazepin-2-one
[0618]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one
[0619]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
3,3-dimethyl-2-oxo-butyl)-1H-1,4-benzodiazepin-2-one
[0620]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one
[0621]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one
[0622]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one
[0623]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
cyclopropylmethyl)-1H-1,4-benzodiazepin-2-one
[0624]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
2-methylbutyl)-1H-1,4-benzodiazepin-2-one
[0625]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-e-
thyl-1H-1,4-benzodiazepin-2-one
[0626]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one
[0627]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-p-
ropyl-1H-1,4-benzodiazepin-2-one
[0628]
3-(N'-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(-
2-methoxyethyl)-1H-1,4-benzodiazepin-2-one
[0629]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(benzyl)-1H-1,4-benzodiazepin-2-one
[0630]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one
[0631]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one
[0632]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one
[0633]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-(isopropyl)-1H-1,4-benzodiazepin-2-one
[0634]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one
[0635]
3-(N'-(4,4,.sup.4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-d-
ihydro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one
[0636]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one
[0637]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one
[0638]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(2-biphenylmethyl)-1H-1,4-benzodiazepin-2-one
[0639]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one
[0640]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(3,3-dimethyl-2-oxo-butyl)-1H-1,4-benzodiazepin-2-one
[0641]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one
[0642]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one
[0643]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one
[0644]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(cyclopropylmethyl)-1H-1,4-benzodiazepin-2-one
[0645]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one
[0646]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(ethyl)-1H-1,4-benzodiazepin-2-one
[0647]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one
[0648]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(propyl)-1H-1,4-benzodiazepin-2-one
[0649]
3-(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydr-
o-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one
[0650]
3-(N'-(L-(+)-mandelyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-d-
imethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0651]
(S)-3-(N'-(N-pyrrolidinylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0652]
3-(N'-(2-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0653]
3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-p-
henyl -1H-1,4-benzodiazepin-2-one
[0654]
3-(N'-(3-(trifluoromethyl)phenylacetic)-L-alaninyl)amino-2,3-dihydr-
o-1-methyl-5-phenyl -1H-1,4-benzodiazepin-2-one
[0655]
3-(N'-(4-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-pheny-
l -1H-1,4-benzodiazepin-2-one
[0656]
3-(N'-(3-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0657]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0658]
3-(N'-(m-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
[0659]
3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0660]
3-(N'-(3-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0661]
3-(N'-(4-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0662]
3-(N'-(2-naphthylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
[0663]
3-(N'-(3-methylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0664]
3-[(N'-(4-methoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-meth-
yl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0665]
3-[(N'-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-
-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0666]
3-[(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-m-
ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0667]
3-[(N'-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0668]
3-[(N'-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methy-
l-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0669]
3-[(N'-(4-ethoxyphenylacetyl)-L-alaninyl)amino]l-2,3-dihydro-1-meth-
yl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0670]
3-[(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihy-
dro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0671]
3-[(N'-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-
-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0672]
3-[(N'-((methylthio)acetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl--
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0673]
3-[(N'-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0674]
3-[(N'-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-m-
ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0675]
3-[(N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-
-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0676]
3-[(N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro--
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0677]
3-[(N'-(4-biphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0678]
3-[(N'-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-m-
ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0679]
3-[(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino]-2,3-dihydro-1-methy-
l-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0680]
3-[(N'-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0681]
3-[(N'-(3-methoxycarbonylpropionyl)-L-alaninyl)amino]-2,3-dihydro-1-
-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0682] 3-[(N'-(2,6-difluoromandelyl)-L-alaninyl]amino
-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0683]
3-[(N'-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0684]
3-[(N'-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methy-
l-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0685]
3-[(N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro--
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0686]
3-[(N'-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-
-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0687]
3-[(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-met-
hyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0688]
3-[(N'-(4-isopropylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-met-
hyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0689]
3-[(N'-(beta-phenyl]actyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0690]
3-[(N'-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyrid-
yl)-1H-1,4-benzodiazepin-2-one
[0691]
3-[(N'-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0692]
3-[(N'-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyr-
idyl)-1H-1,4-benzodiazepin-2-one
[0693]
3-[(N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro--
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0694]
3-[(N'-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-meth-
yl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0695]
3-[(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1--
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0696]
3-[(N'-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0697]
3-[(N'-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0698]
3-[(N'-(4-methocyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-
-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0699]
3-[(N'-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dim-
ethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0700]
3-[(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(-
3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0701]
3-[(N'-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-d-
imethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0702]
3-[(N'-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3--
dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0703]
3-[(N'-(4-ethoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3--
dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0704]
3-[(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihy-
dro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0705]
3-[(N'-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-
-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2--
one
[0706]
3-[(N'-((methylthio)acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-di-
methyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0707]
3-[(N'-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dime-
thyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0708]
3-[(N'-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(-
3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0709]
3-[(N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-
-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0710]
3-[(N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro--
1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0711]
3-[(N'-(4-biphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dime-
thyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0712]
3-[(N'-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(-
3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0713]
3-[(N'-(4-(2-thienyl)butyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-di-
methyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0714]
3-[(N'-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dime-
thyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0715]
3-[(N'-(2,6-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3--
dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0716]
3-[(N'-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dime-
thyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0717]
3-[(N'-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3--
dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0718]
3-[(N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro--
1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0719]
3-[(N'-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-
-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0720]
3-[(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-(3,-
3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0721]
3-[(N'-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3-
,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0722]
3-[(N'-(beta-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dim-
ethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0723]
3-[(N'-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-o-
xobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0724]
3-[(N'-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dime-
thyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0725]
3-[(N'-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-
-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0726]
3-[(N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro--
1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0727]
3-[(N'-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-
-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0728]
3-[(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1--
(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0729]
3-[(N'-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-d-
imethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0730]
3-[(N'-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dime-
thyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0731]
3-[(N'-(4-methoxyphenylacetyl)-L-alaninyl]amino3-2,3-dihydro-1-(2-N-
,N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0732]
3-[(N'-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-d-
iethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0733]
3-[(N'-(N"-acetyl-N"-phenylglycinyl)L-alaninyl)amino]-2,3-dihydro-1-
-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0734]
3-[(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(-
2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0735]
3-[(N'-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-
-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0736]
3-[(N'-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,-
N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0737]
3-[(N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihy-
dro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0738]
3-[(N'-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-
-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2- -one
[0739]
3-[(N'-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-di-
ethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0740]
3-[(N'-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(-
2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0741]
3-[(N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-
-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0742]
3-[(N'-(benzoylformyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-dieth-
yl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0743]
3-[(N'-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(-
2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0744]
3-[(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,-
N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0745]
3-[(N'-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-di-
ethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0746]
3-[(N'-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-di-
ethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0747]
3-[(N'-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,-
N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0748]
3-[(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-(2--
N,N-5 diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0749]
3-[(N'-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-
-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0750]
3-[(N'-(beta-phenyl]actyl)-L-alaninyl)amino3-2,3-dihydro-1-(2-N,N-d-
iethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0751]
3-[(N'-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0752]
3-[(N'-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-di-
ethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0753]
3-[(N'-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0754]
3-[(N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro--
1-(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0755]
3-[(N'-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N-
,N-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0756]
3-[(N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1--
(2-N,N-diethyl
aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0757]
3-[(N'-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-
-diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0758]
3-[(N'-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-di-
ethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0759]
3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-
-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0760]
3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-
-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0761]
3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-
-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0762]
3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis--
(2-methylpropyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0763]
3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis--
(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0764]
3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis--
(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0765]
3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-b-
is-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0766]
3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-b-
is-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0767]
3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-b-
is-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0768]
3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5--
bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0769]
3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5--
bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0770]
3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5--
bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0771]
3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1-
,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0772]
3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1-
,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0773]
3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1-
,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0774]
3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1-
,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0775]
3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1-
,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0776]
3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1-
,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0777]
3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-
-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0778]
3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-
-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0779]
3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-
-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0780]
3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-
-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0781]
3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-
-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0782]
3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-
-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0783]
3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-b-
is-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0784]
3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-b-
is-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0785]
3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-b-
is-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0786]
3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bi-
s-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0787]
3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-l,5-bi-
s-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0788]
3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bi-
s-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0789]
3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-met-
hylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0790]
3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(methy-
l)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0791]
3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclo-
propylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0792]
3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-meth-
ylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0793]
3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(methyl-
)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0794]
3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclop-
ropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0795]
3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-m-
ethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0796]
3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(met-
hyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0797]
3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cyc-
lopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0798]
3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2--
methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0799]
3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(me-
thyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0800]
3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cy-
clopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0801]
3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis--
(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0802]
3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis--
(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0803]
3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis--
(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0804]
3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis--
(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0805]
3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis--
(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0806]
3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis--
(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0807]
3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0808]
3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0809]
3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0810]
3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0811]
3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0812]
3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bi-
s-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0813]
3-[N-(cyclopentylacetyl)-L-serinyl]-amino-2,4-dioxo-1,5-bis-(2-meth-
ylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0814]
3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2-m-
ethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0815]
3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(met-
hyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0816]
3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cyc-
lopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0817]
3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(2-me-
thylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0818]
3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(meth-
yl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0819]
3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(cycl-
opropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0820]
3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-
-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0821]
3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(m-
ethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0822]
3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(c-
yclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0823]
3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2--
methylpropyl)-2,3,4,5-.tetrahydro-1H-1,5-benzodiazepine
[0824]
3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(me-
thyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0825]
3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cy-
clopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0826]
3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis--
(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0827]
3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis--
(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0828]
3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis--
(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0829]
3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-
-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0830]
3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-
-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0831]
3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-
-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0832]
3-[N-(4,4,4-trifluorobutryl)-L-phenytalaninyl]-amino-2,4-dioxo-1,5--
bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0833]
3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5--
bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0834]
3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5--
bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0835]
3-[N-(4,4,4-trifluorobutryl)-phenylglycinyl]-amino-2,4-dioxo-1,5-bi-
s-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0836]
3-[N-(4,4,4-trifluorobutryl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5--
bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0837]
3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo--
1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0838]
3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo--
1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0839]
3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo--
1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0840]
3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo--
1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0841]
3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo--
1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0842]
3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo--
1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0843]
3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo--
1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0844]
3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo--
1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0845]
3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo--
1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0846]
3-[N-(4,4,4-trifluorobutryl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis--
(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0847]
3-[N-(4,4,4-trifluorobutryl)-threoninyl]-amino-2,4-dioxo-1,5-bis-(m-
ethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0848]
3-[N-(4,4,4-trifluorobutryl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis--
(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0849]
3-(3,5-difluorophenylacetyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H--
1,4-benzodiazepin-2-one
[0850]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-eth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0851]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
[0852]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-me-
thyl-5-(1-piperidinyl)-1H-1,4-benzodiazepin-2-one
[0853]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0854]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-7-bromo-2,3-dihy-
dro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[0855]
3-[N'-(3,5-difluorophenylacetyl)-N'-methyl-L-alaninyl)-amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0856]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dih-
ydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one
[0857]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-5-cyclohexyl-2,3-
-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[0858]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-me-
thyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one
[0859]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-me-
thyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[0860]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-valinyl]-amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0861]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-tert-leucinyl]-a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0862]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-me-
thyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[0863]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-met-
hyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[0864]
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0865]
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-valinyl]-amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0866]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1,5-d-
imethyl-1H-1,4-benzodiazepin-2-one
[0867]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-iso-
butyl-5-phenyl)-1H-1,4-benzodiazepin-2-one
[0868]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0869]
3-[N'-(3,5-difluorophenyl-.alpha.-oxoacetyl)-L-alaninyl]amino-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0870]
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
[0871]
3-[N'-(3,5-difluorophenylacetyl)-L-valinyl]amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0872]
3-[N'-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0873]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-iso-
propyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0874]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-cyc-
lopropylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0875]
3-[N'-(3,5-difluorophenyl-.alpha.-fluoroacetyl)-L-alaninyl]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0876]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-n-p-
ropyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0877] 3-[N'-(3-methylbutyryl)-L-phenylglycinyl]amino-2,3-dihydro-l
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0878]
3-[N'-(3,5-difluorophenylacetyl)-L-phenylglycinyl]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0879]
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
[0880]
3-[N'-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
[0881]
3-[N'-(2-phenylthioacetyl)-L-phenylglycinyl]amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0882]
3-[N'-(3-(4-methoxyphenyl)propionyl)-L-alaninyl]amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0883]
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0884]
3-[N'-(4-cyclohexylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0885]
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0886]
3-[N'-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0887]
3-[N'-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0888]
3-[N'-(3,3-dimethylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[0889]
3-[N'-(thien-2-yl-acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(-
2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0890]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-met-
hyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0891]
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-
-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0892]
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0893]
3-[N'-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl--
5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0894]
3-[N'-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro--
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0895]
3-[N'-(3,5-di(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-di-
hydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0896]
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0897]
3-[N'-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5--
(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0898]
3-[N'-(2,3,4,5,6-pentafluorophenoxyacetyl)-L-alaninyl]amino-2,3-dih-
ydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0899]
3-[N'-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0900]
3-[N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1--
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0901]
3-[N'-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methy-
l-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0902]
3-[N'-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-met-
hyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0903]
3-[N'-(4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0904]
3-[N'-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-
-pyridyl)-1H-1,4-benzodiazepin-2-one
[0905]
3-[N'-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-meth-
yl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0906]
3-[N'-(2,6-difluorophenyl)-.alpha.-hydroxyacetyl)-L-alaninyl]amino--
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0907]
3-[N'-(4-fluorophenyl)-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3--
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0908]
3-[N'-(2,5-difluorophenyl)-.alpha.-hydroxyacetyl)-L-alaninyl]amino--
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0909]
3-[N'-(2,4,6-trifluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-
-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0910]
3-[N'-(2-trifluoromethyl4-fluorophenyl)acetyl)-L-alaninyl]amino-2,3-
-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0911]
3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-methy-
l-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0912]
3-[N'-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-met-
hyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0913]
3-[N'-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1--
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0914]
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-
-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0915]
3-[N'-(4-chlorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-d-
ihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0916]
3-[N'-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2--
pyridyl)-1H-1,4-benzodiazepin-2-one
[0917]
3-[N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1--
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0918]
3-[N'-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0919]
3-[N'-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-me-
thyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0920]
3-[N'-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-
-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0921]
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert--
butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0922]
3-[N'-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylc-
arbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0923]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(te-
rt-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0924]
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-bu-
tylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0925]
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-but-
ylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0926]
3-[N'-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-b-
utylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0927]
3-[N'-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro--
1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0928]
3-[N'-(3,5-di-(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-d-
ihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-o-
ne
[0929]
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-but-
ylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0930]
3-[N'-(2-cyclomethylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-bu-
tylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0931]
3-[N'-(2,3,4,5,6-pentafluorophenoxyacetyl)-L-alaninyl]amino-2,3-dih-
ydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0932]
3-[N'-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert--
butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0933]
3-[N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1--
(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0934]
3-[N'-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-
-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0935]
3-[N'-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(te-
rt-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0936]
3-[N'-(4-(2-thienyl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-b-
utylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0937]
3-[N'-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butyl-
carbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0938]
3-[N'-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(ter-
t-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0939]
3-[N'-(2,6-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-
-2-one
[0940]
3-[N'-(4-fluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-d-
ihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-o-
ne
[0941]
3-[N'-(2,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-
-2-one
[0942]
3-[N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1--
(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0943]
3-[N'-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl]amino-2,3-
-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-
-one
[0944]
3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-
-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0945]
3-[N'-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(te-
rt-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0946]
3-[N'-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1--
(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0947]
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-
-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0948]
3-[N'-(4-chlorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-b-
utylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0949]
3-[N'-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylc-
arbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0950]
3-[N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1--
(ter-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0951]
3-[N'-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-1-(tert--
butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0952]
3-[N'-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-(t-
ert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0953]
3-[N'-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-bu-
tylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0954]
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,-
N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0955]
3-[N'-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diet-
hylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0956]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2--
(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0957]
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N--
diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0958]
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-d-
iethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0959]
3-[N'-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-
-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0960]
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-d-
iethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0961]
3-[N'-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-d-
iethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0962]
3-[N'-(2,3,4,5,6-pentafluorophenoxyacetyl)-L-alaninyl]amino-2,3-dih-
ydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-on-
e
[0963]
3-[N'-(2-thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(-
N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0964]
3-[N'-(2-phenyl-2-oxoacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-
-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0965]
3-[N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1--
(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0966]
3-[N'-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N-
,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0967]
3-[N'-((3,4-difluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-(-
2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0968]
3-[N'-((4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N-
,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0969]
3-[N'-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-die-
thylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0970]
3-[N'-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(-
N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0971]
3-[N'-(2,6-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0972]
3-[N'-(4fluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-di-
hydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-o-
ne
[0973]
3-[N'-(2,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0974]
3-[N'-(4-hydroxymethylphenoxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-
-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0975]
3-[N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1--
(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0976]
3-[N'-(2-trifluoromethyl4-fluorophenylacetyl)-L-alaninyl]amino-2,3--
dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-
-one
[0977]
3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N-
,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0978]
3-[N'-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2--
(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0979]
3-[N'-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1--
(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0980]
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-
-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0981]
3-[N'-(4-chlorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-d-
ihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2--
one
[0982]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-3-thienylglyciny-
l]amino-2,4-dioxo-1,5-bis(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-be-
nzodiazepine
[0983]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0984]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
-oxo-1-methyl-5-phenyl-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0985]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amini-L-1H-imidazole[1,-
2-a]-6-phenyl-1,4-benzodiazepine
[0986]
4-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-L-1H-imidazole[1,-
2-a]-2,4-dihydro-6-phenyl-1,4-benzodiazepine
[0987]
4-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-L-4H[1,2,4]triazo-
le[4,3-a]-6-phenyl-1,4-benzodiazepine
[0988]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-
-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0989]
3-[N'-(3,5-difluorophenylacetyl)-(R)-2-thienylglycinyl]amino-2,4-di-
oxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0990]
3-[N'-(cyclopropylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-b-
is-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0991]
3-[N'-(cyclopentylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-b-
is-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0992]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-
-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0993]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2-
,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0994]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-
-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0995]
3-[N'-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-met-
hylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0996]
3-[N'-(cyclopropylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-me-
thylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0997]
3-[N'-(3,5-difluorophenylacetyl)-5-2-phenylglycinyl]-amino-2,4-diox-
o-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0998]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bi-
s-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[0999]
3-[N'-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cycl-
opropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1000]
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino-2,4-dio-
xo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1001]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bi-
s-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1002]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino--
2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiaz-
epine
[1003]
3-[N'-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2,2-d-
imethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1004]
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,4-diox-
o-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1005]
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bi-
s-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1006]
3-[N'-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-phenyl-
-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1007]
3-[N'-(cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino-2,4-dio-
xo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1008]
3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1009]
5-{N'-(cyclopentylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[1010]
5-{N'-(3-cyclopentylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1011]
5-{N'-(cyclohexylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1012]
5-{N'-(t-butylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1013]
5-{N'-(phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[1014]
5-{N'-(3-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1015]
5-{N'-(3-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1016]
5-{N'-(3-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1017]
5-{N'-(3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1018]
5-{N'-(4-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1019]
5-{N'-(hexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b-
,d]azepin-6-one
[1020]
5-{N'-(heptanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one
[1021]
5-{3,4-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1022]
5-{N'-(cyclopropylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[1023]
5-{N'-(2-cyclopentene-1-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[1024]
5-{N'-(3-cyclohexylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1025]
5-{N'-(isovaleryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz-
[b,d]azepin-6-one
[1026]
5-{N'-(citronellyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one
[1027]
5-{N'-(3-benzoylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1028]
5-{N'-(2-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1029]
5-{N'-(4-pentenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one
[1030]
5-{N'-(valeryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,-
d]azepin-6-one
[1031]
5-{N'-(2-thiophenecetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1032]
5-{N'-(4-(2-thienyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1033]
5-{N'-(4-(4-nitrophenyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1034]
5-{N'-(2,4-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1035]
5-{N'-(2,6-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1036]
5-{N'-(4-isopropylphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[1037]
5-{N'-(1-adamantaneacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1038]
5-{N'-(5-cyclohexanepentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1039]
5-{N'-((methylthio)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1040]
5-{N'-(2-thiophenepentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1041]
5-{N'-(2-norbornaneacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1042]
5-{N'-(3,5-difluorophenylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1043]
5-{N'-(3,5-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1044]
5-{N'-(3,5-difluorophenylacetyl)-3-cyclopropylalaninyl}-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1045]
5-{N'-(3,5-difluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1046]
5-{N'-(3,5-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1047]
5-{N'-(3,5-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1048]
5-{N'-(cyclohexylacetyl)4-ethylnorleucinyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[1049]
5-{N'-(cyclopropylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1050]
5-{N'-(isovaleryl)4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[1051]
5-{N'-(3-(trifluoromethyl)phenylacetyl)4ethylnorleucinyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1052]
5-{N'-(3,4-difluorophenylacetyl)4-ethylnorleucinyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1053]
5-{N'-(2,4-difluorophenylacetyl)4-ethylnorleucinyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1054]
5-{N'-(3-fluorophenylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1055]
5-{N'-(cyclopentylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1056]
5-{N'-(cyclohexylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1057]
5-{N'-(cyclopropylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1058]
5-{N'-(2-thiopheneacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[1059]
5-{N'-(isovaleryl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1060]
5-{N'-(3-(trifluoromethyl)phenylacetyl)-4-methylnorleucinyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1061]
5-{N'-(4-fluorophenylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-
-5 dihydro-6H-dibenz[b,d]azepin-6-one
[1062]
5-{N'-(3,4-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1063]
5-{N'-(2,4-difluorophenylacetyl)4-methylnorleucinyl}-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1064]
5-{N'-(3-fluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1065]
5-{N'-(cyclopentylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1066]
5-{N'-(cyclohexylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[1067]
5-{N'-(cyclopropylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1068]
5-{N'-(isovaleryl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1069]
5-{N'-(4-fluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1070]
5-{N'-(3,4-difluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1071]
5-{N'-(2,4-difluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-m-
ethyl-5,7dihydro-6H-dibenz[b,d]azepin-6-one
[1072]
5-{N'-(3-fluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[1073]
5-{N'-(cyclopentylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[1074]
5-{N'-(cyclohexylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1075]
5-{N'-(cyclopropylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[1076]
5-{N'-(isovaleryl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1077]
5-{N'-(3-(trifluoromethyl)phenylacetyl)-6-fluoronorleucinyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1078]
5-{N'-(4-fluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[1079]
5-{N'-(3,4-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1080]
5-{N'-(2,4-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1081]
5-{N'-(4-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1082]
5-{N'-(3-(4-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1083]
5-{N'-(1-naphthylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1084]
5-{N'-(3,4-methylenedioxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1085]
5-{N'-(hydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1086]
5-{N'-(octanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b-
,d]azepin-6-one
[1087]
5-{N'-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1088]
5-{N'-(3-(4-methylphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1089]
5-{N'-(3-(4-chlorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1090]
5-{N'-(3-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
[1091]
5-{N'-(3-(4-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1092]
5-{N'-(3,4,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1093]
5-{N'-(4-(4-methoxyphenyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[1094]
5-{N'-(3-(methoxycarbonyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1095]
5-{N'-(4-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
[1096]
5-{N'-(3-(benzylthio)-propionyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1097]
5-{N'-(3-methylpentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[1098]
5-{N'-(7-carbomethoxyheptanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[1099]
5-{N'-(2-indanylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
[1100]
5-{N'-(5-carbomethoxypentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[1101]
5-{N'-(2-methyl-3-Benzofuranacetyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1102]
5-{N'-(propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one
[1103]
5-{N'-(3-methoxypropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1104]
5-{N'-(3-(4-fluorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1105]
5-{N'-(3-(4-fluorophenoxy)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1106]
5-{N'-(3-pentenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one
[1107]
5-{N'-(4-(2,4-dichlorophenoxy)butyryl)-L-alaninyl}-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1108]
5-{N'-(2,3-dichlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1109]
5-{N'-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1110]
5-{N'-(4'-fluorosuccinanilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1111]
5-{N'-(N-(diphenylmethyl)glutaramyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1112]
5-{N'-(2-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1113]
5-{N'-(cyanoacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one
[1114]
5-{N'-(succinanilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[1115]
5-{N'-(2,4-dichlorophenoxyaceyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1116]
5-{N'-(2-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1117]
5-{N'-(beta-propylhydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1118]
5-{N'-(3-(2,4-dimethylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1119]
5-{N'-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1120]
5-{N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1121]
5-{N'-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1122]
5-{N'-(2-fluoro-4-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1123]
5-{N'-(4-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1124]
5-{N'-(4-methoxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1125]
5-{N'-(2-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1126]
5-{N'-(2-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1127]
5-{N'-(4-benzyloxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1128]
5-{(N'-(4-hydroxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[1129]
5-{N'-(levulinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one
[1130]
5-{N'-(2-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1131]
5-{N'-(3,4-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1132]
5-{N'-(3-(4-methoxybenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[1133]
5-{N'-(3-(4-phenylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1134]
5-{N'-(3-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1135]
5-{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1136]
5-{N'-(thiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1137]
5-{N'-(6-phenylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1138]
5-{N'-(4-cyclohexanebutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1139]
5-{N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1140]
5-{N'-(2,4,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1141]
5-{N'-(vinylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one
[1142]
5-{N'-(3-methylthiopropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1143]
5-{N'-(3-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1144]
5-{N'-(N-tert-butylsuccinamyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1145]
5-{N'-(4-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1146]
5-{N'-(3-(4-fluorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1147]
5-{N'-(o-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1148]
5-{N'-(p-tolylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1149]
5-{N'-(m-tolylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1150]
5-{N'-(3,4-dichlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1151]
5-{N'-(4-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1152]
5-{N'-(3-methylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1153]
5-{N'-(4-isopropylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1154]
5-{N'-(4-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1155]
5-{N'-(phenylmercaptoacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1156]
5-{N'-(4-ethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1157]
5-{N'-(2,5-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1158]
5-{N'-(o-tolylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1159]
5-{N'-(3,3-diphenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1160]
5-{N'-(3-phenoxypropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1161]
5-{N'-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1162]
5-{N'-((4-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[1163]
5-{N'-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1164]
5-{N'-(3-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1165]
5-{N'-(3,4-dichlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1166]
5-{N'-(4-fluorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1167]
5-{N'-(3,4,5-trimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1168]
5-{N'-(2,4-dichlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1169]
5-{N'-(4-thianaphthenacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1170]
5-{N'-(methoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1171]
5-{N'-(ethoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[1172]
5-{N'-(phenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1173]
5-{N'-(3-methoxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1174]
5-{N'-(4-butoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1175]
5-{N'-(3-(2-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1176]
5-{N'-(N,N-dimethylsuccinamyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1177]
5-{N'-(3-(3,4-methylenedioxyphenyl)propionyl)-L-alaninyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1178]
5-{N'-(2-chloro-6-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[1179]
5-{N'-(2,5-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1180]
5-{N'-(2,3,4,5,6-pentafluorophenoxyacetyl)-L-alaninyl}-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1181]
5-{N'-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1182]
5-{N'-(3,5-dimethylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1183]
5-{N'-(4-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1184]
5-{N'-(3-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1185]
5-{N'-(benzo[b]thiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[1186]
5-{N'-(3,5-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1187]
5-{N'-(2,5-dimethylphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1188]
5-{N'-(mesitylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1189]
5-{N'-(4-biphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1190]
5-{N'-(N-(tert-butoxycarbonyl)-3-aminopropionyl)-L-alaninyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1191]
5-{N'-(trans-styrylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1192]
5-{N'-(4-acetamidobutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1193]
5-{N'-(3-(2-chlorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1194]
5-{N'-(butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,-
d]azepin-6-one
[1195]
5-{N'-(trans-3-hexenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1196]
5-{N'-(5-phenylvaleryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
[1197]
5-{N'-(3-(3-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1198]
5-{N'-(4-chloro-beta-methylhydrocinnamyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1199]
5-{N'-(3-(trifluoromethyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7,
-dihydro-6H-dibenz[b,d]azepin-6-one
[1200]
5-{N'-(alpha-naphthoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1201]
5-{N'-(3-(4-phenoxybenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[1202]
5-{N'-(3-(2-trifluoromethylbenzoyl)propionyl)-L-alaninyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1203]
5-{N'-(3-benzoylamino-3-phenyl-propionyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1204]
5-{N'-(4-(hydroxyimino)pentanoyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1205]
5-{N'-(4'-methylglutaranilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1206]
5-{N'-((4-(4-ethyl-phenoxy)-phenoxy)-acetyl)-L-alaninyl}-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1207]
5-{N'-(3-benzoyl-3-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1208]
5-{N'-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl}-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1209]
5-{N'-(4,4,4-trifluorobutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1210]
5-{N'-(3-isobutyrylamino-3-phenyl-propionyl)-L-alaninyl}-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1211]
5-{N'-((2-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[1212]
5-{N'-(3-(phenylsulfonyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1213]
5-{N'-(4-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1214]
5-{N'-(3-ethoxypropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[1215]
5-{N'-(2,3-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1216]
5-{N'-(2,6-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
5-{N'-(4-fluoromandelyl)-L-alaninyl}-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1217]
5-{N'-(2,5-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1218]
5-{N'-(beta-phenyllactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[1219]
5-{N'-(mandelyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6--
one
[1220]
5-{N'-(p-chloromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1221]
5-{N'-(L-alpha-hydroxyisocaproyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1222]
5-{N'-(4-bromomandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
[1223]
5-{N'-(L-(+)-lactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[1224]
5-{N'-(D-3-phenyllactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1225]
5-{N'-(5-methylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[1226]
5-{N'-(3,5-difluorophenylacetyl)-L-methioninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1227]
5-{N'-(3,5-difluorophenylacetyl)-L-2-phenylglycinyl}-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1228]
5-{N'-(3,5-difluorophenylacetyl)-L-leucinyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1229]
5-{N'-(3,5-difluorophenylacetyl)-L-2-cyclohexylglycinyl}-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1230]
5-{N'-(3,5-difluorophenylacetyl)-L-threoninyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[1231]
5-{N'-(3,5-difluorophenylacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1232]
5-{N'-(2-thiopheneacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1233]
5-{N'-(2-thiopheneacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1234]
5-{N'-(2-thiopheneacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepih-6-one
[1235]
5-{N'-(2-thiopheneacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[1236]
5-{N'-(2-thiopheneacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[1237]
5-{N'-(2-thiopheneacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1238]
5-{N'-(isovaleryl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[1239]
5-{N'-(isovaleryl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1240]
5-{N'-(isovaleryl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz-
[b,d]azepin-6-one
[1241]
5-{N'-(isovaleryl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1242]
5-{N'-(isovaleryl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[1243]
5-{N'-(isovaleryl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1244]
5-{N'-(phenylacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
[1245]
5-{N'-(phenylacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1246]
5-{N'-(phenylacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[1247]
5-{N'-(phenylacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1248]
5-{N'-(phenylacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
[1249]
5-{N'-(phenylacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one Preferred cyclic groups
defined by W and --C(H).sub.pC(.dbd.X)-- include cycloalkyl,
lactone, lactam, benzazepinone, dibenzazepinone and benzodiazepine
groups. In one preferred embodiment, the cyclic group defined by W
and --C(H).sub.pC(.dbd.X)--, forms a cycloalkyl group of the
formula: 5
[1250] wherein T is selected from the group consisting of alkylene
and substituted alkylene.
[1251] A preferred cycloalkyl group is represented by the formula:
6
[1252] wherein each V is independently selected from the group
consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an
integer from 0 to 3.
[1253] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[1254] In another preferred embodiment, the cyclic group defined by
W, together with --C(H).sub.pC(.dbd.X)-- is a ring of the formula:
7
[1255] wherein p is zero or one, T is selected from the group
consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
[1256] Particularly preferred alcohol or thiol substituted groups
include 8
[1257] wherein each V is independently selected from the group
consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an
integer from 0 to 3.
[1258] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[1259] Yet another preferred embodiment of the cyclic group defined
by W, together with --C(H).sub.pC(.dbd.X)--, is a ring of the
formula: 9
[1260] wherein p is zero or one, T is selected from the group
consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
[1261] Particularly preferred cyclic ketone and thioketone groups
include: 10
[1262] wherein each V is independently selected from the group
consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an
integer from 0 to 3.
[1263] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[1264] In another preferred embodiment, the cyclic group defined by
W, together with --C(H).sub.pC(.dbd.X)--, forms a ring of the
formula: 11
[1265] wherein p is zero or one, T is selected from the group
consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
[1266] Particularly preferred lactone and thiolactone groups
include: 12
[1267] wherein each V is independently selected from the group
consisting of hydroxy, acyl, acyloxy, alkyl, substituted alky,
alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like;
R.sup.a is selected from the group consisting of alkyl, substituted
alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl,
cyano, halo, and the like; t is an integer from 0 to 4; and w is an
integer from 0 to 3.
[1268] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[1269] In another preferred embodiment, the cyclic group defined by
W and --C(H).sub.pC(.dbd.X)--, forms a lactam ring of the formula:
13
[1270] or a thiolactam ring of the formula: 14
[1271] wherein p is zero or one, T is selected from the group
consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, h-eteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
[1272] Particularly preferred lactam and thiolactam groups include:
15
[1273] wherein A-B is selected from the group consisting of
alkylene, alkenylene, substituted alkylene, substituted alkenylene
and --N.dbd.CH--; Q' is oxygen or sulfur; each V is independently
selected from the group consisting of hydroxy, acyl, acyloxy,
alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, amino,
aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano,
halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,
trihalomethyl and the like; R.sup.a is selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; R.sup.b
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, acyl, aryl, heteroaryl, heterocyclic, and the
like; R.sup.c is selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,
heterocyclic, cycloalkyl, and substituted cycloalkyl; t is an
integer from 0 to 4; t' is an integer from 0 to 3; and w is an
integer from 0 to 3.
[1274] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[1275] In another preferred embodiment, the cyclic group defined by
W, together with --C(H).sub.pC(.dbd.X)--, forms a ring of the
formula: 16
[1276] wherein p is zero or one, T is selected from the group
consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of -O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
[1277] A still further preferred embodiment is directed to a ring
group defined by W, together with --C(H).sub.pC(.dbd.X)--, of the
formula: 17
[1278] wherein p is zero or one, T is selected from the group
consisting of alkylene, substituted alkylene, alkenylene,
substituted alkenylene, --(R.sup.21Z).sub.qR.sub.21-- and
--ZR.sup.21-- where Z is a substituent selected from the group
consisting of --O--, --S-- and >NR.sup.20, each R.sup.20 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted
alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic,
each R.sup.21 is independently alkylene, substituted alkylene,
alkenylene and substituted alkenylene with the proviso that when Z
is --O-- or --S--, any unsaturation in the alkenylene and
substituted alkenylene does not involve participation of the --O--
or --S--, and q is an integer of from 1 to 3.
[1279] This invention also provides for novel pharmaceutical
compositions comprising a pharmaceutically inert carrier and a
compound of the formula I above.
[1280] Still further, this invention provides for novel compounds
of the formula 18
[1281] wherein R.sup.1 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted
alkyl, substituted alkenyl, substituted alkynyl, substituted
cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and
heterocyclic;
[1282] W, together with --C(H).sub.pC(.dbd.X)--, forms a
cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or
substituted cycloalkenyl group wherein each of said cycloalkyl,
cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted
cycloalkenyl group is optionally fused to form a bi- or multi-fused
ring system (preferably no more than 5 fused rings) with one or
more ring structures selected from the group consisting of
cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group
which, in turn, each of such ring structures are optionally
substituted with 1 to 4 substituents selected from the group
consisting of hydroxyl, halo, alkoxy, substituted alkoxy,
thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl,
carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,
N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted
alkylamino, N,N-disubstituted alkylamino, --NHC(O)R.sup.4,
--NHSO.sub.2R.sup.4, --C(O)NH.sub.2, --C(O)NHR.sup.4,
--C(O)NR.sup.4R.sup.4, --S(O)R.sup.4, --S(O).sub.2R.sup.4,
--S(O).sub.2NHR.sup.4 and --S(O).sub.2NR.sup.4R.sup.4 where each
R.sup.4 is independently selected from the group consisting of
alkyl, substituted alkyl, or aryl;
[1283] X is selected from the group consisting of oxo (.dbd.O),
thiooxo (.dbd.S), hydroxyl (--H, --OH), thiol (H,--SH) and hydro
(H,H);
[1284] Y is represented by the formula: 19
[1285] wherein each R.sup.2 is independently selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl
and heterocyclic;
[1286] Z is represented by the formula --T--CX'X"C(O)-- where T is
selected from the group consisting of a bond covalently linking
R.sup.1 to --CX'X"--, oxygen, sulfur, --NR.sup.5 where R.sup.5 is
hydrogen, acyl, alkyl, aryl or heteroaryl group;
[1287] X' is hydrogen, hydroxy or fluoro,
[1288] X" is hydrogen, hydroxy or fluoro, or X' and X" together
form an oxo group;
[1289] m is an integer equal to 0 or 1;
[1290] n is an integer equal to 0, 1 or 2;
[1291] p is an integer equal to 0 or 1 such that when p is zero,
the ring defined by W and --C(H).sub.pC(.dbd.X)-- is unsaturated at
the carbon atom of ring attachment to Y and when p is one, the ring
is saturated at the carbon atom of ring attachment to Y,
[1292] with the following provisos:
[1293] A. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is
--CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
2-(S)-indanol group;
[1294] B. when R.sup.1 is phenyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form a
trans-2-hydroxy-cyclohex-1-yl group;
[1295] C. when R.sup.1 is phenyl, Z is --CH.sub.2C(O)--, m is 1, n
is 0, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a gammabutyrolactone group or a
5,5-dimethyl-gammabutyrolactone group;
[1296] D. when R.sup.1 is phenyl, Z is --CH.sub.2C(O)--, m is 1, n
is 0, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a e-caprolactam group;
[1297] E. when R.sup.1 is cyclopropyl, R.sup.2 is --CH.sub.3, Z is
--CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together with
>CH and >C.dbd.X, does not form an N-methylcaprolactam
group;
[1298] F. when R.sup.1 is 4-chlorobenzoyl-CH.sub.2--, R.sup.2 is
--CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form an
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one;
[1299] G. when R.sup.1 is 2-phenylphenyl, R.sup.2 is --CH.sub.3, Z
is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then W, together
with >CH and >C.dbd.X, does not form an
7-methyl-5,7-dihydro-6H-dibenz[b- ,d]azepin-6-one;
[1300] H. when R.sup.1 is CH.sub.3OC(O)CH.sub.2--, R.sup.2 is
--CH.sub.3, Z is --CH.sub.2C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form an
2,3-dihydro-1-(t-butylC(O)CH.sub-
.2--)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;
[1301] I. when R.sup.1 is 4-ethoxyphenyl, 2,4,6-trimethylphenyl,
4-phenylphenyl, CH.sub.3OC(O)CH.sub.2--, 4-HOCH.sub.2-phenyl,
2,4,6-trifluorophenyl, 2-trifluoromethyl-4-fluorophenyl, or
CH.sub.3S--, R.sup.2 is --CH.sub.3, Z is --CH.sub.2C(O)--, m is 1,
n is 1, and p is 1, then W, together with >CH and >C.dbd.X,
does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2CH.sup.2--)-5-(2-pyridyl)-1H-1,4--
benzodiazepin-2-one;
[1302] J. when R.sup.1 is 2,6-difluorophenyl, R.sup.2 is
--CH.sub.3, Z is --CH(OH)C(O)--, m is 1, n is 1, and p is 1, then
W, together with >CH and >C.dbd.X, does not form a
2,3-dihydro-1-(N,N-diethylamino-CH.sub.2-
CH.sup.2--)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,
[1303] K. when m is 1 and n is 1, then 20
[1304] does not equal cycloalkyl of from 3 to 8 carbon atoms
optionally substituted with 1 to 3 alkyl groups.
[1305] The products of this invention include mixtures of R,S
enantiomers at any stereochemical center. Preferably, however, when
a chiral product is desired, the chiral product corresponds to the
L-amino acid derivative. In the formulas set forth herein, a
mixture of R,S enantiomers at the stereochemical center is
sometimes indicated by a squiggly line as per convention. Other
times, no stereochemical designation is made at the stereochemical
center and this also infers that a mixture of enantiomers is
present.
[1306] Preferred compounds described herein include those set forth
in the tables below:
1TABLE 1-1 21 Ex. R R' X'/X" R.sup.1 1-1 3,5-di-F-.phi.- H H,H
--CH.sub.3
[1307]
2TABLE 2-1 22 Ex. R X'/X" R.sup.1 R.sup.2/R.sup.3 n 2-1
3,5-di-F-.phi.- H,H --CH.sub.3 forms a fused 1 phenyl ring 2-2
3,5-di-F-.phi.- H,H --CH.sub.3 forms a fused 1 phenyl ring 2-3
3,5-di-F-.phi.- H,H --CH.sub.3 forms a fused 1 phenyl ring 2-4
3,5-di-F-.phi.- H,H --CH.sub.3 H,H 2 2-5 3,5-di-F-.phi.- H,H
--CH.sub.3 forms a fused 2 phenyl ring 2-6 3,5-di-F-.phi.- H,H
--CH.sub.3 forms a fused 3 phenyl ring
[1308]
3TABLE 2-2 23 Ex. R X'/X" R.sup.1 2-6 3,5-di-F-.phi.- H,H
--CH.sub.3
[1309]
4TABLE 2-3 24 Ex. R X'/X" R.sup.1 2-7 3,5-di-F-.phi.- H,H
--CH.sub.3
[1310]
5TABLE 3-1 25 Ex. R X'/X" R.sup.1 R.sup.2/R.sup.3 n 3-1
3,5-di-F-.phi.- H,H --CH.sub.3 forms a fused 1 phenyl ring 3-2
.phi.- H,H --CH.sub.3 forms a fused 2 phenyl ring
[1311]
6TABLE 3-2 26 Ex. R X'/X" R.sup.1 3-3 3,5-di-F-.phi.- H,H
--CH.sub.3
[1312]
7TABLE 4-1 27 Ex. R' R.sup.1 R.sup.2/R.sup.3 R.sup.4 R.sup.5 n 4-1
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H,H -- -- 0 4-2
3,4-di-Cl-.phi.- --CH.sub.3 H,H -- -- 0 4-3
cyclopentyl-CH.sub.2C(O)-- --CH.sub.3 forms a fused --CH.sub.3
--CH.sub.3 1 phenyl ring 4-4 3,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.3 forms a fused --CH.sub.3 --CH.sub.3 1 phenyl ring
[1313]
8TABLE 5-1 28 R.sup.4/R.sup.4' (R.sup.4' when Ex. R' R.sup.1
R.sup.2 R.sup.3 n = 2) R.sup.5 n 5-1 3,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.3 H H -- H 0 5-2 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3
H H H H 1 5-3 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H
--CH.sub.2.phi. 1 5-4 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 H H,H H 2 5-5 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H
R.sup.3/R.sup.4 = -- H 1 fused phenyl ring 5-6
3,5-di-F-.phi.-CH.sub.2C- (O)-- --CH.sub.3 H R.sup.3/R.sup.4 = --
--CH.sub.2.phi. 1 fused phenyl ring 5-7
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = -- H H 1
fused phenyl ring 5-8 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3
R.sup.2/R.sup.3 = -- H --CH.sub.2.phi. 1 fused phenyl ring 5-9
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = --
--CH.sub.3 H 1 fused phenyl ring 5-10 3,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.3 R.sup.2/R.sup.3 = -- -.phi. H 1 fused phenyl ring 5-11
3,5-di-F-.phi.-CH.sub.2- C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = -- H H
1 fused phenyl ring with 3-F subs. 5-12
3,5-di-F-.phi.-CH.sub.2C(O)-- - --CH.sub.3 R.sup.2/R.sup.3 = -- H H
1 fused phenyl ring with 4-F subs. 5-13
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = -- H
--CH.sub.2CH.sub.2.phi. 1 fused phenyl ring 5-14
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = -- H
--CH.sub.3 1 fused phenyl ring 5-15 3,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.3 R.sup.2/R.sup.3 = -- H H 1 fused phenyl ring with
3-.phi. subs. 5-16 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3
R.sup.2/R.sup.3 = -- H H 1 fused phenyl ring with 4-.phi. subs.
5-17 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3
R.sup.2/R.sup.3/R.sup.4 -- -- H 1 together with the pendent atoms
form (9-amino- fluroren-1- yl)glycine .delta.-lactam 5-18
.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H,H H 2 5-19
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H,H H 2 5-20
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H,H --CH.sub.2.phi. 2
5-21 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H,H 2-methoxy- 2
ethoxy 5-22 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H,H ethyl
2 5-23 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H ethyl H,H H 2
5-24 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H ethyl H,H H 2 5-25
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H, H 2 benzyl 5-26
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = H H
--CH.sub.2.phi. 1 ethylene 5-27 cyclopentyl-CH.sub.2C(O)--
--CH.sub.3 H H H,H --CH.sub.2.phi. 2 5-28
cyclopentyl-CH.sub.2C(O)-- -.phi. H H H,H --CH.sub.2.phi. 2 5-29
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H,H
--CH.sub.2CH.sub.2.phi. 2 5-30 cyclopentyl-CH.sub.2C(O)-- -.phi. H
H H,H --CH.sub.2CH.sub.2.phi. 2 5-31 3,4-di-Cl-.phi.- --CH.sub.3 H
H H,H H 2 5-32 cyclopropyl-CH.sub.2C(O)-- -.phi. H H H,H --CH.sub.3
2 5-33 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 H H H,H, H 4 H,H
5-34 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = H H
H 1 fused phenyl ring with 4-benzyl subs. 5-35
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = --
--CH.sub.2.phi. H 1 fused phenyl ring 5-36
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = --
-.phi. --CH.sub.3 1 fused phenyl ring 5-37
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = --
pyrid- H 1 fused phenyl 2-yl ring 5-38
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = --
pyrid- H 1 fused phenyl 3-yl ring 5-39
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = --
pyrid- H 1 fused phenyl 4-yl ring 5-40
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 R.sup.2/R.sup.3 = -- --
--CH.sub.3 0 fused phenyl ring 5-41 3,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.3 -.phi. R.sup.3/R.sup.4 = -- --CH.sub.3 1 (trans) fused
phenyl ring 5-42 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 -.phi.
R.sup.3/R.sup.4 = -- --CH.sub.3 1 (cis) fused phenyl ring 5-43
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 -.phi. R.sup.3/R.sup.4 =
-- H 1 (trans) fused phenyl ring
[1314]
9TABLE 6-1 29 Ex. R' R.sup.1 R.sup.2 R.sup.3 Q 6-1
3,5-di-F-.phi.-CH.sub.2C(O)-- - --CH.sub.3 --CH.sub.3 H H 6-2
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.2CH.sub.3 H F
6-16 3,5-di-F-.phi.-CH.sub.2C(O)- -- --CH.sub.3 H -.phi. H
[1315]
10TABLE 6-2 30 Ex. R' n R.sup.1 R.sup.2 R.sup.3 R.sup.4 6-3
3,5-di-F-.phi.-CH.sub.2C(O)-- 0 -- --CH.sub.2CH.sub.3 --CH.sub.3
--CH.sub.3 6-4 3,5-di-F-.phi.-CH.sub.2C(O)-- 1 --CH.sub.3 H H H 6-5
3,5-di-F-.phi.-CH.sub.2C(O)-- 1 --CH.sub.3 --CH.sub.2.phi. H H 6-6
cyclopentyl-CH.sub.2C(O)-- 0 -- --CH.sub.2CH.sub.3 --CH.sub.3
--CH.sub.3 6-7 3,5-di-F-.phi.-CH.sub.2C(O)-- 1 --CH.sub.3
--CH.sub.3 H H 6-8 3,5-di-F-.phi.-CH.sub.2C(O)-- 0 --CH.sub.3
--CH.sub.3 --CH.sub.3 H 6-9 3,5-di-F-.phi.-CH.sub.2C(O)-- 1
--CH.sub.3 --CH.sub.3 --CH.sub.3 H 6-13 3,5-di-F-.phi.-CH.sub.2C(O-
)-- 1 --CH.sub.3 H --CH.sub.3 --CH.sub.3 6-14
3,5-di-F-.phi.-CH.sub.2C(O)-- 1 --CH.sub.3 --CH.sub.3 --CH.sub.3
--CH.sub.3 6-15 3,5-di-F-.phi.-CH(OH)C(O)-- 1 --CH.sub.3 --CH.sub.3
--CH.sub.3 --CH.sub.3 6-17 3,5-di-F-.phi.-CH.sub.2C(O)-- - 1
--CH.sub.3 --CH.sub.2CH.sub.3 --CH.sub.3 --CH.sub.3
[1316]
11TABLE 6-3 31 Ex. R' R.sup.1 R.sup.2 Q' 6-10
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 O 6-11
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.2CH.sub.3 O 6-12
3,5-di-F-.phi.-CH.sub.2C(O)-- - --CH.sub.3 --CH.sub.3 S
[1317]
12TABLE 7-1 32 Ex. R' R.sup.1 R.sup.2 X X' X" 7-1 3,5-di-F-.phi.-
--CH.sub.3 --CH.sub.3 H H H CH.sub.2C(O)-- 7-2 3,5-di-F-.phi.-
--CH.sub.3 --CH.sub.3 H H H CH(OH)C(O)-- 7-3 3,5-di-F-.phi.-
--CH.sub.3 --CH.sub.3 H H H C(O)C(O)-- 7-4 3,5-di-F-.phi.-
--CH(CH.sub.3).sub.2 --CH.sub.3 H H H CH.sub.2C(O)-- 7-5
3,5-di-F-.phi.- --C(CH.sub.3).sub.3 --CH.sub.3 H H H CH.sub.2C(O)--
7-6 3,5-di-F-.phi.- --CH(CH.sub.3).sub.2 --CH.sub.3 H H H
CH(OH)C(O)-- 7-7 3,5-di-F-.phi.- --C(CH.sub.3).sub.3 --CH.sub.3 H H
H CH(OH)C(O)-- 7-8 3,5-di-F-.phi.- --CH.sub.3
--CH.sub.2C(O)OCH.sub.3 H H H CH.sub.2C(O)-- 7-9 3,5-di-F-.phi.-
--CH.sub.3 --CH.sub.2C(O)OH H H H CH.sub.2C(O)-- 7-10
3,5-di-F-.phi.- --CH.sub.3 --CH.sub.2C(O)C(CH.sub.3).sub.3 H H H
CH.sub.2C(O)-- 7-11 3,5-di-F-.phi.- --CH.sub.3 --CH.sub.2--C(O)- H
H H CH.sub.2C(O)-- morpholin-4-yl 7-12 (CH.sub.3).sub.2CH--
--CH.sub.3 --CH.sub.3 H H H CH(OH)C(O)-- 7-13 cyclopentyl-
--CH(CH.sub.3).sub.2 --CH.sub.3 H H H CH(OH)C(O)-- 7-14
(CH.sub.3).sub.3C-- --CH.sub.3 --CH.sub.3 H H H CH(OH)C(O)-- 7-15
cyclopentyl- --C(CH.sub.3).sub.3 --CH.sub.3 H H H CH(OH)C(O)-- 7-16
cyclopentyl- --CH.sub.3 --CH.sub.3 H H H CH(OH)C(O)-- 7-17
3,5-di-F-.phi.- --CH.sub.3 H H H H CH.sub.2C(O)-- 7-18
3,5-di-F-.phi.- --CH.sub.3 --CH.sub.2CH(CH.sub.3).sub.2 H H H
CH.sub.2C(O)-- 7-19 (CH.sub.3).sub.2CH-- --CH(CH.sub.3).sub.2
--CH.sub.3 H H H CH(OH)C(O)-- 7-20 (CH.sub.3).sub.3C-- --CH.sub.3
--CH.sub.3 H H H CH(OH)C(O)-- 7-21 2-(.phi.)-.phi.- --CH.sub.3
--CH.sub.3 H H H 7-22 4-.phi.- --CH.sub.3 --CH.sub.3 H H H
furazan-3-yl 7-24 3,5-di-F-.phi.- --CH.sub.3
--(CH.sub.2).sub.4.phi. H H H CH.sub.2C(O)-- 7-25 3,5-di-F-.phi.-
--CH.sub.3 --CH.sub.2-cyclopropyl H H H CH.sub.2C(O)-- 7-26
3,5-di-F-.phi.- --CH.sub.3 --CH.sub.2CF.sub.3 H H H CH.sub.2C(O)--
7-27 3,5-di-F-.phi.- --CH.sub.3 cyclohexyl H H H CH.sub.2C(O)--
7-28 3,5-di-F-.phi.- --CH.sub.3 --CH.sub.3 F H H CH(OH)C(O)-- 7-29
3,5-di-F-.phi.- --CH.sub.3 --CH.sub.3 H H F CH(OH)C(O)-- 7-30
3,5-di-F-.phi.- --CH.sub.3 --CH.sub.3 H F H CH(OH)C(O)-- 7-31
3,5-di-F-.phi.- --CH.sub.3 --CH.sub.2-cyclopropyl H H H
CH(OH)C(O)-- 7-32 3,5-di-F-.phi.- --CH.sub.3
--(CH.sub.2).sub.4.phi. H H H CH(OH)C(O)-- 7-33 3,5-di-F-.phi.-
--CH(CH.sub.3).sub.2 --CH.sub.2-cyclopropyl H H H CH(OH)C(O)-- 7-34
3,5-di-F-.phi.- --CH(CH.sub.3).sub.2 --(CH.sub.2).sub.4.phi. H H H
CH(OH)C(O)-- 7-35 3,5-di-F-.phi.- --CH(CH.sub.3).sub.2 hexyl H H H
CH(OH)C(O)-- 7-36 3,5-di-F-.phi.- --CH(CH.sub.3).sub.2 --CH.sub.3 H
F H CH(OH)C(O)-- 7-37 3,5-di-F-.phi.- --CH(CH.sub.3).sub.2
--CH.sub.3 H H F CH(OH)C(O)-- 7-38 3,5-di-F-.phi.-
--CH(CH.sub.3).sub.2 --CH.sub.3 F H H CH(OH)C(O)-- 7-39
3,4-di-Cl-.phi.- -.phi. --CH.sub.3 H H H
[1318]
13TABLE 7-2 33 Ex. R' R.sup.1 R.sup.2 7-23 3,5-di-F-.phi.-
--CH.sub.3 --CH.sub.3 CH.sub.2C(O)--
[1319]
14TABLE 7C-1 34 Ex. R' R.sup.1 R.sup.2 7C-1
cyclopentylCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-2
cyctopentylCH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-3
cyclohexylCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-4
(CH.sub.3).sub.3CCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-5
.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-6
3-Br-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-7
3-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-8
3-Cl-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-9
3-CF.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-10
4-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-11
CH.sub.3(CH.sub.2).sub.4C(O)-- --CH.sub.3 --CH.sub.3 7C-12
CH.sub.3(CH.sub.2).sub.3C(O)-- --CH.sub.3 --CH.sub.3 7C-13
3,4-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-14
cyclopropyl-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-15
cyclopent-1-enyl-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-16
cyclohexyl-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-17
(CH.sub.3).sub.2CHCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-18
(CH.sub.3).sub.2CH.dbd.CH(CH.sub.2).sub.2CH(CH.sub.3)-- --CH.sub.3
--CH.sub.3 CH.sub.2C(O)-- 7C-19 .phi.C(O)CH.sub.2--CH.sub.- 2C(O)--
--CH.sub.3 --CH.sub.3 7C-20 2-Cl-.phi.-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-21 CH.sub.2.dbd.CHCH.sub.2--CH.sub.2C(O)-- -
--CH.sub.3 --CH.sub.3 7C-22 CH.sub.3(CH.sub.2).sub.3C(O)--
--CH.sub.3 --CH.sub.3 7C-23 thien-2-yl-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-24 thien-2-yl-(CH.sub.2).sub.3C(O)-- --CH.sub.3
--CH.sub.3 7C-25 4-NO.sub.2-.phi.-(CH.sub.2).sub.3C(O)-- --CH.sub.3
--CH.sub.3 7C-26 2,4-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-27 2,6-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-28 4-(CH.sub.3).sub.2CH-.phi.-CH.sub.2C(O- )--
--CH.sub.3 --CH.sub.3 7C-29 adamantan-1-yl-CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-30 cyclohexyl-(CH.sub.2).sub.4C(O)--
--CH.sub.3 --CH.sub.3 7C-31 CH.sub.3SCH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-32 thien-2-yl-(CH.sub.2).sub.4C(O)-- --CH.sub.3
--CH.sub.3 7C-33 norbornan-2-yl-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-34 3,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2 --CH.sub.3 7C-35
3,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3 --CH.sub.3 7C-36
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.2-cyclopropyl --CH.sub.3
7C-37 3,5-di-F-.phi.-CH.sub.2C(O- )-- --CH.sub.2CH.sub.2-cyclohexyl
--CH.sub.3 7C-38 3,5-di-F-.phi.-CH.sub.2C(O)--
--(CH.sub.2).sub.5CH.sub.2F --CH.sub.3 7C-39
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.3)CH.sub.2CH.su-
b.3 --CH.sub.3 7C-40 cyclohexyl-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2 --CH.sub.3 7C-41
cyclopropyl-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.2CH.sub.3).sub.2
--CH.sub.3 7C-42 (CH.sub.3).sub.2CHCH.sub.2C(O)--
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2 --CH.sub.3 7C-43
3-CF.sub.3-.phi.-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2 --CH.sub.3 7C-44
3,4-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.2CH.sub.3).sub.2
--CH.sub.3 7C-45 2,4-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2 --CH.sub.3 7C-46
3-F-.phi.-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.3)CH- .sub.2CH.sub.3
--CH.sub.3 7C-47 cyclopentyl-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3 --CH.sub.3 7C-48
cyclohexyl-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3
--CH.sub.3 7C-49 cyclopropyl-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3 --CH.sub.3 7C-50
thien-2-yl-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3
--CH.sub.3 7C-51 (CH.sub.3).sub.2CHCH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3 --CH.sub.3 7C-52
3-CF.sub.3-.phi.-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3 --CH.sub.3 7C-53
4-F-.phi.-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.3)CH- .sub.2CH.sub.3
--CH.sub.3 7C-54 3,4-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3 --CH.sub.3 7C-55
2,4-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3 --CH.sub.3 7C-56
3-F-.phi.-CH.sub.2C(O)-- --CH.sub.2CH.sub.2cycloh- exyl --CH.sub.3
7C-57 cyclopentyl-CH.sub.2C(O)-- --CH.sub.2CH.sub.2cyclohexyl
--CH.sub.3 7C-58 cyclohexyl-CH.sub.2C(O)--
--CH.sub.2CH.sub.2cyclohexyl --CH.sub.3 7C-59
cyclopropyl-CH.sub.2C(O)-- --CH.sub.2CH.sub.2cyclohexyl --CH.sub.3
7C-60 (CH.sub.3).sub.2CHCH.sub.2C(O)-- --CH.sub.2CH.sub.2cyclohexy-
l --CH.sub.3 7C-61 4-F-.phi.-CH.sub.2C(O)--
--CH.sub.2CH.sub.2cyclo- hexyl --CH.sub.3 7C-62
3,4-F-.phi.-CH.sub.2C(O)-- --CH.sub.2CH.sub.2cyclohexyl --CH.sub.3
7C-63 2,4-F-.phi.-CH.sub.2C(O)-- --CH.sub.2CH.sub.2cyclohexyl
--CH.sub.3 7C-64 3-F-.phi.-CH.sub.2C(O)--
--(CH.sub.2).sub.5CH.sub.2F --CH.sub.3 7C-65
cyclopentyl-CH.sub.2C(O)-- --(CH.sub.2).sub.5CH.sub.2F --CH.sub.3
7C-66 cyclohexyl-CH.sub.2C(O)-- --(CH.sub.2).sub.5CH.su- b.2F
--CH.sub.3 7C-67 cyclopropyl-CH.sub.2C(O)--
--(CH.sub.2).sub.5CH.sub.2F --CH.sub.3 7C-68
(CH.sub.3).sub.2CHCH.sub.2C(O)-- --(CH.sub.2).sub.5CH.sub.2F
--CH.sub.3 7C-69 3-CF.sub.3-.phi.-CH.sub.2C(O)--
--(CH.sub.2).sub.5CH.sub.2F --CH.sub.3 7C-70
4-F-.phi.-CH.sub.2C(O)-- --(CH.sub.2).sub.5CH.sub- .2F --CH.sub.3
7C-71 3,4-F-.phi.-CH.sub.2C(O)-- --(CH.sub.2).sub.5CH.sub.2F
--CH.sub.3 7C-72 2,4-F-.phi.-CH.sub.2C(O)--
--(CH.sub.2).sub.5CH.sub.2F --CH.sub.3 7C-73
4-CH.sub.3O-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-74
4-CH.sub.3O-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-75 naphth-1-yl-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-76
3,4-methylenedioxy-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-77
.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-78
CH.sub.3(CH.sub.2).sub.6C(O)-- --CH.sub.3 --CH.sub.3 7C-79
3-HO-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-80
4-CH.sub.3-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-81
4-Cl-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-82
CH.sub.3CH(.phi.)CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-83
4-HO-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-84
3,4,5-tri-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-85
4-CH.sub.3O-.phi.-CH.sub.2CH.sub.2CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-86 CH.sub.3OC(O)CH.sub.2CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-87 .phi.-CH.sub.2CH.sub.2CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-88 .phi.-CH.sub.2--S--CH.sub.2CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-89
CH.sub.3CH.sub.2CH(CH.sub.3)CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-90 CH.sub.3OC(O)(CH.sub.2).sub.6C(O)-- --CH.sub.3 --CH.sub.3
7C-91 indan-2-yl-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-92
CH.sub.3OC(O)(CH.sub.2).sub.4C(O)-- --CH.sub.3 --CH.sub.3 7C-93
(2-methylbenzofuran-3-yl)CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-94
CH.sub.3CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-95
CH.sub.3OCH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-96
4-F-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-97
4-F-.phi.-OCH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-99
CH.sub.3CH.dbd.CHCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-100
2,4-di-Cl-.phi.-O-(CH.sub.2).sub.3C(O)-- --CH.sub.3 --CH.sub.3
7C-101 2,3-di-C-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-102 4-Cl-.phi.C(O)--CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-103 4-F-.phi.-NHC(O)CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-104 (.phi.).sub.2CHNHC(O)CH.sub.2CH.sub.2CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-105 2-F-.phi.-CH.sub.2--C(O)-- --CH.sub.3
--CH.sub.3 7C-107 .phi.-NHC(O)CH.sub.2CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-108 2,4-di-Cl-.phi.-O--CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-109 2-NO.sub.2-.phi.-CH.sub.2--C(O)-- --CH.sub.3
--CH.sub.3 7C-110 CH.sub.3(CH.sub.2).sub.2CH(.phi.)CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-111
2,4-di-CH.sub.3-.phi.-C(O)(CH.sub.2).sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-112 2-F-3-CF.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-113 2,4,6-tri-F-.phi.-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-114 4-F-2-CF.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-115 2-F-4-CF.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-116 4-HO-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-117 4-CH.sub.3O-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-118 2-CH.sub.3O-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-119 2-Br-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-120
4-.phi.-CH.sub.2O-).phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-121 4-HO-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-122
CH.sub.3C(O)CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-123
2-HO-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-124
3,4-di-CH.sub.3O-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-125
4-CH.sub.3O-.phi.(CO)--CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-126 .phi.(CO)--CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-127 3-HO-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-128
CH.sub.3C(O)N(.phi.)CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-129
thien-3-yl-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-130
.phi.-(CH.sub.2).sub.5C(O)-- --CH.sub.3 --CH.sub.3 7C-131
cyclohexyl-(CH.sub.2).sub.3C(O)-- --CH.sub.3 --CH.sub.3 7C-132
2,3,5-tri-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-133
2,4,5-tri-F-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-134
CH.sub.2.dbd.CHCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-135
CH.sub.3S(CH.sub.2).sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-136
3-NO.sub.2-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-137
(CH.sub.3).sub.3CNHC(O)CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-138 4-Br-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-139
4-F-.phi.C(O)--CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-140
2-Cl-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-141
4-CH.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-142
3-CH.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-143
3,4-di-Cl-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-144
4-Cl-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-145
3-CH.sub.3-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-146
4-(CH.sub.3).sub.2CH-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-147 4-(.phi.-O)-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-148 .phi.SCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-149
4-C.sub.2H.sub.5O-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-150
2,5-di-CH.sub.3O-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-151
2-CH.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-152
(.phi.).sub.2CHCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-153
.phi.OCH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-154
4-CF.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-155
4-CH.sub.3-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-156
2-(.phi.-O)-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-157
3-(.phi.-O)-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-158
3,4-di-Cl-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-159
4-F-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-160
3,4,5-tri-CH.sub.3O-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-161 2,4-di-Cl-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-162
thianaphthen-4-yl-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-163
CH.sub.3OCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-164
C.sub.2H.sub.5OCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-165
.phi.OCH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-166
3-CH.sub.3O-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-167
4-C.sub.4H.sub.9O-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-168
2-CH.sub.3O-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-169 (CH.sub.3).sub.2NC(O)CH.sub.2CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-170 3,4-methylenedioxy-.phi.-CH.sub.2CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-171 2-Cl-6-F-.phi.-CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-172 2,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-173 2,3,4,5,6-penta-F-.phi.-O--CH.sub.2C(-
O)-- --CH.sub.3 --CH.sub.3 7C-174
3,5-di-CF.sub.3-.phi.-CH.sub.2C(O- )-- --CH.sub.3 --CH.sub.3 7C-175
3,5-di-CH.sub.3-.phi.-O--CH.sub.2C- (O)-- --CH.sub.3 --CH.sub.3
7C-176 4-Cl-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-177
3-Cl-.phi.-O--CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-178
benzo[b]thien-3-yl-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-179
3,5-di-CH.sub.3O-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-180
2,5-di-CH.sub.3-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-181
2,4,6-tri-CH.sub.3-.phi.-CH.sub.2C(O)- -- --CH.sub.3 --CH.sub.3
7C-182 4-(.phi.)-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-183
(CH.sub.3).sub.3COC(O)NH(CH.sub.2).su- b.2C(O)-- --CH.sub.3
--CH.sub.3 7C-184 trans-styryl-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-185 H.sub.2NC(O)(CH.sub.2).sub.3C(O)-- --CH.sub.3 --CH.sub.3
7C-186 2-Cl-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-187 CH.sub.3CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-188
CH.sub.3CH.sub.2CH.dbd.CHCH.sub.2C(O)- -- --CH.sub.3 --CH.sub.3
(trans) 7C-189 .phi.(CH.sub.2).sub.4C(O)-- --CH.sub.3 --CH.sub.3
7C-190 3-CH.sub.3O-.phi.-CH.sub.2CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-191 4-Cl-.phi.-CH(CH.sub.3)CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-192 CH.sub.3CH(CF.sub.3)CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-194 naphthalen-1-yl-O--CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-196 2-(CF.sub.3)-.phi.-C(O)CH.sub.2CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-197
.phi.C(O)NHCH(.phi.)CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3
7C-198 CH.sub.3CH(.dbd.NHOH)CH.sub.2CH.sub.2- C(O)-- --CH.sub.3
--CH.sub.3 7C-199 4-CH.sub.3-.phi.-NHC(O)CH.sub.2-
CH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-200
4-(C.sub.2H.sub.5-.phi.-O).phi.-O--CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7C-201 .phi.C(O)CH(.phi.)CH.sub.2CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-202 4-(HOCH.sub.2)-.phi.-O--CH.sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-203 CF.sub.3(CH.sub.2).sub.2C(O)--
--CH.sub.3 --CH.sub.3 7C-204 (CH.sub.3).sub.2CHC(O)NHCH(.phi.)CH.s-
ub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-205
2-CH.sub.3-.phi.-O--CH.sub.- 2C(O)-- --CH.sub.3 --CH.sub.3 7C-206
.phi.SO.phi.CH.sub.2CH.sub.2C(- O)-- --CH.sub.3 --CH.sub.3 7C-207
4-NO.sub.2-.phi.-CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-208
C.sub.2H.sub.5OCH.sub.2CH.sub.2C(O)-- --CH.sub.3 --CH.sub.3 7C-209
2,3-di-F-.phi.-CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-210
2,6-di-F-.phi.-CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-211
4-F-.phi.-CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-212
2,5-di-F-.phi.-CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-213
.phi.-CH.sub.2CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-214
.phi.-CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-215
4-Cl-.phi.-CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-216
(CH.sub.3).sub.2CHCH.sub.2CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-217
4-Br-.phi.-CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-218
CH.sub.3CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-219
.phi.-CH.sub.2CH(OH)C(O)-- --CH.sub.3 --CH.sub.3 7C-220
(CH.sub.3).sub.2CHCH.sub.2CH.sub.2CH.sub.2C(O)-- --CH.sub.3
--CH.sub.3 7-C221 3,5-di-F-.phi.-CH.sub.2C(O)--
--CH.sub.2CH.sub.2SCH.sub.3 --CH.sub.3 7-C222
3,5-di-F-.phi.-CH.sub.2C(O)-- -.phi. --CH.sub.3 7-C223
3,5-di-F-.phi.-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.3).sub.2
--CH.sub.3 7-C224 3,5-di-F-.phi.-CH.sub.2C(O)-- cyclohexyl
--CH.sub.3 7-C225 3,5-di-F-.phi.-CH.sub.2C(O)-- --CH(OH)CH.sub.3
--CH.sub.3 7-C226 3,5-di-F-.phi.-CH.sub.2C(O)-- thien-2-yl
--CH.sub.3 7-C227 thien-2-yl-CH.sub.2C(O)--
--CH.sub.2CH.sub.2SCH.sub.3 --CH.sub.3 7-C228
thien-2-yl-CH.sub.2C(O)-- -.phi. --CH.sub.3 7-C229
thien-2-yl-CH.sub.2C(O)-- --CH.sub.2CH(CH.sub.3).sub.2 --CH.sub.3
7-C230 thien-2-yl-CH.sub.2C(O)-- cyclohexyl --CH.sub.3 7-C231
thien-2-yl-CH.sub.2C(O)-- --CH(OH)CH.sub.3 --CH.sub.3 7-C232
thien-2-yl-CH.sub.2C(O)-- thien-2-yl --CH.sub.3 7-C233
(CH.sub.3).sub.2CHCH.sub.2C(O)-- --CH.sub.2CH.sub.2SCH.sub.3
--CH.sub.3 7-C234 (CH.sub.3).sub.2CHCH.sub.2C(O)-- -.phi.
--CH.sub.3 7-C235 (CH.sub.3).sub.2CHCH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3).sub.2 --CH.sub.3 7-C236
(CH.sub.3).sub.2CHCH.sub.2C(O)-- cyclohexyl --CH.sub.3 7-C237
(CH.sub.3).sub.2CHCH.sub.2C(O)-- --CH(OH)CH.sub.3 --CH.sub.3 7-C238
(CH.sub.3).sub.2CHCH.sub.2C(O)--
- thien-2-yl --CH.sub.3 7-C239 .phi.-CH.sub.2C(O)--
--CH.sub.2CH.sub.2S--CH.sub.3 --CH.sub.3 7-C240
.phi.-CH.sub.2C(O)-- -.phi. --CH.sub.3 7-C241 .phi.-CH.sub.2C(O)--
--CH.sub.2CH(CH.sub.3).sub.2 --CH.sub.3 7-C242 .phi.-CH.sub.2C(O)--
cyclohexyl --CH.sub.3 7-C243 .phi.-CH.sub.2C(O)-- --CH(OH)CH.sub.3
--CH.sub.3 7-C244 .phi.-CH.sub.2C(O)-- thien-2-yl --CH.sub.3
[1320]
15TABLE 8-1 35 R.sup.2 = 1 position; R.sup.3 = 5 position; R.sup.4
= 7 position Ex. R R' X'/X" R.sup.1 R.sup.2 R.sup.3 R.sup.4 n 8-1
3,5-di-F-.phi.- -- H,H -- --CH.sub.3 -.phi. H 0 8-2 3,5-di-F-.phi.-
H H,H --CH.sub.3 --CH.sub.2CH.sub.3 -.phi. H 1 8-3 3,5-di-F-.phi.-
H H,H --CH.sub.3 H -.phi. H 1 8-4 3,5-di-F-.phi.- H H,H --CH.sub.3
--CH.sub.3 piperidin- H 1 1-yl 8-5 3,5-di-F-.phi.- H H,H --CH.sub.3
--CH.sub.3 -.phi. Cl 1 8-6 3,5-di-F-.phi.- H H,H --CH.sub.3
--CH.sub.3 2-F-.phi.- Br 1 8-7 3,5-di-F-.phi.- --CH.sub.3 H,H
--CH.sub.3 --CH.sub.3 -.phi. H 1 8-8 3,5-di-F-.phi.- H H,H
--CH.sub.3 --CH.sub.3 2-Cl-.phi.- CH 1 8-9 3,5-di-F-.phi.- H H,H
--CH.sub.3 --CH.sub.3 cyclohexyl H 1 8-10 3,5-di-F-.phi.- H H,H
--CH.sub.3 --CH.sub.3 -.phi. NO.sub.2 1 8-11 3,5-di-F-.phi.- H H,H
--CH.sub.3 --CH.sub.3 2-F-.phi.- H 1 8-12 3,5-di-F-.phi.- H OH,H
--CH(CH.sub.3).sub.2 --CH.sub.3 -.phi. H 1 8-13 3,5-di-F-.phi.- H
OH,H --C(CH.sub.3).sub.3 --CH.sub.3 -.phi. H 1 8-14 3,5-di-F-.phi.-
H H,H --CH.sub.3 --CH.sub.3 3-F-.phi.- H 1 8-15 3,5-di-F-.phi.- H
H,H --CH.sub.3 --CH.sub.3 4-F-.phi.- H 1 8-16 cyclopentyl H OH,H
--CH.sub.3 --CH.sub.3 -.phi. H 1 8-17 cyclopentyl H OH,H
--CH(CH.sub.3).sub.2 --CH.sub.3 -.phi. H 1 8-18 3,5-di-F-.phi.- H
H,H --CH.sub.3 --CH.sub.3 --CH.sub.3 H 1 8-19 3,5-di-F-.phi.- H H,H
--CH.sub.3 CH.sub.2CH(CH.sub.3).sub.2 -.phi. H 1 8-20
3,5-di-F-.phi.- H OH,H --CH.sub.3 --CH.sub.3 -.phi. H 1 8-21
3,5-di-F-.phi.- H .dbd.O --CH.sub.3 --CH.sub.3 -.phi. H 1 8-22
CH.sub.3S-- H H,H --CH.sub.3 --CH.sub.3 -.phi. H 1 8-23
3,5-di-F-.phi.- H H,H --CH(CH.sub.3).sub.2 --CH.sub.3 -.phi. H 1
8-24 3,5-di-F-.phi.- H H,H --C(CH.sub.3).sub.3 --CH.sub.3 -.phi. H
1 8-25 3,5-di-F-.phi. H H,H --CH.sub.3 --CH(CH.sub.3).sub.2 -.phi.
H 1 8-26 3,5-di-F-.phi.- H H,H --CH.sub.3 1-cyclopropyl- -.phi. H 1
methyl 8-27 3,5-di-F-.phi.- H F,H --CH.sub.3 --CH.sub.3 -.phi. H 1
8-28 3,5-di-F-.phi.- H H,H --CH.sub.3 --CH.sub.2CH.sub.2CH.sub.3
-.phi. H 1 8-29 (CH.sub.3).sub.2CH-- H H,H -.phi. --CH.sub.3 -.phi.
H 1 8-30 3,5-di-F-.phi.- H H,H -.phi. --CH.sub.3 -.phi. H 1 8-31
.phi.-S-- H H,H --CH.sub.3 --CH.sub.3 -.phi. H 1 8-32
(CH.sub.3).sub.2CH-- H H,H --CH.sub.3 --CH.sub.3 -.phi. H 1 8-33
.phi.-S-- H H,H -.phi. --CH.sub.3 -.phi. H 1 8-34
4-CH.sub.3O-.phi.- H H,H --CH.sub.3 --CH.sub.3 -.phi. H 1
CH.sub.2-- 8-35 3-Br-.phi.- H H,H --CH.sub.3 --CH.sub.3 -.phi. H 1
8-36 cyclohexyl- H H,H --CH.sub.3 --CH.sub.3 -.phi. H 1
CH.sub.2CH.sub.2-- 8-37 4-CH.sub.3O-.phi.- H H,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-38 (CH.sub.3).sub.2CH-- H OH,H
--CH.sub.3 --CH.sub.3 -.phi. H 1 8-39 (CH.sub.3).sub.2CH-- H OH,H
--CH.sub.2(CH.sub.3).sub.2 --CH.sub.3 -.phi. H 1 8-40
(CH.sub.3).sub.3C-- H OH,H --CH.sub.3 --CH.sub.3 -.phi. H 1 8-41
2-thienyl H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-42
3,5-di-F-.phi.- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-43
3-Br-.phi.- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-44
.phi.-S-- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-45
4-CH.sub.3CH.sub.2O-.phi.- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H
1 8-46 4-CF.sub.3-.phi.- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1
8-47 3,5-di-CF.sub.3-.phi.- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H
1 8-48 CH.sub.3S-- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-49
cyclohexyl H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-50
2,3,4,5,6- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1
penta-F-.phi.-O- 8-51 3-thio- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl
H 1 naphthalyl 8-52 2,4,6-tri- H H,H --CH.sub.3 --CH.sub.3
2-pyridyl H 1 CH.sub.3-.phi.- 8-53 (4-.phi.)-.phi. H H,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-54 3,4-di-F-.phi.- H H,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-55 2-thienyl- H H,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-56
(CH.sub.3).sub.2CH-- H H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1
CH.sub.2CH.sub.2-- 8-57 CH.sub.3OC(O)CH.sub.2-- H H,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-60 2,6-di-F-.phi.- H OH,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-61 4-F-.phi.- H OH,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-62 2,5-di-F-.phi.- H OH,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-63 2,4,6-tri-F-.phi.- H H,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-64 2-CF.sub.3-4-F-.phi. H H,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-65 CF.sub.3CH.sub.2-- H H,H --CH.sub.3
--CH.sub.3 2-pyridyl H 1 8-66 (4-(CH.sub.3).sub.2CH-- H H,H
--CH.sub.3 --CH.sub.3 2-pyridyl H 1 .phi.- 8-67 .phi.-CH.sub.2-- H
OH,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-68 .phi.- H OH,H
--CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-69 4-CH-.phi.- H OH,H
--CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-70 (CH.sub.3).sub.2CH-- H H,H
--CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-71 2,3,5-tri-F-.phi.- H H,H
--CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-72 CH.sub.3S--CH.sub.2-- H
H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-73 (CH.sub.3).sub.2CH-- H
OH,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-74 3-NO.sub.2-.phi.- H
H,H --CH.sub.3 --CH.sub.3 2-pyridyl H 1 8-75 4-CH.sub.3O-.phi.- H
H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2--
8-76 2-thienyl H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H
1 CH.sub.2-- 8-77 3,5-di-F-.phi.- H H,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-78 3-Br-.phi.- H
H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2--
8-79 .phi.-S-- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H
1 CH.sub.2-- 8-80 4-CH.sub.3CH.sub.2O-- H H,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 .phi.- CH.sub.2-- 8-81
4-CF.sub.3-.phi.- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)--
2-pyridyl H 1 CH.sub.2-- 8-82 3,5-di-CF.sub.3-.phi.- H H,H
--CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-83
CH.sub.3S-- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1
CH.sub.2-- 8-84 cyclohexyl H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)--
2-pyridyl H 1 CH.sub.2-- 8-85 2,3,4,5,6- H H,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 penta-F-.phi.-O-- CH.sub.2--
8-86 3-thio- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1
naphthalyl CH.sub.2-- 8-87 2,4,6-tri-CH.sub.3-- H H,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 .phi.- CH.sub.2-- 8-88
(4-.phi.)-.phi.- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl
H 1 CH.sub.2-- 8-89 3,4-di-F-.phi.- H H,H --CH.sub.3
(CH).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-90 thien-2-yl- H H,H
--CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2CH.sub.2--
CH.sub.2-- 8-91 (CH.sub.3).sub.2CH(CH.sub.2).sub.2-- H H,H
--CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-92
CH.sub.3OC(O)CH.sub.2-- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)--
2-pyridyl H 1 CH.sub.2-- 8-95 2,6-di-F-.phi.- H OH,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-96 4-F-.phi.- H
OH,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2--
8-97 2,5-di-F-.phi.- H OH,H --CH.sub.3 (CH.sub.3).sub.3CC(O)--
2-pyridyl H 1 CH.sub.2-- 8-98 2,4,6-tri-F-.phi.- H H,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-99
2-CF.sub.3-4-F-.phi.- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)--
2-pyridyl H 1 CH.sub.2-- 8-100 CF.sub.3CH.sub.2-- H H,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-101
4-(CH.sub.3).sub.2CH-.phi.- H H,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-102
.phi.CH.sub.2-- H OH,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl
H 1 CH.sub.2-- 8-103 .phi.- H OH,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-104 4-Cl-.phi.-
H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2
8-105 (CH.sub.3).sub.2CH-- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)--
2-pyridyl H 1 CH.sub.2-- 8-106 2,3,5-tri-F-.phi.- H H,H --CH.sub.3
(CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-107
CH.sub.3S--CH.sub.2-- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)--
2-pyndyl H 1 CH.sub.2-- 8-108 (CH.sub.3).sub.2CH-- H OH,H
--CH.sub.3 (CH.sub.3).sub.3CC(O)-- 2-pyridyl H 1 CH.sub.2-- 8-109
3-NO.sub.2-.phi.- H H,H --CH.sub.3 (CH.sub.3).sub.3CC(O)--
2-pyridyl H 1 CH.sub.2-- 8-110 4-CH.sub.3O-.phi.- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- - 2-pyridyl H 1 CH.sub.2CH.sub.2--
8-111 2-thienyl H H,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N--
2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-112 3,5-di-F-.phi.- H H,H
--CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1
CH.sub.2CH.sub.2-- 8-113 3-Br-.phi.- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-114
.phi.-S- H H,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1
CH.sub.2CH.sub.2-- 8-115 (4-CH.sub.3CH.sub.2O)-.phi.- H H,H
--CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1
CH.sub.2CH.sub.2-- 8-116 --CH.sub.3S-- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-117
cyclohexyl H H,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H
1 CH.sub.2CH.sub.2-- 8-118 2,3,4,5,6- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 penta-F-.phi.-O-
CH.sub.2CH.sub.2-- 8-119 3-thio- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 naphthalyl
CH.sub.2CH.sub.2-- 8-120 .phi.- H .dbd.O --CH.sub.3
(CH.sub.3CH).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-121
2,4,6-tri-CH.sub.3- H H,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N--
2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-122 (4-.phi.)-.phi.- H H,H
--CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1
CH.sub.2CH.sub.2-- 8-123 3,4-di-F-.phi.- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-124
thien-2-yl- H H,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl
H 1 CH.sub.2CH.sub.2-- CH.sub.2CH.sub.2 8-125
(CH.sub.3).sub.2CH(CH.sub.2).sub.2-- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-126
CH.sub.3OC(O)CH.sub.2-- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-129
2,6-di-F-.phi.- H OH,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- -
2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-130 4-F-.phi. H OH,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-131
2,5-di-F-.phi.- H OH,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N--
2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-132 4-HOCH.sub.2-.phi.-O- H H,H
--CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1
CH.sub.2CH.sub.2-- 8-133 2,4,6-tri-F-.phi.- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2- N-- 2-pyridyl H 1 CH.sub.2CH.sub.2--
8-134 2-CF.sub.3-4-F-.phi.- H H,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-135
CF.sub.3CH.sub.2-- H H,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N--
2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-136 (CH.sub.3).sub.2CH-.phi.- H
H,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1
CH.sub.2CH.sub.2-- 8-137 .phi.CH.sub.2-- H OH,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-138
.phi.- H OH,H --CH.sub.3 (CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1
CH.sub.2CH.sub.2-- 8-139 4-Cl-.phi.- H OH,H --CH.sub.3
(CH.sub.3CH.sub.2).sub.2N-- 2-pyridyl H 1 CH.sub.2CH.sub.2-- 8-166
3,5-di-F-.phi.- H H,H --CH.sub.3 --CH.sub.3 -.phi. H 1
[1321]
16TABLE 8-2 36 R.sup.2 = 1 position; R.sup.3 = 5 position; R.sup.4
= 7 position Ex. R X'/X" R' R.sup.1 R.sup.2 R.sup.3 R.sup.4 n 8-140
3,5-di-F-.phi.- OH,H H thien-3- --CH.sub.2C(CH.sub.3).sub.3
--CH.sub.2C(CH.sub.3).sub.3 H 1 yl 8-141 3,5-di-F-.phi.- OH,H H
--CH.sub.3 -.phi. --CH.sub.3 H 1 8-142 3,5-di-F-.phi.- OH,H H
--CH.sub.3 --CH.sub.3 -.phi. H 1 8-146 3,5-di-F-.phi.- H,H H
--CH.sub.3 --CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 H 1 8-147
3,5-di-F-.phi.- H,H H 2-thienyl --CH(CH.sub.3).sub.2
--CH(CH.sub.3).sub.2 H 1 8-148 cyclopropyl H,H H 2-thienyl
--CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 H 1 8-149 cyclopentyl H,H
H 2-thienyl --CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 H 1 8-150
3,5-di-F-.phi.- H,H H --CH.sub.3 --CH.sub.3 --CH.sub.3 H 1 8-151
3,5-di-F-.phi.- OH,H H --CH.sub.3 --CH.sub.3 --CH.sub.3 H 1 8-152
3,5-di-F-.phi.- H,H H --CH.sub.3 --CH.sub.2CH(CH.sub.3).sub.2
--CH.sub.2CH(CH.sub.3).sub.2 H 1 8-153 cyclopentyl H,H H --CH.sub.3
--CH.sub.2CH(CH.sub.3).sub.2 --CH.sub.2CH(CH.sub.3).sub.2 H 1 8-154
cyclopropyl H,H H --CH.sub.3 --CH.sub.2CH(CH.sub.3).sub.2
--CH.sub.2CH(CH.sub.3).sub.2 H 1 8-155 3,5-di-F-.phi.- H,H H -.phi.
--CH.sub.2CH(CH.sub.3).sub.2 --CH.sub.2CH(CH.sub.3).sub.2 H 1 8-156
3,5-di-F-.phi.- H,H H --CH.sub.3 1-cyclopropyl- 1-cyclopropyl- H 1
methyl methyl 8-157 cyclopentyl H,H H --CH.sub.3 1-cyclopropyl-
1-cyclopropyl- H 1 methyl methyl 8-158 cyclopentyl OH,H H
--CH.sub.3 1-cyclopropyl- 1-cyclopropyl- H 1 methyl methyl 8-159
3,5-di-F-.phi.- H,H H --CH.sub.3 --CH.sub.2C(CH.sub.3).sub.3
--CH.sub.2C(CH.sub.3).sub.3 H 1 8-160 3,5-di-F-.phi.- OH,H H
--CH.sub.3 --CH.sub.2C(CH.sub.3).sub.3 --CH.sub.2C(CH.sub.3).sub.3
H 1 8-161 cyclopentyl H,H H --CH.sub.3 --CH.sub.2C(CH.sub.3).sub.3
--CH.sub.2C(CH.sub.3).sub.3 H 1 8-162 cyclopentyl OH,H H --CH.sub.3
--CH.sub.2C(CH.sub.3).sub.3 --CH.sub.2C(CH.sub.3).sub.3 H 1 8-163
3,5-di-F-.phi.- H,H H --CH.sub.3 -.phi. -.phi. H 1 8-164
cyclopentyl H,H H --CH.sub.3 -.phi. -.phi. H 1 8-165 cyclopentyl
OH,H H --CH.sub.3 -.phi. -.phi. H 1
[1322]
17TABLE 8-3 37 R.sup.2 = 1 position; R.sup.3 = 5 position; R.sup.4
= 7 position Ex. R X'/X" R' R.sup.1 R.sup.2 R.sup.3 R.sup.4 n 8-142
3,5-di-F-.phi.- OH,H H --CH.sub.3 --CH.sub.3 -.phi. H 1
[1323]
18TABLE 8-4 38 Ex. R X'/X" R.sup.1 R.sup.2 A-B 8-143
3,5-di-F-.phi.- H,H --CH.sub.3 -.phi. --CH.dbd.CH-- 8-144
2,5-di-F-.phi.- H,H --CH.sub.3 -.phi. --CH.sub.2--CH.sub.2-- 8-145
3,5-di-F-.phi.- H,H --CH.sub.3 -.phi. --N.dbd.CH--
[1324]
19TABLE 8-5 39 Ex. R X'/X" R.sup.1 R.sup.2 8-167 3,5-di-F-.phi.-
H,OH --CH.sub.3 --CH.sub.3
[1325]
20TABLE 8C-1 40 R.sup.2 = 1 position; R.sup.3 = 5 position; R.sup.4
= 7 position X and Iso. R X' R.sup.1 R.sup.2 R.sup.3 R.sup.4 (at *)
3,4-methylenedioxy-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
2-CH.sub.3O-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
4-[(CH.sub.3).sub.2CH].phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H
R,S CH.sub.3CH.sub.2O-- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
4-(.phi.-O-).phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
4-CH.sub.3CH.sub.2O-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
2,5-di-CH.sub.3O-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
2-CH.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
(.phi.).sub.2CH-- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
.phi.-O-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
indol-3-yl- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
4-CF.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
4-CH.sub.3-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
4-HOCH.sub.2-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
2-(.phi.-O-).phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
3-(.phi.-O-).phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
3,4-di-Cl-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
4-F-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S CH.sub.3S-- H,H
--CH.sub.3 --CH.sub.3 -.phi. H R,S CH.sub.3O-- H,H --CH.sub.3
--CH.sub.3 -.phi. H R,S .phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H
S .phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
.phi.-CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
3-CH.sub.3O-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-(n-C.sub.4H.sub.9O).phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2-CH.sub.3O-.phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
(CH.sub.3).sub.2CH-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
1-.phi.-tetrazol-5-yl H,H --CH.sub.3 --CH.sub.3 -.phi. H S
3-(3,4-methylene- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
dioxy).phi.-CH.sub.2-- cyclopentyl-CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S cyclopenten-2-yl- H,H --CH.sub.3 --CH.sub.3
-.phi. H S 2-F-6-Cl-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
cyclohexyl- H,H --CH.sub.3 --CH.sub.3 -.phi. H S 2,5-di-F-.phi.-
H,H --CH.sub.3 --CH.sub.3 -.phi. H S 2,3,4,5,6-penta-F-.phi.-O- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S 3,5-di-CH.sub.3-.phi.-O- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S 4-Cl-.phi. H,H --CH.sub.3
--CH.sub.3 -.phi. H S 3-Cl-.phi.-O- H,H --CH.sub.3 --CH.sub.3
-.phi. H S benzo[b]thiophen-3-yl H,H --CH.sub.3 --CH.sub.3 -.phi. H
S .phi.- .dbd.O --CH.sub.3 --CH.sub.3 -.phi. H S
3,5-di-CH.sub.3O-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2,5-di-CH.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2,6-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2,4-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S mesityl H,H
--CH.sub.3 --CH.sub.3 -.phi. H S .phi.-.phi.- H,H --CH.sub.3
--CH.sub.3 -.phi. H S 3,4-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3
-.phi. H S trans-styryl H,H --CH.sub.3 --CH.sub.3 -.phi. H S
.phi.-C(O)CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
CH.sub.3CH.sub.2CH.dbd.CH- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
(trans) CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S 4-CH.sub.3-.phi.-CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S 4-Cl-.phi.-CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S CH.sub.3CH(.phi.)- H,H --CH.sub.3 --CH.sub.3
-.phi. H S 4-CH.sub.3O-.phi.-CH.sub.2CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S CH.sub.3OC(O)CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S .phi.-CH.sub.2CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S .phi.CH.sub.2SCH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S CH.sub.3CH.sub.2CH(CH.sub.3)-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S 41 H,H --CH.sub.3 --CH.sub.3 -.phi. H S
indan-2-yl H,H --CH.sub.3 --CH.sub.3 -.phi. H S 4-CH.sub.3O-.phi.-
H,H --CH.sub.3 --CH.sub.3 -.phi. H S 2-Cl-.phi.-O- H,H --CH.sub.3
--CH.sub.3 -.phi. H S 2-thienyl H,H --CH.sub.3 --CH.sub.3 -.phi. H
S 2-CF.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-CH.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2,6-di-F-.phi.- H,OH --CH.sub.3 --CH.sub.3 -.phi. H S
4-CH.sub.3O-.phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
3-CH.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S 3-F-.phi.-
H,H --CH.sub.3 --CH.sub.3 -.phi. H S 4-Cl-.phi.-O-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S 2-naphthyl H,H --CH.sub.3 --CH.sub.3 -.phi. H
S 3-Cl-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
3-CH.sub.3-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
3,4-methylenedioxy-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2-CH.sub.3O-.phi.-O-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-[(CH.sub.3).sub.2CH].phi.-O-- H,H --CH.sub.3 --CH.sub.3 -.phi. H
S 4-.phi.-O-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S .phi.-S--
H,H --CH.sub.3 --CH.sub.3 -.phi. H S 4-CH.sub.3CH.sub.2O-.phi.- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S 2,5-di-CH.sub.3O-.phi.- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S 2-CH.sub.3-.phi.- H,H --CH.sub.3
--CH.sub.3 -.phi. H S (.phi.).sub.2CH-- H,H --CH.sub.3 --CH.sub.3
-.phi. H S .phi.-O-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
indol-3-yl- H,H --CH.sub.3 --CH.sub.3 -.phi. H S 4-CF.sub.3-.phi.-
H,H --CH.sub.3 --CH.sub.3 -.phi. H S 3,5-di-CF.sub.3-.phi.- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S 2-(.phi.-O-).phi.- H,H --CH.sub.3
--CH.sub.3 -.phi. H S 3-(.phi.-O-).phi.- H,H --CH.sub.3 --CH.sub.3
-.phi. H S 4-F-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2,4-di-Cl-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S CH.sub.3S--
H,H --CH.sub.3 --CH.sub.3 -.phi. H S 4-F-.phi.- H,OH --CH.sub.3
--CH.sub.3 -.phi. H S 4-thionaphthenyl H,H --CH.sub.3 --CH.sub.3
-.phi. H S CH.sub.3O-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
CH.sub.3CH.sub.2O-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2-Cl-.phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
CH.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
CH.sub.3CH.sub.2CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi.
H S .phi.CH.sub.2CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3
-.phi. H S thien-2-yl-CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3
-.phi. H S 3-CH.sub.3O-.phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3
-.phi. H S (CH.sub.3).sub.2CHCH.sub.2CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. H S .phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3
-.phi. H S CH.sub.3(CH.sub.2).sub.5-- H,H --CH.sub.3 --CH.sub.3
-.phi. H S 3-HO-.phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H
S 4-HO-.phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
3,4,5-CF.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
cyclopentyl H,H --CH.sub.3 --CH.sub.3 -.phi. H S 42 H,H --CH.sub.3
--CH.sub.3 -.phi. H S 2-CH.sub.3-benzofuran-3-- yl H,H --CH.sub.3
--CH.sub.3 -.phi. H S CH.sub.3-- H,H --CH.sub.3 --CH.sub.3 -.phi. H
S cyclopropyl H,H --CH.sub.3 --CH.sub.3 -.phi. H S
CH.sub.3OCH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
thienyl-CH.sub.2CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi.
H S 4-F-.phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-F-.phi.-O-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
norbornan-2-yl H,H --CH.sub.3 --CH.sub.3 -.phi. H S 2,3-di-F-.phi.-
H,OH --CH.sub.3 --CH.sub.3 -.phi. H S CH.sub.3CH.dbd.CH-- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S 2,4-di-Cl-.phi.-O- H,H --CH.sub.3
--CH.sub.3 -.phi. H S CH.sub.2CH.sub.2-- 2,3-di-Cl-.phi.-O- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S 2-F-.phi.- H,H --CH.sub.3
--CH.sub.3 -.phi. H S 2-NO.sub.2-.phi.- H,H --CH.sub.3 --CH.sub.3
-.phi. H S 4-HOCH.sub.2-.phi.-O-- H,H --CH.sub.3 --CH.sub.3 -.phi.
H S 2-F-3-CF.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2,4,6-tri-CF.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-F-2-CF.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
CF.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2-F-4-CF.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-Br-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-F-.phi.-C(O)CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2-CH.sub.3-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-CH.sub.3O-.phi.-O- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
.phi.SO.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2-CH.sub.3O-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S 2-Br-.phi.-
H,H --CH.sub.3 --CH.sub.3 -.phi. H S 4-[(CH.sub.3).sub.2CH].phi.-
H,H --CH.sub.3 --CH.sub.3 -.phi. H S CH.sub.2.dbd.CHCH.sub.2-- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S 4-HO-.phi.-O- H,H --CH.sub.3
--CH.sub.3 -.phi. H S CH.sub.3OCH.sub.2-- H,H --CH.sub.3 --CH.sub.3
-.phi. H S 2-HO-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
3,4-di-CH.sub.3O-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
4-CH.sub.3O-.phi.-C(O)CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. H
S thien-3-yl H,H --CH.sub.3 --CH.sub.3 -.phi. H S
.phi.CH.sub.2CH.sub.2CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3
-.phi. H S (CH.sub.3).sub.2CH-- H,H --CH.sub.3 --CH.sub.3 -.phi. H
S 2,3,5-tri-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
2,4,5-tri-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H S
adamantan-1-yl H,H --CH.sub.3 --CH.sub.3 -.phi. H S cyclohexyl- H,H
--CH.sub.3 --CH.sub.3 -.phi. H S CH.sub.2CH.sub.2CH.sub.2--
thien-2-yl H,H -.phi. --CH.sub.3 -.phi. H S 3-CF.sub.3-.phi.- H,H
-.phi. --CH.sub.3 -.phi. H S 3,5-di-F-.phi.- H,H -.phi. --CH.sub.3
-.phi. H S 3-CH.sub.3-.phi.- H,H -.phi. --CH.sub.3 -.phi. H S
3-F-.phi.- H,H -.phi. --CH.sub.3 -.phi. H S 3-Br-.phi.- H,H -.phi.
--CH.sub.3 -.phi. H S 3-Cl-.phi. H,H -.phi. --CH.sub.3 -.phi. H S
3,4-methylenedioxy-.phi.- H,H -.phi. --CH.sub.3 -.phi. H S .phi.-S-
H,H -.phi. --CH.sub.3 -.phi. H S 3,5-di-CF.sub.3-.phi.- H,H -.phi.
--CH.sub.3 -.phi. H S CH.sub.3S-- H,H -.phi. --CH.sub.3 -.phi. H S
.phi.-O- H,H -.phi. --CH.sub.3 -.phi. H S .phi.- H,H -.phi.
--CH.sub.3 -.phi. H S cyclohexyl H,H -.phi. --CH.sub.3 -.phi. H S
2,5-di-F-.phi.- H,H -.phi. --CH.sub.3 -.phi. H S
benzo[b]thiophen-3-yl H,H -.phi. --CH.sub.3 -.phi. H S .phi.-
.dbd.O -.phi. --CH.sub.3 -.phi. H S 2,6-di-F-.phi.- H,H -.phi.
--CH.sub.3 -.phi. H S 2,4-di-F-.phi.- H,H -.phi. --CH.sub.3 -.phi.
H S 3,4-di-F-.phi.- H,H -.phi. --CH.sub.3 -.phi. H S
CH.sub.3CH.sub.2-- H,H -.phi. --CH.sub.3 -.phi. H S
CH.sub.3(CH.sub.2).sub.4-- H,H -.phi. --CH.sub.3 -.phi. H S
thien-2-yl-CH.sub.2CH.sub.2-- H,H -.phi. --CH.sub.3 -.phi. H S
(CH.sub.3).sub.2CHCH.sub.2CH.sub.2-- H,H -.phi. --CH.sub.3 -.phi. H
S .phi.CH.sub.2-- H,H -.phi. --CH.sub.3 -.phi. H S cyclopentyl H,H
-.phi. --CH.sub.3 -.phi. H S CH.sub.3-- H,H -.phi. --CH.sub.3
-.phi. H S 3,4,5-CF.sub.3-.phi.- H,H -.phi. --CH.sub.3 -.phi. H S
CH.sub.2CH.sub.2-- H,H -.phi. --CH.sub.3 -.phi. H S 2-thienyl H,H
--CH.sub.3 --CH.sub.2CH.sub.2-- -.phi. H R,S CH.sub.2CF.sub.3
2-thienyl H,H --CH.sub.3 --CH.sub.2C(O).phi. -.phi. H R,S 2-thienyl
H,H --CH.sub.3 --CH.sub.3 2-thiazolyl H R,S 2-thienyl H,H
--CH.sub.3 --CH.sub.3 -.phi. Cl R,S 2-thienyl H,H --CH.sub.3
--CH.sub.3 2-Cl-.phi. Cl R,S 2-thienyl H,H --CH.sub.3 --CH.sub.3
2-thienyl H R,S 2-thienyl H,H --CH.sub.3 --CH.sub.3 cyclohexyl H
R,S 2-thienyl H,H --CH.sub.3 --CH.sub.3 -2-F-.phi. Br R,S
3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.2CH.sub.2-- -.phi. H R,S
CH.sub.2CF.sub.3 3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.2C(O).phi.
-.phi. H R,S 3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 2-thiazolyl
H R,S 3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. Cl R,S
3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S
3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 thien-2-yl H R,S
3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -cyclohexyl H R,S
3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 2-F-.phi.- Br R,S
3-F-.phi.- H,H --CH.sub.3 --CH.sub.2CH.sub.2-- -.phi. H R,S
CH.sub.2CF.sub.3 3-F-.phi.- H,H --CH.sub.3 --CH.sub.2C(O).phi.
-.phi. H R,S 3-F-.phi.- H,H --CH.sub.3 --CH.sub.3 2-thiazolyl H R,S
3-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. Cl R,S 3-F-.phi.- H,H
--CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S 3-F-.phi.- H,H --CH.sub.3
--CH.sub.3 thien-2-yl H R,S 3-F-.phi.- H,H --CH.sub.3 --CH.sub.3
cyclohexyl H R,S 3-F-.phi.- H,H --CH.sub.3 --CH.sub.3 2-F-.phi.- Br
R,S CH.sub.3S-- H,H --CH.sub.3 --CH.sub.2CH.sub.2-- -.phi. H R,S
CH.sub.2CF.sub.3 CH.sub.3S-- H,H --CH.sub.3 --CH.sub.2C(O).phi.
-.phi. H R,S CH.sub.3S-- H,H --CH.sub.3 --CH.sub.3 2-thiazolyl H
R,S CH.sub.3S-- H,H --CH.sub.3 --CH.sub.3 -.phi. Cl R,S CH.sub.3S--
H,H --CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S CH.sub.3S-- H,H
--CH.sub.3 --CH.sub.3 2-thienyl H R,S CH.sub.3S-- H,H --CH.sub.3
--CH.sub.3 cyclohexyl H R,S CH.sub.3S-- H,H --CH.sub.3 --CH.sub.3
2-F-.phi.- Br R,S .phi.- H,H --CH.sub.3 --CH.sub.2CH.sub.2-- -.phi.
H R,S CH.sub.2CF.sub.3 .phi.- H,H --CH.sub.3 --CH.sub.2C(O).phi.
-.phi. H R,S .phi.- H,H --CH.sub.3 --CH.sub.3 2-thiazolyl H R,S
.phi.- H,H --CH.sub.2 --CH.sub.3 -.phi. Cl R,S .phi.- H,H
--CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S .phi.- H,H --CH.sub.3
--CH.sub.3 2-thienyl H R,S .phi.- H,H --CH.sub.3 --CH.sub.3
cyclohexyl H R,S .phi.- .dbd.O --CH.sub.3 --CH.sub.2CH.sub.2 .phi.
H R,S CH.sub.2CF.sub.3 .phi.- .dbd.O --CH.sub.2 --CH.sub.2C(O).phi.
-.phi. H R,S .phi.- .dbd.O --CH.sub.3 --CH.sub.3 2-thiazalyl H R,S
.phi.- .dbd.O --CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S .phi.-
.dbd.O --CH.sub.3 --CH.sub.3 2-thienyl H R,S .phi.- .dbd.O
--CH.sub.3 --CH.sub.3 cyclohexyl H R,S .phi.- .dbd.O --CH.sub.3
--CH.sub.3 2-F-.phi.- Br R,S CH.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.2CH.sub.2-- -.phi. H R,S CH.sub.2CF.sub.3
CH.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.2C(O).phi. -.phi. H R,S
CH.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 2-thiazolyl H R,S
CH.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 -.phi. Cl R,S
CH.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S
CH.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 2-thienyl H R,S
CH.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 cyclohexyl H R,S
CH.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 2-F-.phi.- Br R,S
(2-thienyl)-CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.2CH.sub.2--
-.phi. H R,S CH.sub.2CF.sub.3 (2-thienyl)-CH.sub.2CH.sub.2-- H,H
--CH.sub.3 --CH.sub.2C(O).phi. -.phi. H R,S
(2-thienyl)-CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3
2-thiazolyl H R,S (2-thienyl)-CH.sub.2CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. Cl R,S (2-thienyl)-CH.sub.2CH.sub.2-- H,H
--CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S
(2-thienyl)-CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3 2-thienyl
H R,S (2-thienyl)-CH.sub.2CH.sub.2-- H,H --CH.sub.3 --CH.sub.3
cyclohexyl H R,S (2-thienyl)-CH.sub.2CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 2-F-.phi.- Br R,S cyclopentyl H,H --CH.sub.3
--CH.sub.2CH.sub.2-- -.phi. H R,S CH.sub.2CF.sub.3 cyclopentyl H,H
--CH.sub.3 --CH.sub.2C(O).phi. -.phi. H R,S cyclopentyl H,H
--CH.sub.3 --CH.sub.3 2-thiazolyl H R,S cyclopentyl H,H --CH.sub.3
--CH.sub.3 -.phi. Cl R,S cyclopentyl H,H --CH.sub.3 --CH.sub.3
2-Cl-.phi.- Cl R,S cyclopentyl H,H --CH.sub.3 --CH.sub.3 2-thienyl
H R,S cyclopentyl H,H --CH.sub.3 --CH.sub.3 cyclohexyl H R,S
cyclopentyl H,H --CH.sub.3 --CH.sub.3 2-F-.phi.- Br R,S 43 H,H
--CH.sub.3 --CH.sub.2CH.sub.2--CH.sub.2CF.sub.3 -.phi. H R,S 44 H,H
--CH.sub.3 --CH.sub.2C(O).phi. -.phi. H R,S 45 H,H --CH.sub.3
--CH.sub.3 2-thiazolyl H R,S 46 H,H --CH.sub.3 --CH.sub.3 -.phi. Cl
R,S 47 H,H --CH.sub.3 --CH.sub.3 2-Cl-.phi. Cl R,S 48 H,H
--CH.sub.3 --CH.sub.3 2-thienyl H R,S 49 H,H --CH.sub.3 --CH.sub.3
cyclohexyl H R,S 50 H,H --CH.sub.3 --CH.sub.3 2-F-.phi.- Br R,S
CF.sub.3CH.sub.2-- H,H --CH.sub.3 --CH.sub.2CH.sub.2-- -.phi. H
R,S
CH.sub.2CF.sub.3 CF.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.2C(O).phi. -.phi. H R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 2-thiazolyl H R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 -.phi. Cl R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 2-Cl-.phi.- Cl R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 2-thienyl H R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 cyclohexyl H R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.3 2-F-.phi.- Br R,S (CH.sub.3).sub.2CH-- H,H --CH.sub.3
--CH.sub.2CH.sub.2-- -.phi. H R,S CH.sub.2CF.sub.3
(CH.sub.3).sub.2CH-- H,H --CH.sub.3 --CH.sub.2C(O).phi. -.phi. H
R,S (CH.sub.3).sub.2CH-- H,H --CH.sub.3 --CH.sub.3 2-thiazolyl H
R,S (CH.sub.3).sub.2CH-- H,H --CH.sub.3 --CH.sub.3 -.phi. Cl R,S
(CH.sub.3).sub.2CH-- H,H --CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S
(CH.sub.3).sub.2CH-- H,H --CH.sub.3 --CH.sub.3 2-thienyl H R,S
(CH.sub.3).sub.2CH-- H,H --CH.sub.3 --CH.sub.3 cyclohexyl H R,S
(CH.sub.3).sub.2CH-- H,H --CH.sub.3 --CH.sub.3 2-F-.phi.- Br R,S
(CH.sub.3).sub.2CHCH.sub.2-- H,OH --CH.sub.3 --CH.sub.2CH.sub.2--
-.phi. H R,S CH.sub.2CF.sub.3 (CH.sub.3).sub.2CHCH.sub.2-- H,OH
--CH.sub.3 --CH.sub.2C(O).phi. -.phi. H R,S
(CH.sub.3).sub.2CHCH.sub.2-- H,OH --CH.sub.3 --CH.sub.3 2-thiazolyl
H R,S (CH.sub.3).sub.2CHCH.sub.2-- H,OH --CH.sub.3 --CH.sub.3
-.phi. Cl R,S (CH.sub.3).sub.2CHCH.sub.2-- H,OH --CH.sub.3
--CH.sub.3 2-Cl-.phi.- Cl R,S (CH.sub.3).sub.2CHCH.sub.2-- H,OH
--CH.sub.3 --CH.sub.3 2-thienyl H R,S (CH.sub.3).sub.2CHCH.sub.2--
H,OH --CH.sub.3 --CH.sub.3 cyclohexyl H R,S
(CH.sub.3).sub.2CHCH.sub.2-- - H,OH --CH.sub.3 --CH.sub.3
2-F-.phi.- Br R,S -.phi. H,OH --CH.sub.3 --CH.sub.2CH.sub.2--
-.phi. H R,S CH.sub.2CF.sub.3 -.phi. H,OH --CH.sub.3
--CH.sub.2C(O).phi. -.phi. H R,S -.phi. H,OH --CH.sub.3 --CH.sub.3
2-thiazolyl H R,S -.phi. H,OH --CH.sub.3 --CH.sub.3 -.phi. Cl R,S
-.phi. H,OH --CH.sub.3 --CH.sub.3 2-Cl-.phi.- Cl R,S -.phi. H,OH
--CH.sub.3 --CH.sub.3 2-thienyl H R,S -.phi. H,OH --CH.sub.3
--CH.sub.3 cyclohexyl H R,S -.phi. H,OH --CH.sub.3 --CH.sub.3
2-F-.phi.- Br R,S 3,5-di-F-.phi.- H,H --CH.sub.3 3-F-.phi.- -.phi.
H R,S 3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.2.phi. -.phi. H R,S
3,5-di-F-.phi.- H,H --CH.sub.3 4-t-butyl- -.phi. H R,S
CH.sub.2.phi. 3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.2CH.sub.2--
-.phi. H R,S cyclohexyl 3,5-di-F-.phi.- H,H --CH.sub.3
3,3-dimethyl- -.phi. H R,S butyl 3,5-di-F-.phi.- H,H --CH.sub.3
CH.sub.3OC(O)-- -.phi. H R,S CH(.phi.)- 3,5-di-F-.phi.- H,H
--CH.sub.3 2-ethyl- -.phi. H R,S butyl 3,5-di-F-.phi.- H,H
--CH.sub.3 cyclohexyl- -.phi. H R,S methyl 3,5-di-F-.phi.- H,H
--CH.sub.3 2-.phi.-ethyl- -.phi. H R,S 3,5-di-F-.phi.- H,H
--CH.sub.3 3-.phi.-propyl- -.phi. H R,S 3,5-di-F-.phi.- H,H
--CH.sub.3 2-(N- -.phi. H R,S phthalimidyl) ethyl 3,5-di-F-.phi.-
H,H --CH.sub.3 2-biphenyl- -.phi. H R,S methyl 3,5-di-F-.phi.- H,H
--CH.sub.3 2-tetrahydro- -.phi. H R,S furanyl- methyl
3,5-di-F-.phi.- H,H --CH.sub.3 2-(1,4-benzo- -.phi. H R,S dioxanyl)
methyl 3,5-di-F-.phi.- H,H --CH.sub.3 3-(5-chloro- -.phi. H R,S
benzol[b]thien -yl)methyl 3,5-di-F-.phi.- H,H --CH.sub.3
3,3-dimethyl- -.phi. H R,S 2-oxo-propyl 3,5-di-F-.phi.- H,H
--CH.sub.3 5-benzofuraz- -.phi. H R,S anylmethyl 3,5-di-F-.phi.-
H,H --CH.sub.3 3-(.phi.)-O)- -.phi. H R,S propyl 3,5-di-F-.phi.-
H,H --CH.sub.3 6-(2-CF.sub.3- -.phi. H R,S quinolinyl) methyl
3,5-di-F-.phi.- H,H --CH.sub.3 2-methylbutyl -.phi. H R,S
3,5-di-F-.phi.- H,H --CH.sub.3 ethyl -.phi. H R,S 3,5-di-F-.phi.-
H,H --CH.sub.3 3-pyridyl- -.phi. H R,S methyl 3,5-di-F-.phi.- H,H
--CH.sub.3 2-oxo-2-(N- -.phi. H R,S indolinyl)- ethyl
3,5-di-F-.phi.- H,H --CH.sub.3 4-(3,5-di- -.phi. H R,S methyl-
isoxazolyl) methyl 3,5-di-F-.phi.- H,H --CH.sub.3 2-CH.sub.3O-ethyl
-.phi. H R,S cyclopentyl H,H --CH.sub.3 --CH.sub.2.phi. -.phi. H
R,S cyclopentyl H,H --CH.sub.3 (4-t-butyl-) -.phi. H R,S
CH.sub.2.phi. cyclopentyl H,H --CH.sub.3 --CH.sub.2CH.sub.2--
-.phi. H R,S cyclohexyl cyclopentyl H,H --CH.sub.3 3,3-dimethyl-
-.phi. H R,S butyl cyclopentyl H,H --CH.sub.3 isopropyl -.phi. H
R,S cyclopentyl H,H --CH.sub.3 CH.sub.3OC(O)-- -.phi. H R,S
CH(.phi.)- cyclopentyl H,H --CH.sub.3 2-ethyl- -.phi. H R,S butyl
cyclopentyl H,H --CH.sub.3 cyclohexyl- -.phi. H R,S methyl
cyclopentyl H,H --CH.sub.3 2-.phi.-ethyl- -.phi. H R,S cyclopentyl
H,H --CH.sub.3 3-.phi.-propyl- -.phi. H R,S cyclopentyl H,H
--CH.sub.3 2-(N- -.phi. H R,S phthalimidyl) ethyl cyclopentyl H,H
--CH.sub.3 2-biphenyl- -.phi. H R,S methyl cyclopentyl H,H
--CH.sub.3 3-(5-chloro- -.phi. H R,S benzol[b]thien -yl)methyl
cyclopentyl H,H --CH.sub.3 3,3-dimethyl- -.phi. H R,S 2-oxo-butyl
cyclopentyl H,H --CH.sub.3 5-benzofuraz- -.phi. H R,S anylmethyl
cyclopentyl H,H --CH.sub.3 3-(.phi.)-O)- -.phi. H R,S propyl
cyclopentyl H,H --CH.sub.3 6-(2-CF.sub.3- -.phi. H R,S quinolinyl)
methyl cyclopentyl H,H --CH.sub.3 cyclopropyl- -.phi. H R,S methyl
cyclopentyl H,H --CH.sub.3 2-methyl- -.phi. H R,S butyl cyclopentyl
H,H --CH.sub.3 ethyl -.phi. H R,S cyclopentyl H,H --CH.sub.3
4-(3,5-di- -.phi. H R,S methyl- isoxazolyl) methyl cyclopentyl H,H
--CH.sub.3 propyl -.phi. H R,S cyclopentyl H,H --CH.sub.3
2-CH.sub.3O-ethyl -.phi. H R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
--CH.sub.2.phi. -.phi. H R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
(4-t-butyl)- -.phi. H R,S CH.sub.2.phi. CF.sub.3CH.sub.2-- H,H
--CH.sub.3 --CH.sub.2CH.sub.2-- -.phi. H R,S cyclohexyl
CF.sub.3CH.sub.2-- H,H --CH.sub.3 3,3-dimethyl- -.phi. H R,S butyl
CF.sub.3CH.sub.2-- H,H --CH.sub.3 isopropyl -.phi. H R,S
CF.sub.3CH.sub.2-- H,H --CH.sub.3 CH.sub.3OC(O)-- -.phi. H R,S
CH(.phi.)- CF.sub.3CH.sub.2-- H,H --CH.sub.3 2-ethyl- -.phi. H R,S
butyl CF.sub.3CH.sub.2-- H,H --CH.sub.3 cyclohexyl- -.phi. H R,S
methyl CF.sub.3CH.sub.2-- H,H --CH.sub.3 3-.phi.-propyl- -.phi. H
R,S CF.sub.3CH.sub.2- H,H --CH.sub.3 2-biphenyl- -.phi. H R,S
methyl CF.sub.3CH.sub.2-- H,H --CH.sub.3 3-(5-chloro- -.phi. H R,S
benzo[b]thien -yl)methyl CF.sub.3CH.sub.2-- H,H --CH.sub.3
3,3-dimethyl- -.phi. H R,S 2-oxo-butyl CF.sub.3CH.sub.2-- H,H
--CH.sub.3 5-benzofuraz- -.phi. H R,S anylmethyl CF.sub.3CH.sub.2--
H,H --CH.sub.3 3-(.phi.-O)- -.phi. H R,S propyl CF.sub.3CH.sub.2--
H,H --CH.sub.3 6-(2-CF.sub.3- -.phi. H R,S quinolinyl) methyl
CF.sub.3CH.sub.2-- H,H --CH.sub.3 cyclopropyl- -.phi. H R,S methyl
CF.sub.3CH.sub.2-- H,H --CH.sub.3 2-methyl- -.phi. H R,S butyl
CF.sub.3CH.sub.2-- H,H --CH.sub.3 ethyl -.phi. H R,S
CF.sub.3CH.sub.2-- H,H --CH.sub.3 4-(3,5-di- -.phi. H R,S methyl-
isoxazolyl) methyl CF.sub.3CH.sub.2-- H,H --CH.sub.3 propyl -.phi.
H R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3 2-CH.sub.3O-ethyl -.phi. H
R,S N-pyrrolidinyl H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
2-Cl-.phi.-O-- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S 2-thienyl H,H
--CH.sub.3 --CH.sub.3 -.phi. H R,S 3-CF.sub.3-.phi.- H,H --CH.sub.3
--CH.sub.3 -.phi. H R,S 4-CH.sub.3-.phi.- H,H --CH.sub.3 --CH.sub.3
-.phi. H R,S 4-CH.sub.3O-.phi.-CH.sub.2-- H,H --CH.sub.3 --CH.sub.3
-.phi. H R,S 3,5-di-F-.phi.- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
3-CH.sub.3-.phi. H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S 3-F-.phi.-
H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S 3-Br-.phi.- H,H --CH.sub.3
--CH.sub.3 -.phi. H R,S 4-Cl-O-.phi.- H,H --CH.sub.3 --CH.sub.3
-.phi. H R,S 2-naphthyl H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
3-CH.sub.3-.phi.-O-- H,H --CH.sub.3 --CH.sub.3 -.phi. H R,S
[1326]
21TABLE 8C-2 51 R.sup.2 = 1 position; R.sup.3 = 5 position; R.sup.4
= 7 position Iso. R X/X' R.sup.1 R.sup.2 R.sup.3 R.sup.4 (at *)
2-thienyl H,H --CH.sub.3 2,2-di-CH.sub.3- 2,2-di- H R,S propyl
CH.sub.3-propyl 3,5-di-F-.phi.- H,H --CH.sub.3 2,2-di-CH.sub.3-
2,2-di- H R,S propyl CH.sub.3-propyl 3-F-.phi.- H,H --CH.sub.3
2,2-di-CH.sub.3- 2,2-di- H R,S propyl CH.sub.3-propyl CH.sub.3S--
H,H --CH.sub.3 2,2-di-CH.sub.3- 2,2-di- H R,S propyl
CH.sub.3-propyl .phi.- H,H --CH.sub.3 2,2-di-CH.sub.3- 2,2-di- H
R,S propyl CH.sub.3-propyl .phi.- .dbd.O --CH.sub.3
2,2-di-CH.sub.3- 2,2-di- H R,S propyl CH.sub.3-propyl
CH.sub.3CH.sub.2-- H,H --CH.sub.3 2,2-di-CH.sub.3- 2,2-di- H R,S
propyl CH.sub.3-propyl 2-thienyl--CH.sub.3CH.sub.2-- H,H --CH.sub.3
2,2-di-CH.sub.3- 2,2-di- H R,S propyl CH.sub.3-propyl cyclopentyl
H,H --CH.sub.3 2,2-di-CH.sub.3- 2,2-di- H R,S propyl
CH.sub.3-propyl 52 H,H --CH.sub.3 2,2-di-CH.sub.3- propyl 2,2-di-
CH.sub.3-propyl H R,S CF.sub.3CH.sub.2-- H,H --CH.sub.3
2,2-di-CH.sub.3- 2,2-di- H R,S propyl CH.sub.3-propyl
(CH.sub.3).sub.2CH-- H,H --CH.sub.3 2,2-di-CH.sub.3- 2,2-di- H R,S
propyl CH.sub.3-propyl (CH.sub.3).sub.2CHCH.sub.3-- OH,H --CH.sub.3
2,2-di-CH.sub.3- 2,2-di- H R,S propyl CH.sub.3-propyl .phi.- OH,H
--CH.sub.3 2,2-di-CH.sub.3- 2,2-di- H R,S propyl
CH.sub.3-propyl
[1327] Also included within the scope of this invention are
prodrugs of the compounds of formula I above including acylated
forms of alcohols and thiols, aminals of one or more amines, and
the like.
DETAILED DESCRIPTION OF THE INVENTION
[1328] As above, this invention relates to compounds which inhibit
.beta.-amyloid peptide release and/or its synthesis, and,
accordingly, have utility in treating Alzheimer's disease. However,
prior to describing this invention in further detail, the following
terms will first be defined.
Definitions
[1329] The term ".beta.-amyloid peptide" refers to a 3943 amino
acid peptide having a molecular weight of about 4.2 kD, which
peptide is substantially homologous to the form of the protein
described by Glenner, et al..sup.1 including mutations and
post-translational modifications of the normal .beta.-amyloid
peptide. In whatever form, the .beta.-amyloid peptide is an
approximate 39-43 amino acid fragment of a large membrane-spanning
glycoprotein, referred to as the .beta.-amyloid precursor protein
(APP). Its 43-amino acid sequence is:
22 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln
Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31
Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr (SEQ ID NO:
1)
[1330] or a sequence which is substantially homologous thereto.
"Alkyl" refers to monovalent alkyl groups preferably having from 1
to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This
term is exemplified by groups such as methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.
[1331] "Substituted alkyl" refers to an alkyl group, preferably of
from 1 to 10 carbon atoms, having from 1 to 5 substituents, and
preferably 1 to 3 substituents, selected from the group consisting
of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl,
carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl,
aryloxy, heteroaryl, heteroaryloxy, heterocyclic, hydroxyamino,
alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl,
-SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl,
--SO.sub.2-aryl, -SO.sub.2-heteroaryl, and mono- and di-alkylamino,
mono- and di-(substituted alkyl)amino, mono- and di-arylamino,
mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and
unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocyclic.
[1332] "Alkylene" refers to divalent alkylene groups preferably
having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon
atoms. This term is exemplified by groups such as methylene
(--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--), the propylene
isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2--) and the like.
[1333] "Substituted alkylene" refers to an alkylene group,
preferably of from 1 to 10 carbon atoms, having from 1 to 3
substituents selected from the group consisting of alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl,
aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl,
thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl,
heterocyclic, nitro, and mono- and di-alkylamino, mono- and
di-(substituted alkyl)amino, mono- and di-arylamino, mono- and
di-heteroarylamino, mono- and di-heterocyclic amino, and
unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocyclic. Additionally, such substituted alkylene groups
include those where 2 substituents on the alkylene group are fused
to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl
groups fused to the alkylene group. Preferably such fused
cycloalkyl groups contain from 1 to 3 fused ring structures.
[1334] "Alkenylene" refers to divalent alkenylene groups preferably
having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon
atoms. This term is exemplified by groups such as ethenylene
(--CH.dbd.CH--), the propenylene isomers (e.g.,
--CH.sub.2CH.dbd.CH-- and --C(CH.sub.3).dbd.CH--) and the like.
[1335] "Substituted alkenylene" refers to an alkenylene group,
preferably of from 2 to 10 carbon atoms, having from 1 to 3
substituents selected from the group consisting of alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl,
aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl,
thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl,
heterocyclic, nitro, and mono- and di-alkylamino, mono- and
di-(substituted alkyl)amino, mono- and di-arylamino, mono- and
di-heteroarylamino, mono- and di-heterocyclic amino, and
unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocyclic. Additionally, such substituted alkylene groups
include those where 2 substituents on the alkylene group are fused
to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl
groups fused to the alkylene group.
[1336] "Alkaryl" refers to -alkylene-aryl groups preferably having
from 1 to 8 carbon atoms in the alkylene moiety and from 6 to 10
carbon atoms in the aryl moiety. Such alkaryl groups are
exemplified by benzyl, phenethyl and the like.
[1337] "Alkoxy" refers to the group "alkyl-O--". Preferred alkoxy
groups include, by way of example, methoxy, ethoxy, n-propoxy,
iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,
n-hexoxy, 1,2-dimethylbutoxy, and the like.
[1338] "Substituted alkoxy" refers to the group "substituted
alkyl-O--" where substituted alkyl is as defined above.
[1339] "Alkylalkoxy" refers to the group "-alkylene-O-alkyl" which
includes by way of example, methylenemethoxy (--CH.sub.2OCH.sub.3),
ethylenemethoxy (--CH.sub.2CH.sub.2OCH.sub.3),
n-propylene-iso-propoxy
(--CH.sub.2CH.sub.2CH.sub.2OCH(CH.sub.3).sub.2), methylene-t-butoxy
(--CH.sub.2--O--C(CH.sub.3).sub.3) and the like.
[1340] "Alkylthioalkoxy" refers to the group "-alkylene-5-alkyl"
which includes by way of example, methylenethiomethoxy
(--CH.sub.2SCH.sub.3), ethylenethiomethoxy
(--CH.sub.2CH.sub.2SCH.sub.3), n-propylene-thio-iso-propoxy
(--CH.sub.2CH.sub.2CH.sub.2SCH(CH.sub.3).sub- .2),
methylenethio-t-butoxy (--CH.sub.2SC(CH.sub.3).sub.3) and the
like.
[1341] "Alkenyl" refers to alkenyl groups preferably having from 2
to 10 carbon atoms and more preferably 2 to 6 carbon atoms and
having at least 1 and preferably from 1-2 sites of alkenyl
unsaturation. Preferred alkenyl groups include ethenyl
(--CH.dbd.CH.sub.2), n-propenyl (--CH.sub.2CH.dbd.CH.sub.2),
iso-propenyl (--C(CH.sub.3).dbd.CH.sub.2), and the like.
[1342] "Substituted alkenyl" refers to an alkenyl group as defined
above having from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy,
amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl,
carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl,
heteroaryl, heterocyclic, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl,
--SO.sub.2-heteroaryl, and mono- and di-alkylamino, mono- and
di-(substituted alkyl)amino, mono- and di-arylamino, mono- and
di-heteroarylamino, mono- and di-heterocyclic amino, and
unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocyclic.
[1343] "Alkynyl" refers to alkynyl groups preferably having from 2
to 10 carbon atoms and more preferably 2 to 6 carbon atoms and
having at least 1 and preferably from 1-2 sites of alkynyl
unsaturation. Preferred alkynyl groups include ethynyl
(--CH.ident.CH.sub.2), propargyl (--CH.sub.2C.ident.--CH) and the
like.
[1344] "Substituted alkynyl" refers to an alkynyl group as defined
above having from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy,
amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl,
carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl,
heteroaryl, heterocyclic, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl,
--SO.sub.2-heteroaryl, and mono- and di-alkylamino, mono- and
di-(substituted alkyl)amino, mono- and di-arylamino, mono- and
di-heteroarylamino, mono- and di-heterocyclic amino, and
unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocyclic.
[1345] "Acyl" refers to the groups alkyl-C(O)--, substituted
alkyl-C(O)--, cycloalkyl-C(O)--, substituted cycloalkyl-C(O)--,
aryl-C(O)--, heteroaryl-C(O)-- and heterocyclic-C(O)-- where alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
heteroaryl and heterocyclic are as defined herein.
[1346] "Acylamino" refers to the group --C(O)NRR where each R is
independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,
or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl
and heterocyclic are as defined herein.
[1347] "Aminoacyl" refers to the group --NRC(O)R where each R is
independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,
or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl
and heterocyclic are as defined herein.
[1348] "Aminoacyloxy" refers to the group --NRC(O)OR where each R
is independently hydrogen, alkyl, substituted alkyl, aryl,
heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl,
heteroaryl and heterocyclic are as defined herein.
[1349] "Acyloxy" refers to the groups alkyl-C(O)O--, substituted
alkyl-C(O)O--, cycloalkyl-C(O)O--, aryl-C(O)O--,
heteroaryl-C(O)O--, and heterocyclic-C(O)O-- wherein alkyl,
substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic
are as defined herein.
[1350] "Aryl" refers to an unsaturated aromatic carbocyclic group
of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or
multiple condensed (fused) rings (e.g., naphthyl or anthryl).
Preferred aryls include phenyl, naphthyl and the like.
[1351] Unless otherwise constrained by the definition for the aryl
substituent, such aryl groups can optionally be substituted with
from 1 to 5 substituents selected from the group consisting of
acyloxy, 1 to 5 and preferably 1 to 3 substituents selected from
the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl,
alkynyl, substituted alkyl, substituted alkoxy, substituted
alkenyl, substituted alkynyl, amino, aminoacyl, acylamino, alkaryl,
aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro,
heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy,
substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl,
--SO.sub.2-heteroaryl, trihalomethyl, mono- and di-alkylamino,
mono- and di-(substituted alkyl)amino, mono- and di-arylamino,
mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and
unsymmetric di-substituted amines having different substituents
selected from alkyl, substituted alkyl, aryl, heteroaryl and
heterocyclic, and the like. Preferred substituents include alkyl,
alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
[1352] "Aryloxy" refers to the group aryl-O-- wherein the aryl
group is as defined above including optionally substituted aryl
groups as also defined above.
[1353] "Carboxyalkyl" refers to the group "--C(O)Oalkyl" where
alkyl is as defined above.
[1354] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 12
carbon atoms having a single cyclic ring or multiple condensed
rings. Such cycloalkyl groups include, by way of example, single
ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclooctyl, and the like, or multiple ring structures such as
adamantanyl, and the like.
[1355] "Substituted cycloalkyl" refers to cycloalkyl groups having
from 1 to 5 (preferably 1 to 3) substituents selected from the
group consisting of hydroxy, acyl, acyloxy, alkyl, substituted
alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl,
aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
[1356] "Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to
8 carbon atoms having a single cyclic ring and at least one point
of internal unsaturation. Examples of suitable cycloalkenyl groups
include, for instance, cyclobut-2-enyl, cyclopent-3-enyl,
cyclooct-3-enyl and the like.
[1357] "Substituted cycloalkenyl" refers to cycloalkenyl groups
having from 1 to 5 substituents selected from the group consisting
of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy,
carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
[1358] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo
and preferably is either fluoro or chloro.
[1359] "Heteroaryl" refers to an aromatic carbocyclic group of from
1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen,
nitrogen and sulfur within at least one ring (if there is more than
one ring).
[1360] Unless otherwise constrained by the definition for the
heteroaryl substituent, such heteroaryl groups can be optionally
substituted with 1 to 5 substituents selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy,
substituted thioalkoxy, thioaryloxy, trihalomethyl and the like.
Such heteroaryl groups can have a single ring (e.g., pyridyl or
furyl) or multiple condensed rings (e.g., indolizinyl or
benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and
furyl.
[1361] "Heterocycle" or "heterocyclic" refers to a monovalent
saturated or unsaturated group having a single ring or multiple
condensed rings, from 1 to 15 carbon atoms and from 1 to 4 hetero
atoms selected from nitrogen, sulfur or oxygen within the ring.
[1362] Unless otherwise constrained by the definition for the
heterocyclic substituent, such heterocyclic groups can be
optionally substituted with 1 to 5 substituents selected from the
group consisting of alkyl, substituted alkyl, alkoxy, substituted
alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy,
substituted thioalkoxy, thioaryloxy, trihalomethyl, and the like.
Such heterocyclic groups can have a single ring or multiple
condensed rings. Preferred heterocyclics include morpholino,
piperidinyl, and the like.
[1363] Examples of nitrogen heterocycles and heteroaryls include,
but are not limited to, pyrrole, imidazole, pyrazole, pyridine,
pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,
indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline,
pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,
phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,
indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like
as well as N-alkoxy-nitrogen containing heterocycles.
[1364] "Oxyacylamino" refers to the group --OC(O)NRR where each R
is independently hydrogen, alkyl, substituted alkyl, aryl,
heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl,
heteroaryl and heterocyclic are as defined herein.
[1365] "Thiol" refers to the group --SH.
[1366] "Thioalkoxy" refers to the group --S-alkyl.
[1367] "Substituted thioalkoxy" refers to the group -S-substituted
alkyl.
[1368] "Thioaryloxy" refers to the group aryl-S-- wherein the aryl
group is as defined above including optionally substituted aryl
groups also defined above.
[1369] "Thioheteroaryloxy" refers to the group heteroaryl-S--
wherein the heteroaryl group is as defined above including
optionally substituted aryl groups as also defined above.
[1370] As to any of the above groups which contain 1 or more
substituents, it is understood, of course, that such groups do not
contain any substitution or substitution patterns which are
sterically impractical and/or synthetically non-feasible.
[1371] "Pharmaceutically acceptable salt" refers to
pharmaceutically acceptable salts of a compound of Formula I which
salts are derived from a variety of organic and inorganic counter
ions well known in the art and include, by way of example only,
sodium, potassium, calcium, magnesium, ammonium,
tetraalkylammonium, and the like; and when the molecule contains a
basic functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,
oxalate and the like can be used as the pharmaceutically acceptable
salt.
[1372] The term "protecting group" or "blocking group" refers to
any group which when bound to one or more hydroxyl, amino or
carboxyl groups of the compounds (including intermediates thereof
such as the aminolactams, aminolactones, etc.) prevents reactions
from occurring at these groups and which protecting group can be
removed by conventional chemical or enzymatic steps to reestablish
the hydroxyl, amino or carboxyl group. The particular removable
blocking group employed is not critical and preferred removable
hydroxyl blocking groups include conventional substituents such as
allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine,
phenacyl, t-butyl-diphenylsilyl and any other group that can be
introduced chemically onto a hydroxyl functionality and later
selectively removed either by chemical or enzymatic methods in mild
conditions compatible with the nature of the product.
[1373] Preferred removable amino blocking groups include
conventional substituents such as t-butyoxycarbonyl (t-BOC),
benzyloxycarbonyl (CBZ), and the like which can be removed by
conventional conditions compatible with the nature of the
product.
[1374] Preferred carboxyl protecting groups include esters such as
methyl, ethyl, propyl, t-butyl etc. which can be removed by mild
hydrolysis conditions compatible with the nature of the
product.
Compound Preparation
[1375] When n is one or two, the compounds of formula I are readily
prepared by conventional amidation of a carboxyl acid as shown in
reaction (1) below where, for the sake of illustration, n is one:
53
[1376] wherein R.sup.1, R.sup.2, W, X, Z and m are as defined
above. The reaction is conventionally conducted by using at least a
stoichiometric amount of carboxylic acid 1 and amine 2. This
reaction is conventionally conducted for peptide synthesis and
synthetic methods used therein can also be employed to prepare
compound 3 which is a compound of formula I above. For example,
well known coupling reagents such as carbodiimides with or without
the use of well known additives such as N-hydroxysuccinimide,
1-hydroxybenzotriazole, etc. can be used to facilitate coupling.
The reaction is conventionally conducted in an inert aprotic polar
diluent such as dimethylformamide, dichloromethane, chloroform,
acetonitrile, tetrahydrofuran and the like. Alternatively, the acid
halide of compound 1 can be employed in reaction (1) and, when so
employed, it is typically employed in the presence of a suitable
base to scavenge the acid generated during the reaction. Suitable
bases include, by way of example, triethylamine,
diisopropylethylamine, N-methylmorpholine and the like.
[1377] When n is zero, the compounds of formula I can be prepared
by N-substitution reactions of compound 2. For example, when m=0
and n=0, N-arylation reactions on compound 2 lead to compounds of
formula I. When m=1 and n=0, ) reaction of compound 2 with an
acetic acid derivative represented by the formula
R.sup.1--T--CH.sub.2--COOH also lead to compounds of formula I.
Both reactions are described below.
Synthesis of Carboxylic Acid Starting Materials
[1378] Carboxylic acids 1 can be prepared by several divergent
synthetic routes with the particular route selected relative to the
ease of compound preparation, commercial availability of starting
materials, whether m is zero or one, whether n is one or two,
etc.
[1379] A. Synthesis of Carboxylic Acids
[1380] When m is zero and n is one, a first synthetic method
involves the introduction of the R.sup.1 group to the amino acid
NH.sub.2CH(R.sup.2)COOH or ester thereof.
[1381] The introduction of the R.sup.1 group onto the amino acid
NH.sub.2CH(R.sup.2)COOH or ester thereof can be accomplished in
several methods. For example, conventional coupling of a halo
acetic acid with a primary amine forms an amino acid as shown in
reaction (2) below: 54
[1382] wherein R.sup.1 and R.sup.2 are as defined above and Z' is a
halo group such as chloro or bromo. Alternatively, leaving groups
other than halo may be employed such as triflate and the like.
Additionally, suitable esters of 4 may be employed in this
reaction.
[1383] As above, reaction (2) involves coupling of a suitable
haloacetic acid derivative 4 with a primary amine 5 under
conditions which provide for amino acid 6. This reaction is
described by, for example, Yates, et al..sup.14 and proceeds by
combining approximately stoichiometric equivalents of haloacetic
acid 4 with primary amine 5 in a suitable inert diluent such as
water, dimethylsulfoxide (DMSO) and the like. The reaction employs
an excess of a suitable base such as sodium bicarbonate, sodium
hydroxide, etc. to scavenge the acid generated by the reaction. The
reaction is preferably conducted at from about 25.degree. C. to
about 100.degree. C. until reaction completion which typically
occurs within 1 to about 24 hours. This reaction is further
described in U.S. Pat. No. 3,598,859, which is incorporated herein
by reference in its entirety. Upon reaction completion,
N-substituted amino acid 6 is recovered by conventional methods
including precipitation, chromatography, filtration and the
like.
[1384] In reaction (2), each of the reagents (haloacetic acid 4,
primary amine 5 and alcohol 6 are well known in the art with a
plurality of each being commercially available.
[1385] In an alternative embodiment, the R.sup.1 group can be
coupled to an alanine ester (or other suitable amino acid ester) by
conventional N-arylation. For example, a stoichiometric equivalent
or slight excess of the amino acid ester can be dissolved in a
suitable diluent such as DMSO and coupled with a halo-R.sup.1
compound, Z'--R.sup.1 where Z' is a halo group such as chloro or
bromo and R.sup.1 is as defined above. The reaction is conducted in
the presence of an excess of base such as sodium hydroxide to
scavenge the acid generated by the reaction. The reaction typically
proceeds at from 15.degree. C. to about 250.degree. C. and is
complete in about 1 to 24 hours. Upon reaction completion,
N-substituted amino acid ester is recovered by conventional methods
including chromatography, filtration and the like. This ester is
then hydrolyzed by conventional methods to provide for carboxylic
acid 1 for use in reaction (1).
[1386] In still another alternative embodiment, the esterified
amino acids of formula I above can be prepared by reductive
amination of a suitable pyruvate ester in the manner illustrated in
reaction (3) below: 55
[1387] wherein R is typically an alkyl group and R.sup.1 and
R.sup.2 are as defined above.
[1388] In reaction (3), approximately stoichiometric equivalents of
pyruvate ester 7 and amine 5 are combined in an inert diluent such
as methanol, ethanol and the like and the reaction solution treated
under conditions which provide for imine formation (not shown). The
imine formed is then reduced under conventional conditions by a
suitable reducing agent such as sodium cyanoborohydride,
H.sub.2/palladium on carbon and the like to form the /N-substituted
amino acid ester 8. In a particularly preferred embodiment, the
reducing agent is H.sub.2/palladium on carbon which is incorporated
into the initial reaction medium which permits imine reduction in
situ in a one pot procedure to provide for the N-substituted amino
acid ester {fraction (8)}.
[1389] The reaction is preferably conducted at from about
20.degree. C. to about 80.degree. C. at a pressure of from 1 to 10
atmospheres until reaction completion which typically occurs within
1 to about 24 hours. Upon reaction completion, N-substituted amino
acid ester 8 is recovered by conventional methods including
chromatography, filtration and the like.
[1390] Subsequent hydrolysis of the ester 8 leads to the
corresponding carboxylic acid derivative 1 which can be employed in
reaction (1) above.
[1391] For compounds where m is zero and n is two, conventional
coupling of a second amino acid (e.g., NH.sub.2CH(R.sup.2)C(O)OR
where R is typically an alkyl group) to the amino acid produced
above (i.e., R.sup.1NHCH(R.sup.2)COOH) provides for esters of an
analogue of carboxylic acid 1 which are then conventionally
de-esterified to provide for an analogue of compound 1.
[1392] Alternatively, an ester such as
H.sub.2NCH(R.sup.2)C(O)NHCH(R.sup.2- )COOR where each R.sup.2 is
independently as defined above and R is typically an alkyl group
can first be formed by conventional peptide synthetic procedures,
N-substitution can be conducted in the manner described above
followed by de-esterification to provide for analogues of
carboxylic acids 1 where n is two.
[1393] When m is one and n is one, a first synthetic method
involves conventional coupling of an acetic acid derivative with a
primary amine of an esterified amino acid as shown in reaction (4)
below: 56
[1394] wherein R is typically an alkyl group and R.sup.1, R.sup.2,
X' and X" are as defined above.
[1395] Reaction (4) merely involves coupling of a suitable acetic
acid derivative 9 with the primary amine of amino acid ester 10
under conditions which provide for the N-acetyl derivative 11. This
reaction is conventionally conducted for peptide synthesis and
synthetic methods used therein can also be employed to prepare the
N-acetyl amino acid esters 11 of this invention. For example, well
known coupling reagents such as carbodiimides with or without the
use of well known additives such as N-hydroxysuccinimide,
1-hydroxybenzotriazole, etc. can be used to facilitate coupling.
The reaction is conventionally conducted in an inert aprotic polar
diluent such as dimethylformamide, dichloromethane, chloroform,
acetonitrile, tetrahydrofuran and the like. Alternatively, the acid
halide of compound 9 can be employed in reaction (4) and, when so
employed, it is typically employed in the presence of a suitable
base to scavenge the acid generated during the reaction. Suitable
bases include, by way of example, triethylamine,
diisopropylethylamine, N-methylmorpholine and the like.
[1396] Reaction (4) is preferably conducted at from about 0.degree.
C. to about 60.degree. C. until reaction completion which typically
occurs within 1 to about 24 hours. Upon reaction completion,
N-acetyl amino acid ester 11 is recovered by conventional methods
including precipitation, chromatography, filtration and the like or
alternatively is hydrolyzed to the corresponding acid without
purification and/or isolation other than conventional work-up
(e.g., aqueous extraction, etc.).
[1397] In reaction (4), each of the reagents (acetic acid
derivative 9 and amino acid ester 10) are well known in the art
with a plurality of each being commercially available.
[1398] When m is one and n is two, a further amino acid ester is
coupled to the amino acid ester 11 by first de-esterifying 11 and
then using well known peptide coupling chemistry with well known
coupling reagents such as carbodiimides with or without the use of
well known additives such as N-hydroxysuccinimide,
1-hydroxybenzotriazole, etc. which can be used to facilitate
coupling. The reaction is conventionally conducted in an inert
aprotic polar diluent such as dimethylfornamide, dichloromethane,
chloroform, acetonitrile, tetrahydrofuran and the like.
De-esterification of the resulting ester provides for carboxylic
acids 1 having n equal to 2.
[1399] Alternatively, carboxylic acids 1 having n equal to 2 can be
prepared by first forming the ester, N-acetylating these esters and
then de-esterifying the resulting product.
[1400] Carboxylic acids 1 having m equal to 1 and n equal to 1 or 2
can also be prepared by use of polymer supported forms of
carbodiimide peptide coupling reagents. A polymer supported form of
EDC, for example, has been described (Tetrahedron Letters, 34(48),
7685 (1993)).sup.10. Additionally, a new carbodiimide coupling
reagent, PEPC, and its corresponding polymer supported forms have
been discovered and are very useful for the preparation of such
compounds.
[1401] Polymers suitable for use in making a polymer supported
coupling reagent are either commercially available or may be
prepared by methods well known to the artisan skilled in the
polymer arts. A suitable polymer must possess pendant sidechains
bearing moieties reactive with the terminal amine of the
carbodiimide. Such reactive moieties include chloro, bromo, iodo
and methanesulfonyl. Preferably, the reactive moiety is a
chloromethyl group. Additionally, the polymer's backbone must be
inert to both the carbodiimide and reaction conditions under which
the ultimate polymer bound coupling reagents will be used.
[1402] Certain hydroxymethylated resins may be converted into
chloromethylated resins useful for the preparation of polymer
supported coupling reagents. Examples of these hydroxylated resins
include the 4-hydroxymethylphenylacetamidomethyl resin (Pam Resin)
and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from
Advanced Chemtech of Louisville, Ky., USA (see Advanced Chemtech
1993-1994 catalog, page 115). The hydroxymethyl groups of these
resins may be converted into the desired chloromethyl groups by any
of a number of methods well known to the skilled artisan.
[1403] Preferred resins are the chloromethylated
styrene/divinylbenzene resins because of their ready commercial
availability. As the name suggests, these resins are already
chloromethylated and require no chemical modification prior to use.
These resins are commercially known as Merrifield's resins and are
available from Aldrich Chemical Company of Milwaukee, Wis., USA
(see Aldrich 1994-1995 catalog, page 899). Methods for the
preparation of PEPC and its polymer supported forms are outlined in
the following scheme. 57
[1404] Such methods are described more fully in U.S. patent
application Ser. No. 60/019,790 filed Jun. 14, 1996 which
application is incorporated herein by reference in its entirety.
Briefly, PEPC is prepared by first reacting ethyl isocyanate with
1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with
4-toluenesulfonyl chloride to provide PEPC. The polymer supported
form is prepared by reaction of PEPC with an appropriate resin
under standard conditions to give the desired reagent.
[1405] The carboxylic acid coupling reactions employing these
reagents are performed at about ambient to about 45.degree. C., for
from about 3 to 120 hours. Typically, the product may be isolated
by washing the reaction with CHCl.sub.3 and concentrating the
remaining organics under reduced pressure. As discussed supra,
isolation of products from reactions where a polymer bound reagent
has been used is greatly simplified, requiring only filtration of
the reaction mixture and then concentration of the filtrate under
reduced pressure.
Preparation of Cyclic Amino Compounds
[1406] Cyclic amino compounds 2 employed in reaction (1) above are
generally aminolactams, aminolactones, aminothiolactones and
aminocycloalkyl compounds which can be represented by the formula:
58
[1407] where X is as defined above, Q is preferably selected from
the group consisting of --O--, --S--, >NR.sup.6, and
>CR.sup.7R.sup.8 where each of R.sup.6, R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, heteroaryl and heterocyclic with the
proviso that if Q is --O--, --S-- or >NR.sup.6, then X is oxo or
dihydro, and W" together with Q, C.dbd.X and CH forms a lactone,
thiolactone, lactam, cyclic ketone, cyclic alcohol, a heterocycle,
and the like.
[1408] The aminolactams, aminolactones and aminothiolactones of the
formula above can be prepared by use or adaptation of known
chemical syntheses which syntheses are well described in the
literature. See, e.g., Ogliaruso and Wolfe, Synthesis of Lactones
and Lactams, Patai, et al. Editor, J. Wiley & Sons, New York,
N.Y., USA, pp. 1085 et seq. (1993).sup.15.
[1409] Specifically, 3-amino substituted lactams 13 with 5, 6 or 7
ring atoms may be prepared by the direct cyclization of a suitable
alpha, omega-diamino acid ester 12 as shown in reaction (5) below:
59
[1410] wherein L is a linking group (typically an alkylene group)
of from 24 atoms, Pr is a suitable protecting group such as
t-butoxycarbonyl, carbobenzyloxy, or the like and R.sup.9 is an
alkoxy or aryloxy group such as methoxy, ethoxy, p-nitrophenoxy,
N-succinimidoxy, and the like. The reaction may be carried out in a
solvent such as water, methanol, ethanol, pyridine, and the like.
Such reactions are exemplified by cyclization of a lysine ester to
a caprolactam as described by Ugi, et al., Tetrahedron,
52(35):11657-11664 (1996).sup.16. Alternatively, such a cyclization
can also be conducted in the presence of dehydrating agents such as
alumina or silica to form lactams as described by Blade-Font,
Tetrahedron Lett., 21:2443 (1980).sup.17.
[1411] The preparation of aminolactams alkylated on the amino group
of the cyclic lactam is described by Freidinger, et al., J. Org.
Chem., 47:104-109 (1982).sup.18 and illustrated in reaction (6)
below: 60
[1412] wherein L and R.sup.6 are as defined above.
[1413] In reaction (6), reductive amination of 14 with aldehyde 15
and subsequent ring closure by methods using, for example, EDC
provides for aminolactam 16. The preparation of 6 membered lactams
using this general procedure is described by Semple, et al., J.
Med. Chem., 39:4531-4536 (1996).sup.19.
[1414] The internal cyclization of an amide anion with a halide or
equivalent thereof can sometimes be used to particular advantage in
the synthesis of smaller ring lactams where the stereochemistry of
the amino-lactam center is available from the standard amino-acid
pool. This approach is illustrated in reaction (7) below: 61
[1415] where R.sup.6 is as defined above.
[1416] The approach of reaction (7) is presented by Semple, et al.,
supra..sup.19, and Freidinger, et al., J. Org. Chem., 47:104-109
(1982).sup.18 where a dimethylsulfonium leaving group is generated
from methyl iodide treatment of an alkyl methyl sulfide 17 to
provide for lactam 18. A similar approach using a Mitsunobu
reaction on an omega alcohol is found Holladay, et al., J. Org.
Chem., 56:3900-3905 (1991).sup.20.
[1417] In another method, lactams 20 can be prepared from cyclic
ketones 19 using either the well known Beckmnann rearrangement
(e.g., Donaruma, et al., Organic Reactions, 11:1-156 (1960)).sup.21
or the well known Schmidt reaction (Wolff, Organic Reactions,
3:307-336 (1946)).sup.22 as shown in reaction (8) below: 62
[1418] wherein L is as defined above.
[1419] Application of these two reactions leads to a wide variety
of lactams especially lactams having two hydrogen atoms on the
carbon alpha to the lactam carbonyl which lactams form a preferred
group of lactams in the synthesis of the compounds of formula I
above. In these reactions, the L group can be highly variable
including, for example, alkylene, substituted alkylene and hetero
containing alkylene with the proviso that a heteroatom is not
adjacent to the carbonyl group of compound 19. Additionally, the
Beckmann rearrangement can be applied to bicyclic ketones as
described in Krow, et al., J. Org. Chem., 61:5574-5580
(1996).sup.23.
[1420] The preparation of lactones can be similarly conducted using
peracids in a Baeyer-Villiger reaction on ketones. Alternatively,
thiolactones can be prepared by cyclization of an omega -SH group
to a carboxylic acid and thiolactams can be prepared by conversion
of the oxo group to the thiooxo group by P.sub.2S.sub.5 or by use
of the commercially available Lawesson's Reagent, Tetrahedron,
35:2433 (1979).sup.24.
[1421] One recently reported route for lactam synthesis is a
variation of the Schmidt reaction through the use of an alkyl
azide, either intermolecularly or intramolecularly, through a
tethered alkylazide function that attacks a ketone under acidic
conditions. Gracias, et al., J. Am. Chem. Soc., 117:8047-8048
(1995).sup.25 describes the intermolecular version whereas
Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995).sup.26
describes the intramolecular version. One example of the
intramolecular version is illustrated in reaction (9) below: 63
[1422] where R.sup.10 is exemplified by alkyl, substituted alkyl,
alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and
heterocyclic.
[1423] In this reaction, ketone 21 is converted to an
.alpha.-(.omega.-alkyl)ketone 22 which is cyclized to form bicyclic
lactam 23. Such intramolecular reactions are useful in forming
bicyclic lactams having 5-7 members and the lactam ring of 6-13
members. The use of hetero atoms at non-reactive sites in these
rings is feasible in preparing heterobicyclic lactams.
[1424] Still another recent approach to the synthesis of lactams is
described by Miller, et al., J. Am. Chem. Soc., 118:9606-9614
(1996).sup.27 and references cited and is illustrated in reaction
(10) below: 64
[1425] where R.sup.6 and Pr are as defined above and R.sup.11 is
exemplified by halo, alkyl, substituted alkyl, alkoxy, substituted
alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic wherein the
aryl, heteroaryl, cycloalkyl and heterocyclic group is optionally
fused to the lactam ring structure.
[1426] Specifically, in reaction (10), lactam 26 is formed from an
appropriate unsaturated amide (e.g., 24) through a ruthenium or
molybdenum complexes catalyzed olefin metathesis reaction to form
unsaturated lactam 25 which can be used herein without further
modification. However, the unsaturation in 25 permits a myriad of
techniques such a s hydroboration, Sharpless or Jacobsen
epoxidations, Sharpless dihydroxylations, Diels-Alder additions,
dipolar cycloaddition reactions and many more chemistries to
provide for a wide range of substituents on the lactam ring.
Moreover, subsequent transformations of the formed substitution
leads to other additional substituents (e.g., mesylation of an
alcohol followed by nucleophilic substitution reactions). See, for
example, March, et al. for a recitation of numerous such possible
reactions..sup.28 Saturated amides used in this reaction are
conventional with amide 24 being commercially available.
[1427] Related chemistry to cyclize amides to form lactams is
disclosed by Colombo, et al., Tetrahedron Lett., 35(23):4031-4034
(1994).sup.29 and is illustrated in reaction (11) below: 65
[1428] In this reaction, proline derivative 27 is cyclized via a
tributyltin-radical cyclization to provide for lactam 28.
[1429] Some of the lactams described above contain the requisite
amino group alpha to the lactam carbonyl whereas others did not.
However, the introduction of the required amino group can be
achieved by any of several routes delineated below which merely
catalogue several recent literature references for this
synthesis.
[1430] For example, in a first general synthetic procedure, azide
or amine displacement of a leaving group alpha to the carbonyl
group of the lactam leads to the alpha-aminolactams. Such general
synthetic procedures are exemplified by the introduction of a
halogen atom followed by displacement with phthalimide anion or
azide and subsequent conversion to the amine typically by
hydrogenation for the azide as described in Rogriguez, et al.,
Tetrahedron, 52:7727-7736 (1996).sup.30, Parsons, et al., Biochem.
Biophys. Res. Comm., 117:108-113 (1983).sup.31 and Watthey, et al.,
J. Med. Chem., 28:1511-1516 (1985).sup.32. One particular method
involves iodination and azide displacement on, for example,
benzyllactams as described by Armstrong, et al., Tetrahedron Lett.,
35:3239 (1994).sup.33 and by King, et al., J. Org. Chem., 58:3384
(1993).sup.34.
[1431] Another example of this first general procedure for the
synthesis of alpha-aminolactams from the corresponding lactam
involves displacement of a triflate group by an azido group as
described by Hu, et al., Tetrahedron Lett., 36(21):3659-3662
(1995).sup.35.
[1432] Still another example of this first general procedure uses a
Mitsunobu reaction of an alcohol and a nitrogen equivalent (either
--NH.sub.2 or a phthalimido group) in the presence of an
azodicarboxylate and a triarylphosphine as described in Wada, et
al., Bull. Chem. Soc. Japan, 46:2833-2835 (1973).sup.36 using an
open chain reagent.
[1433] Yet another example of this first general procedure involves
reaction of alpha-chlorolactams with anilines or alkyl amines in a
neat mixture at 120.degree. C. to provide for 2-(N-aryl or
N-alkyl)lactams as described by Gaetzi, Chem. Abs.,
66:28690m..sup.37
[1434] In a second general synthetic procedure, reaction of an
enolate with an alkyl nitrite ester to prepare the alpha oxime
followed by reduction yields the alpha-aminolactam compound. This
general synthetic procedure is exemplified by Wheeler, et al.,
Organic Syntheses, Coll. Vol. VI, p. 840.sup.38 which describes the
reaction of isoamyl nitrite with a ketone to prepare the desired
oxime. The reduction of the oxime methyl ester (prepared from the
oxime by reaction with methyl iodide) is described in the J. Med.
Chem., 28(12):1886 (1985).sup.39 and the reduction of alpha-oximino
caprolactams by Raney-nickel and palladium catalysts is described
by Brenner, et al., U.S. Pat. No. 2,938,029..sup.40
[1435] In a third general synthetic procedure, direct reaction of
an enolate with an electrophilic nitrogen transfer agent can be
used. The original reaction employed toluenesulfonyl azide but was
improved as described by Evans, et al., J. Am. Chem. Soc.,
112:4011-4030 (1990).sup.41. Specifically, direct introduction of
an azido group which can be reduced to the amine by hydrogenation
is described by Micouin, et al., Tetrahedron, 52:7719-7726
(1996).sup.42. Likewise, the use of triisopropylbenzenesulfonyl
azide as the azide transferring agent for reaction with an enolate
is described by Evans, et al., supra. The use of triphenylphosphine
to reduce the alpha-azidolactams to the corresponding aminolactams
in the benzodiazepine series is disclosed by Butcher, et al.,
Tetrahedron Lett., 37(37):6685-6688 (1996)..sup.43 Lastly, diazo
transfer of beta-diketones and subsequent reduction of the diazo
group to the amino group is exemplified by Hu, et al., Tetrahedron
Lett., 36(21):3659-3662 (1995).sup.35 who used Raney-nickel and
hydrogen in acetic acid and acetic anhydride as the solvent.
[1436] In a fourth general procedure, N-substituted lactams are
first converted to the 3-alkoxycarbonyl derivatives by reaction
with a dialkyl carbonate and a base such as sodium hydride. See,
for example, M. L. Reupple, et al., J. Am. Chem. Soc., 93:7021 et
seq. (1971).sup.44 The resulting esters serve as starting materials
for conversion to the 3-amino derivatives. This conversion is
achieved via the Curtius reaction as shown in reaction (12) below:
66
[1437] where Pr is as defined above and R.sup.12 is typically
hydrogen, an alkyl or an aryl group.
[1438] The Curtius reaction is described by P. A. S. Smith, Organic
Reactions, 3:337-449 (1946)..sup.45 Depending on the reaction
conditions chosen, Pr.dbd.H or a protecting group such as Boc. For
example, when R.dbd.H, treatment of the acid with
diphenylphosphoryl azide in the presence of t-butanol provides the
product wherein Pr.dbd.Boc.
[1439] The alpha-aminolactams employed as the cyclic amino
compounds 2 in reaction (1) above include ring N-substituted
lactams in addition to ring N--H lactams. Some methods for
preparing ring N-substituted lactams have been described above.
More generally, however, the preparation of these compounds range
from the direct introduction of the substituent after lactam
formation to essentially introduction before lactam formation. The
former methods typically employ a base and an primary alkyl halide
although it is contemplated that a secondary alkyl halide can also
be employed although yields may suffer.
[1440] Accordingly, a first general method for preparing
N-substituted lactams is achieved via reaction of the lactam with
base and alkyl halide (or acrylates in some cases). This reaction
is quite well known and bases such as sodamide, sodium hydride,
LDA, LiHMDS in appropriate solvents such as THF, DMF, etc. are
employed provided that the selected base is compatible with the
solvent. See for example: K. Orito, et al., Tetrahedron,
36:1017-1021 (1980).sup.46 and J. E. Semple, et al., J. Med. Chem.,
39:4531-4536 (1996).sup.19 (use of LiHMDS with either R-X or
acrylates as electrophiles).
[1441] A second general method employs reductive amination on an
amino function which is then cyclized to an appropriate ester or
other carbonyl function.
[1442] A third general method achieves production of the
N-substitution during lactam formation. Literature citations report
such production from either photolytic or thermal rearrangement of
oxaziridines, particularly of N-aryl compounds. See, for example,
Krimm, Chem. Ber., 91:1057 (1958).sup.47 and Suda, et al., J. Chem.
Soc. Chem Comm., 949-950, (1994)..sup.48 Also, the use of methyl
hydroxylamine for the formation of nitrones and their rearrangement
to the N-methyl derivatives is reported by Barton, et al., J. Chem.
Soc., 1764-1767 (1975)..sup.49 Additionally, the use of the
oxaziridine process in chiral synthesis has been reported by
Kitagawa, et al., J. Am. Chem. Soc., 117:5169-5178
(1975)..sup.50
[1443] A more direct route to obtain N-phenyl substituted lactams
from the corresponding NH lactams through the use of
t-butyltetramethylguanidine and triphenylbismuth dichloride is
disclosed by Akhatar, et al., J. Org. Chem., 55:5222-5225
(1990).sup.51 as shown in reaction (13) below. 67
[1444] Given that numerous methods are available to introduce an
alpha-amino group onto a lactam (or lactone) ring, the following
lactams (and appropriate corresponding lactones) are contemplated
for use in the synthesis of compounds of formula I above. Similar
alcohol functions at the carbonyl position are derivative of either
amine ring opening of cyclic epoxides, ring opening of aziridines,
displacement of appropriate halides with amine or alcohol
nucleophiles, or most likely reduction of appropriate ketones.
These ketones are also of interest to the present invention.
[1445] Monocyclic lactams as described by Nedenskov, et al., Acta
Chem. Scand., 12:1405-1410 (1958).sup.52 are represented by the
formula: 68
[1446] where R.sub.1 and R.sub.2 are exemplified by alkyl, aryl or
alkenyl (e.g., allyl).
[1447] Monocyclic lactams containing a second nitrogen ring atom as
described by Sakakida, et al., Bull. Chem. Soc. Japan, 44:478-480
(1971).sup.53 are represented by the formula: 69
[1448] where R is exemplified by CH.sub.3-- or PhCH.sub.2--.
[1449] Monocyclic lactams having hydroxyl substitution on the ring
as described by Hu, et al., Tetrahedron Lett., 36(21):3659-3662
(1995).sup.35 are represented by the formula: 70
[1450] where R is exemplified by benzyl (includes both the cis and
trans hydroxy lactams).
[1451] The direct preparation N-substituted lactams of 5-8 members
from the corresponding ketones is described by Hoffman, et al.,
Tet. Lett., 30:4207-4210 (1989)..sup.54 These lactams are
represented by the formula: 71
[1452] wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or
benzyl.
[1453] N-Methoxylactams prepared from cyclohexanone and
dimethoxyamine are described by Vedejs, et al., Tet. Lett.,
33:3261-3264 (1992)..sup.55 These structures are represented by the
formula: 72
[1454] Substituted 3-aminoazetidinone derivatives prepared by a
variety of routes including those described by van der Steen, et
al., Tetrahedron, 47, 7503-7524 (1991).sup.56, Hart, et al., Chem
Rev., 89:1447-1465 (1989).sup.57 and references cited therein are
represented by the formula: 73
[1455] where R.sub.1 and R.sub.2 are independently selected from
alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl,
heteroaryl, heterocyclic or are fused to form a cyclic group.
[1456] Ring substituted lactams are described by Lowe, et al.,
Bioorg. Med. Chem. Lett., 4:2877-2882 (1994).sup.58 and are
represented by the formula: 74
[1457] wherein R.sub.2 and R.sub.3 are exemplified by aryl and
substituted aryl and R.sub.1 is exemplified by alkyl or
hydrogen.
[1458] The synthesis of substituted 3-aminopyrrolidones from
alpha-bromoketones is described by McKennis, Jr., et al., J. Org.
Chem., 28:383-387 (1963).sup.59. These compounds are represented by
the formula: 75
[1459] where R.sup.1 is aryl or heteroaryl and R.sup.2 corresponds
to any substituent for which the corresponding amine
R.sup.2--NH.sub.2 exists.
[1460] Additional references for the synthesis of alpha
aminolactams are as follows:
[1461] 1. Shirota, et al., J. Med. Chem., 20:1623-1627
(1977).sup.60 which describes the synthesis of 76
[1462] 2. Overberger, et al., J. Am. Chem. Soc., 85:3431
(1963).sup.61 which describes the preparation of optically active
.beta.-methylcaprolactam of the formula: 77
[1463] 3. Herschmann, Helv. Chim. Acta, 32:2537 (1949).sup.62
describes the synthesis of a disubstituted caprolactam from the
Beckman rearrangement of menthone which is represented by the
formula: 78
[1464] 4. Overberger, et al., Macromolecules, 1:1 (1968).sup.63
describes the synthesis of eight-membered lactams from
3-methylcycloheptanone as shown below: 79
[1465] 5. The synthesis of benzolactams (benzazepinones) has been
reported by Busacca, et al., Tet. Lett., 33:165-168 (1992).sup.64:
80
[1466] by Croisier, et al., U.S. Pat. No. 4,080,449.sup.65: 81
[1467] and by J. A. Robl, et al., Tetrahedron Lett.,
36(10):1593-1596 (1995).sup.66 who employed an internal
Friedel-Crafts like cyclization to prepare the tricyclic
benzyllactams shown below where Pht is the phthalimido protecting
group: 82
[1468] Another tricyclic lactam series is disclosed by Flynn, et
al., J. Med. Chem., 36:2420-2423 (1993).sup.67 and references cited
therein.
[1469] 6. Orito, et al., Tetrahedron, 36:1017-1021 (1980).sup.68
discloses phenyl substituted benzazepinones represented by the
formula: 83
[1470] wherein R.dbd.H or CH.sub.3--;
[1471] Kawase, et al., J. Org. Chem., 54:3394-3403 (1989).sup.69
discloses a N-methoxy benzazepinone represented by the formula:
84
[1472] 7. Lowe, et al., J. Med. Chem., 37:3789-3811 (1994).sup.70
describes several synthetic pathways to substituted benzazepinones
of the formula: 85
[1473] where R.sub.1 is substituted aryl or cyclohexyl, X is a
suitable substituent and R.sub.2 can be H or alkyl. The syntheses
described in Lowe are, however, adaptable to form numerous R.sup.1
substituents.
[1474] 8. Robl, et al., Bioorg. Med. Chem. Lett., 4:1789-1794
(1994).sup.71 and references cited therein as well as Skiles, et
al., Bioorg. Med. Chem. Lett., 3:773-778 (1993).sup.72 disclose
benzofused lactams which contain additional heteroatoms in the
lactam ring. These compounds are represented by the formula: 86
[1475] where X is O and R.sub.2.dbd.H or CH.sub.3 or X.dbd.S and
R.sub.2.dbd.H. In either case, R.sub.1.dbd.H or alkyl. Also, in
Skiles, the thio group of the thiolactam can be oxidized to the
SO.sub.2 group. These structures are also presented from Beckmann
rearrangement in Grunewald, et al., J. Med. Chem., 39(18):3539
(1996)..sup.73
[1476] 9. Also syntheses for the benzoheterolactam series is
presented in Thomas, et al., J. Chem. Soc., Perkin II, 747
(1986).sup.74 which could lead to compounds of the formula: 87
[1477] where X is O or H.sub.2 and R is CO.sub.2R.
[1478] 10. Further examples of benzazepinones are found in
Warshawsky, et al., Bioorg. Med. Chem. Lett., 6:957-962
(1996).sup.75 which discloses 88
[1479] The synthesis can be generalized to produce R=alkyl or
aryl.
[1480] 11. Ben-Ishai, et al., Tetrahedron, 43:439450 (1987).sup.76
describes syntheses which could lead to several benzolactams of the
formula 89
[1481] wherein n=0,1,2 and R.dbd.--CH.sub.3, PhCH.sub.2-- and
H.
[1482] 12. van Niel et al., Bioorg. Med. Chem. Lett., 5:1421-1426
(1995).sup.77 reports the synthesis of 90
[1483] wherein X is --OH, --NH.sub.2 or --NR.sup.6R.sup.6 where
R.sup.6 is as defined above. The reported ketone is a versatile
synthetic intermediate which can be modified by conventional
methods such as reductive amination, reduction, etc.
[1484] 13. Kawase, et al., J. Org. Chem., 54:3394-3403
(1989).sup.78 describes a synthetic method for the preparation of:
91
[1485] In addition to the above, saturated bicyclic
alpha-aminolactams are also contemplated for use in the synthesis
of compounds of formula I. Such saturated bicyclic
alpha-aminolactams are well known in the art. For example, Edwards,
et al., Can. J. Chem., 49:1648-1658 (1971).sup.79 describes several
syntheses of bicyclic lactams of the formula: 92
[1486] Similarly, Milligan, et al., J. Am. Chem. Soc.,
117:10449-10459 (1995).sup.80 and references cited therein report
the synthesis of lactams of the formula: 93
[1487] wherein R1 and R2 are H or --CH.sub.3, ring A can have from
6-13 members and ring B can have from 5-7 members. R can be alkyl,
aryl, cycloalkyl, and the like.
[1488] The introduction of a heteroatom into the saturated cyclic
structure fused to the lactam ring is disclosed by Curran et al.,
Tet. Lett., 36:191-194 (1995).sup.81 who describe a synthetic
method which can be used to obtain a lactam of the formula: 94
[1489] by Slusarchyk, et al., Bioorg. Med. Chem. Lett., 5:753-758
(1995).sup.82 who describe syntheses which could lead to a lactam
of the formula: 95
[1490] and by Wyvratt, et al., Eur. Pat. Appl. 61187 (1982).sup.83
who describe a lactam of the formula: 96
[1491] Lactams having further heteroatom(s) in the cyclic lactam
structure (in addition to the nitrogen of the amido group of the
lactam) are described by Cornille, et al., J. Am. Chem. Soc.,
117:909-917 (1995).sup.84 who describe lactams of the formula:
97
[1492] J. Kolc, Coll. Czech. Chem. Comm., 34:630 (1969).sup.85 who
describes lysines suitable for cyclization to lactams which have a
hetero lactam ring atom as shown by the formula: 98
[1493] where X.dbd.O, S and NR where R is, for example, alkyl,
substituted alkyl, aryl, heteroaryl, heterocyclic, and the
like.
[1494] Similarly, each of Dickerman, et al., J. Org. Chem., 14:530
(1949).sup.86, Dickerman, et al., J. Org. Chem., 20:206
(1955).sup.87, and Dickerman, et al., J. Org. Chem., 19:1855
(1954).sup.88 used the Schmidt and Beckmann reactions on
substituted 4-piperidones to provide for lactams of the formula:
99
[1495] where R is acyl, alkyl, substituted alkyl, aryl, heteroaryl
or heterocyclic provided that R is not an acid labile group such as
t-Boc; and R' is hydrogen, alky, substituted alkyl, alkoxy,
substituted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy,
heterocyclic, heterocyclicoxy, halo, cyano, nitro, trihalomethyl,
and the like.
[1496] An internal cyclization of appropriate ethylenediamine
amides onto a ketone or aldehyde is described by Hoffman, et al.,
J. Org. Chem., 27:3565 (1962).sup.89 as follows: 100
[1497] Ring expansion methodology based on beta lactams to provide
for larger ring lactams containing an aza group has twice been
reported in Wasserman, et al., J. Am. Chem. Soc., 103:461-2
(1981).sup.90 and in Crombie, et al., Tetrahedron Lett.,
27(42):5151-5154 (1986)..sup.91
[1498] Dieckmann methodology has been used to prepare aza
caprolactams from unsymmetrical amines such as shown below by
Yokoo, et al., Bull, Chem. Soc. Jap., 29:631 (1956)..sup.92 101
[1499] where R is as defined in this reference. The disclosure of
Yokoo, et al. can be extended to cover R being alkyl, substituted
alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl,
heterocyclic, alkenyl, substituted alkenyl, and the like.
[1500] The synthesis of various members of the oxalactam series has
been reported by Burkholder, et al., Bioorg. Med. Chem. Lett.,
2:231 (1993).sup.93 and references cited therein which oxalactams
are represented by the formula: 102
[1501] where 'R is as defined in the reference and R can be alkyl,
substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl,
cycloalkyl, heterocyclic, alkenyl, substituted alkenyl, and the
like.
[1502] The synthesis of thialactams (generally oxalactams can be
made by the same methodology) has been reported by Freidinger, et
al., J. Org. Chem., 47:104-109 (1982).sup.18 who prepared
thialactams of the formula: 103
[1503] This reference provides a series of procedures having broad
application for synthesis of lactams permitting R in the above
formula to be derived from any amine (alkyl, aryl, heteroaryl,
etc.) with the restriction being that the R-group does not contain
any functional groups reactive with formaldehyde (e.g., primary and
secondary amines). The general synthetic scheme provided by
Freidlinger, et al. is: 104
[1504] The coupling agent is any standard reagent used in the
formation of typical peptide or amide bonds, for example,
carbodiimide reagents. See, also, Karanewsky, U.S. Pat. No.
4,460,5799 and Kametani, et al., Heterocycles, 9:831-840
(1978)..sup.95
[1505] The Friedinger procedure can be extended to afford
disubstituted thialactams of the following structure: 105
[1506] In practical terms, R.sub.2 will be limited to aryl and
heteroaryl groups and sterically hindered alkyl groups such as
t-butyl. R.sub.1 can be highly variable and is limited only by
subsequent reaction steps.
[1507] Still further is the Kametani procedure which provides for
lactams as follows: 106
[1508] In principle, the Kametani procedure allows for a wide
selection of R1 and R2 groups limited primarily by stability to the
reaction conditions.
[1509] See, for example, Yanganasawa, et al., J. Med. Chem.,
30:1984-1991 (1987).sup.96 and J. Das et al., Biorg. Med. Chem.
Lett., 4:2193-2198 (1994).sup.97 which describes general methods
for the synthesis of isomeric 7-membered thialactams of the
following structure: 107
[1510] R.sub.2 can be highly variable (e.g., alkyl, substituted
alkyl, aryl, heteroaryl, heterocyclic and the like) since a number
of well documented routes exist for the synthesis of nitroethylene
derivatives from aldehydes and nitromethane (Henry reaction)
followed by dehydration. R.sub.1 is limited to groups that can
undergo alkylation reactions.
[1511] The second compound series can be prepared as follows:
108
[1512] In this synthesis, R.sub.2 can be highly variable. The
starting component required to introduce R.sub.2 can be readily
derived by the reduction of any known alpha-BOC-amino acid to the
alcohol derivative followed by formation of the mesylate.
[1513] As noted above, the primary approaches to the preparation of
lactams is the Beckmann/Schmidt ring expansion reaction using
either inter- or intramolecular approaches serves to prepare
lactams of various ring sizes. The intramolecular approach
generates bicyclic materials with the lactam nitrogen incorporated
into the ring fusion. Additional approaches set forth above are at
the base of the methodology are internal cyclization of omega-amino
acids/esters where the construction of the substituent pattern
takes place prior to cyclization, and internal cyclization of an
electrophilic center onto a nucleophilic functional group as in the
Friedel Crafts type cyclization at the center of the Ben-Ishal
procedure for making benzazepinones. This latter procedure is
applicable to a wide variety of heteroaromatics as well as
benzenoid rings, and may also be applied to non-aromatic double or
triple bonds to generate a wide array of substituents or ring
fusions.
[1514] Deoxygenation of the lactam by reagents such as diborane,
LiAlH.sub.4, and the like leads to azaheterocycles (.dbd.X is
dihydro).
[1515] Similarly, for X.dbd.H, OH, such compounds can be prepared
by epoxidation of cycloalkenyl groups followed by oxirane opening
by, e.g., ammonia. After formation of compounds of formula I,
.dbd.X being H, OH can be oxidized to provide for cycloalkylones
(.dbd.X being oxo).
[1516] Additionally, the 5,7-dihydro-6H-diben[b,d]azepin-6-one
derivatives employed in this invention can be prepared using
conventional procedures and reagents. For example, an appropriately
substituted N-tert-Boc-2-amino-2'-methylbiphenyl compound can be
cyclized to form the corresponding
5,7-dihydro-6H-diben[b,d]azepin-6-one derivative by first treating
the biphenyl compound with about 2.1 to about 2.5 equivalents of a
strong base, such as sec-butyl lithium. This reaction is typically
conducted at a temperature ranging from about -80.degree. C. to
about -60.degree. C. in an inert diluent such as THF. The resulting
dianion is then treated with dry carbon dioxide at a temperature of
about -78.degree. C. to afford the
5,7-dihydro-6H-diben[b,d]azepin-6-one. This procedure is described
further in R. D. Clark et al., Tetrahedron, 49(7), 1351-1356 (1993)
and references cited therein.
[1517] After forming the 5,7-dihydro-6H-diben[b,d]azepin-6-one, the
amide nitrogen can be readily alkylated by first treating the
dibenazepinone with about 1.1 to about 1.5 equivalents of a strong
base, such as sodium hydride, in an inert diluent, such as DMF.
This reaction is typically conducted at a temperature ranging from
about -10.degree. C. to about 80.degree. C. for about 0.5 to about
6 hours. The resulting anion is then contacted with an excess,
preferably about 1.1 to about 3.0 equivalents, of an alkyl halide,
typically an alkyl chloride, bromide or iodide. Generally, this
reaction is conducted at a temperature of about 0.degree. C. to
about 100.degree. C. for about 1 to about 48 hours.
[1518] An amino group can then be introduced at the 5-position of
the 7-alkyl-5,7-dihydro-6H-diben[b,d]azepin-6-one using
conventional procedures and reagents. For example, treatment of
7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one with an excess of
butyl nitrite in the presence of a strong base, such as potassium
1,1,1,3,3,3-hexamethyldisilazane (KHMDS), affords
5-oximo-7-methyl-5,7-di- hydro-6H-diben[b,d]azepin-6-one.
Subsequent reduction of the oximo group by hydrogenation in the
presence of a catalyst, such as palladium on carbon, then provides
5-amino-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-- one. Other
conventional amination procedures, such as azide transfer followed
by reduction of the azido group, may also be employed.
[1519] Similarly, various benzodiazepine derivatives suitable for
use in this invention can be prepared using conventional procedures
and reagents. For example, a 2-aminobenzophenone can be readily
coupled to .alpha.-(isopropylthio)-N-(benzyloxycarbonyl)glycine by
first forming the acid chloride of the glycine derivative with
oxayl chloride, and then coupling the acid chloride with the
2-aminobenzophenone in the presence of a base, such as
4-methylmorpholine, to afford the
2-[.alpha.-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-aminobenzopheno-
ne. Treatment of this compound with ammonia gas in the presence of
an excess, preferably about 1.1 to about 1.5 equivalents, of
mercury (II) chloride then affords the
2-[N-(.alpha.-amino)-N'-(benzyloxycarbonyl)-gly-
cinyl]aminobenzophenone. This intermediate can then be readily
cyclized by treatment with glacial acetic acid and ammonium acetate
to provide the
3-(benzyloxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-on-
e1. Subsequent removal of the Cbz group affords the
3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one.
[1520] Alternatively,
2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones can be readily
aminated at the 3-position using conventional azide transfer
reactions followed by reduction of the resulting azido group to
form the corresponding amino group. The conditions for these and
related reactions are described in the examples set forth below.
Additionally, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones are
readily alkylated at the 1-position using conventional procedures
and reagents. For example, this reaction is typically conducted by
first treating the benzodiazepinone with about 1.1 to about 1.5
equivalents of a base, such as sodium hydride, potassium
tert-butoxide, potassium 1,1,1,3,3,3-hexamethyldisilazane, cesium
carbonate, in an inert diluent, such as DMF. This reaction is
typically conducted at a temperature ranging from about -78.degree.
C. to about 80.degree. C. for about 0.5 to about 6 hours. The
resulting anion is then contacted with an excess, preferably about
1.1 to about 3.0 equivalents, of an alkyl halide, typically an
alkyl chloride, bromide or iodide. Generally, this reaction is
conducted at a temperature of about 0.degree. C. to about
100.degree. C. for about 1 to about 48 hours.
[1521] Additionally, the
3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzo- diazepines
employed in this invention are typically prepared by first coupling
malonic acid with a 1,2-phenylenediamine. Conditions for this
reaction are well known in the art and are described, for example,
in PCT Application WO 96-US8400 960603. Subsequent alkylation and
amination using conventional procedures and reagents affords
various
3-amino-1,5-bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
s. Such procedures are described in further detail in the example
set forth below.
[1522] Accordingly, a vast number of lactams, lactones and
thiolactones are available by art recognized procedures. Similarly,
the art is replete with examples of aminocycloalkyl compounds for
use in the synthesis of compounds of formula I above.
[1523] In the synthesis of compounds of formula I using the
synthetic methods described above, the starting materials can
contain a chiral center (e.g., alanine) and, when a racemic
starting material is employed, the resulting product is a mixture
of R,S enantiomers. Alternatively, a chiral isomer of the starting
material can be employed and, if the reaction protocol employed
does not racemize this starting material, a chiral product is
obtained. Such reaction protocols can involve inversion of the
chiral center during synthesis.
[1524] Accordingly, unless otherwise indicated, the products of
this invention are a mixture of R,S enantiomers. Preferably,
however, when a chiral product is desired, the chiral product
corresponds to the L-amino acid derivative. Alternatively, chiral
products can be obtained via purification techniques which
separates enantiomers from a R,S mixture to provide for one or the
other stereoisomer. Such techniques are well known in the art.
Pharmaceutical Formulations
[1525] When employed as pharmaceuticals, the compounds of formula I
are usually administered in the form of pharmaceutical
compositions. These compounds can be administered by a variety of
routes including oral, rectal, transdermal, subcutaneous,
intravenous, intramuscular, and intranasal. These compounds are
effective as both injectable and oral compositions. Such
compositions are prepared in a manner well known in the
pharmaceutical art and comprise at least one active compound.
[1526] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, one or more of the
compounds of formula I above associated with pharmaceutically
acceptable carriers. In making the compositions of this invention,
the active ingredient is usually mixed with an excipient, diluted
by an excipient or enclosed within such a carrier which can be in
the form of a capsule, sachet, paper or other container. When the
excipient serves as a diluent, it can be a solid, semi-solid, or
liquid material, which acts as a vehicle, carrier or medium for the
active ingredient. Thus, the compositions can be in the form of
tablets, pills, powders, lozenges, sachets, cachets, elixirs,
suspensions, emulsions, solutions, syrups, aerosols (as a solid or
in a liquid medium), ointments containing, for example, up to 10%
by weight of the active compound, soft and hard gelatin capsules,
suppositories, sterile injectable solutions, and sterile packaged
powders.
[1527] In preparing a formulation, it may be necessary to mill the
active compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g. about 40 mesh.
[1528] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as
methyl- and propylhydroxy-benzoates; sweetening agents; and
flavoring agents. The compositions of the invention can be
formulated so as to provide quick, sustained or delayed release of
the active ingredient after administration to the patient by
employing procedures known in the art.
[1529] The compositions are preferably formulated in a unit dosage
form, each dosage containing from about 5 to about 100 mg, more
usually about 10 to about 30 mg, of the active ingredient. The term
"unit dosage forms" refers to physically discrete units suitable as
unitary dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active material calculated
to produce the desired therapeutic effect, in association with a
suitable pharmaceutical excipient. Preferably, the compound of
formula I above is employed at no more than about 20 weight percent
of the pharmaceutical composition, more preferably no more than
about 15 weight percent, with the balance being pharmaceutically
inert carrier(s).
[1530] The active compound is effective over a wide dosage range
and is generally administered in a pharmaceutically effective
amount. It, will be understood, however, that the amount of the
compound actually administered will be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[1531] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, 0.1 to about 500 mg of the active ingredient of the
present invention.
[1532] The tablets or pills of the present invention may be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can separated by enteric layer which serves to resist
disintegration in the stomach and permit the inner component to
pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[1533] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include aqueous solutions suitably flavored syrups,
aqueous or oil suspensions, and flavored emulsions with edible oils
such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as
well as elixirs and similar pharmaceutical vehicles.
[1534] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. Preferably the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in preferably
pharmaceutically acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be breathed directly from the
nebulizing device or the nebulizing device may be attached to a
face masks tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions may be
administered, preferably orally or nasally, from devices which
deliver the formulation in an appropriate manner.
[1535] The following formulation examples illustrate the
pharmaceutical compositions of the present invention.
Formulation Example 1
[1536] Hard gelatin capsules containing the following ingredients
are prepared:
23 Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch
305.0 Magnesium stearate 5.0
[1537] The above ingredients are mixed and filled into hard gelatin
capsules in 340 mg quantities.
Formulation Example 2
[1538] A tablet formula is prepared using the ingredients
below:
24 Quantity Ingredient (mg/tablet) Active Ingredient 25.0
Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0
Stearic acid 5.0
[1539] The components are blended and compressed to form tablets,
each weighing 240 mg.
Formulation Example 3
[1540] A dry powder inhaler formulation is prepared containing the
following components:
25 Ingredient Weight % Active Ingredient 5 Lactose 95
[1541] The active ingredient is mixed with the lactose and the
mixture is added to a dry powder inhaling appliance.
Formulation Example 4
[1542] Tablets, each containing 30 mg of active ingredient, are
prepared as follows:
26 Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch
45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0
mg (as 10% solution in sterile water) Sodium carboxymethyl starch
4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg
[1543] The active ingredient, starch and cellulose are passed
through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution
of polyvinyl-pyrrolidone is mixed with the resultant powders, which
are then passed through a 16 mesh U.S. sieve. The granules so
produced are dried at 50.degree. to 60.degree. C. and passed
through a 16 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate, and talc, previously passed through a No. 30
mesh U.S. sieve, are then added to the granules which, after
mixing, are compressed on a tablet machine to yield tablets each
weighing 150 mg.
Formulation Example 5
[1544] Capsules, each containing 40 mg of medicament are made as
follows:
27 Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg
Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg
[1545] The active ingredient, starch, and magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into
hard gelatin capsules in 150 mg quantities.
Formulation Example 6
[1546] Suppositories, each containing 25 mg of active ingredient
are made as follows:
28 Ingredient Amount Active Ingredient 25 mg Saturated fatty acid
glycerides to 2,000 mg
[1547] The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2.0 g capacity and
allowed to cool.
Formulation Example 7
[1548] Suspensions, each containing 50 mg of medicament per 5.0 ml
dose are made as follows:
29 Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%) 50.0 mg Microcrystalline
cellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and
Color q.v. Purified water to 5.0 ml
[1549] The active ingredient, sucrose and xanthan gum are blended,
passed through a No. 10 mesh U.S. sieve, and then mixed with a
previously made solution of the microcrystalline cellulose and
sodium carboxymethyl cellulose in water. The sodium benzoate,
flavor, and color are diluted with some of the water and added with
stirring. Sufficient water is then added to produce the required
volume.
Formulation Example 8
[1550]
30 Formulation Example 8 Quantity Ingredient (mg/capsule) Active
Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total
425.0 mg
[1551] The active ingredient, starch, and magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into
hard gelatin capsules in 560 mg quantities.
Formulation Example 9
[1552] A subcutaneous formulation may be prepared as follows:
31 Ingredient Quantity Active Ingredient 1.0 mg corn oil 1 ml
[1553] (Depending on the solubility of the active ingredient in
corn oil, up to about 5.0 mg or more of the active ingredient may
be employed in this formulation, if desired).
Formulation Example 10
[1554] A topical formulation may be prepared as follows:
32 Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30
g Liquid Paraffin 20 g White Soft Paraffin to 100 g
[1555] The white soft paraffin is heated until molten. The liquid
paraffin and emulsifying wax are incorporated and stirred until
dissolved. The active ingredient is added and stirring is continued
until dispersed. The mixture is then cooled until solid.
[1556] Another preferred formulation employed in the methods of the
present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art.
See. e.g., U.S. Pat. No. 5,023,252,issued Jun. 11, 1991, herein
incorporated by reference. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[1557] Frequently, it will be desirable or necessary to introduce
the pharmaceutical composition to the brain, either directly or
indirectly. Direct techniques usually involve placement of a drug
delivery catheter into the host's ventricular system to bypass the
blood-brain barrier. One such implantable delivery system used for
the transport of biological factors to specific anatomical regions
of the body is described in U.S. Pat. No. 5,011,472 which is herein
incorporated by reference.
[1558] Indirect techniques, which are generally preferred, usually
involve formulating the compositions to provide for drug
latentiation by the conversion of hydrophilic drugs into
lipid-soluble drugs. Latentiation is generally achieved through
blocking of the hydroxy, carbonyl, sulfate, and primary amine
groups present on the drug to render the drug more lipid soluble
and amenable to transportation across the blood-brain barrier.
Alternatively, the delivery of hydrophilic drugs may be enhanced by
intra-arterial infusion of hypertonic solutions which can
transiently open the blood-brain barrier.
[1559] Other suitable formulations for use in the present invention
can be found in Remington's Pharmaceutical Sciences, Mace
Publishing Company, Philadelphia, Pa., 17th ed. (1985).
Utility
[1560] The compounds and pharmaceutical compositions of the
invention are useful in inhibiting .beta.-amyloid peptide release
and/or its synthesis, and, accordingly, have utility in diagnosing
and treating Alzheimer's disease in mammals including humans.
[1561] As noted above, the compounds described herein are suitable
for use in a variety of drug delivery systems described above.
Additionally, in order to enhance the in vivo serum half-life of
the administered compound, the compounds may be encapsulated,
introduced into the lumen of liposomes, prepared as a colloid, or
other conventional techniques may be employed which provide an
extended serum half-life of the compounds. A variety of methods are
available for preparing liposomes, as described in, e.g., Szoka, et
al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each of
which is incorporated herein by reference.
[1562] The amount of compound administered to the patient will vary
depending upon what is being administered, the purpose of the
administration, such as prophylaxis or therapy, the state of the
patient, the manner of administration, and the like. In therapeutic
applications, compositions are administered to a patient already
suffering from AD in an amount sufficient to at least partially
arrest further onset of the symptoms of the disease and its
complications. An amount adequate to accomplish this is defined as
"therapeutically effective dose." Amounts effective for this use
will depend on the judgment of the attending clinician depending
upon factors such as the degree or severity of AD in the patient,
the age, weight and general condition of the patient, and the like.
Preferably, for use as therapeutics, the compounds described herein
are administered at dosages ranging from about 1 to about 500
mg/kg/day.
[1563] In prophylactic applications, compositions are administered
to a patient at risk of developing AD (determined for example by
genetic screening or familial trait) in an amount sufficient to
inhibit the onset of symptoms of the disease. An amount adequate to
accomplish this is defined as "prophylactically effective dose."
Amounts effective for this use will depend on the judgment of the
attending clinician depending upon factors such as the age, weight
and general condition of the patient, and the like. Preferably, for
use as prophylactics, the compounds described herein are
administered at dosages ranging from about 1 to about 500
mg/kg/day.
[1564] As noted above, the compounds administered to a patient are
in the form of pharmaceutical compositions described above. These
compositions may be sterilized by conventional sterilization
techniques, or may be sterile filtered. The resulting aqueous
solutions may be packaged for use as is, or lyophilized, the
lyophilized preparation being combined with a sterile aqueous
carrier prior to administration. The pH of the compound
preparations typically will be between 3 and 11, more preferably
from 5 to 9 and most preferably from 7 and 8. It will be understood
that use of certain of the foregoing excipients, carriers, or
stabilizers will result in the formation of pharmaceutical
salts.
[1565] The compounds described herein are also suitable for use in
the administration of the compounds to a cell for diagnostic and
drug discovery purposes. Specifically, the compounds may be used in
the diagnosis of cells releasing and/or synthesizing .beta.-amyloid
peptide. In addition the compounds described herein are useful for
the measurement and evaluation of the activity of other candidate
drugs on the inhibition of the cellular release and/or synthesis of
.beta.-amyloid peptide.
[1566] The following synthetic and biological examples are offered
to illustrate this invention and are not to be construed in any way
as limiting the scope of this invention.
EXAMPLES
[1567] In the examples below, the following abbreviations have the
following meanings. If an abbreviation is not defined, it has its
generally accepted meaning.
33 BEMP = 2-tert-butylimino-2-diethylamino-1,3-
dimethylperhydro-1,3,2-diazaphosphorine Boc = t-butoxycarbonyl BOP
= benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate bd = broad doublet bs = broad singlet d =
doublet dd = doublet of doublets DIC = diisopropylcarbodiimide DMF
= dimethylformamide DMAP = dimethylaminopyridine DMSO =
dimethylsulfoxide EDC = ethyl-1-(3-dimethyaminopropyl)carbodiimide
eq. = equivalents EtOAc = ethyl acetate g = grams HOBT =
1-hydroxybenzotriazole hydrate Hunig's base = diisopropylethylamine
L = liter m = multiplet M = molar max = maximum meq =
milliequivalent mg = milligram mL = milliliter mm = millimeter mmol
= millimole MOC = methoxyoxycarbonyl N = normal N/A = not available
ng = nanogram nm = nanometers OD = optical density PEPC =
1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodi- imide PP-HOBT =
piperidine-piperidine-1-hydroxybenzotrizole psi = pounds per square
inch .phi. = phenyl q = quartet quint. = quintet rpm = rotations
per minute s = singlet t = triplet TFA = trifluoroacetic acid THF =
tetrahydrofuran tlc = thin layer chromatography .mu.L = microliter
UV = ultra-violet
[1568] In the examples below, all temperatures are in degrees
Celcius (unless otherwise indicated). The compounds set forth in
the examples below were prepared using the following general
procedures as indicated.
[1569] In the following examples and procedures, the term "Aldrich"
indicates that the compound or reagent used in the procedure is
commercially available from Aldrich Chemical Company, Inc., 1001
West Saint Paul Avenue, Milwaukee, Wis. 53233 USA; the term "Fluka"
indicates that the compound or reagent is commercially available
from Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma N.Y.
11779 USA; the term "Lancaster" indicates that the compound or
reagent is commercially available from Lancaster Synthesis, Inc.,
P.O. Box 100 Windham, N.H. 03087 USA; the term "Sigma" indicates
that the compound or reagent is commercially available from Sigma,
P.O. Box 14508, St. Louis Mo. 63178 USA; the term "Chemservice"
indicates that the compound or reagent is commercially available
from Chemservice Inc., Westchester, Pa.; the term "Bachem"
indicates that the compound or reagent is commercially available
from Bachem Biosciences Inc., 3700Horizon Drive, Renaissance at
Gulph Mills, King of Prussia, Pa. 19406 USA; the term "Maybridge"
indicates that the compound or reagent is commercially available
from Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW
United Kingdom; and the term "TCI" indicates that the compound or
reagent is commercially available from TCI America, 9211 North
Harborgate Street, Portland Oreg. 97203; the term "Alfa" indicates
that the compound or reagent is commercially available from Johnson
Matthey Catalog Company, Inc. 30 Bond Street, Ward Hill, Mass.
01835-0747; the term "Novabiochem" indicates that the compound or
reagent is commercially available from Calbiochem-Novabiochem Corp.
10933 North Torrey Pines Road, P.O. Box 12087, La Jolla Calif.
92039-2087; the term "Oakwood" indicates that the compound or
reagent is commercially available from Oakwood, Columbia, S.C.; the
term "Advanced Chemtech" indicates that the compound or reagent is
commercially available from Advanced Chemtech, Louisville, Ky.; and
the term "Pfaltz & Bauer" indicates that the compound or
reagent is commercially available from Pfaltz & Bauer,
Waterbury, Conn., USA.
[1570] I. Coupling Procedures
General Procedure A
First EDC Coupling Procedure
[1571] To a 1:1 mixture of the corresponding carboxylic acid and
the corresponding amino acid ester or amide in CH.sub.2Cl.sub.2 at
0.degree. C. was added 1.5 equivalents triethylamine, followed by
2.0 equivalents hydroxybenzotriazole monohydrate and then 1.25
equivalents of ethyl-3-(3-dimethylamino)propyl carbodiimide HCl.
The reaction mixture was stirred overnight at room temperature and
then transferred to a separatory funnel. The mixture was washed
with water, saturated aqueous NaHCO.sub.3, 1N HCl and saturated
aqueous NaCl, and then dried over MgSO.sub.4. The resulting
solution was stripped free of solvent on a rotary evaporator to
yield the crude product.
General Procedure B
Second EDC Coupling Procedure
[1572] A mixture of the corresponding acid (1 eqv),
N-1-hydroxybenzotriazole (1.6 eqv), the corresponding amine (1
eqv), N-methylmorpholine (3 eqv) and dichloromethane (or DMF for
insoluble substrates) was cooled in an ice-water bath and stirred
until a clear solution was obtained. EDC (1.3 eqv) was then added
to the reaction mixture. The cooling bath was then allowed to warm
to ambient temperature over 1-2 h and the reaction mixture was
stirred overnight. The reaction mixture was then evaporated to
dryness under vacuum. To the residue was added 20% aqueous
potassium carbonate and the mixture was shaken throughly and then
allowed to stand until the oily product solidified (overnight if
necessary). The solid product was then collected by filteration,
washed thoroughly with 20% aqueous potassium carbonate, water, 10%
HCl, and water to give the product, usually in pure state. No
racemization was observed.
General Procedure C
Third EDC Coupling Procedure
[1573] The carboxylic acid was dissolved in methylene chloride. The
corresponding amino acid ester or amide (1 eq.), N-methylmorpholine
(5 eq.) and hydroxybenzotriazole monohydrate (1.2 eq.) were added
in sequence. A cooling bath was applied to the round bottomed flask
until the solution reached 0.degree. C. At that time, 1.2 eq. of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was
added. The solution was allowed to stir overnight and come to room
temperature under nitrogen pressure. The reaction mixture was
worked up by washing the organic phase with saturated aqueous
sodium carbonate, 0.1M citric acid, and brine before drying with
sodium sulfate. The solvents were then removed to yield crude
product.
General Procedure D
Fourth EDC Coupling Procedure
[1574] A round bottom flask was charged with the corresponding
carboxylic acid (1.0 eq.), hydroxybenzotriazole hydrate (1.1 eq.)
and the corresponding amine (1.0 eq.) in THF under nitrogen
atmosphere. An appropriate amount (1.1 eq for free amines and 2.2
eq. for hydrochloride amine salts) of base, such as Hunig's base
was added to the well stirred mixture followed by EDC (1.1 eq.).
After stirring from 4 to 17 hours at room temperature the solvent
was removed at reduced pressure, the residue taken up in ethyl
acetate (or similar solvent) and water, washed with saturated
aqueous sodium bicarbonate solution, 1 N HCl, brine, dried over
anhydrous sodium sulfate and the solvent removed at reduced
pressure to provide the product.
General Procedure E
BOP Coupling Procedure
[1575] To a stirred solution of N-(3,5-difluorophenylacetyl)alanine
(2 mmol) in DMF, cooled in an ice-water bath, was added BOP (2.4
mmol) and N-methylmorpholine (6 mmol). The reaction mixture was
stirred for 50 min. and then a solution of
.alpha.-amino-.gamma.-lactam (2 mmol) in DMF cooled at 0 .degree.
C. was added. The cooling bath was allowed to warm to ambient
temperature over 1-2 h and the reaction mixture was then stirred
overnight. A 20% aqueous potassium carbonate solution (60 mL) was
added and this mixture shaken throughly. No solid formed. The
mixture was then washed with ethyl acetate (150 mL) and evaporated
to dryness under vacuum to give a white solid. Water (50 mL) was
then added and this mixture shaken throughly. The precipitate that
formed was collected by filtration, then washed thoroughly with
water, followed by 1 mL of diethyl ether to give the product (51
mg, 0.16 mmol, 7.8%).
General Procedure F
Coupling of an Acid Chloride with an Amino Acid Ester
[1576] To a stirred solution of (D,L)-alanine isobutyl ester
hydrochloride (4.6 mmol) in 5 ml of pyridine was added 4.6 mmol of
the acid chloride. Precipitation occurred immediately. The mixture
was stirred for 3.5 h, dissolved in 100 mL of diethyl ether, washed
with 10% HCl three times, brine once, 20% potassium carbonate once
and brine once. The solution was dried over magnesium sulfate,
filtered, and evaporated to yield the product. Other amino acid
esters may also be employed in this procedure.
General Procedure G
Coupling of a Carboxylic Acid with an Amino Acid Ester
[1577] A solution of the carboxylic acid (3.3 mmol) and
1,1'-carbodiimidazole (CDI) in 20 mL THF was stirred for 2 h.
(D,L)-alanine isobutyl ester hydrochloride (3.6 mmol) was added,
followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction
mixture was stirred overnight. The reaction mixture was dissolved
in 100 mL of diethyl ether, washed with 10% HCl three times, brine
once, 20% potassium carbonate once and brine once. The solution was
dried over magnesium sulfate, filtered, and evaporated to yield the
product. Other amino acid esters may also be employed in this
procedure.
General Procedure H
Fifth EDC Coupling Procedure
[1578] In a round bottom flask was added a carboxylic acid (1.1
eq.) in THF, an amine hydrochloride (1.0 eq.),
1-hydroxybenzotriazole hydrate (1.1 eq.), N,N-diisopropylethylamine
(2.1 eq.), followed by
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(1.1 eq.). The reaction mixture stirred at room temperature for
10-20 hours under an atmosphere of nitrogen. The mixture was
diluted with EtOAc and washed with 0.1 M HCl (1.times.10 mL),
saturated NaHCO.sub.3 (1.times.10 mL), H.sub.2O (1.times.10 mL),
and brine and dried over MgSO.sub.4. The drying agent was removed
by filtration and the filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
followed by trituration from EtOAc and hexanes.
General Procedure I
Sixth EDC Coupling Procedure
[1579] To a solution or suspension of the amine or amine
hydrochloride (1.0 eq.) in THF (0.05-0.1 M) under N.sub.2 at
0.degree. C. was added the carboxylic acid (1.0-1.1 eq.),
hydroxybenzotriazole monohydrate (1.1-1.15 eq.), Hunig's base (1.1
eq. for free amines and 1.1-2.3 eq. for hydrochloride amine salts),
followed by 1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide
hydrochloride (1.1-1.15 eq.). The cooling bath was removed and the
mixture allowed to warm to room temperature for 10-24 hours. The
solution or mixture was diluted with EtOAc, in a 3-5 volume
multiple of the initial THF volume, and washed with 0.1-1.0 M aq.
HCl (1 or 2.times.), dilute NaHCO.sub.3 (1 or 2.times.), and brine
(1.times.). Then, the organic phase was dried over either
MgSO.sub.4 or Na.sub.2SO.sub.4, filtered, concentrated to provide
the crude product, which was either further purified or utilized
without further purification.
General Procedure J
EEDQ Coupling Procedure
[1580] To a solution of the amine in THF (1.0 eq., 0.05-0.08 M,
final molarity) under N.sub.2 at room temperature was added the
N-t-Boc protected amino acid (1.1 eq., either as a solid or in THF
via cannula), followed by EEDQ (Aldrich, 1.1 eq.). The pale yellow
solution was stirred at room temperature for 16-16.5 hours, then
diluted with EtOAc (in a 3-5 volume multiple of the initial THF
volume), and washed with 1M aq. HCl (2.times.), dilute aq.
NaHCO.sub.3 (2.times.), and brine (1.times.). The organic phase was
dried over either Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concentrated.
[1581] II. Carboxylic Acids
General Procedure II-A
Ester Hydrolysis to Free Acid
[1582] Ester hydrolysis to the free acid was conducted by
conventional methods. Below are two examples of such conventional
de-esterification methods.
[1583] Method A: To a carboxylic ester compound in a 1:1 mixture of
CH.sub.3OH/H.sub.2O was added 2-5 equivalents of K.sub.2CO.sub.3.
The mixture was heated to 50.degree. C. for 0.5 to 1.5 hours until
tlc showed complete reaction. The reaction was cooled to room
temperature and the methanol was removed on a rotary evaporator.
The pH of the remaining aqueous solution was adjusted to .about.2,
and ethyl acetate was added to extract the product. The organic
phase was then washed with saturated aqueous NaCl and dried over
MgSO.sub.4. The solution was stripped free of solvent on a rotary
evaporator to yield the product.
[1584] Method B: The amino acid ester was dissolved in
dioxane/water (4:1) to which was added LiOH (.about.2 eq.) that was
dissolved in water such that the total solvent after addition was
about 2:1 dioxane:water. The reaction mixture was stirred until
reaction completion and the dioxane was removed under reduced
pressure. The residue was dissolved in water and washed with ether.
The layers were separated and the aqueous layer was acidified to pH
2. The aqueous layer was extracted with ethyl acetate. The ethyl
acetate extracts were dried over Na.sub.2SO.sub.4 and the solvent
was removed under reduced pressure after filtration. The residue
was purified by conventional methods (e.g., recrystallization).
General Procedure II-B
Acid Chloride Preparation
[1585] 3,5:Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich)
was dissolved in dichloromethane and this solution was cooled to
0C. DMF (0.5 mL, catalytic) was added followed by the dropwise
addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute
period. The reaction was stirred for 3 h and then rotoevaporated at
reduced pressure to give an oil which was placed on a high vacuum
pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin
yellow oil. Other acid chlorides can be prepared in a similar
manner.
General Procedure II-C
Schotten-Baumann Procedure
[1586] 3,5-Difluorophenylacetyl chloride (from General Procedure
II-B) was added dropwise to a 0.degree. C. solution of L-alanine
(Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43
mol). The reaction was stirred for 1 h at 0.degree. C. and then
overnight at room temperature. The reaction was diluted with water
(100 mL), then extracted with ethyl acetate (3.times.150 mL). The
organic layer was then washed with brine (200 mL), dried over
MgSO.sub.4, and rotoevaporated at reduced pressure to a residue.
Recrystallization of the residue from ethyl acetate/hexanes
afforded the desired product (34.5 g, 82% yield). Other acid
chlorides may be used in this procedure to provide for
intermediates useful in this invention.
General Procedure II-D
Reductive Amination
[1587] To a solution of the arylamine in ethanol in a hydrogenation
flask was added 1 equivalent of the 2-oxocarboxylic acid ester
(e.g., pyruvate ester), followed by 10% palladium on carbon (25
weight percent based on the arylamine). The reaction was
hydrogenated at 20 psi H.sub.2 on a Parr shaker until complete
reaction was indicated by tlc (30 minutes to 16 hours). The
reaction mixture was then filtered through a pad of Celite 545
(available from Aldrich Chemical Company, Inc.) and stripped free
of solvent on a rotary evaporator. The crude product residue was
then further purified via chromatography.
Example A
Synthesis of N-(Phenylacetyl)-L-alanine
[1588] Using General Procedure II-C, the title compound was
prepared from phenylacetyl chloride (Aldrich) and L-alanine
(Aldrich) as a solid having a melting point of 102-104.degree.
C.
[1589] NMR data was as follows:
[1590] .sup.1H-nmr (CDCl.sub.3): .delta.=9.14 (br s, 1H), 7.21-7.40
(m, 5H), 6.20 (d, J=7.0 Hz, 1H), 4.55 (m, 1H), 3.61 (s, 2H), 1.37
(d, J=7.1 Hz, 3H).
[1591] .sup.13C-nmr (CDCl.sub.3): .delta.=176.0, 171.8, 134.0,
129.4, 127.5, 48.3, 43.2, 17.9.
Example B
Synthesis of N-(3,5-Difluorophenylacetyl)-L-alanine
[1592] Using General Procedure II-C, the title compound was
prepared from 3,5-difluorophenylacetyl chloride (General Procedure
II-B) and L-alanine (Aldrich).
[1593] NMR data was as follows:
[1594] .sup.1H-nmr (CD.sub.3OD): .delta.=8.32 (br s, 0.3H), 6.71
(m, 2H), 6.60 (m, 1H), 4.74 (br s, 1.7H), 4.16 (m, 1H), 3.36 (s,
2H), 1.19 (d, J=7.3 Hz, 3H).
[1595] .sup.13C-nmr (CD.sub.3OD): .delta.=175.9, 172.4, 164.4 (dd,
J=13.0, 245.3 Hz), 141.1, 113.1 (dd, J=7.8, 17.1 Hz), 102.9 (t,
J=25.7 Hz), 49.5, 42.7, 17.5.
Example C
Synthesis of N-(Cyclopentylacetyl)-L-phenylglycine
Step A--Preparation of N-(Cyclopentylacetyl)-L-phenylglycine Methyl
Ester
[1596] Following General Procedure A above using cyclopentylacetic
acid (Aldrich) and phenylglycine methyl ester hydrochloride
(Novabiochem), the title compound was prepared as a solid having a
melting point of 83-86.degree. C. The reaction was monitored by tlc
on silica gel (Rf=0.28 in 25% ethyl acetate/hexanes) and
purification was by recrystallization from ethyl
acetate/hexanes.
[1597] NMR data was as follows:
[1598] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35 (s, 5H), 6.44 (bd,
1H), 5.6 (d, 1H), 3.72 (s, 3H 2.24 (bs, 3H), 1.9-1.4 (m, 6H),
1.2-1.05 (m, 2H).
[1599] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 171.7, 136.7,
129.0, 128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38,
24.8.
[1600] C.sub.16H.sub.21NO.sub.3 (MW=275.35); mass spectroscopy
(M+Na) 298.
Step B--Preparation of N-(Cyclopentylacetyl)-L-phenylglycine
[1601] Following General Procedure II-A above using
N-(cyclopentylacetyl)-L-phenylglycine methyl ester (from Step A),
the title compound was prepared as a solid having a melting point
of 155-158.degree. C. The reaction was monitored by tlc on silica
gel (Rf=0.18 in 10% methanol/dichloromethane).
[1602] NMR data was as follows:
[1603] .sup.1H-nmr (CDCl.sub.3): .delta.=8.60 (d, J=7.8 Hz, 1H),
7.45 (m, 5H0, 5.41 (d, J=7.2 Hz, 1H), 2.20 (m, 3H), 1.8-1.1 (m,
8H).
[1604] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 172.0, 137.5,
128.7, 128.1, 127.8, 56.2, 40.9, 36.8, 31.8, 24.5.
[1605] C.sub.15H.sub.19NO.sub.3 (MW=261.32); mass spectroscopy
(M+Na) 284.
Example D
Synthesis of N-(Cyclopentylacetyl)-L-alanine
Step A--Preparation of N-(Cyclopentylacetyl)-L-alanine Methyl
Ester
[1606] Following General Procedure A above using cyclopentylacetic
acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma),
the title compound was prepared as a solid having a melting point
of 43-46.degree. C. Purification was by recrystallization from
ethyl acetate/hexanes.
[1607] NMR data was as follows:
[1608] .sup.1H-nmr (CDCl.sub.3): .delta.=6.38 (d, 1H), 4.50 (m,
1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30,
3H), 11H).
[1609] .sup.13C-nmr (CDCl.sub.3): .delta.=173.7, 172.5, 52.1, 47.6,
42.3, 36.8, 32.15, 32.14, 18.0.
[1610] C.sub.11H.sub.19NO.sub.3 (MW=213.28); mass spectroscopy
(MH.sup.+) 214.
Step B--Preparation of N-(Cyclopentylacetyl)-L-alanine
[1611] Following General Procedure II-A above using
N-(cyclopentylacetyl)-L-alanine methyl ester (from Step A), the
title compound was prepared. The reaction was monitored by tlc on
silica gel (Rf=0.18 in 10% methanol/dichloromethane).
[1612] NMR data was as follows:
[1613] .sup.1H-nmr (DMSO-d.sub.6): .delta.=12.45 (bs, 1H), 8.12 (d,
J=7.2 Hz, 1H), 4.24 (quint, J=7.2 Hz, 1H), 2.14 (m, 3H), 1.8-1.4
(m, 6H), 1.29 (d, J=7.2 Hz, 3H), 1.2-1.0 (m, 3H).
[1614] .sup.13C-nmr (DMSO-d.sub.6): .delta.=174.6, 171.9, 47.3,
41.1, 36.7, 31.8, 24.5, 17.2.
[1615] C.sub.10H.sub.17NO.sub.3 (MW=199.25); mass spectroscopy
(MH.sup.+) N/A.
Example E
Synthesis of N-(Cyclopropylacetyl)-L-alanine
Step A--Preparation of N-(Cyclopropylacetyl)-L-alanine Methyl
Ester
[1616] Following General Procedure A above using cyclopropylacetic
acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma),
the title compound was prepared as an oil. The reaction was
monitored by tlc on silica gel (Rf=0.15 in 25% ethyl
acetate/hexanes) and purification was by flash column
chromatography using 25% ethyl acetate/hexanes as the eluant.
[1617] NMR data was as follows:
[1618] .sup.1H-nmr (CDCl.sub.3): .delta.=6.60 (d, 1H), 4.55 (m,
1H), 3.69 (s, 3H), 2.10 (m, 2H), 1.34 (d, 3H), 0.95 (m, 1H), 0.58
(m, 2H), 0.15 (m, 2H).
[1619] .sup.13C-nmr (CDCl.sub.3): .delta.=173.7, 172.3, 52.3, 47.7,
41.0, 18.2, 6.7, 4.27, 4.22.
[1620] C.sub.9H.sub.15NO.sub.3 (MW=185.22); mass spectroscopy
(MH.sup.+) N/A.
Step B--Preparation of N-(Cyclopentylacetyl)-L-alanine
[1621] Following General Procedure II-A above using
N-(cyclopropylacetyl)-L-alanine methyl ester (from Step A), the
title compound was prepared as an oil. The reaction was monitored
by tlc on silica gel (Rf=0.27 in 10% methanol/dichloromethane).
[1622] NMR data was as follows:
[1623] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.18 (d, 1H), 4.25 (m,
1H), 2.08 (m, 2H), 1.30 (d, 3H), 1.00 (m, 1H), 0.50 (m, 2H), 0.19
(m, 2H).
[1624] .sup.13C-nmr (DMSO-d.sub.6): .delta.=174.6, 171.7, 47.4,
17.3, 7.6, 4.12, 4.06.
[1625] C.sub.8H.sub.13NO.sub.3 (MW=199.25); mass spectroscopy
(MH.sup.+) N/A.
Example F
Synthesis of N-(Cyclopropylacetyl)-L-phenylglycine
Step A--Preparation of N-(Cyclopropylacetyl)-L-glycine Methyl
Ester
[1626] Following General Procedure A above using cyclopropylacetic
acid (Aldrich) and L-phenylglycine methyl ester, the title compound
was prepared as a solid having a melting point of 74-76.degree. C.
The reaction was monitored by tlc on silica gel (Rf=0.61 in 50%
ethyl acetate/hexanes) and purification was by recrystallization
from ethyl acetate/hexanes.
[1627] NMR data was as follows:
[1628] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35 (m, 5H), 6.97 (bd,
J=7.2 Hz, 1H), 5.59 (d, J=7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m, 2H),
1.05-0.95 (m, 1H), 0.62 (m, 2H), 0.20 (m, 2H).
[1629] .sup.13C-nmr (CDCl.sub.3): .delta.=171.9, 174.6, 136.6,
129.0, 128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33.
[1630] C.sub.14H.sub.17NO.sub.3 (MW=247.30); mass spectroscopy
(MH.sup.+) N/A.
Step B--Preparation of N-(Cyclopentylacetyl)-L-phenylglycine
[1631] Following General Procedure II-A above using
N-(cyclopropylacetyl)-L-phenylglycine methyl ester (from Step A),
the title compound was prepared as a solid having melting point of
152-157.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.23 in 10% methanol/dichloromethane) and purification was by
recrystallization from ethyl acetate/hexanes.
[1632] NMR data was as follows:
[1633] .sup.1H-nmr (CDCl.sub.3): .delta.=8.47 (d, J=7.69 Hz, 1H),
7.35 (m, 5H), 5.34 (d, J=7.69 Hz, 1H), 2.10 (m, 2H), 0.90 (m, 1H),
0.40 (m, 2H), 0.10 (m, 2H).
[1634] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 171.8, 137.6,
128.7, 56.2, 7.7, 4.0.
[1635] C.sub.13H.sub.15NO.sub.3 (MW=233.27); mass spectroscopy
(MH.sup.+) N/A.
Example H
Synthesis of N-(2-Biphenyl)-D,L-alanine
[1636] 2-Aminobiphenyl (2 g, 11.8 mmol, Aldrich), triethylamine
(1.2 eq.) and ethyl 2-bromopropionate (1.1 eq., Aldrich) were
combined and heated to 85.degree. C. with stirring. After 7 days,
the mixture was diluted with chloroform and washed with water. The
organic portion was dried and concentrated to yield an oil which
was purified by silica gel chromatography (1:1
CH.sub.2Cl.sub.2/hexanes). The resulting oil was dissolved in a 1:2
mixture of water/dioxane (200 mL) and LiOH (2 eq.) was added. After
2 hours, the mixture was concentrated to yield an oil which was
dissolved in water. The aqueous solution was washed with ether then
was adjusted to pH 3 with 5N HCl and extracted with ethyl acetate.
The organic portion was dried and concentrated to yield an oil
which was purified by silica gel chromatography (EtOAc) to yield
the title compound.
Example I
Synthesis of N-(Phenyl-furazan-3-yl)-D,L-alanine
[1637] Following General Procedure II-D and using
4-phenyl-furazan-3-ylami- ne (Maybridge) and ethyl pyruvate
(Aldrich), the ethyl ester was prepared. Following General
Procedure II-A, Method B (LiOH/H.sub.2O/dioxane) and using the
ethyl ester, the title compound was prepared.
Example L
Synthesis of S-(+)-3,5-Difluoromandelic Acid
Step A--Preparation of Methyl S-(.+-.)-3.5-difluoromandelate
[1638] To a solution of 3,5-difluorobenzaldehyde (Aldrich) in
CH.sub.2Cl.sub.2 (100 mL) was added ZnCl.sub.2 (6.7 g, 21.1 mmol)
to form a slurry. Trimethysilyl cyanide (21.0 g, 211.2 mmol)
dissolved in CH.sub.2Cl.sub.2 (100 mL) was slowly added to the
slurry at 0.degree. C. The resulting solution was stirred at room
temperature for 4 h. The reaction mixture was then diluted with
water and the organic layer separated. The combined organic layers
were concentrated to a residue. The residue was dissolved with MeOH
(200 mL) at 0.degree. C. and anhydrous HCl gas bubbled into the
solution for 10 min. After stirring at room temperature for 18 h,
the solution was concentrated to a solid. The solid was dissolved
in CH.sub.2Cl.sub.2/H.sub.2O and the aqueous portion extracted with
CH.sub.2Cl.sub.2. The combined organics were washed with brine,
dried over anhydrous MgSO.sub.4 and concentrated to a solid (37.4
g, 87.6%), mp=77-78.degree. C.
[1639] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=6.97 (dd, J=9.6
Hz, J=1.79 Hz, 2H), 6.74 (dt, J=8.82, J=2.28 Hz, 1H), 5.14 (d,
J=4.64 Hz, 1H), 3.78 (s, 3H), 3.54 (d, J=5.1 Hz, 1H).
Step B--Preparation of Methyl S-(+)-3,5-difluoromandelate
[1640] Methyl (.+-.)-3,5-difluoromandelate was separated via
preparative chiral HPLC to give a white solid having a melting
point of 70-71.degree. C.
[1641] C.sub.9H.sub.8F.sub.2O.sub.3 (MW=202.17); mass spectroscopy
found (M+NH.sub.4.sup.+) 220.0.
[1642] Anal. calcd for C.sub.9H.sub.8F.sub.2O.sub.3: C, 53.47; H,
3.99. Found: C, 53.40; H, 3.89.
Step C--Preparation of S-(+)-3.5-Difluoromandelic acid
[1643] A solution of methyl S-(+)-3,5-difluoromandelate (1 eq.) in
74% aqueous THF was cooled to 0.degree. C. and treated with lithium
hydroxide. After 40 minutes at 0.degree. C. the reaction was
complete by TLC. The contents were transferred to a separatory
funnel and partitioned between CH.sub.2Cl.sub.2 and saturated
aqueous NaHCO.sub.3. The aqueous layer was acidified with 0.5 N
NaHSO.sub.4 and extracted thrice with ethyl acetate. The combined
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to a white solid having a melting point
of 119-122.degree. C. The .sup.1H NMR was consistent with known
3,5-difluoromandelic acid.
Example M
Synthesis of 2-Azido-(3,5-difluorophenyl)acetic Acid
[1644] Step A: To a three-necked flask equipped with a mechanical
stirrer and a nitrogen inlet tube was added
3,5-difluorophenylacetic acid and THF. The reaction mixture was
cooled to -78.degree. C. and 1.2 eq. of triethylamine was added,
followed by dropwise addition of trimethylacetyl chloride (1.05
eq.). During the addition, the temperature was maintained at
-78.degree. C. The cold bath was then removed and replaced with an
ice bath. The temperature was allowed to warm to 0.degree. C. and
stirring was continued for 1 hour. The reaction mixture was then
re-cooled to -78.degree. C. To a second flask charged with THF,
triphenylmethane (cat, 0.1 mole %) and
(S)-(-)-4-benzyl-2-oxazolidione (1.1 eq.) (Aldrich) at -78.degree.
C. was added an n-butyl lithium solution dropwise until an orange
color persisted. This reaction mixture was stirred at -78.degree.
C. for 30 min. and then cannulated into the first reaction mixture.
The resulting mixture was allowed to stir at -78.degree. C. for 1
hour and then quenched with 2.2 eq. of acetic acid. The solvent was
removed under reduced pressure and the residue was redissolved in
dichloromethane and this solution washed with water, followed by 1M
potassium carbonate. The organic layer was then dried over sodium
sulfate, filtered and concentrated. The residue was purified by LC
2000 chromatography, eluting with EtOAC/Hexane (15:85). The
resulting oil was slurried in hexane to afford a white solid which
was collected by filtration to give
(S)-(-)-3-(3,5-difluorophenyacetyl)-4-benzyl-2-oxazolidione.
[1645] Step B: To
(S)-(-)-3-(3,5-difluorophenyacetyl)-4-benzyl-2-oxazolidi- one (3.0
mM) in 20 mL of dry THF cooled to -78.degree. C. was added LiHMDS
(1.05 eq.) dropwise while maintaining the temperature at
-78.degree. C. The reaction mixture was allowed o stir at
-78.degree. C. for 15 min. and then a pre-cooled (-60.degree. C.)
solution of trisyl azide (1.12 eq.) in 10 mL of THF was added. The
reaction mixture was allowed to stir an additional 10 min. and then
was quenched with 4.4 eq. of acetic acid. Using a warm water bath,
the temperature was raised to 30-40.degree. C. for 6 hrs. The
reaction mixture was then poured into a separatory funnel and
extracted into dichloromethane. The organic layer was washed with
bicarbonate solution, followed by brine, and then dried over sodium
sulfate, filtered and solvent removed. The residue was purified by
LC 2000 chromatography to afford methyl
2-azido-2-(3,5-difluorophenyl)acetat- e.
[1646] Step C: To a solution of methyl
2-azido-2-(3,5-difluorophenyl)aceta- te in THF/H.sub.2O (2.6:1)
cooled to 0.degree. C. was added 1.7 eq. of lithium hydroxide. The
reaction mixture was stirred at room temperature for 3 hours and
then poured into a separatory funnel. The mixture was extracted
into water and washed with ether. The aqueous layer was acidified
with 1N HCl and extracted with ethyl acetate. The organic layer was
then washed with water and brine. The organic layer was dried over
sodium sulfate, filtered and concentrated under reduced pressure to
give 2-azido-2-(3,5-difluorophenyl)acetic acid.
Example N
Synthesis of (R)-N,N'-Di-BOC-2-Hydrazinopropionic Acid
[1647] Step A: To (S)-(-)-4-benzyl-2-oxazolidanone (Aldrich) in THF
cooled to -50.degree. C. was added n-butyl lithium 1.1 eq. (1.6 M
in hexane) dropwise. The reaction mixture was allowed to warm to
-20.degree. C. and then was re-cooled to -78.degree. C. and
propionyl chloride (1.1 eq) was added in one portion. The reaction
mixture was allowed to stir an additional 15 min. at -78.degree. C.
and then was allowed to warm to room temperature. The reaction was
then quenched with a saturated solution of sodium bicarbonate and
extracted with ethyl acetate. The organic extracts were washed with
water, followed by brine and then dried over sodium sulfate,
filtered and concentrated to give (S)-(-)-3-propionyl-4-benzyl-2-
-oxazolidanone.
[1648] Step B: To a solution of
(S)-(-)-3-propionyl-4-benzyl-2-oxazolidano- ne in THF at
-78.degree. C. was added KHMDS (1.05 eq.) (Aldrich) dropwise. The
reaction mixture was allowed to stir at -78.degree. C. for 30 min.
and then a precooled solution of di-tert-butyl-azodicarboxylate
(Aldrich) was added via a cannula. After 5 min. 2.6 eq. of acetic
acid was added. The reaction mixture was then extracted with
dichloromethane and the organic layer was washed with 1M potassium
phosphate. The organic layer was then dried over sodium sulfate,
filtered and concentrated to give
(S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4-benzyl-2-oxazolidanone-
.
[1649] Step C: To
(S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4-benzy-
l-2-oxazolidanone (0.49 moles) at 0.degree. C. in 8 mL of THF and 3
mL of water was added LiOH (1.7 eq.) and H.sub.2O.sub.2 (3.0 eq.)
and the reaction mixture was stirred at room temperature for 3
hours. The reaction mixture was then poured into a separatory
funnel and diluted with water. The aqueous mixture was extracted
with ethyl acetate and then acidified to pH 2.0 with 1N HCl and
extracted with ethyl acetate. The organic layer was then dried over
sodium sulfate, filtered and solvent removed to give
(R)-N,N'-di-BOC-2-hydrazinopropionic acid which was used without
further purification.
Example O
Synthesis of 3,5-Difluorophenyl-.alpha.-oxoacetic Acid
[1650] Step A: Ethyl 3,5-difluorophenyl-.alpha.-oxoacetate was
prepared from 1-bromo -3,5-difluorobenzene (Aldrich) according to
the procedure described in J. Org. Chem., 45 (14), 2883-2887
(1980).
[1651] Step B: Ethyl 3,5-difluorophenyl-.alpha.-oxoacetate was
hydrolyzed using General Procedure II-A (Method B) to afford
3,5-difluorophenyl-.alp- ha.-oxoacetic acid.
Example P
Synthesis of Cyclopentyl-.alpha.-hydroxyacetic Acid
[1652] The title compound (CAS No. 6053-71-0) was prepared in two
steps from cyclopentylmethanal (CAS No. 872-53-7, Wiley) using the
procedure described by Gibby, W. A.; Gubler, C. J. Biochemical
Medicine 1982, 27, 15-25.
Example Q
Synthesis of N-(3,4-dichlorophenyl)alanine
[1653] Using the procedure set forth in U.S. Pat. No. 3,598,859,
the disclosure of which is incorporated herein by reference in its
entirety, N-(3,4-dichlorophenyl)alanine was prepared. Specifically,
to a solution of 3,4-dichloroaniline (1 equivalent) (Aldrich) in
isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added
water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic
acid (2 equivalents) (Aldrich). This mixture is warmed to
40.degree. C. and sodium bicarbonate (0.25 equivalents) is added in
successive portions before heating under reflux for 4-5 days. After
cooling, the reaction mixture is poured into water and the
unreacted 3,4-dichloroaniline is removed by filtration. The
filtrate is acidified to pH 3-4 with concentrated hydrochloric acid
and the resultant precipitate is filtered, washed and dried to
yield the title compound, m.p.=148-149.degree. C.
Example R
Synthesis of N-(3,5-difluorophenyl)alanine
[1654] Using the procedure set forth in U.S. Pat. No. 3,598,859 and
Example Q above, N-(3,5-difluorophenyl)alanine was prepared using
3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid
(Aldrich).
Example S
Synthesis of .alpha.-Fluoro-3,5-difluorophenylacetic Acid
Step A--Synthesis of Methyl 3,5-Difluoromandelate
[1655] To a solution of 3,5-difluoromandelic acid (Fluorochem) in
methanol was bubbled HCl gas for 10 minutes. The reaction was
refluxed overnight. The mixture was then concentrated in vacuo and
the residue was taken up in ethyl acetate and washed with saturated
NaHCO.sub.3 and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the title
intermediate as a white solid.
[1656] C.sub.9H.sub.8F.sub.2O.sub.3 (MW=202.17); mass spectroscopy
202.
[1657] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.00 (2H, d,
J=6.58 Hz), 6.76 (1H, t, J=8.86 Hz), 5.16 (1H, d, J=5.29 Hz), 3.81
(3H, s), 3.54 (1H, d, J=5.39 Hz).
Step B--Synthesis of Methyl
.alpha.-Fluoro-3,5-difluorophenylacetate
[1658] A solution of diethylaminosulfur trifluoride (DAST) (1.1 eq)
in methylene chloride was cooled to 0.degree. C. and a pre-cooled
solution of methyl 3,5-difluoromandelate (1 eq) in methylene
chloride was added. The transfer flask was rinsed with a small
portion of methylene chloride. After 15 minutes, the cooling bath
was removed and the reaction mixture was stirred an additional 40
minutes at ambient temperature. The mixture was poured over ice and
the layers separated. The organic phase was washed with saturated
NaHCO.sub.3 and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified via HPLC eluting with 7% ethyl acetate/hexanes providing
the title intermediate as a yellow oil.
[1659] C.sub.9H.sub.7F.sub.3O.sub.2 (MW=204.16); mass spectroscopy
204.
[1660] Anal. calcd for C.sub.9H.sub.7F.sub.3O.sub.2: C, 52.95; H,
3.46. Found: C, 52.80; H, 3.73.
Step C--Synthesis of .alpha.-Fluoro-3,5-difluorophenylacetic
Acid
[1661] Following General Procedure II-A, Method B and using methyl
.alpha.-fluoro-3,5-difluorophenylacetate, the title intermediate
was prepared as a white solid having a melting point of
100-102.degree. C.
[1662] C.sub.8H.sub.5F.sub.3O.sub.2 (MW=190.13); mass spectroscopy
190.
[1663] Anal. calcd for C.sub.8H.sub.5F.sub.3O.sub.2: C, 50.54; H,
2.65. Found: C, 50.47; H, 2.79.
[1664] III. Cycloalkyl, Lactam. Lactone and Related Compounds
[1665] 1. Cycloalkane Derivatives
Example 1-1
Synthesis of
1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-aminodibenzosube-
rane
[1666] Following General Procedure C above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
1-aminodibenzosuberane, the title compound was prepared. The
product was purified by chromatography (silica, 2.5%
MeOH/CHCl.sub.3), followed by recrystallization from
n-chlorobutane/acetonitrile.
[1667] NMR data was as follows:
[1668] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.53 (m, 1H), 6,37 (d,
1H).
[1669] C.sub.26H.sub.24N.sub.2O.sub.2F.sub.2 (MW=434.48); mass
spectroscopy (MH.sup.+) 434.
[1670] 2. Cyclic Alcohol Derivatives
Example 2-A
Synthesis of 5-Amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol
Hydrochloride
Step A--Synthesis of
5-Oximo-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one
[1671] A round bottom flask was charged with
5,7-dihydro-6H-dibenzo[a,c]cy- clohepten-6-one (1.0 g, 4.81
mmol)(CAS# 1139-82-8, prepared as described in Tetrahedron Letters,
Vol. 28, No. 23, (1987), pp 2633-2636) and butyl nitrite (0.673 ml,
5.77 mmol) (Aldrich) in Et.sub.2O. The solution was cooled to
0.degree. C. and treated drop-wise with a saturated solution of
HCl(g)/Et.sub.2O. After 5 h at 0.degree. C. the resulting
precipitate was filtered, rinsed with cold Et.sub.2O and vacuum
dried to give the title compound as a colorless solid.
[1672] NMR data was as follows:
[1673] .sup.1H-nmr (CDCl.sub.3): .delta.=7.26-7.74 (m, 8H), 3.84
(m, 2H).
[1674] C.sub.15H.sub.11NO.sub.2 (MW=237.26); mass spectroscopy
(MH+) 238.
[1675] Anal. Calcd for C.sub.15H.sub.11NO.sub.2; C, 75.93 H, 4.67
N, 5.90. Found: C, 75.67 H, 4.83 N, 5.67.
Step B--Synthesis of
5-Amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol
Hydrochloride
[1676] The compound isolated above (0.489 g, 2.04 mmol) was
dissolved in THF and added drop-wise to a well-stirred mixture of
LAH (10.2 ml, 10.2 mmol)/THF. After heating to reflux for 25 h
under N.sub.2 atmosphere the solution was quenched and worked-up
according to Fieser's method. The resulting solid was rinsed with
NH.sub.3 sat/CHCl.sub.3, the filtrate evaporated and the title
compound purified by chromatography (SiO.sub.2, CHCl.sub.3).
[1677] C.sub.15H.sub.15NO (MW=225.290); mass spectroscopy (MH+)
226.
[1678] Anal. Calcd for C.sub.15H.sub.15NO; C, 79.97 H, 6.71 N,
6.22. Found: C, 80.19 H, 6.71 N, 5.91.
Example 2-1
Synthesis of
1-(R)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-2-(S)--
indanol
[1679] Following General Procedure C and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Example B) and
1-(R)-amino-2-(S)-indanol, the title compound was prepared.
Example 2-2
Synthesis of
1-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-2-(R)--
indanol
[1680] Following the General Procedure C and using
N-(3,5-difluorophenylac- etyl)-L-alanine (Example B) and
1-(S)-amino-2-(R)-indanol, the title compound was prepared.
Example 2-3
Synthesis of
1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-2-indanol
[1681] Following General Procedure C and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Example B) and
1-amino-2-indanol, the title compound was prepared.
Example 2-4
Synthesis of
trans-2-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-1-cy-
clohexanol
[1682] Following General Procedure C above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
trans-2-aminocyclohexanol hydrochloride (Aldrich), the title
compound was prepared as a solid having a melting point of
189-191.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.85 in 9% methanol/dichloromethane) and purification was by
flash chromatography using 9% methanol/dichloromethane as the
eluant.
[1683] NMR data was as follows:
[1684] .sup.1H-nmr (CD.sub.3OD): .delta.=6.8-6.6 (m, 3H), 4.1 (m,
J=7.2 Hz, 1H), 3.4 (m, 4H), 3.1 (m, 1H), 1.8-1.4 (m, 4H), 1.1 (m,
7H).
[1685] .sup.13C-nmr (CD.sub.3OD) .delta.=175.4, 173.0, 113.9,
113.6, 103.9, 103.6, 74.3, 56.9, 51.4, 51.4, 50.4, 43.4, 43.3,
43.31, 36.0, 35.5, 32.9, 32.8, 26.2, 26.2, 25.9, 25.8, 18.8,
18.7.
[1686] C.sub.17H.sub.22N.sub.2O.sub.3F.sub.2 (MW=340.37); mass
spectroscopy (MH.sup.+) 341.
Example 2-5
Synthesis of
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1,2,3,4-te-
trahydro-2-naphthol
[1687] Following General Procedure C and using using
N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and
1-amino-1,2,3,4-tetrahydro-2-naphthol, the title compound was
prepared.
Example 2-6
Synthesis of
1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-aminobenz[f]cycl-
oheptan-2-ol
[1688] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Example B) and
cis-1-amino-2-hydroxybenzosuberane (prepared using the procedure
described in C. H. Senanayake et al., Tetrahedron Lett. (1995)
36(42), 7615-7618), the title compound was prepared. The reaction
was monitored by tlc on silica gel (Rf=0.4 in 10%
methanol/dichloromethane) and purification was by silica gel
chromatography using 10% methanol/dichloromethane as the
eluant.
[1689] NMR data was as follows:
[1690] Mixture of cis isomers:
[1691] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.46 (m, 1H), 5.05 (d,
1H).
[1692] C.sub.22H.sub.23N.sub.2O.sub.3F.sub.2 (MW=402.44); mass
spectroscopy (MH.sup.+) 402.
[1693] Using the above procedure, followed by crystallization from
acetonitrile gave a single isomer:
[1694] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.46 (m, 1H), 5.03 (d,
1H).
[1695] C.sub.22H.sub.23N.sub.2O.sub.3F.sub.2 (MW=402.44); mass
spectroscopy (MH.sup.+) 402.
Example 2-7
Synthesis of
5-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-
-6H-dibenzo[a,c]cyclohepten-6-ol
[1696] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
5-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohept- en-6-ol hydrochloride
(Example 2-A), the title compound was prepared as a colorless
solid. The product was purified by flash chromatography using 98:2
CHCl.sub.3/MeOH.
[1697] C.sub.26H.sub.24F.sub.2N.sub.2O.sub.3 (MW=450.48); mass
spectroscopy (MH+) 451.
[1698] Anal. Calcd for C.sub.26H.sub.24F.sub.2N.sub.2O.sub.3; C,
69.32 H, 5.37 N, 6.22. Found: C, 69.02 H, 5.53, N, 6.34.
[1699] 3. Cyclic Ketone Derivatives
General Procedure 3-A
Jones Oxidation Procedure
[1700] The compound to be oxidized was stirred in acetone and the
Jones reagent was added in portions until the starting material was
consumed. The reaction mixture was quenched with isopropanol and
the mixture was filtered through Celite and concentrated under
reduced pressure. The residue was partitioned between ethyl acetate
and water and the organic portion was dried over sodium sulfate and
then concentrated under reduced pressure. The crude product was
purified by silica gel chromatography and/or recrystallization.
General Procedure 3-B
Swern Oxidation Procedure
[1701] To a stirred mixture of oxalyl chloride (0.1.5 mL, 1.2 mmol)
in 10 mL of dichloromethane cooled to -78.degree. C. was added DMSO
(0.106 mL, 1.5 mmol) and the mixture was stirred for 10 minutes. A
solution of th alcohol (0.1828 g, 0.60 mmol) in 20 mL of chloroform
was added dropwise. The reaction mixture was stirred at -78.degree.
C. for 2 hours, and then 0.5 mL (3.6 mmol) of triethylamine was
added. Stirring was continued for 1 hour and then the mixture was
allowed to warm to room temperature and stirring was continued at
ambient temperature overnight. The mixture was then diluted with 50
mL of dichloromethane, washed with brine (3.times.), dried over
magnesium sulfate, filtered and evaporated to dryness to give the
crude product which as typically purified by column
chromatography.
Example 3-1
Synthesis of
1-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-aminoindan-2-
-one
[1702] Following General Procedure 3-A using the product from
Example 2A-2, the title compound was prepared as a solid having a
melting point of 221-224.degree. C. The reaction was monitored by
tlc on silica gel (Rf=0.4 in 15% methanol/dichloromethane) and
purification was by silica gel chromatography using 5%
methanol/dichloromethane as the eluant, followed by
recrystallization from 1-chlorobutane/acetonitrile.
[1703] NMR data was as follows:
[1704] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.25 (d, 3H), 4.34 (m,
1H), 5.22 (d, 1H), 8.37 (d, 1H), 8.72 (d, 1H).
[1705] C.sub.20H.sub.18N.sub.2O.sub.3F.sub.2 (MW=372.38); mass
spectroscopy (M.sup.+) 372.34.
Example 3-2
Synthesis of
2-(N'-(Phenylacetyl)-L-alaninyl)aminocyclohexan-1-one
[1706] Following General Procedure 3-B above using
2-(N'-(phenylacetyl)-L-- alaninyl)-amino-1-cyclohexanol (Example
2-4), the title compound was prepared as a solid having a melting
point of 150-157.degree. C. Purification was by silica gel
chromatography using 3% methanol/dichloromethane as the eluant.
[1707] NMR data was as follows:
[1708] .sup.1H-nmr (CDCl.sub.3): .delta.=7.24-7.40 (m, 5H), 6.7-6.9
(m, 1H), 6.1 (m, 1H), 4.5 (m, 1H), 4.40 (m, 1H), 3.61 (s, 2H), 3.59
(s, 2H), 2.55 (m, 2H), 2.38 (m, 1H0, 2.13 (m, 1H0, 1.72-1,92 (m,
2H), 1.63 (m, 1H), 1.32 (m, 4H).
[1709] .sup.13C-nmr (CDCl.sub.3) .delta.=207.3, 171.75, 171.69,
170.8, 170.6, 134.6, 134.5, 129.3, 129.2, 128.9, 127.3, 127.2,
57.93, 57.88, 48.8, 48.7, 43.5, 40.99, 40.96, 35.0, 34.8, 27.8,
23.96, 23.92, 18.7, 18.4.
[1710] C.sub.17H.sub.27N.sub.3O.sub.3 (MW=302.38).
Example 3-3
Synthesis of
5-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-
-6H-dibenzo[a,c]cyclohepten-6-one
[1711] Using General Procedure 3-A and using
5-[N'-(3,5-Difluorophenylacet-
yl)-L-alaninyl]-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol
(Example 2-7), the title compound was prepared. The product was
purified by flash chromatography using 97:3 CHCl.sub.3/MeOH.
[1712] NMR data was as follows:
[1713] .sup.1H-nmr (CDCl.sub.3): .delta.=7.61-7.16 (m, 8H), 6.78
(m, 2H), 6.69 (m, 1H), 6.31 and 6.21 (two d, 1H), 5.51 (d, 1H),
4.67 (m,1H), 3.66 (m, 2H), 3.49 (two s, 2H), 1.49 and 1.38 (two m,
3H).
[1714] C.sub.26H.sub.22F.sub.2N.sub.2O.sub.3 (MW=448.46); mass
spectroscopy (MH+) 449.
[1715] Anal. Calcd for C.sub.26H.sub.22F.sub.2N.sub.2O.sub.3; C,
69.63 H, 4.94 N, 6.25. Found: C, 69.67 H, 4.85, N, 6.23.
Example 3-4
Synthesis of
1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-aminobenz[f]cycl-
oheptan-2-one
[1716] Following General Procedure 3-A and using
1-(N'-(3,5-difluorophenyl-
-acetyl)-L-alaninyl)-aminobenz[f]cycloheptan-2-ol (Example 2-6),
the title compound was prepared.
[1717] 4. Lactones
Example 4-1
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-.gamma.-bu-
tyrolactone
[1718] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
.alpha.-amino-.gamma.-butyrolactone hydrobromide (Aldrich), the
title compound was prepared as a solid having a melting point of
174-177.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.52 in 10% methanol/dichloromethane) and purification was by
silica gel chromatography.
[1719] NMR data was as follows:
[1720] .sup.1H-nmr (CDCl.sub.3): .delta.=8.4 (m, 2H), 7.1 (m, 1H);
7.0 (m, 2H); 4.6 (m, 1H); 4.4 (m, 2H); 3.52 (s, 2H); 2.2 (m, 2H);
1.22 (m, 3H).
[1721] .sup.13C-nmr (CDCl.sub.3): .delta.=175.6, 172.7, 169.2,
112.8, 106.6, 102.2, 65.6, 48.5, 48.3, 41.6, 28.6, 18.7.
[1722] C.sub.15H.sub.16F.sub.2N.sub.2O.sub.4 (MW=326); mass
spectroscopy (MH.sup.+) 327.
Example 4-2
Synthesis of
3-(N'-(3,4-dichlorophenyl)-D,L-alaninyl)amino-.gamma.-butyrol-
actone
[1723] Following General Procedure A and using
N-(3,4-dichlorophenyl)-D,L-- alanine (Example A) and
.alpha.-amino-.gamma.-butyrolactone hydrobromide (Aldrich), the
title compound was prepared. The reaction was monitored by tlc on
silica gel (Rf=0.19 in 60% EtOAc/hexane) and purification was by
silica gel chromatography using 60% EtOAc/hexanes as the
eluent.
[1724] NMR data was as follows:
[1725] .sup.1H-nmr (CDCl.sub.3): .delta.=1.56 (d, J=7 Hz, 3H),
2.0-2.15 (m, 1H), 2.75-2.9 (m, 1H), 3.75-3.90 (m, 1H), 4.0 (brs,
1H), 4.2-4.35 (m, 1H), 4.45 (t, J=7, 1H), 4.5-4.7 (m, 1H), 6.4-6.5
(m, 1H), 6.67 (d, J=3 Hz, 1H), 7.0-7.1 (m, 1H), 7.2-7.3 (m,
1H).
[1726] .sup.13C-nmr (CDCl.sub.3): .delta.=20.0, 30.7, 49.4, 55.,
66.5, 113.7, 115.5, 112.8, 131.5, 133.7, 146.3, 174.5, 175.5.
[1727] C.sub.13H.sub.14C.sub.2N.sub.2O.sub.3 (MW=317.17); mass
spectroscopy (M.sup.+) 317.
Example 4-3
Synthesis of
4-(N'-(Cyclopentylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-iso-
chromanone
[1728] Following General Procedure A above using
N-(cyclopentylacetyl)-L-a- lanine and
4-amino-1,1-dimethyl-3-isochromanone, the title compound could be
prepared.
Example 4-4
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,1-dimethy-
l-3-isochromanone
[1729] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine and
4-amino-1,1-dimethyl-3-isochromanone, the title compound could be
prepared.
[1730] 5. Lactams
General Procedure 5-A
N-Alkylation of Lactams
[1731] To a stirred solution of a BOC-protected
.alpha.-aminocaprolactam (6.87 g, 30 mmol) in DMF (150 mL) was
added in portions 97% NaH (1.08 g, 45 mmol). Bubbling occured
immediately and followed by heavy precipitation. After 10 min.,
benzyl bromide (3.93 mL, 33 mmol) was added. The precipitate
dissolved quickly and in about 10 min. a clear solution was
obtained. The reaction mixture was stirred overnight and then
evaporated as completely as possible on a rotovap at 30.degree. C.
Ethyl acetate (100 mL) was added to the residue and this mixture
was washed with water, brine, and dried over magnesium sulfate.
After filtration and concentration, a thick liquid (10 g) was
obtained which was then chromatographed over silica gel with 1:3
ethyl acetate/hexane as the eluant to provide 5.51 g (58%) of the
N-benzylated product as an oil. Other lactams and alkylating agents
may be used in this procedure to obtain a wide variety of
N-alkylating agents may be used in this procedure to obtain a wide
variety of N-alkylated lactams. Various bases, such as
LiN(SiMe.sub.3), may also be employed.
General Procedure 5-B
BOC Removal Procedure
[1732] The BOC-protected compound in a 1:1-2:1 mixture of
CH.sub.2Cl.sub.2 and 2 hours. The solution was then stripped to
dryness and the residue was taken up in ethyl acetate or
CH.sub.2Cl.sub.2. The solution was washed with saturated aqueous
NaHCO.sub.3 and the aqueous phase was adjusted to a basic pH, then
extracted with ethyl acetate or CH.sub.2Cl.sub.2. The organic phase
was washed with saturated aqueous NaCl and dried over MgSO.sub.4.
The solution was stripped free of solvent on a rotary evaporator to
yield the product.
General Procedure 5-C
Synthesis of .alpha.-Aminolactams
[1733] The Schmidt reaction was conducted on 4-ethylcyclohexanone
using hydroxyamine sulfonic acid as described in Olah, Org Synth.
Collective, Vol. VII, page 254, to provide 5-ethylcaprolactam in
76% yield. Using the procedure described in Watthey, et al., J.
Med. Chem., 1985, 28, 1511-1516, this lactam was then dichlorinated
with PCl.sub.5 at the alpha position and reduced by hydrogenation
to provide four isomeric monochlorides (two racemic mixture). The
two racemic mixtures were separated from each other by column
chromatography using silica gel and each racemic mixture was
reacted with sodium azide to yield the corresponding azide which
was hydrogenated to provide the corresponding .alpha.-aminolactans.
Other cycloalkanones may be employed in this procedure to provide a
wide variety of .alpha.-aminolactams. In some cases, such as when
preparing the 9-membered ring .alpha.-aminolactam, longer reaction
times, higher reaction temperatures and an excess of sodium azide
may be required. For example, the 9-membered ring
.alpha.-aminolactam required 5 equivalents of sodium azide, a
reaction temperature of 120.degree. C. and a reaction time of 4
days. Such conditions can be readily determined by those of
ordinary skill in the art.
General Procedure 5-D
Synthesis of 4-Amino-1.2,3,4-tetrahydroisoquinoline-3-ones
[1734] The 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivatives
employed in this invention can be prepared by the following
art-recognized procedures. The conditions for these reactions are
further described in D. Ben-Ishai, et al., Tetrahedron, 43, 439-450
(1987). The following intermediates were prepared via this
procedure:
[1735] 3-amino-1,2,3,4-tetrahydroisoquinolin3-one
[1736] 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1737] 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1738] cis and
trans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1739] 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1740] 4-amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1741] 9-amino(fluoren-1-yl)glycine
.delta.-lactam-1,2,3,4-tetrahydroisoqu- inolin-3-one.
[1742] Step A--Preparation of N-Bismethoxycarbonylaminoacetic Acid:
To one mole equivalent of glyoxylic acid in 2 liters of
ethanol-free chloroform was added two mole equivalents of methyl
carbamate and 0.1 mole equivalent of naphthalene sulfonic acid. The
reaction mixture was then brought to a reflux for 6 hours. Water
was removed using an inverse Dean Stark trap. The reaction was then
cooled and the product filtered and washed with chloroform. The
white solid was recrystallized from ethyl acetate/hexanes to give a
white powder in 65% yield.
[1743] Step B--Coupling Procedure: To 0.0291 moles of
N-bismethoxycarbonylaminoacetic acid (or the appropriate
carboxcyclic acid) in 200 mL of THF was added one mole equivalent
of EDC.HCl, a benzylamine, HOBT, and diisopropylethylamine. The
reaction was allowed to stir at room temperature for 18 hours and
then poured into a separatory funnel and extracted into ethyl
acetate. The ethyl acetate solution was washed with 1 molar
K.sub.2CO.sub.3 and then 1 molar HCl. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and solvent removed to give the
crystalline benzylamide of N-bismethoxycarbonylaminoacetic acid.
This material was used without further purification. Typical yields
range from 40-55%.
[1744] Step C--Cyclization Procedure: The benzylamide of
N-bismethoxycarbonylaminoacetic acid (0.008 moles) was dissolved in
75 mL of methanesulfonic acid and allowed to stir over night at
room temperature. The reaction mixture was poured over ice and
extracted into ethyl acetate. The ethyl acetate extract was washed
with 1 molar K.sub.2CO.sub.3 and then 1 N HCl. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and the solvent removed
to give the crystalline
4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one in
50-90% yield. This material was used without further
purification.
[1745] Step D--Removal of the Methoxyoxycarbonyl Grout (MOC): To
the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one
(3.4 mmoles) in 30 mL of acetonitrile was added 2 mole equivalents
of trimethylsilyliodide (TMSI). The reaction mixture was heated to
50-80.degree. C. for 3 hrs and then cooled and poured into a
seperatory funnel. The reaction mixture was diluted with ethyl
acetate and washed with 1 molar K.sub.2CO.sub.3 and then with 5%
NaHSO.sub.3. The organic layer was dried over Na.sub.2SO.sub.4 and
filtered. The solvent was removed under reduced pressure to give
the 4-amino-1,2,3,4-tetrahydroisoq- uinoline-3-one derivative.
Typical yields range from 50-87%.
[1746] Step E--Alternative Procedure for Removal of the
Methoxyoxycarbonyl Group: To 3.8 mmoles of the MOC-protected
compound was added 10 mL of 30% HBr in acetic acid and this
reaction mixture was heated to 60.degree. C. for 3 hrs. The mixture
was then cooled and hexanes were added. The hexanes layer was
decanted off and the residue as placed under reduced pressure to
give a tan solid. This solid was slurried in ether and filtered to
give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one hydrobromide
salt. Typical yields range from 57-88%.
Example 5-A
Synthesis of 3-Amino-1,2,3,4-tetrahydroquinolin-2-one
[1747] Step A: Sodium (0.30 g, 110M %) was added to anhydrous
ethanol (45 mL) and the reaction mixture was stirred until
homogenous. Diethyl N-acetylaminomalonate (2.51 g, 100 M %) was
added in one portion and this mixture was stirred for 1 h.
2-Nitrobenzyl bromide (2.5 g, 100 M %) was then added in one
portion and the reaction mixture was stirred for 3 h. The reaction
was poured into water and extracted with ethyl acetate (3.times.)
and then backwashed with water (3.times.) and brine (1.times.).
Treatment with MgSO.sub.4, rotoevaporation, and chromatography (30%
EtOAc/hexanes) yielded diethyl N-acetylamino-2-nitrobenzylmalonate
in 82% yield.
[1748] Step B: Diethyl N-acetylamino-2-nitrobenzylmalonate (1 g,
100M %) was dissolved in a minimum amount of EtOH. Pd/C (10%, 0.05
g) was added and the reaction mixture was subjected to 50 psi of
H.sub.2 for 3 hours. The reaction was then filtered thru a pad of
celite. Additional EtOH (25 mL) and TsOH (catalytic amount, 0.01 g)
were added and this mixture was refluxed for 2 hours. The reaction
was rotoevaporated to a residue and then partitioned between water
and ethyl acetate. The water layer was extracted with ethyl acetate
(3.times.) and the combined ethyl acetate extracts were washed with
water (3.times.) and then brine (1.times.). Treatment with
MgSO.sub.4 and rotoevaporation yielded pure
3-(N-acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one
(89% yield).
[1749] Step C:
3-(N-Acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-- 2-one
(0.75 g, 100M %) was suspended in 6N HCl (25 mL) and the mixture
was heated to 100.degree. C. for 3 hours. The reaction was cooled,
rotoevaporated to a residue and then partitioned between water and
ethyl acetate. The water was extracted with ethyl acetate
(3.times.) and the combined ethyl acetate extracts were then washed
with water (3.times.) and then brine (1.times.). Treatment with
MgSO.sub.4 followed by rotoevaporation yielded
3-(R,S)-amino-1,2,3,4-tetrahydroquinolin-2-one (72% yield).
Example 5-B
Synthesis of
4-Amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one
[1750] Step A: To a solution of 4-cyanopyridine (Aldrich) (0.150
moles) in 300 mL of dry ether was added 1.1 eq. of phenylmagnesium
bromide (Aldrich) dropwise. The reaction was refluxed for 2 hours
and then stirred overnight at room temperature. Sodium borohydride
(1.0 eq.) was added dropwise as a solution in 200 mL of methanol
(CAUTION--very exothermic). The reaction was then heated to reflux
for 6 hours, cooled and quenched with a saturated solution of
ammonium chloride. The solution was decanted from the salt in the
reaction mixture and acidified with 1N HCl. After washing the
aqueous layer with ethyl acetate, the pH of aqueous layer was
adjusted to about 9.0 with 1N sodium hydroxide (cold). The aqueous
layer was then extracted with ethyl acetate and the organic
extracts washed with brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated to give 4-pyridyl-.alpha.-benzyl amine as a thick
yellow oil.
[1751] Step B: Following General Procedure 5-D and using
4-pyridyl-.alpha.-benzyl amine, the title compound was
prepared.
Example 5-C
Synthesis of
4-Amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one
[1752] Step A: 2-Pyridyl-.alpha.-benzyl amine was prepared by
substituting 2-cyanopyridine (Aldrich) for 4-cyanopyridine in the
procedure described in Example 5-B.
[1753] Step B: Following General Procedure 5-D and using
4-pyridyl-.alpha.-benzyl amine, the title compound was
prepared.
Example 5-D
Synthesis of
4-Amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one
[1754] Step A: Following the procedure described in J. Med. Chem.,
1982, 25, 1248, and using 3-benzoyl-pyridine (Aldrich),
3-pyridyl-.alpha.-benzy- l amine was prepared.
[1755] Step B: Following General Procedure 5-D and using
3-pyridyl-.alpha.-benzyl amine, the title compound was
prepared.
Example 5-E
Synthesis of
4-Amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1756] Step A: To a Parr bottle containing 3-benzoylbenzoic acid
(0.044 moles) (Aldrich) in 150 mL of ethyl acetate and 4.5 mL of
concentrated H.sub.2SO.sub.4 was added 10 grams of 5% Pd/C. The
mixture was hydrogenated on a Parr apparatus under hydrogen (45
psi) overnight. The reaction mixture was then filtered through
Hyflo, washing with ethyl acetate. The filterate was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give an oil. The oil
was slurried in hexane and the resulting white solid was collected
by filtration to afford 3-benzylbenzoic acid, which was used
without further purification.
[1757] Step B: To the product from Step A (0.0119 moles) was added
150 mL of CH.sub.2Cl.sub.2, one drop of DMF, 10 mL of oxalyl
chloride, and the mixture was stirred at room temperature for 3
hours. After cooling to 10.degree. C., 30 mL of NH.sub.4OH
(exothermic) was added and the mixture was stirred for 30 min. The
reaction mixture was then concentrated and the resulting residue
diluted with ethyl acetate. The organic layer was washed with 1N
NaOH, brine, dried over Na.sub.2SO.sub.4, and concentrated to give
the 3-(benzyl)benzamide as a white solid, which was used without
further purification.
[1758] Step C: To a solution of 3-(benzyl)benzamide (0.0094 moles)
from Step B in 70 of toluene was added 8 mL of Red-Al.RTM. (65+wt.
% solution of sodium bis(2-methoxyethoxy)aluminum hydride in
toluene, Aldrich) (CAUTION--reaction very exothermic). The reaction
mixture was then heated at 60.degree. C. for 2 hours and then
poured over ice. The resulting mixture was extracted with ethyl
acetate and the combined extracts were washed with water and brine.
The organic layer was extracted with 1N HCl and the aqueous layer
washed with ethyl acetate. The pH of the aqueous layer was then
adjusted to about 9.0 with 1N NaOH and extracted with ethyl
acetate. The organic extracts were washed with water and brine and
then concentrated to give 3-(benzyl)benzyl amine.
[1759] Step D: Following General Procedure 5-D and using
3-(benzyl)benzyl amine, the title compound was prepared.
Example 5-F
Synthesis of
4-Amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1760] Step A: To a solution of 4-biphenylcarboxamide (Aldrich)
(0.025 mole) in 150 mL of THF cooled to 10.degree. C. was added a
solution of 1.5 eq of LAH (1M in THF) dropwise. The reaction
mixture turned from a white slurry to a green homogenous solution
and then to a yellow homogeneous solution. The reaction was then
quenched with 2.5 mL of 1N NaOH. The mixture was then filtered
through Hyflo and extracted with ethyl acetate. The organic layer
was then washed with 1N HCl. The pH of the resulting aqueous layer
was adjusted to about 9 with 1N NaOH and extracted with ethyl
acetate. The organic extracts were washed with water and brine, and
then dried over Na.sub.2SO.sub.4, filtered and concentrated to give
4-(phenyl)benzyl amine as a white solid.
[1761] Step B: Following General Procedure 5-D and using
4-(phenyl)benzyl amine, the title compound was prepared.
Example 5-G
Synthesis of cis- and
trans-4-Amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin- -3-one
[1762] Step A: Following General Procedure 5-D and using
.alpha.-phenylbenzylamine (Aldrich),
4-amino-1-phenyl-1,2,3,4-tetrahydroi- soquinolin-3-one was
prepared.
[1763] Step B: To a solution of
4-amino-1-phenyl-1,2,3,4-tetrahydroisoquin- olin-3-one (0.00158
moles) from Step A in 20 mL of CH.sub.2Cl.sub.2 was added 2.0 eq.
of triethylamine and Boc anhydride (1.1 eq.). The reaction was
stirred overnight at room temperature and then concentrated. The
residue was diluted with ethyl acetate and water. The pH of the
aqueous layer was adjusted to 3.0 with sodium bisulfate and the
layers were separated. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by LC 2000, eluting with ethyl acetate/hexanes (70:30) to
give a white solid containing a 1:1 mixture of cis- and
trans-4-(N-Boc-amino)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-o-
ne isomers. This mixture was recrystallized from ethyl acetate to
give the pure trans isomer and a cis isomer-enriched mixture of cis
and trans isomers. This mixture was recrystallized again from ethyl
acetate/hexanees (70:30) to give the pure cis isomer.
[1764] Step C: The cis isomer and the trans isomer from Step B were
separately deprotected using General Procedure 8-J to give
cis-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one and
trans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one.
Example 5-H
Synthesis of
4-Amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1765] Step A: To a solution of 1-bromo-3-phenylbenzene (Aldrich)
(0.0858 moles) in 300 mL of dry THF cooled to -78.degree. C. was
added tert-butyl lithium (2 eq.) (1.7M in hexane) dropwise. The
reaction mixture was stirred for 40 min. at -78.degree. C. and then
quenched with 2 eq. of DMF (13.24 mL). The resulting mixture was
stirred for 20 min. and then poured into a separatory funnel and
extracted with CH.sub.2Cl.sub.2. The organic extracts were washed
with water, dried over Na.sub.2SO.sub.4, filtered and concentrated
to give a brown oil. This oil was purified by LC 2000
chromatography, eluting with ethyl acetate/hexanes (5:95) to give
3-biphenylcarboxaldehyde.
[1766] Step B: To a solution of 3-biphenylcarboxaldehyde (0.011
eq.) in 30 mL of methanol was added 10 eq. of 7N NH.sub.3/MeOH and
NaCNBH.sub.4 (2 eq.). A yellow gum precipitated from solution. The
solution was then heated at 60.degree. C. until gum dissolved and
the solution was stirred at room temperature overnight. The
reaction mixture was then concentrated and the resulting residue
diluted with ice water and ethyl acetate. The organic layer was
then washed with brine and extracted with 5N HCl. The pH of the
aqueous layer was then adjusted to 12 and the aqueous layer was
extracted with cold ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
3-(phenyl)benzyl amine as an oil.
[1767] Step C: Following General Procedure 5-D and using
3-(phenyl)benzyl amine, the title compound was prepared.
Example 5-I
Synthesis of
4-Amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1768] Step A: To a solution of benzoyl chloride (0.123 moles)
(Aldrich) in 600 mL of CH.sub.2Cl.sub.2 was added 2.0 eq. of
phenethylamine (Aldrich) dropwise. The reaction mixture was stirred
at room temperature for 3 hours and then poured into a separatory
and extracted with CH.sub.2Cl.sub.2. The organic extracts were
washed with water and 1N HCl, and then dried over Na.sub.2SO.sub.4,
filtered and concentrated to give N-phenethyl benzamide.
[1769] Step B: Reduction of N-phenethyl benzamide using the
procedure of Example 5-E, Step C afforded N-benzyl-N-phenethylamine
as an oil.
[1770] Step C: Following General Procedure 5-D and using
N-benzyl-N-phenethylamine, the title compound was prepared.
Example 5-J
Synthesis of 3-Amino-1-methyl-2-indolinone Monohydrochloride
[1771] Step A: (2,3-Dihydro-1-methyl-2-oxo-1H-indol-3-yl)carbamic
acid methyl ester (CAS No. 110599-56-9) was prepared using the
procedure described in Ben-Ishai, D.; Sataty, I.; Peled, N.;
Goldshare, R. Tetrahedron 1987, 43, 439-450. The starting materials
for this preparation were N-methylaniline (CAS# 100-61-8, Eastman
Kodak Co.), glyoxylic acid (CAS# 298-12-4, Aldrich), and methyl
carbamate (CAS# 598-55-0, Aldrich).
[1772] Step B: The product from Step A (333.5 mg) in 31% HBr in
AcOH (10 mL) was heated to 50-60.degree. C. for 2 hours. The
resulting orange solution was concentrated to a thick orange oil
which was dissolved in EtOAc (15 mL) and the product extracted into
1 M aq. HCl (10 mL). The aqueous acid was neutralized with aq.
NaHCO.sub.3 and the product extracted into CH.sub.2Cl.sub.2
(10.times.10 mL). HCl (gas) was passed through the combined
CH.sub.2Cl.sub.2 extracts to form a purple solution. The solution
was concentrated to provide the title compound (262.8 mg) as a
purple solid.
Example 5-K
Synthesis of
3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/Tin
Complex
Step A:--Synthesis of 4-Phenyl-3,4-dihydrocarbostyril
[1773] 4-Phenyl-3,4-dihydrocarbostyril (CAS# 4888-33-9) was
prepared in two steps using the procedure described by Conley, R.
T.; Knopka, W. N. J. Org. Chem. 1964, 29, 496-497. The starting
materials for this preparation were cinnamoyl chloride (Aldrich)
and aniline (Aldrich). The title compound was purified by flash
chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (4:1).
Step B:--Synthesis of 1-Methyl-4-phenyl-3,4-dihydrocarbostyril
[1774] To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion
in mineral oil) in THF (50 mL) under N.sub.2 at 0.degree. C. was
added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via
cannula over a period of 5 minutes. The resulting pale yellow
mixture was stirred at 0.degree. C. for 10 minutes, then MeI (2.0
eq., 1.39 mL) was added. The opaque yellow mixture was allowed to
slowly (ice bath not removed) warm to ambient temperature with
stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were
added and the phases partitioned. The organic phase was washed with
dilute NaHCO.sub.3 (1.times.100 mL), brine (1.times.100 mL), then
dried over MgSO.sub.4, filtered, concentrated, and the residue
purified by flash chromatography eluting with
CH.sub.2Cl.sub.2/EtOAc (19:1 gradient to 15:1) to provide
1-methyl-4-phenyl-3,4-dihydrocarbostyr- il.
Step C:--Synthesis of
3-Azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyr- il
[1775] Following General Procedure 8-K,
3-azido-1-methyl-4-phenyl-3,4-tran- s-dihydrocarbostyril was
prepared as a white solid. The product was purified by flash
chromatography eluting with CH.sub.2Cl.sub.2/hexanes/Et- OAc
15:15:1.
[1776] Selected .sup.1H-NMR data for the title compound
(CDCl.sub.3): .delta.=4.46 (d, 1H, J=10.57 Hz), 4.18 (d, 1H,
J=10.63 Hz).
Step D:--Synthesis of
3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyr- il/Tin
Complex
[1777] To a mixture of SnCl.sub.2 (350.7 mg) in MeOH (7 mL) under
N.sub.2 at 0.degree. C. was added the product from Step C (257.4
mg) in MeOH/THF (5 mL/5 mL) via cannula over a period of 1 minute.
The cooling bath was removed the solution allowed to warm to
ambient temperature for 8 hours (No starting material by TLC). The
solution was concentrated to a yellow foam, THF (10 mL) was added
and the mixture was re-concentrated and used without further
purification.
Example 5-L
Synthesis of
3-Amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril
Step A:--Synthesis of
3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyr- il
[1778] 3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril was
prepared following General Procedure 8-F using
3-azido-1-methyl-4-phenyl-3,4-trans- -dihydrocarbostyril from
Example 5-K, Step C. The product was purified by L.C. 2000 eluting
with EtOAc/hexanes (4:1) to yield a white solid.
[1779] Selected .sup.1H-NMR data for the title compound
(CDCl.sub.3): .delta.=4.03 (d, 1H, J=12.8 Hz), 3.92 (d, 1H, J=12.7
Hz).
Step B:--Synthesis of
3-(4-Chlorobenzylimine)-1-methyl-4-phenyl-3,4-trans--
dihydrocarbostyril
[1780] To a solution of the product from Step A (1 eq., 239.6 mg)
in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2 at ambient temperature
was added 4-chlorobenzaldehyde (1.05 eq., 140 mg, Aldrich),
Et.sub.3N (1.4 eq., 185 mL), and MgSO.sub.4 (3.6 eq., 411 mg). The
resultant mixture was stirred at room temperature for 73 hours. The
solids were removed by filtration through a plug of Celite, rinsing
with CH.sub.2Cl.sub.2, and the filtrate concentrated to provide
3-(4-chlorobenzylimine)-1-methyl-4-phenyl-3,4-tra-
ns-dihydrocarbostyril as a thick white foam.
Step C:--Synthesis of
3-Amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril
[1781] To a solution of diisopropylamine (1.05 eq., 0.132 mL) in
THF (5 mL) under N.sub.2 at -78.degree. C. was added a solution of
n-BuLi (1.05 eq., 0.588 mL of a 1.6 M solution in hexanes) and the
result solution was stirred for 30 minutes. To this solution was
added the product from Step B (1.0 eq., 336 mg) in THF (2 mL) via
cannula. The solution was allowed to warm to 0.degree. C., then
quenched with 1 M aq. HCl (3 mL) and allowed to warm to room
temperature with stirring overnight. The product was extracted into
H.sub.2O and washed with EtOAc (1.times.), then the aqueous acid
was basified with 1 M aq. K.sub.2CO.sub.3 and the product extracted
into EtOAc. The EtOAc extract was dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give
3-amino-1-methyl-4-phenyl-3,4-cis-dihy- drocarbostyril.
[1782] Selected .sup.1H-NMR data for the title compound
(CDCl.sub.3): .delta.=4.31 (d, 1H, J=6.6 Hz).
Example 5-M
Synthesis of
3-Amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbo-
styril/Tin Complex
Step A:--Synthesis of
1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyri- l
[1783] 1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril was
prepared from the product of Example 5-K, Step A (CAS# 4888-33-9)
by the Boc procedure for aryl amides described by Grehn, L.;
Gunnarsson, K.; Ragnarsson, U. Acta Chemica Scandinavica B 1986,
40, 745-750; employing (Boc).sub.2O (Aldrich) and catalytic DMAP
(Aldrich) in acetonitrile. The product was purified by flash
chromatography eluting with CH.sub.2Cl.sub.2 gradient to
CH.sub.2Cl.sub.2/EtOAc (19:1) and isolated as a pale yellow
oil.
Step B--Synthesis of
3-Azido-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihy-
drocarbostyril
[1784] Following General Procedure 8-K using the product from Step
A, the title compound was prepared as a 12.4:1 mixture of trans/cis
isomers which were separated by flash chromatography eluting with
hexanes/Et.sub.2O (6:1 gradient to 4:1) in the first column and
hexanes/EtOAc (12:1) in a second column. The pure trans isomer was
used in Step C.
[1785] Selected .sup.1H-NMR data for the title compound
(CDCl.sub.3): .delta.=4.45 (d, 1H, J=11.1 Hz), 4.24 (d, 1H, J=11.2
Hz).
Step C:--Synthesis of
3-Amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dih-
ydrocarbostyril/Tin Complex
[1786] To a mixture of SnCl.sub.2 (450.6 mg) in MeOH (9 mL) under
N.sub.2 at 0.degree. C. was added the product from Part D (433.0
mg) in MeOH (15 mL) via cannula over a period of 1 minute. The
cooling bath was removed the solution allowed to warm to ambient
temperature for 17 hours. The solution was concentrated to an
amorphous yellow solid and used without further purification.
Example 5-N
Synthesis of (S)-3-Amino-1-benzyl-.delta.-valerolactam
Step A:--Synthesis of L-(+)-Ornithine Methyl Ester
Hydrochloride
[1787] Into a stirred suspension of L-(+)-ornithine hydrochloride
(Aldrich) in methanol was bubbled anhydrous hydrochloric acid gas
until the solution was saturated. The reaction mixture was capped
with a rubber septum and stirring was continued overnight at room
temperature. The solvent was then stripped under reduced pressure
and the residue triturated with ether. The resulting solid was
dried under reduced pressure to afford L-(+)-ornithine methyl ester
hydrochloride as a white solid (97% yield).
Step B:--Synthesis of (S)-3-Amino-.delta.-valerolactam
[1788] Sodium spheres in oil (2.0 eq.) (Aldrich) were washed with
hexanes (2.times.) and methanol (2.3 mL/mmol) was slowly added. The
reaction mixture was stirred under nitrogen until the sodium
dissolved and then L-(+)-ornithine methyl ester hydrochloride (1
eq.) in methanol (2.3 mL/mmol) was added dropwise. The reaction
mixture was stirred for 16 hours and then diluted with diethyl
ether (5 mL/mmol) and filtered to remove the solids. The solvent
was then removed under reduced pressure and the residue was heated
at 70.degree. C. for 3 hours under reduced pressure. The residue
was then triturated with dichloromethane/ether, the solvent
decanted and the resulting residue dried under reduced pressure to
afford (S)-3-amino-.delta.-valerolactam (44% yield).
Step C:--Synthesis of N-Boc-(S)-3-Amino-.delta.-valerolactam
[1789] (S)-3-Amino-.delta.-valerolactam (1 eq.) was dissolved in
dioxane and the solution was chilled to 0.degree. C. BOC-anhydride
(1.3 eq.) was added and the ice bath was removed allowing the
solution to come to room temperature and stirring was continued for
16 hours. The solution was rotory evaporated to afford
N-Boc-(S)-3-amino-.delta.-valerolactam.
Step D:--Synthesis of (S)-3-Amino-1-benzyl-.delta.-valerolactam
[1790] Following General Procedure 5-A and using
N-Boc-(S)-3-amino-.delta.- -valerolactam and benzyl bromide
provided N-Boc-(S)-3-amino-1-benzyl-.delt- a.-valerolactam. Removal
of the Boc group using General Procedure 5-B afford the title
compound.
Example 5-O
Synthesis of 4-Amino-2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane
Hydrochloride
Step A:--Synthesis of 2-Aza-3-oxobicyclo[3.2.1]octane and
3-Aza-2-oxobicyclo[3.2.]octane (9:1 Mixture)
[1791] To (.+-.)-norcamphor (Aldrich) in 1 mL/mmole of acetic acid
was added 1.5 eq. of hydroylamine-O-sulfonic acid. The reaction
mixture was heated to reflux under nitrogen for 1 hour and then
saturated sodium carbonate and dilute sodium hydroxide were added.
The resulting mixture was extracted with dichloromethane and the
organic extracts washed with brine, dried over sodium sulfate, and
the solvent removed under reduced pressure. Purification of the
residue by column chromatography afforded a 9:1 mixture of
2-aza-3-oxobicyclo[3.2.1]octane and
3-aza-2-oxobicyclo[3.2.1]octane.
Step B:--Synthesis of 2-Aza-2-benzyl-3-oxobicyclo[3.2.1]octane
[1792] Following General Procedure 5-A and using the product for
Step A and benzyl bromide, 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane
was prepared.
Step C:--Synthesis of
2-Aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane
[1793] To a solution of 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane in
THF was added 2.5 eq. of 1M t-BuOK/THF (Aldrich) and the resulting
mixture was stirred for 30 minutes. Isoamyl nitrite (1.5 eq.) was
then added dropwise and the reaction mixture was stirred overnight.
To the reaction mixture was added 3N HCl and this mixture was
extracted with ethyl acetate and the organic extracts washed with
water, dried, and concentrated under reduced pressure. The residue
was triturated with ether/hexanes, the solvents decanted and the
residue dried under reduced pressure to afford
2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane as a tan liquid
(41% yield). This procedure is further described in Y. Kim,
Tetrahedron Lett. 30(21), 2833-2636 (1989).
Step D:--Synthesis of
2-Aza-2-benzyl-4-amino-3-oxobicyclo[3.2.1]octane
[1794] A solution of
2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane in 10 mL/mmole
of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5 g/mmole of 10%
Pd/C was saturated with hydrogen gas to 45 psi. The mixture was
shaken for 3 hours and then filtered through a layer of Celite. The
filtrate was dried over sodium sulfate and concentrated under
reduced pressure to afford the title compound as a solid (86%
yield). This procedure is further described in E. Reimann, Arch.
Pharm. 310, 102-109 (1977).
Example 5-1
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-.gamma.-bu-
tyrolactam
[1795] Following General Procedure E above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-.gamma.-butyrolactam (prepared by the procedure of S.
Wilkinson, J. Chem. Soc. 1951, 104), the title compound was
prepared as a solid having a melting point of 217-222.degree. C.
The reaction was monitored by tlc on silica gel (Rf=0.19 in 1:9
methanol/dichloromethane).
[1796] NMR data was as follows:
[1797] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.20 (m, 3H), 1.75 (m,
1H), 2.27 (m, 1H), 3.15 (m, 2H), 3.51 (s, 1H), 3.52 (s, 1H), 4.28
(m, 2H), 6.99 (m, 2H), 7.09 (m, 1H), 7.85 (m, 1H), 8.19 (m, 1H),
8.34 (d, J=7.8 Hz, 1H).
[1798] .sup.13C-nmr (DMSO-d.sub.6): .delta.=18.7, 28.4, 28.5,
37.98, 38.00, 41.3, 41.5, 48.07, 48.11, 49.4, 49.5, 101.9 (t,
J=25.3 Hz), 112.2 (m), 140.8, 162.1 (dd, J=13.5, 243.6 Hz), 168.6,
168.7, 172.27, 172.29, 174.2, 174.3.
[1799] C.sub.15H.sub.17N.sub.3O.sub.3F.sub.2 (MW=325.32); mass
spectroscopy (MH.sup.+) 326.
Example 5-2
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-.delta.-val-
erolactam
[1800] Following General Procedure A and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Example B) and
3-amino-.delta.-valerolactam (prepared by the procedure of D. W.
Adamson, J. Chem. Soc. 1943, 39), the title compound was
prepared.
Example 5-3
Synthesis of
1-Benzyl-3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-ami-
no-.delta.-valerolactam
[1801] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-benzyl-.delta.-valerolactam (Example 5-N), the title
compound was prepared as a solid having a melting point of
172-175.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.39 in 10% methanol/dichloromethane) and purification was by
silica gel chromatography.
[1802] NMR data was as follows:
[1803] .sup.1H-nmr (CDCl.sub.3): .delta.=7.5 (m, 1H); 7.37 (d,
J=7.7, 1H); 7.3 (m, 5H); 6.80 (d, J=7.9, 2H); 6.65 (t, J=9.1, 8.9,
1H); 4.7 (m, 2H); 4.6 (m, 1H); 4.3 (m, 1H); 3.50 (s, 2H); 3.2 (m,
2H); 1.9 (m, 4H); 1.3 (m, 3H).
[1804] .sup.13C-nmr (CDCl.sub.3): .delta.=173.2, 170.3, 169.8,
165.2, 161.9, 139.4, 137.1, 129.3, 128.4, 113.0, 112.8, 103.4,
102.0, 51.5, 51.3, 49.5, 47.1, 43.2, 27.7, 21.5, 19.4.
[1805] C.sub.23H.sub.25F.sub.2N.sub.3O.sub.3 (MW=429); mass
spectroscopy (MH.sup.+) 430.
Example 5-4
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-4-methyl-.e-
psilon.-caprolactam
[1806] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-4-methyl-.epsilon.-caprolactam (General Procedure--C), the
title compound was prepared as a mixture of diasteromers. The
reaction was monitored by tlc on silica gel (Rf=0.18 in 5%
MeOH/dichloromethan).
[1807] NMR data was as follows:
[1808] .sup.1H-nmr (DMSO-d.sub.6; 2 diasteromers): .delta.=8.36 (m,
1H), 7.78 (m, 2H), 7.06 (1H), 6.96 (m, 2H), 4.32 (m, 2H), 3.50 (s,
2H), 3.14 (m, 1H), 3.04 (m, 1H), 1.80 (m, 1H), 1.70 (m, 1H),
1.08-1.55 (m, 3H), 1.20 (d, J=7.1 Hz, 3H), 0.80 (m, 3H).
[1809] .sup.3C-nmr (DMSO-d.sub.6; 2 diasteromers): .delta.=174.1,
174.0, 171.9, 171.8, 169.1, 168.9, 162.4 (dd, J=13.6, 246.0 Hz),
140.9 (t, J=10.1 Hz), 112.4 (dd, J=2.4, 24.2 Hz) 102.0, (t, J=26.0
Hz), 54.2, 54.0, 48.5 (overlapping), 41.4, 36.7, 36.4, 34.5, 34.3,
28.2, 28.0, 18.9, 18.8, 18.6, 18.0.
[1810] C.sub.18H.sub.23N.sub.3O.sub.3F.sub.2 (MW=367.40); mass
spectroscopy (M+Na) 390.5.
Example 5-5
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tet-
rahydroquinolin-2-one
[1811] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1,2,3,4-tetrahydroquinolin-2-one (Example 5-A), the title
compound was prepared as a mixture of diasteromers. The reaction
was monitored by tlc on silica gel (Rf=0.38 in 25% ethyl
acetate/hexanes) and purification was by flash chromatography using
25% ethyl acetate/hexanes as the eluant.
[1812] NMR data was as follows:
[1813] .sup.1H-nmr (DMSO-d.sub.6; 2 diasteromers): .delta.=10.34
(d, 1H), 8.41 (d, 1H), 8.23 (t, 1H), 7.20-6.86 (m, 7H), 4.40 (m,
2H), 3.52 (s, 2H), 3.52 (s, 2H), 3.05-2.79 (m, 2H), 1.29 (d, 1.5H),
1.24 (d, 1.5H).
[1814] .sup.13C-nmr (DMSO-d.sub.6; 2 diasteromers): .delta.=172.66,
169.31, 169.21, 169.13, 168.89, 137.85, 128.58, 126.46, 127.94,
122.88, 122.79, 122.69, 122.64, 115.48, 112.97, 112.88, 112.73.
112.59, 112.51, 102.24, 48.61, 48.17, 41.68, 31.72, 18.96,
18.87.
[1815] C.sub.20H.sub.19N.sub.3O.sub.3F.sub.2 (MW=387.39).
Example 5-6
Synthesis of
1-Benzyl-3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,-
2,3,4-tetrahydroquinolin-2-one
[1816] Following General Procedure C above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1-benzyl-1,2,3,4-tetrahydroquinolin-- 2-one (General
Procedure 5-A), the title compound was prepared as a solid having a
melting point of 196-199.degree. C. The reaction was monitored by
tlc on silica gel (Rf=0.35 in 5% methanol/dichloromethane) and
purification was by flash chromatography using 5%
methanol/dichloromethan- e as the eluant.
[1817] NMR data was as follows:
[1818] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4-6.8 (m, 12H), 6.7 (m,
1H), 6.45 (d, 1H), 5.4 (d, 1H), 4.9 (d, 1H), 4.6 (m, 2H), 3.55 (s,
2H), 3.45-3.40 (2.times.d, 1H), 2.85 (t, 1H), 1.45 (t, 3H).
[1819] .sup.13C-nmr (CDCl.sub.3): .delta.=172.7, 172.6, 169.9,
169.7, 169.2, 169.2, 165.4, 165.2, 162.1, 161.9, 139.3, 138.7,
138.6, 136.8, 129.4, 129.3, 128.7, 128.0, 126.9, 124.8, 124.8,
124.6, 124.5, 116.5, 113.1, 113.05, 113.0, 112.9, 112.86, 112.8,
112.8, 112.7, 103.8, 103.5, 103.1, 50.1, 49.7, 49.6, 48.0, 47.9,
43.5, 32.3, 32.12, 32.1, 19.4, 19.2.
[1820] C.sub.27H.sub.25N.sub.3O.sub.3F.sub.2 (MW=477.51); mass
spectroscopy (MH.sup.+) 478.
Example 5-7
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tet-
rahydroisoquinolin-3-one
[1821] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine and
4-amino-1,2,3,4-tetrahydroisoquinoline-3-one, the title compound
was prepared as a solid having a melting point of 243-244.degree.
C.
[1822] NMR data was as follows:
[1823] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.46 (bt, J=8.25 Hz,
2H), 8.36-8.38 (bd, J=4 Hz, 1H), 7.3-7.0 (m, 7H), 5.34-5.39 (bd,
J=10 Hz, 1H), 4.5-4.4 (m, 2H), 4.2-4.23 (m, 1H), 3.56 (s, 2H), 1.33
(d, J=7 Hz, 3H).
[1824] C.sub.20H.sub.19N.sub.3O.sub.3F.sub.2 (MW=387.1); mass
spectroscopy: 387.
Example 5-8
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-benzyl-1,-
2,3,4-tetrahydroisoquinolin-3-one
[1825] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-2-benzyl-1,2,3,4-tetrahydroisoquinol- ine-3-one (General
Procedure 5-D), the title compound was prepared as a solid having a
melting point of 144-145.degree. C.
[1826] NMR data was as follows:
[1827] .sup.1H-nmr (DMSO-d.sub.6): .delta.=7.8 (bd, 0.5H), 7.57
(bd, 0.5H), 7.26-7.0 (m, 9H), 6.8-6.6 (m, 2H), 6.66-6.3 (m, 1H),
5.5-5.43 (m, 1H), 4.79-4.45 (m, 5H), 4.10 (t, J=14 Hz, 1H), 3.49
(s, 2H), 5.52 (d, J=7.0 Hz, 1.5H), 1.49 (d, J=7.0 Hz, 1.5H).
[1828] C.sub.27H.sub.25N.sub.3O.sub.3F.sub.2 (MW=477); mass
spectroscopy: 477.
Example 5-9
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,-
2,3,4-tetrahydroisoquinolin-3-one
[1829] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-1-methyl-1,2,3,4-tetrahydroisoquinol- ine-3-one (General
Procedure 5-D), the title compound was prepared as a solid having a
melting point of 205-206.degree. C.
[1830] NMR data was as follows:
[1831] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.6-8.24 (m, 3H),
7.3-7.0 (m, 7H aromatic), 5.4-5.39 (m, 1H), 4.58-4.4 (m, 2H), 3.54
(s, 2H), 1.49-1.38 (m, 1H), 1.35-1.3 (m, 6H).
[1832] C.sub.21H.sub.21N.sub.3O.sub.3F.sub.2 (MW=401); mass
spectroscopy: 401.
Example 5-10
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-phenyl-1,-
2,3,4-tetrahydroisoquinolin-3-one
[1833] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinol- ine-3-one (General
Procedure 5-D), the title compound was prepared as a solid having a
melting point of 200-205.degree. C.
[1834] NMR data was as follows:
[1835] .sup.1H-nmr (DMSO-d.sub.6): .delta.=9.06 (bt, J=2 Hz, 1H),
8.69-8.43 (m, 2Hz), 7.55-7.0 (m, 2H), 6.1 (bd, J=8 Hz, 0.25H),
5,7-5.5 (m, 1H), 5.5 (bd, J=8 Hz, 0.25H), 5.2-5.19 (bd, J=8 Hz,
0.5H), 4.48-4.4 (m, 1H), 3.57-3.5 (m, 2H), 315 (s, 1H), 1.4-1.2 (m,
3H).
[1836] C.sub.26H.sub.23N.sub.3O.sub.3F.sub.2 (MW=463); mass
spectroscopy: 463.2.
[1837] By employing the above procedure using
trans-4-amino-1-phenyl-1,2,3- ,4-tetrahydroisoquinoline-3-one and
purifying the resulting product by LC 2000 chromatography, eluting
with dichloromethane/methanol (97:3), the following isomers of
trans-4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)am-
ino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one were prepared:
[1838] Isomer 1: m.p.=249-250.degree. C.
[1839] Isomer 2: m.p.=232-233.degree. C.
[1840] By employing the above procedure using
cis-4-amino-1-phenyl-1,2,3,4- -tetrahydroisoquinoline-3-one and
purifying the resulting product by LC 2000 chromatography, eluting
with dichloromethane/methanol (97:3), the following isomers of
cis4-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-
-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one were prepared:
[1841] Isomer 1: m.p.=244.1-244.5.degree. C.
[1842] Isomer 2: m.p.=247-248.degree. C.
Example 5-11
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-6fluoro-1,2-
,3,4-tetrahydroisoquinolin-3-one
[1843] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-6-fluoro-1,2,3,4-tetrahydroisoquinol- ine-3-one (General
Procedure 5-D), the title compound was prepared as a solid having a
melting point of 195-200.degree. C.
[1844] NMR data was as follows:
[1845] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.6-8.41 (m, 3H),
7.4-7.24 (m, 1H), 7.09-6.98 (m, 4H), 6.8-6.77 (bd, J=9 Hz, 1H),
5.43-5.30 (m, 1H), 4.46-4.42 (m, 2H), 4.23-4.19 (m, 1H), 3.34 (s,
2H), 1.37-1.31 (m, 3H).
[1846] C.sub.19H.sub.18N.sub.3O.sub.3F.sub.2 (MW=405.3); mass
spectroscopy: 405.
Example 5-12
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-fluoro-1,-
2,3,4-tetrahydroisoquinolin-3-one
[1847] Following General Procedure D above using
N-(3,5-difluorophenyl)ace- tyl-L-alanine (Example B) and
4-amino-7-fluoro-1,2,3,4-tetrahydroisoquinol- ine-3-one (Example
5-E), the title compound was prepared. The product was purified by
slurrying in ether/hexanes (1:1) and by LC 2000 chromatography,
eluting with methanol/ethyl acetate (1:99), to give the product as
a solid (Isomer 1: m.p.=230-235.degree. C.; Isomer 2:
m.p.=195-200.degree. C.).
[1848] NMR data was as follows:
[1849] .sup.1H-nmr (DMSO-d.sub.6): .delta.=7.25-6.9 (m, 6H), 5.4
(d, J=8 Hz, 1H), 4.6-4.4 (m, 2H), 3.55 (s, 2H), 1.35 (d, J=7.5 Hz,
1.5H), 1.32 (d, J=7.2 Hz, 1.5H).
[1850] C.sub.20H.sub.18N.sub.3O.sub.3F.sub.3 (MW=405); mass
spectroscopy: 405.
Example 5-13
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-phenethyl-
-1,2,3,4-tetrahydroisoquinolin-3-one
[1851] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-2-phenethyl-1,2,3,4-tetrahydroisoqui- noline-3-one (General
Procedure 5-D), the title compound was prepared as a solid having a
melting point of 75-76.degree. C.
[1852] C.sub.28H.sub.27N.sub.3O.sub.3F.sub.2 (MW=491); mass
spectroscopy: 491.2.
Example 5-14
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1,-
2,3,4-tetrahydroisoquinolin-3-one
[1853] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-2-methyl-1,2,3,4-tetrahydroisoquinol- ine-3-one (General
Procedure 5-D), the title compound was prepared as a solid having a
melting point of 174-175.degree. C.
[1854] NMR data was as follows:
[1855] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.57-8.47 (m, 1H), 8.45
(d, J=7.6 Hz, 1H), 7.26-7.06 (m, 7H aromatic), 5.38 (d, J=8.3 Hz,
1H), 4.68 (d, J=16 Hz, 1H), 4.41 (pentet, J=8 Hz, 1H), 4.42 (d,
J=16 Hz, 1H), 3.5 (s, 2H), 2.9 (s, 3H), 1.34 (d, J=8 Hz, 1.5 Hz),
1.32 (d, J=8 Hz, 1.5H).
[1856] C.sub.21H.sub.21N.sub.3O.sub.3F.sub.2 (MW=401); mass
spectroscopy: 401.
Example 5-15
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-6phenyl-1,2-
,3,4-tetrahydroisoquinolin-3-one
[1857] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinol- ine-3-one (General
Procedure 5-D), the title compound was prepared. The product was
purified by LC 2000 chromatography, eluting with ethyl acetate.
[1858] NMR data was as follows:
[1859] .sup.1H-nmr (CD.sub.3OD/CDCl.sub.3): .delta.=8.8 (bd, 0.5H),
7.74 (bd, 0.5H), 7.4-7.16 (m, 6H), 6.69 (bs, 1H), 6.69 (bs, 1H),
6.5 (m, 1H), 5.39 (bs, 1H), 4.45-3.95 (m, 4H), 1.37-1.33 (m,
3H).
[1860] C.sub.26H.sub.23N.sub.3O.sub.3F.sub.2 (MW=463.49); mass
spectroscopy: 463.4.
Example 5-16
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-phenyl-1,-
2,3,4-tetrahydroisoquinolin-3-one
[1861] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-7-phenyl-1,2,3,4-tetrahydroisoquinol- ine-3-one (Example
5-H), the title compound was prepared as a solid having a melting
point>240.degree. C. (dec.).
[1862] NMR data was as follows:
[1863] .sup.1H-nmr (CDCl.sub.3): .delta.=7.5-7.18 (m, 10H),
6.85-6.74 (m, 4H), 4.9-4.57 (m, 1H), 4.56-4.37 (m, 2H), 3.58 (s,
1H), 3.55 (s, 1H), 1.53 (d, J=6 Hz, 1.5H), 1.47 (d, J=6 Hz,
1.5H).
[1864] C.sub.26H.sub.23N.sub.3O.sub.3F.sub.2 (MW=463); mass
spectroscopy: 463.
Example 5-17
Synthesis of
(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-(9-aminofluroren-1-
-yl)glycine .delta.-Lactam
[1865] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
(9-aminofluroren-1-yl)glycine .delta.-lactam (General Procedure
5-D), the title compound was prepared as a solid having a melting
point>240.degree. C. (dec.).
[1866] NMR data was as follows:
[1867] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.0-6.8 (bm, 10H),
6.3-5.75 (bs, 1H), 5.75-5.4 (bs, 1H), 4.1-4.5 (bs, 1H), 3.7-3.35
(bm, 2H), 3.3 (s, 2H), 1.4-1.0 (bm, 3H)
[1868] C.sub.26H.sub.21N.sub.3O.sub.3F.sub.2 (MW=461); mass
spectroscopy: 461.
Example 5-18
Synthesis of
3-(N'-(Phenylacetyl)-L-alaninyl)amino-.epsilon.-caprolactam
[1869] Following General Procedure B above using
N-(phenylacetyl)-L-alanin- e (Example A) and
3-amino-.epsilon.-caprolactam (Sigma), the title compound was
prepared as a solid having a melting point of 200-202.degree. C.
The reaction was monitored by tlc on silica gel (Rf=0.30 in 1:9
methanol/dichloromethane).
[1870] NMR data was as follows:
[1871] .sup.1H-nmr (DMSO-d.sub.6): .delta.=8.35 (m, 1H), 7.85 (m,
2H), 7.28-7.32 (m, 5H), 4.2-24.40 (m, 2H), 3.46 (s, 2H), 2.98-3.13
(m, 2H), 1.53-1.90 (m, 4H), 1.26-1.40 (m, 1H), 1.20 (m, 4H).
[1872] .sup.13C-nmr (DMSO-d.sub.6) .delta.=174.05, 174.02, 171.2,
171.1, 169.9, 169.8, 136.31, 131.29, 129.1, 129.0, 128.2, 126.3,
51.3, 48.3, 42.0, 40.6, 31.2, 31.0, 28.8, 27.6, 18.2, 18.1.
[1873] C.sub.17H.sub.23N.sub.3O.sub.3 (MW=317.39); mass
spectroscopy (MH.sup.+) 316.
Example 5-19
Synthesis of
3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-.epsil-
on.-caprolactam
[1874] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-.epsilon.-caprolactam (Aldrich), the title compound was
prepared as a solid having a melting point>225C. The reaction
was monitored by tlc on silica gel (Rf=0.36 in 1:9
methanol/dichloromethane).
[1875] NMR data was as follows:
[1876] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.10-1.40 (m, 2H), 1.21
(d, J=7.1 Hz, 3H), 1.55-1.90 (m, 4H), 3.05 (m, 1H), 3.17 (m, 1H),
3.52 (s, 2H), 4.29 (m, 2H), 6.98 (m, 2H), 7.08 (m, 1H), 7.84 (m,
2H), 8.43 (d, J=7.3 Hz, 1H).
[1877] .sup.13C-nmr (DMSO-d.sub.6) .delta.=18.0, 27.6, 28.8, 31.0,
40.6, 41.3, 48 .4, 51.3, 101.9 (t, J=25.6 Hz), 112.3 (dd, J=7.5,
16.8 Hz), 140.6, 162.1 (dd, J=13.2, 243.9 Hz), 168.8, 171.1,
174.0.
[1878] C.sub.17H.sub.21N.sub.3O.sub.3F.sub.2 (MW=353.37 ); mass
spectroscopy (MH.sup.+) 354.
Example 5-20
Synthesis of
3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzy-
l-.epsilon.-caprolactam
[1879] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-benzyl-.epsilon.-caprolactam (prepared from
3-(S)-amino-.epsilon.-caprolactam and benzyl bromide using the
procedure of Example 6-A and General Procedure 6-B), the title
compound was prepared as a solid having a melting point of
176-178.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.44 in 10% methanol/dichloromethane) and purification was by
precipitation from water.
[1880] NMR data was as follows:
[1881] .sup.1H-nmr (CDCl.sub.3): .delta.=1.20 (m, 1H), 1.39 (d,
J=7.0 Hz, 3H), 1.50 (m, 1H), 1.65-2.06 (m, 4H), 3.24 (m, 1H), 3.45
(m, 1H), 3.54 (s, 2H), 4.51 (m, 2H), 4.60 (m, 1H), 4.72 (d, 14.5
Hz, 1H), 6.48.(d, J=7.1 Hz, 1H), 6.72 (m, 1H), 6.83 (m, 2H),
7.20-7.41 (m, 6H).
[1882] .sup.13C-nmr (CDCl.sub.3): .delta.=19.0, 26.9, 27.5, 31.7,
42.8, 48.0, 49.0, 51.5, 52.4, 102.6 (t, J=25.2 Hz), 112.2 (dd,
J=8.0, 17.0 Hz), 127.6, 128.1, 128.7, 136.7, 138.4, 162.9 (dd,
J=12.8, 247.3 Hz), 169.0, 171.0, 172.5.
[1883] C.sub.24H.sub.27N.sub.3O.sub.3F.sub.2 (MW=443.50); mass
spectroscopy (MH.sup.+) 444.
Example 5-21
Synthesis of
3-(S)-N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(2-Met-
hoxyethyl)-.epsilon.-caprolactam
[1884] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-(2-methoxyethyl)-.epsilon.-cap- rolactam (prepared
from 3-(S)-amino-.epsilon.-caprolactam and 2-methoxyethyl bromide
using the procedure of Example 6-A and General Procedure 6-B), the
title compound was prepared as a solid having a melting point of
102-106.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.08 in 5% methanol/dichloromethane).
[1885] NMR data was as follows:
[1886] .sup.1H-nmr (CDCl.sub.3): .delta.=1.38 (d, J=7.1 Hz, 3H),
1.48 (m, 2H), 1.82 (m, 2H), 1.96 (m, 2H), 3.35 (s, 3H), 3.38 (m,
1H), 3.47-3.70 (m, 7H), 4.55 (m, 2H), 6.75 (m, 2H), 6.85 (m, 2H),
7.42 (d, J=6.0 Hz, 1H).
[1887] .sup.13C-nmr (CDCl.sub.3): .delta.=19.0, 27.1, 27.6, 31.7,
42.8, 48.7, 49.0, 49.9, 52.4, 58.8, 70.9, 102.6 (t, J=25.2 Hz),
112.2 (dd, J=7.8, 16.9 Hz), 138.4, (164.5, 161.4, 161.2 as
multiplet), 169.0, 171.0, 172.4.
[1888] C.sub.20H.sub.27N.sub.3O.sub.4F.sub.2 (MW=411.45); mass
spectroscopy (MH.sup.+) 412.
Example 5-22
Synthesis of
3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-
-.epsilon.-caprolactam
[1889] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-ethyl-.epsilon.-caprolactam (prepared from
3-(S)-amino-.epsilon.-caprolactam and ethyl iodide using the
procedure of Example 6-A and General Procedure 6-B), the title
compound was prepared as a solid having a melting point of
162-165.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.43 in 10% methanol/dichloromethane).
[1890] NMR data was as follows:
[1891] .sup.1H-nmr (CDCl.sub.3): .delta.=1.12 (t, J=7.1 Hz, 3H),
1.40 (m, 2H), 1.36 (d, J=7.0 Hz, 3H), 1.70-2.00 (m, 4H), 3.24 (m,
1H), 3.50 (m, 3H), 3.53 (s, 2H), 4.50 (m, 2H), 6.70 (m, 2H), 6.83
(m, 2H), 7.39 (d, J=6.0 Hz, 1H).
[1892] .sup.13C-nmr (CDCl.sub.3): .delta.=13.1, 19.1, 27.6, 27.7,
31.7, 42.8, 43.5, 48.1, 49.0, 52.3, 102.6 (t, J=25.1 Hz), 112.2
(dd, J=7.9, 17.0 Hz), 138.3, 138.4, 163.0 (dd, J=12.8, 247.1 Hz),
168.9, 170.9, 171.8.
[1893] C.sub.19H.sub.25N.sub.3O.sub.3F.sub.2 (MW=381.43); mass
spectroscopy (MH.sup.+) 382.
Example 5-23
Synthesis of
3-N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-.eps-
ilon.-caprolactam
[1894] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-5-ethyl-.epsilon.-caprolactam (General Procedure 5-C), the
title compound was prepared as a solid. The reaction was monitored
by tic on silica gel (Rf=0.13 in 5% methanol/dichloromethane).
[1895] NMR data was as follows:
[1896] .sup.1H-nmr (CDCl.sub.3): .delta.=0.98 (t, J=7.4 Hz, 3H),
1.31 (d, J=7.0 Hz, 1.5H), 1.35 (d, J=7.1 Hz, 1.5H), 1.55 (m, 1H),
1.65 (m, 3H), 1.82 (m, 2H), 1.95 (m, 1H), 3.06 (m, 1H), 3.41 (m,
1H), 3.49 (s, 1H), 3.52 (s, 1H), 4.55-4.72 (m, 2H), 6.38 (m, 0.5H),
6.63-6.90 (m, 4.5H), 7.37 (d, J=6.0 Hz, 0.5H), 7.52 (d, J=6.2 Hz,
0.5H).
[1897] .sup.13C-nmr (CDCl.sub.3): .delta.=12.07, 12.11, 19.0, 19.2,
24.4, 24.5, 31.9, 32.0, 35.0, 35.3, 35.7, 36.9, 37.0, 42.8, 47.4,
47.6, 48.8, 48.9, 102.7 (t),.102.6 (t), 122.2 (multiplet of 8),
138.35, 138.41, 138.5, 163.0 (dd, J=12.8, 247.1 Hz), 168.9, 169.2,
171.1, 171.3, 174.8, 174.9.
[1898] C.sub.19H.sub.25N.sub.3O.sub.3F.sub.2 (MW=381.43); mass
spectroscopy (MH.sup.+) 382.
Example 5-24
Synthesis of
3-N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-.eps-
ilon.-caprolactam
[1899] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-5-ethyl-.epsilon.-caprolactam (General Procedure 5-C), the
title compound was prepared as a solid having a melting point of
201-204.degree. C. (decom.). The reaction was monitored by tlc on
silica gel (Rf=0.04 in 5% methanol/dichloromethane).
[1900] NMR data was as follows:
[1901] .sup.1H-nmr (CD.sub.3OD): .delta.=0.70 (t, J=7.1 Hz, 3H),
0.78-1.20 (m, 7H), 1.49 (m, 1H), 1.68 (m, 2H), 3.07 (m, 2H), 3.38
(s, 2H), 4.19 (m, 1H), 4.31 (d, J=11.0 Hz, 1H), 6.61 (m, 1H), 6.72
(m, 2H).
[1902] .sup.13C-nmr (CD.sub.3OD): .delta.=11.47, 11.49, 17.8, 17.9,
31.0, 35.97, 36.03, 38.2, 38.3, 41.6, 42.7 (multiplet of 7), 50.7,
50.8, 52.3, 103.0 (2 triplets of 6), 113.2 (2 dd of 8), 140.9,
141.0, 164.3 (dd, J=15.5, 258.3 Hz), 172.5 (overlapping of 2),
173.7, 173.9, 176.5, 176.6.
[1903] C.sub.19H.sub.25N.sub.3O.sub.3F.sub.2 (MW=381.43); mass
spectroscopy (MH.sup.+) 382.
Example 5-25
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl-amino)-7-benzyl-.-
epsilon.-caprolactam
[1904] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-7-benzyl-.epsilon.-caprolactam (General Procedure 5-C), the
title compound was prepared as an oil. The reaction was monitored
by tlc on silica gel (Rf=0.04 in 5% methanol/dichloromethane).
[1905] NMR data was as follows:
[1906] .sup.1H-nmr (CDCl.sub.3): .delta.=1.35 (m, 3H), 1.45 (m,
1H), 1.80 (m, 2H), 2.05 (d, J=7.2 Hz, 2H), 2.10 (m, 1H), 2.97 (m,
2H), 3.51 and 3.52 (2 s, 3H), 4.60 (m, 2H), 6.50-6.85 (m, 5H), 7.15
(m, 2H), 7.26 (m, 3H), 7.45 (m, 1H).
[1907] .sup.13C-nmr (CDCl.sub.3): .delta.=18.7, 20.0, 21.6, 30.2,
30.4, 30.7, 39.1, 39.3, 42.5, 48.70, 48.74, 53.02, 53.06, 53.89,
53.97, 102.5 (, J=25.4 Hz), 112.2 (dd, J=8.3, 17.2 Hz), 126.68,
126.74, 128.67, 128.71, 128.9, 138.0, 138.1, 138.6, 138.7, 138.8,
163.0 (dd, J=13.0, 249.0 Hz), 169.5, 169.6, 172.0, 174.4,
175.0.
[1908] C.sub.24H.sub.27N.sub.3O.sub.3F.sub.2 (MW=443.50).
Example 5-26
Synthesis of
3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-benzy-
1-4,7-methano-.epsilon.-caprolactam
[1909] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-benzyl-4,7-methano-.epsilon.-c- aprolactam (i.e.,
4-amino-2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane hydrochloride from
Example 5-O), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel (Rf=0.42 in 10%
methanol/dichloromethane) and purification was by silica gel
chromatography.
[1910] NMR data was as follows:
[1911] .sup.1H-nmr (CDCl.sub.3): .delta.=7.3 (m, 5H); 6.82 (t,
J=6.3, 6.0, 2H); 6.6 (m, 1H); 5.14 (dd, J=6.5, 8.5, 6.4, 1H); 4.6
(m, 2H); 3.79( dd, J=10.3, 4.5, 10.4, 1H). 3.56 (s, 1H); 3.51 (s,
2H); 2.8 (m, 1H); 2.57 (s, 1HO; 1.96 (d, J=12.1, 1H); 1.7 (m, 4H);
1.34 (d, J=7.0, 3H).
[1912] .sup.13C-nmr (CDCl.sub.3): .delta.=173.4, 170.3, 168.9,
165.2, 139.4, 137.3, 129.3, 128.5, 128.2, 112.9, 112.8, 112.7,
112.6, 103.4, 103.0, 102.7, 59.0, 49.6, 43.1, 38.1, 37.8, 36.6,
32.6, 22.7, 19.2.
[1913] C.sub.25H.sub.27F.sub.2N.sub.3O.sub.3 (MW=455); mass
spectroscopy (MH.sup.+) 456.
Example 5-27
Synthesis of
3-(S)-(N'-(Cyclopentylacetyl)-L-alaninyl)amino-1-benzyl-.epsi-
lon.-caprolactam
[1914] Following General Procedure A above using
N-(cyclopentylacetyl)-L-a- lanine (Example D) and
(S)-3-amino-1-benzyl-.epsilon.-caprolactam (prepared from
3-(S)-amino-.epsilon.-caprolactam and benzyl bromide using the
procedure of Example 6-A and General Procedure 6-B), the title
compound was prepared. The reaction was monitored by tlc on silica
gel (Rf=0.37 in 5% methanol/dichloromethane) and purification was
by preparative thin layer chromatography using 5%
methanol/dichloromethane as the eluant.
[1915] NMR data was as follows:
[1916] .sup.1H-nmr (CDCl.sub.3): .delta.=7.42 (d, J=6.0 Hz, 1H),
7.15-7.05 (m, 5H), 6.36 (d, 7.2 Hz, 1H), 4.8-4.4 (m, 4H), 3.5-3.3
(m, 1H), 3.3-3.1 (m, 1H), 2.3-1.0 (m 20H).
[1917] .sup.3C-nmr (CDCl.sub.3): .delta.=172.8, 172.4, 171.5,
136.9, 128.7, 128.2, 127.7, 52.3, 51.4, 48.6, 47.9, 47.6, 42.6,
36.9, 32.34, 32.28, 31.6, 27.5, 26.8, 24.8, 19.0, 18.4.
[1918] C.sub.23H.sub.33N.sub.3O.sub.3 (MW=399.54); mass
spectroscopy (M+Na) 422.
Example 5-28
Synthesis of
3-(S)-(N'-(Cyclopentylacetyl)-L-phenylglycinyl)amino-1-benzyl-
-.epsilon.-caprolactam
[1919] Following General Procedure A above
N-(cyclopentylacetyl)-L-2-pheny- lglycine (Example C) and
3-(S)-amino-1-benzyl-.epsilon.-caprolactam (prepared from
3-(S)-amino-.epsilon.-caprolactam and benzyl bromide using the
procedure of Example 6-A and General Procedure 6-B), the title
compound was prepared. The reaction was monitored by tlc on silica
gel (Rf=0.40 in 5% methanol/dichloromethane) and purification was
by preparative thin layer chromatography using 5%
methanol/dichloromethane as the eluant.
[1920] NMR data was as follows:
[1921] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4-7.15 (m, 11H), 6.79
(d, J=6.6 Hz, 1H), 5.48 (d, J=7.2 Hz, 1H), 4.5 (m, 3H), 3.4-3.1 (m,
2H), 2.3-1.0 (m, 17H).
[1922] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 172.1, 168.9,
138.0, 129.0, 128.6, 128.2, 128.1, 127.6, 127.0, 57.1, 52.6, 51.3,
47.8, 42.5, 36.8, 32.33, 32.27, 31.4, 27.4, 26.8, 24.7.
[1923] C.sub.23H.sub.33N.sub.3O.sub.3 (MW=461.61); mass
spectroscopy (M+Na) 484.
Example 5-29
Synthesis of
3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(2-ph-
enethyl)-.epsilon.-caprolactam
[1924] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-(2-phenethyl)-.epsilon.-caprol- actam (prepared from
3-(S)-amino-.epsilon.-caprolactam and 2-phenethyl bromide using the
procedure of Example 6-A and General Procedure 6-B), the title
compound was prepared. The reaction was monitored by tlc on silica
gel (Rf=0.36 in 5% methanol/dichloromethane) and purification was
by preparative thin layer chromatography using 5%
methanol/dichloromethan- e as the eluant.
[1925] NMR data was as follows:
[1926] .sup.1H-nmr (CDCl.sub.3): .delta.=7.60 (d, J=6.3 Hz, 1H),
7.3-7.1 (m, 6H), 6.81 (m, 2H), 6.66 (m, 1H), 4.6 (m, 2H), 3.75 (m,
1H), 3.51 (s, 2H), 3.5-3.4 (m, 2H), 3.05 (m, 1H), 2.8 (m, 2H),
1.95-1.6 (m, 4H), 1.5-1.1 (m (includes d at 1.36, J=7.2 Hz, 3H),
5H).
[1927] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 171.5, 169.2,
164.6, 164.5, 161.4, 161.2, 139.0, 138.8, 138.7, 138.6, 128.6,
128.5, 126.4, 112.3, 112.2, 112.05, 111.95, 102.7, 102.3, 102.0,
52.2, 50.8, 49.2, 48.9, 42.4, 34.1, 31.5, 27.3, 27.1, 18.8.
[1928] C.sub.25H.sub.29F.sub.2N.sub.3O.sub.3 (MW=457.52); mass
spectroscopy (M+Na) 480.
Example 5-30
Synthesis of
3-(S)-(N'-(Cyclopentylacetyl)-L-phenylglycinyl)amino-1-(2-phe-
nethyl)-.epsilon.-caprolactam
[1929] Following General Procedure A above using
N-(cyclopentylacetyl)-L-p- henylglycine (Example C) and
3-(S)-amino-1-(2-phenethyl)-.epsilon.-caprola- ctam (prepared from
3-(S)-amino-.epsilon.-caprolactam and 2-phenethyl bromide using the
procedure of Example 6-A and General Procedure 6-B), the title
compound was prepared. The reaction was monitored by tlc on silica
gel (Rf=0.47 in 5% methanol/dichloromethane) and purification was
by preparative thin layer chromatography using 5%
methanol/dichloromethan- e as the eluant.
[1930] NMR data was as follows:
[1931] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4-7.1 (m, 11H), 6.88 (d,
J=7.2 Hz, 1H), 5.49 (d, J=7.2 Hz, 1H), 4.2 (m, 1H), 3.7-3.6 (m,
1H), 3.5-3.3 (m, 2H), 3.1-3.0 (m, 1H), 2.9-2.7 (m, 2H), 2.3-1.0 (m,
17H).
[1932] .sup.13C-nmr (CDCl.sub.3): .delta.=172.2, 171.0, 169.0,
138.6, 138.2, 129.0, 128.7, 128.6, 128.2, 127.0, 126.5, 57.0, 52.6,
50.8, 49.3, 44.4, 42.5, 36.9, 34.2, 32.4, 32.3, 31.4, 27.5, 27.2,
24.8.
[1933] C.sub.29H.sub.37N.sub.3O.sub.3 (MW=475.64); mass
spectroscopy (M+Na) 498.
Example 5-31
Synthesis of
3-(N'-(3,4-Dichlorophenyl)-D,L-alaninyl)amino-.epsilon.-capro-
lactam
[1934] Following General Procedure A above using
N-(3,4-dichlorophenyl)-D,- L-alanine (Example Q) and
3-(S)-amino-.epsilon.-caprolactam (Sigma), the title compound was
prepared as a solid having a melting point of 199.degree. C. The
reaction was monitored by tlc on silica gel (Rf=0.4 in 50% ethyl
acetate/hexanes) and purification was by preparative thin layer
chromatography using 50% ethyl acetate/hexanes as the eluant.
[1935] NMR data was as follows:
[1936] .sup.1H-nmr (DMSO-d.sub.6): .delta.=7.2(d, 1H); 6.7 (d,
1H,); 6.4 (dd, 1H); 4.30 (bs, 1H); 4.1 (m, 2H); 2.9 (m, 2H); 1.7
(m, 6H); 1.3 (t, 3H).
[1937] .sup.13C-nmr (DMSO-d.sub.6) .delta.=175; 171; 146.7; 133;
131; 121; 114.9; 112.6; 52.4; 28.3; 27.5; 19.5; 18.2; 18.1.
[1938] C.sub.15H.sub.19N.sub.3O.sub.2Cl.sub.2 (MW=344.24); mass
spectroscopy (MH.sup.+) 345.
Example 5-32
Synthesis of
3-(S)-(N'-(cyclopropylacetyl)-L-phenylglycinyl)amino-1-methyl-
-.epsilon.-caprolactam
[1939] Following General Procedure A above using
N-(eyclopropylacetyl)-L-p- henylglycine (Example F) and
3-(S)-amino-1-methyl-.epsilon.-caprolactam (prepared from
3-(S)-amino-.epsilon.-caprolactam and methyl iodide using the
procedure of Example 6-A and General Procedure 6-B), the title
compound was prepared as a solid having a melting
point>200.degree. C. The reaction was monitored by tlc on silica
gel (Rf=0.41 in 10% methanol/dichloromethane) and purification was
by recrystallization from ethyl acetate and hexanes.
[1940] NMR data was as follows:
[1941] .sup.1H-nmr (CDCl.sub.3): .delta.=7.5-7.2 (m, 7H), 5.49 (d,
J=6.6 Hz, 1H), 4.46 (m, 1H), 3.50 (m, 1H), 3.10 (m, 1H), 2.97 (s,
3H), 2.1-1.7 (m, 4H), 1.5-1.3 (m, 2H), 1.0 (m, 1H), 0.6 (m, 2H),
0.2 (m, 2H).
[1942] .sup.13C-nmr (CDCl.sub.3): .delta.=172.1, 171.8, 168.9,
138.1, 129.0, 128.3, 127.0, 57.0, 52.4, 50.2, 41.1, 35.8, 31.3,
27.5, 26.4, 6.8, 4.4.
[1943] C.sub.20H.sub.27N.sub.3O.sub.3 (MW=357.46).
Example 5-33
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-8-octanelac-
tam
[1944] Following General Procedure B above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-8-octanelactam (i.e., 2-oxo-1-azacyclononane prepared as
described in General Procedure 5-C), the title compound was
prepared as a solid having a melting point of >220.degree.
C.
[1945] NMR data was as follows:
[1946] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.00-1.85 (m, 12H), 2.73
(m, 1H), 3.33 (br s, 2H), 3.49 (br s, 2H), 4.07 (m, 1H), 4.28 (m,
1H), 6.95 (m, 2H), 7.06 (m, 1H), 7.75-7.90 (m, 2H), 8.30 (d, J=7.2
Hz, 1H).
[1947] .sup.13C-nmr (DMSO-d.sub.6): .delta.=18.2, 18.6, 21.1, 23.5,
27.9, 28.1, 32.3, 32.6, 41.3, 48.0, 48.1, 52.9, 53.0, 102.0 (t,
J=25.9 Hz), 112.4 (d, J=24.1 Hz), 141.0 (t, J=11.2 Hz), 162.3 )dd,
J=13.5, 244.5 Hz), 168.9, 171.9, 173.1, 173.2.
[1948] C.sub.19H.sub.25N.sub.3O.sub.3F.sub.2 (MW=381.43); mass
spectroscopy (M-H) 380.
Example 5-34
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-benzyl-1,-
2,3,4-tetrahydroisoquinolin-3-one
[1949] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinol- ine-3-one (General
Procedure 5-D), the title compound was prepared as a solid having a
melting point of 159-166.degree. C.
[1950] C.sub.27H.sub.25N.sub.3O.sub.3F.sub.2 (MW=477); mass
spectroscopy: 477.
Example 5-35
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,-
2,3,4-tetrahydroisoquinolin-3-one
[1951] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-1-benzyl-1,2,3,4-tetrahydroisoquinol- ine-3-one (Example
5-I), the title compound was prepared as a solid having a melting
point of 106-107.degree. C.
[1952] C.sub.27H.sub.25N.sub.3O.sub.3F.sub.2 (MW=477.52); mass
spectroscopy: 478.
Example 5-36
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1--
phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
[1953] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-2-methyl-1-phenyl-1,2,3,4-tetrahydro- isoquinoline-3-one
(General Procedure 5-D), the title compound was prepared as a solid
having a melting point of 115.degree. C.
[1954] C.sub.27H.sub.24N.sub.3O.sub.3F.sub.2 (MW=476); mass
spectroscopy: 477.
Example 5-37
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-2--
yl)-1,2,3,4-tetrahydroisoquinolin-3-one
[1955] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroiso- quinoline-3-one
(Example 5-C), the title compound was prepared as a solid having a
melting point of 100.degree. C.
[1956] C.sub.25H.sub.22N.sub.4O.sub.3F.sub.2 (MW=464); mass
spectroscopy: 464.1.
Example 5-38
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-3--
yl)-1,2,3,4-tetrahydroisoquinolin-3-one
[1957] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroiso- quinoline-3-one
(Example 5-D), the title compound was prepared as a solid having a
melting point of 100-120.degree. C.
[1958] C.sub.25H.sub.22N.sub.4O.sub.3F.sub.2 (MW=464); mass
spectroscopy: 464.
Example 5-39
Synthesis of
4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-4--
yl)-1,2,3,4-tetrahydroisoquinolin-3-one
[1959] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
4-amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroiso- quinoline-3-one
(Example 5-B), the title compound was prepared as a solid having a
melting point of 100.degree. C.
[1960] C.sub.25H.sub.22N.sub.4O.sub.3F.sub.2 (MW=464); mass
spectroscopy: 464.
Example 5-40
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-1-methyl-2-
-indolinone
[1961] Following General Procedure I above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1-methyl-2-indolinone monohydrochloride (Example 5-J), the
title compound, as a .about.1:1 diastereomeric mixture at C3 of the
indolinone, was prepared as a white solid having a decomposition
point of 215-220.degree. C. Purification was by flash
chromatography eluting with 3:1 CH.sub.2Cl.sub.2/EtOAc gradient to
straight EtOAc followed by recrystalization from CHCl.sub.3.
R.sub.f=0.16 and 0.22 (EtOAc).
[1962] C.sub.20H.sub.19F.sub.2N.sub.3O.sub.3 (MW 387.39); mass
spectroscopy (MH+) 387.0.
[1963] Anal. Calcd for C.sub.20H.sub.19F.sub.2N.sub.3O.sub.3: C,
62.01; H, 4.94; N, 10.85. Found: C, 61.76; H, 5.17; N, 10.65.
Example 5-41
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-1-methyl-4--
phenyl-3,4-trans-dihydrocarbostyril
[1964] Following General Procedure I above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and the tin
complex of 3-amino-1-methyl-4-phenyl- -3,4-trans-dihydrocarbostyril
(Example 5-K), the title compound, as a .about.1:1.8 diastereomeric
mixture of the two 3,4-trans-dihydrocarbostyr- il isomers, was
prepared as a white solid (melting point=118-128.degree. C.).
Purification was by flash chromatography eluting with straight
EtOAc. R.sub.f=0.37 (EtOAc).
[1965] C.sub.27H.sub.25F.sub.2N.sub.3O.sub.3 (MW 477.52); mass
spectroscopy (MH+) 477.
[1966] Anal. Calcd for C.sub.27H.sub.25F.sub.2N.sub.3O.sub.3: C,
67.91; H, 5.28; N, 8.80. Found: C, 67.78; H, 5.35; N, 8.55.
Example 5-42
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-1-methyl-4p-
henyl-3,4cis-dihydrocarbostyril
[1967] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1-methyl4-phenyl-3,4-cis-dihydrocarb- ostyril (Example
5-L), the title compound was prepared as a white solid (m.p.
152-153.degree. C.).
[1968] C.sub.27H.sub.25F.sub.2N.sub.3O.sub.3 (MW 477.52); mass
spectroscopy (MH+) 478.2, (MH-) 476.2.
[1969] Anal. Calcd for C.sub.27H.sub.25F.sub.2N.sub.3O.sub.3: C,
67.91; H, 5.28; N, 8.80. Found: C, 67.61; H, 5.41; N, 8.78.
Example 5-43
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-4phenyl-3,4-
-trans-dihydrocarbostyril
[1970] Step A: Following General Procedure I above using
N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and the tin
complex of
3-amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyril
(Example 5-M),
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-1-tert--
butoxycarbonyl4-phenyl-3,4-trans-dihydrocarbostyril was
prepared.
[1971] Step B: The title compound was prepared following General
Procedure 5-B using the product from Step A, as a .about.1:1.4
diastereomeric mixture of the two 3,4-trans-dihydrocarbostyril
isomers. The product was purified by flash chromatography eluting
with CH.sub.2Cl.sub.2/MeOH (98:2 gradient to 94:6) and a second
flash chromatography eluting with straight EtOAc to yield a white
solid (melting point=137-147.degree. C.). R.sub.f=0.42 (EtOAc).
[1972] C.sub.26H.sub.23F.sub.2N.sub.3O.sub.3 (MW 463.49); mass
spectroscopy (M+) 463.1
[1973] Anal. Calcd for C.sub.26H.sub.23F.sub.2N.sub.3O.sub.3: C,
67.38; H, 5.00; N, 9.07. Found: C, 67.12; H, 5.06; N, 8.88.
[1974] 6. Benzazepinone Derivatives and Related Compounds
General Procedure 6-A
Alkylation of 1-Amino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
[1975] Step A:
1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-- one
was prepared according to the procedure of Ben-Ishai et al.,
Tetrahedron, 1987, 43, 430.
[1976] Step B:
1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-- one
(2.0 g, 100 M %) was dissolved in DMF (30 mL) and NaH (95%, 0.17 g,
100M %) was added in one portion. The reaction mixture was stirred
for 1 hour and then the appropriate alkyl iodide (300M %) was added
and the mixture was stirred for 12 hours. The reaction was poured
into water and extracted with ethyl acetate (3.times.). The ethyl
acetate extracts were then washed with water (3.times.) and brine
(1.times.). Treatment with MgSO.sub.4, rotoevaporation, and
chromotography (30% EtOAc/hexanes) yielded
1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin--
2-one in 87% yield.
[1977] Step C:
1-Ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benza-
zepin-2-one (1.0 g, 100M %) was suspended in 30 mL of 30% HBr/HOAc
and heated to 100.degree. C. The reaction mixture was stirred for 5
hours at this temperature and then the reaction was cooled and
rotoevaporated to yield
1-amino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one as the
hydrobromide salt (100% yield).
General Procedure 6-B
Alkylation of 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[1978] Step A: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was
prepared from .alpha.-tetralone using the methods described in
Armstrong et al. Tetrahedron Letters. 1994, 35, 3239. The following
compounds were as prepared by this procedure for use in the
following steps:
[1979] 5-methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
(from 4-methyl-.alpha.-tetralone (Aldrich)); and
[1980]
5,5-dimethyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from
4,4-dimethyul-.alpha.-tetralone (Aldrich)).
[1981] Step B: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
(4.43 g, 100M %) was suspended in t-butanol (30 mL) and
BOC-anhydride (7.5 mL, 130M %) was added dropwise. The reaction was
stirred for 2 hours and then it was rotoevaporated to a residue
which was chromatographed with 60% ethyl acetate/hexanes to yield
BOC-protected 3-amino-1,3,4,5-tetrahydro-2- H-1-benzazepin-2-one in
87% yield.
[1982] Step C: BOC-protected
3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-- one (1.5 g, 100M %)
was dissolved in DMF (20 mL) and NaH (95%, 0.13 g, 100M %) was
added in one portion. The reaction mixture was stirred for 1 hour
and then the appropriate alkyl iodide (300M %) was added and
stirring was continued for 12 hours. The reaction was poured into
water and extracted with ethyl acetate (3.times.). The ethyl
acetate extracts were washed with water (3.times.) and then brine
(1.times.). Treatment with MgSO.sub.4, rotoevaporation, and
chromatography (30% EtOAc/hexanes) yielded a BOC-protected
3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepi- n-2-one in 80%
yield.
[1983] Step D: The BOC-protected
3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-b- enzazepin-2-one (1.0 g,
100M %) was suspended in 30 mL of 1:1
CH.sub.2Cl.sub.2/triflouroacetic acid and the mixture was stirred
for 4 hours. The reaction was then rotoevaporated to yield the
3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100%
yield).
Example 6-A
Synthesis of
3-Amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[1984] Step A:
3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was
prepared from 4-methyl-.alpha.-tetralone using the methods
described in Armstrong et al. Tetrahedron Letters. 1994, 35,
3239.
[1985] Step B:
3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (9.3 g
100M %) was dissolved in dioxane (300 mL) and the solution was
chilled to 0.degree. C. BOC-anhydride (13.89 g 130M %) was added
and the ice bath was removed allowing the solution to come to room
temperature and stirring was continued for 16 hours. The solution
was rotory evaporated to remove dioxane to provide an off white
solid. This solid was recrystallized from CHCl.sub.3 to yield
BOC-protected
3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 55%
yield.
[1986] Step C: BOC-protected
3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benz- azepin-2-one (100 M
%) was dissolved in DMF (20 mL) and NaH (95%, 100 M %) was added in
one portion and the reaction mixture was stirred for 1 hour. Methyl
iodide (300 M %) was added and this mixture was stirred for 12
hours. The reaction was then poured into water and extracted with
ethyl acetate (3.times.) then backwashed with water (3.times.) and
then brine (1.times.). Treatment with MgSO.sub.4, rotoevaporation,
and chromatography (5% MeOH/CH.sub.2Cl.sub.2) yielded BOC-protected
3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in
75% yield.
[1987] Step D: BOC-protected
3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-- benzazepin-2-one
(100 M %) was suspended in 30 mL of 1:1
CH.sub.2Cl.sub.2/triflouroacetic acid. The reaction mixture was
stirred for 4 hours. The reaction was then rotoevaporated to yield
3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100%
yield).
Example 6-B
Synthesis of
5-(L-Alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]az-
epin-6-one Hydrochloride
[1988] Following the procedure of Example 7-I and using
5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one
hydrochloride (Example 6-C), the title compound was prepared.
Example 6-C
Synthesis of
5-Amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one
Hydrochloride
[1989] Step A: Following General Procedure 5-A and using
N-t-Boc-5-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one
(General Procedure 6-B, following by Boc protection) and methyl
iodide,
N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one
was prepared.
[1990] Step B: Following General Procedure 8-N and using
N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one,
the title compound was prepared.
Example 6-D
Synthesis of
3-(S)-Amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-
-2-one
[1991] Step A:
3-(S)-Amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was
prepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene
(Aldrich) using the method of R. J. DeVita et al., Bioorganic and
Medicinal Chemistry Lett. 1995, 5(12)1281-1286.
[1992] Step B: Following General Procedure 5-A and using the
product from Step A, the title compound was prepared.
Example 6-E
Synthesis of
3-(S)-Amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin--
2-one
[1993] Step A:
3-(S)-Amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was
prepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene
(Aldrich) using the method of R. J. DeVita et al., Bioorganic and
Medicinal Chemistry Lett. 1995, 5(12)1281-1286.
[1994] Step B: Following General Procedure 5-A and using the
product from Step A, the title compound was prepared.
Example 6-F
Synthesis of
3-(S)-Amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepi-
n-2-one
[1995] The title compound was prepared from N-Boc-cystine (Novabio)
and 2-fluoro-1-nitrobenzene (Aldrich) using the method of R. J.
DeVita et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12)
1281-1286, followed by General Procedure 5-A.
Example 6-1
Synthesis of
1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-3-methyl-1,-
3,4,5-tetrahydro-2H-3-benzazepin-2-one
[1996] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
1-amino-3-methyl-1,3,4,5-tetrahydro-2H-3-ben- zazepin-2-one, the
title compound was prepared. The reaction was monitored by tlc on
silica gel (Rf=0.15 in ethyl acetate) and purification was by flash
chromatography using ethyl acetate as the eluant.
[1997] NMR data was as follows:
[1998] .sup.1H-nmr (CDCl.sub.3; 2 diasteromers): .delta.=8.10 (m,
1H), 7.58 (d, 0.5H), 7.42 (d, 0.5H), 7.05 (m, 4H0, 6.65 (m, 3H),
6.29 (m, 1H), 4.80 (t, 1H), 4.20 (m, 1H), 3.36 (s, 0.5H), 3.34 (s,
0.5H), 3.26 (bd, 2H), 3.10 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H),
1.36 (d, 3H), 1.29 (s, 3H).
[1999] .sup.13C-nmr (CDCl.sub.3; 2 diasteromers): .delta.=168.2,
167.9, 165.3, 165.2, 165.1, 164.9, 160.3, 160.1, 157.0, 156.8,
134.4, 134.3, 130.1, 129.9, 129.0, 128.8, 126.0, 123.3, 122.5,
119.5, 119.1, 107.9, 107.8, 107.6, 98.3, 98.0, 97.6, 47.6, 47.4,
44.6, 44.5, 43.7, 43.6, 38.0, 37.8, 30.6, 30.5, 26.6, 14.6,
14.1.
[2000] C.sub.22H.sub.23N.sub.3O.sub.3F.sub.2 (MW=415.44); mass
spectroscopy (M.sup.+) 415.
Example 6-2
Synthesis of
1-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-3-ethyl-
-7-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
[2001] Following General Procedure C above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
1-(S)-amino-3-ethyl-7-fluoro-1,3,4,5-tetrahy-
dro-2H-3-benzazepin-2-one (General Procedure 6-A), the title
compound was prepared. Purification was by flash chromatography
using 5% methanol/dichloromethane as the eluant.
[2002] NMR data was as follows:
[2003] .sup.1H-nmr (CDCl.sub.3): .delta.=7.8-7.7 (2.times.d, J=7
Hz, 1H0 7.1-7.0 (m, 2H), 6.8 (m, % H), 6.2 (t, 1H), 4.7 (t, 1H0,
4.2 (m, 1H), 3.6-3.4 (m, 6H), 3.2 (m, 2H), 1.5-1.3 (2.times.d, J=7
Hz, 3H), 1.1 (2.times.t, J=7 Hz, 3H).
[2004] .sup.13C-nmr (CDCl.sub.3): .delta.=177.3, 172.5, 172.1,
169.6, 169.4, 163.8, 160.5, 126.3, 126.2, 125.9, 125.8, 117.4,
117.2, 117.1, 116.9, 113.7, 113.4, 112.4, 112.3, 112.1, 112.0,
103.0, 102.9, 102.7, 102.6, 102.2., 53.3, 51.7, 51.4, 49.2, 49.0,
44.8, 44.5, 42.6, 42.5, 42.4, 42.3, 32.2, 19.0, 13.0, 12.9.
[2005] C.sub.23H.sub.24N.sub.3O.sub.3F.sub.3 (MW=447.19); mass
spectroscopy (MH.sup.+) N/A.
Example 6-4
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,3,4,5-tet-
rahydro-2H-1-benzazepin-2-one
[2006] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2- -one (General
Procedure 6-B), the title compound was prepared. The reaction was
monitored by tlc on silica gel (Rf=0.15 in 12%
methanol/dichloromethane) and purification was by flash
chromatography using 12% methanol/dichloromethane as the
eluant.
[2007] NMR data was as follows:
[2008] .sup.1H-nmr (CDCl.sub.3): .delta.=9.87 (s, 1H), 8.28 (d,
1H), 8.11 (d, 1H), 7.30-6.96 (m, 7H), 4.23 (m, 1H), 4.18 (m, 1H),
3.49 (s, 2H), 2.68 (m, 2H), 2.24 (m, 1H), 1.97 (m, 1H), 1.15 (s,
3H).
[2009] .sup.13C-nmr (CDCl.sub.3): .delta.=171.95, 171.54, 189.00,
160.74, 141.06, 138.01, 133.91, 129.90, 127.84, 125.58, 122.41,
112.79, 112.46, 102.23, 49.06, 48.47, 41.67, 35.50, 28.39,
18.99.
[2010] C.sub.21H.sub.21N.sub.3O.sub.3F.sub.2 (MW=401.42); mass
spectroscopy (MH.sup.+) 402.
Example 6-5
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,-
3,4,5-tetrahydro-2H-3-benzazepin-2-one
[2011] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1-benzyl-1,3,4,5-tetrahydro-2H-3-ben- zazepin-2-one
(General Procedure 6-B), the title compound was prepared.
Purification was by flash chromatography.
[2012] NMR data was as follows:
[2013] .sup.1H-nmr (CDCl.sub.3; 2 diasteromers): .delta.=7.20 (m,
9H), 6.73 (m, 3H), 5.26 (dd, 1H), 4.76 (dd, 1H), 4.53 (p, 1H), 4.44
(m, 1H), 3.44 (s, 1H), 2.40 (m, 3H) 1.83 (m, 1H), 1.28 (dd,
3H).
[2014] .sup.13C-nmr (CDCl.sub.3; 2 diasteromers): .delta.=172.2,
172.1, 171.2, 171.1, 170.0, 169.8, 1565.2, 165.0, 162.0, 140.7,
139.2, 137.4, 136.6, 129.9, 129.1, 128.9, 128.7, 128.5, 128.1,
127.6, 124.0, 112.9, 112.8, 112.7, 112.6, 103.4, 103.1, 102.8,
52.6, 52.5, 50.3, 49.5, 49.4, 43.1, 36.6, 36.5, 28.7, 28.6, 19.4,
19.2.
[2015] C.sub.28H.sub.27N.sub.3O.sub.3F.sub.2 (MW=491.54); mass
spectroscopy (MH.sup.+) 491.
Example 6-7
Synthesis of
3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-methy-
l-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[2016] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-methyl-1,3,4,5-tetrahydro-2H-1- -benzazepin-2-one
(General Procedure 6-B), the title compound was prepared. The
reaction was monitored by tlc on silica gel (Rf=0.21 in 3%
methanol/dichloromethane) and purification was by flash
chromatography using 3% methanol/dichloromethane as the eluant.
[2017] NMR data was as follows:
[2018] .sup.1H-nmr (CDCl.sub.3): .delta.=7.20 (m, 4H), 6.86 (d,
1H), 6.68 (m, 3H), 6.33 (d, 1H), 4.40 (m, 3H), 3.46 (s, 2H), 3.36
(s, 3H), 2.78 (m, 1H), 2.57 (m, 2H), 1.84 (m, 1H), 1.29 (d,
3H).
[2019] .sup.13C-nmr (CDCl.sub.3): .delta.=171.5, 171.0, 169.4,
165.3, 165.1, 162.0, 161.8, 141.9, 138.7, 135.1, 129.9, 128.6,
127.5, 123.4, 113.0, 112.5, 103.6, 103.3, 103.0, 50.4, 49.5, 43.5,
36.7, 36.1, 28.8, 19.5.
[2020] C.sub.22H.sub.23N.sub.3O.sub.3F.sub.2 (MW=415.44); mass
spectroscopy (M.sup.+) 415.
Example 6-8
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,5-dimethy-
l-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[2021] Following General Procedure C above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1- -benzazepin-2-one
(prepared from 4-methyltetralone (Aldrich) using General Procedure
6-A), the title compound was prepared as a solid having a melting
point of 115-119.degree. C. Purification was by flash
chromatography using 5% methanol/dichloromethane as the eluant.
[2022] NMR data was as follows:
[2023] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2-7.0 (m, 5H), 6.8-6.5
(m, 4H), 4.5 (m, J=7 Hz, 1H), 4.3 (m, J=4 Hz, 1H), 3.5 (s, 2H),
3.35 (s, 3H), 3.05 (m, J=6.5 Hz, 1H), 2.2 (m, J=4.5 Hz, 1H), 1.95
(m, 1H), 1.3 (2.times.d, J=7 Hz, 6H).
[2024] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 166.4, 165.9,
164.4, 164.3, 160.0, 159.9, 156.6, 139.9, 136.4, 133.6, 133.2,
122.8, 122.4, 120.5, 118.1, 107.6, 107.3, 98.2, 97.9, 97.5, 95.5,
45.0, 44.9, 44.0, 43.9, 39.8, 39.7, 37.9, 30.7, 30.7, 26.0, 14.0,
13.8, 12.4.
[2025] C.sub.23H.sub.2N.sub.3O.sub.3F.sub.2 (MW=429.47); mass
spectroscopy (MH.sup.+) 430.
Example 6-9
Synthesis of
3-(3,5-Difluorophenylacetyl)amino-1,5-dimethyl-1,3,4,5-tetrah-
ydro-2H-1-benzazepin-2-one
[2026] Following General Procedure C above using
N-(3,5-difluorophenyl)ace- tic acid (Oakwood) and
3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzaz- epin-2-one
(Example 6-A), the title compound was prepared as a solid having a
melting point of 185-187.degree. C. Purification was by flash
chromatography using 5% methanol/dichloromethane as the eluant.
[2027] NMR data was as follows:
[2028] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4-7.1 (m, 4H), 6.9-6.6
(m, 4H), 4.3 (m, J=8 Hz, 1H), 3.5 (s, 2H), 3.35 (s, 3H), 3.05 (m,
J=6.5 Hz, 1H), 2.3 (m, J=8 Hz, 1H), 1.95 (m, J=7 Hz, 1H), 1.3 (d,
J=7.1 Hz, 3H).
[2029] .sup.13C-nmr (CDCl.sub.3): .delta.=166.1, 163.8, 160.0,
159.8, 156.7, 156.5, 136.4, 133.8, 133.7, 133.3, 122.8, 122.5,
120.5, 118.1, 107.6, 107.5, 107.3, 107.2, 98.2, 97.8, 97.5, 45.1,
39.9, 38.0, 30.6, 26.0, 12.5.
[2030] C.sub.20H.sub.20N.sub.2O.sub.2F.sub.2 (MW=358.39); mass
spectroscopy (MH.sup.+) 359.
Example 6-10
Synthesis of 3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)
amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[2031] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-methyl-5-oxa-1,3,4,5-tetrahydr-
o-2H-1-benzazepin-2-one (Example 6-D), the title compound was
prepared as a solid having a melting point of 110-114.degree. C.
The reaction was monitored by tlc on silica gel (Rf=0.38 in 10%
methanol/dichloromethane) and purification was by silica gel
chromatography.
[2032] NMR data was as follows:
[2033] .sup.1H-nmr (CDCl.sub.3): .delta.=7.25 (d, J=4.2, 1H); 7.2
(m, 4H); 6.79 (d, J=5.7, 2H), 6.70 (t, J=2.1, 2.1, 1H); 6.61 (d,
J=7.5, 1H); 4.83 (dq, J=7.2, 11.1, 7.5, 1H); 4.55 (dt, J=7.8, 9.3,
5.1, 2H); 4.11 (dd, J=9.9, 11.1, 1H); 3.48 (s, 2H); 3.39 (s, 3H);
1.30 (d, J=6.6, 3H).
[2034] .sup.3C-nmr (CDCl.sub.3): .delta.=167.3, 164.4, 160.0,
156.7, 145.2, 133.5, 131.2, 122.9, 120.9, 118.5, 118.1, 107.6,
107.4, 98.3, 37.9, 37.6, 44.5, 44.0, 37.8, 36.6, 14.0.
[2035] C.sub.21H.sub.21F.sub.2N.sub.3O.sub.4 (MW=417); mass
spectroscopy (MH.sup.+) 418.
Example 6-11
Synthesis of
3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-
-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[2036] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-
-2H-1-benzazepin-2-one (Example 6-E), the title compound was
prepared as a solid having a melting point of 188-191.degree. C.
The reaction was monitored by tlc on silica gel (Rf=0.43 in 10%
methanol/dichloromethane) and purification was by recrystallization
from ether/hexanes.
[2037] NMR data was as follows:
[2038] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2 (m, 4H); 7.1 (m, 1H);
6.79 (dd, J=6.0, 6.6, 2H); 6.71 (t, J=2.2, 2.2, 1H); 6.43 (dd,
J=7.2, 8.8, 1H); 4.8 (m, 1H); 4.6 (m, 2H); 4.2 (m, 2H); 3.50 (s,
2H); 1.31 (d, J=7.1, 3H); 1.16 (t, J=7.1, 7.1, 3H).
[2039] .sup.13C-nmr (CDCl.sub.3): .delta.=172.9, 167.5, 164.8,
164.3, 146.6, 130.2, 123.6, 121.4, 119.3, 118.5, 108.0, 107.7,
98.4, 44.9, 44.4, 39.0, 38.3, 14.3.
[2040] C.sub.22H.sub.23F.sub.2N.sub.3O.sub.4 (MW=431); mass
spectroscopy (MH.sup.+) 432.
Example 6-12
Synthesis of
3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-methy-
l-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[2041] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-(S)-amino-1-methyl-5-thia-1,3,4,5-tetrahyd-
ro-2H-1-benzazepin-2-one (Example 6-F), the title compound was
prepared as a solid having a melting point of 156-159.degree. C.
The reaction was monitored by tlc on silica gel (Rf=0.17 in 10%
methanol/dichloromethane) and purification was by silica gel
chromatography.
[2042] NMR data was as follows:
[2043] .sup.1H-nmr (CDCl.sub.3): .delta.=7.63 (d, J=6.05, 1H);
.7.43 (t, J=7.7, 7.7, 1H); 7.2 (m, 3H); 6.79 (d, J=6.05, 2H); 6.54
(t, J=7.1, 7.1, 1H); 6.35 (d, J=7.7, 1H); 4.5 (m, 2H); 3.7 (m, 1H);
2.79 (t, J=11.0, 11.5, 1H); 1.29 (d, J=6.6, 3H).
[2044] .sup.13C-nmr (CDCl.sub.3): .delta.=172.9, 166.8, 165.8,
164.7, 141.4, 133.8, 131.4, 126.2, 123.4, 122.7, 120.2, 108.0,
107.7, 98.4, 45.3, 44.5, 40.1, 38.3, 33.8, 32.0, 14.3.
[2045] C.sub.21H.sub.21F.sub.2N.sub.3O.sub.3S (MW=433); mass
spectroscopy (MH.sup.+) 434.
Example 6-13
Synthesis of
5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl}-amino-3,3-dimeth-
yl-5,7-dihydro-6H-benz[b]azepin-6-one
[2046] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Ex. B) and
5-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-- 6-one, the
title compound was prepared. The reaction was monitored by tlc
(Rf=0.1, 5% MeOH/CHCl.sub.3) and product was purified by
chromatography (silica, 6% MeOH/CHCl.sub.3).
[2047] NMR data was as follows:
[2048] .sup.1H-nmr (d.sup.6-DMSO): .delta.=3.50 (d,2H); 9.55 (d,
1H). MW=429.47; mass spectroscopy (M+) 429.
Example 6-14
Synthesis of
5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-3,3,7-trime-
thyl-5,7-dihydro-6H-benz[b]azepin-6-one
[2049] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Ex. B) and
5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azep- in-6-one
hydrochloride (Example 6-C), the title compound was prepared. The
reaction was monitored by tlc (Rf=0.4, 5% MeOH/CHCl.sub.3) and
product was purified by chromatography (silica, 5% MeOH/CHCl.sub.3)
and crystallization from acetonitrile.
[2050] NMR data was as follows:
[2051] .sup.1H-nmr (d.sup.6-DMSO): .delta.=3.48 (d,2H); 4.25
(m,2H). MW=443.50; mass spectroscopy (M+) 443.
Example 6-15
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-3,3,7-trime-
thyl-5,7-dihydro-6H-benz[b]azepin-6-one
[2052] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H--
benz[b]azepin-6-one hydrochloride (Example 6-B), the title compound
was prepared. The product was purified by chromatography (silica,
3% MeOH/CHCl.sub.3).
[2053] NMR data was as follows:
[2054] .sup.1H-nmr (CDCl.sub.3): .delta.=3.35 (d, 3H); 5.07 (d,
1H). MW=459.49; mass spectroscopy (MH+) 460.
Example 6-16
Synthesis of
1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-1,-
3,4,5-tetrahydro-2H-3-benzazepin-2-one
[2055] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood) and
1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ph-
enyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, the title compound
was prepared. Purification was by LC 2000 chromatography using
ethyl acetate as the eluant.
[2056] C.sub.27H.sub.25N.sub.3O.sub.3F.sub.2 (MW=477); mass
spectroscopy (MH.sup.+) 478.1.
[2057] Anal. Calc. for C.sub.27H.sub.25N.sub.3O.sub.3F.sub.2: C,
67.91; H, 5.28; N, 8.8. Found: C, 68.2; H, 5.35; N, 8.58.
Example 6-17
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5,5-
-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
[2058] Following General Procedure C above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahy-
dro-2H-1-benzazepin-2-one (General Procedure 6-B), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.23,
30% EtOAc/hexanes) and the product was purified by flash
chromatography using EtOAc/hexanes as the eluant.
[2059] NMR data was as follows:
[2060] .sup.1H-nmr (CDCl.sub.3): .delta.=7.1-7.4 (m, 6H), 6.70 (m,
2H), 6.62 (t, 1H), 4.46 (m, 1H), 4.39 (m, 1H), 3.64 (m, 1H), 3.57
(d, 2H), 2.52 (m, 1H), 1.90 (m, 1H), 1.30 (m, 12H).
[2061] .sup.13C-nmr (CDCl.sub.3): .delta.=167.3, 167.2, 165.7,
165.0, 164.9, 160.2, 160.1, 156.9, 156.8, 136.4, 136.3, 134.5,
134.4, 123.4, 122.5, 122.0, 119.7, 107.9, 107.8, 107.6, 97.9, 97.8,
45.5, 44.9, 44.9, 44.37, 44.34, 40.0, 39.9, 37.9, 30.6, 36.7, 24.4,
14.2, 14.1, 9.15, 9.12.
[2062] C.sub.24H.sub.29N.sub.3O.sub.3F.sub.2 (MW=457.52); mass
spectroscopy (MH.sup.+) N/A.
Example 6-18
Synthesis of
3-(3,5-Difluorophenylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,-
5-tetrahydro-2H-1-benzazepin-2-one
[2063] Following General Procedure C above using
N-(3,5-difluorophenyl)ace- tic acid (Oakwood) and
3-amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H--
1-benzazepin-2-one (General Procedure 6-B), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.28, 25%
EtOAc/hexanes) and the product was purified by flash chromatography
using EtOAc/hexanes as the eluant.
[2064] NMR data was as follows:
[2065] .sup.1H-nmr (CDCl.sub.3): .delta.=7.38 (d, 1H), 7.20 (m,
4H), 6.81 (d, 2H), 4.42 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.29
(s, 2H), 2.45 (m, 1H), 1.38 (s, 3H), 1.30 (t, 3H), 1.24 (s,
3H).
[2066] .sup.13C-nmr (CDCl.sub.3): .delta.=166.2, 164.2, 160.3,
160.1, 157.0, 156.8, 136.5, 136.3, 134.3, 123.4, 122.6, 122.1,
119.8, 107.9, 107.8, 107.7, 107.6, 98.4, 98.0, 97.7, 45.7, 44.9,
40.0, 38.2, 36.6, 26.8, 24.5, 9.2.
[2067] C.sub.22H.sub.24N.sub.2O.sub.2F.sub.2 (MW=386.45).
Example 6-19
Synthesis of
3-(N'-(Cyclopentylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-t-
etrahydro-2H-1-benzazepin-2-one
[2068] Following General Procedure C above using
N-(cyclopentylacetyl)-L-a- lanine (Example D) and
3-amino-1-ethyl-5,5-trimethyl-1,3,4,5-tetrahydro-2H-
-1-benzazepin-2-one (General Procedure 6-B), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.25, 30%
EtOAc/hexanes) and the product was purified by flash chromatography
using EtOAc/hexanes as the eluant.
[2069] NMR data was as follows: .sup.1H-nmr (CDCl.sub.3):
.delta.=7.38 (d, 1H), 7.20 (m, 1H), 6.42 (t, 1H), 4.43 (m, 1H),
3.93 (m, 1H), 3.83 (m, 1H), 2.42 (m, 1H), 2.19 (s, 2H), 1.68 (m,
2H), 1.50 (m, 2H), 1.35 (s, 3H), 1.22 (t, 3H), 1.21 (s, 3H), 1.05
(m, 2H).
[2070] .sup.13C-nmr (CDCl.sub.3): .delta.=168.1, 168.0, 167.16,
167. 11, 165.7, 136.5, 136.4, 123.3, 122.52, 122.50, 122.14, 122.1,
119.8, 119.7, 55.8, 45.6, 45.5, 44.8, 44.7, 44.08, 44.05, 40.07,
40.01, 38.1, 32.5, 30.67, 30.65, 27.9, 27.8, 26.8, 24.5, 20.3,
14.37, 14.32, 9.58, 9.2, 9.1.
[2071] C.sub.24H.sub.35N.sub.3O.sub.3 (MW=413.56); mass
spectroscopy (MH.sup.+) N/A.
[2072] 7. Dibenzazepinone Derivatives and Related Compounds
General Procedure 7-A
Preparation of
5-Amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Derivatives
[2073] Step A:
[2074] Following General Procedure 5-A and using
5,7-dihydro-6H-dibenz[b,d- ]azepin-6-one and an alkyl halide, the
7-alkyl-5,7-dihydro-6H-dibenz[b,d]a- zepin-6-one was prepared.
[2075] Step B: The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(1 eq.) was dissolved in THF and isoamylnitrite (1.2 eq.) was
added. The mixture was cooled to 0.degree. C. in an ice bath.
NaHMDS (1.1 eq., 1M in THF) was added dropwise. After stirring for
1 hour or until the reaction was complete, the mixture was
concentrated then acidified with 1N HCl and extracted with EtOAc.
The organic portion was dried and concentrated to yield a crude
product which was purified by silica gel chromatography.
[2076] Step C: The resulting oxime was dissolved in EtOH/NH.sub.3
(20:1) and hydrogenated in a bomb using Raney nickel and hydrogen
(500 psi) at 100.degree. C. for 10 hours. The resulting mixture was
filtered and concentrated to provide an oil which was purified by
silica gel chromatography to yield the title compound.
General Procedure 7-B
Preparation of Fluoro-substituted
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Derivatives
[2077] A modification of the procedure of Robin D. Clark and
Jahangir, Tetrahedron, Vol. 49, No. 7, pp. 1351-1356, 1993 was
used. Specifically, an appropriately substituted
N-t-Boc-2-amino-2'-methylbiphenyl was dissolved in THF and cooled
to -78.degree. C. s-Butyl lithium (1.3M in cyclohexane, 2.2 eq.)
was added slowly so that the temperature remained below -65.degree.
C. The resulting mixture was allowed to warm to -25.degree. C. and
was stirred at that temperature for 1 hour. The mixture was cooled
to -78.degree. C. Dry CO.sub.2 was bubbled through the mixture for
30 seconds. The mixture was allowed to warm to ambient temperature
then was carefully quenched with water. The mixture was
concentrated under reduced pressure then was adjusted to pH 3 with
1N HCl. The mixture was extracted with EtOAc and the organic
portion was dried and concentrated to yield a crude material. The
crude material was dissolved in methanol and the solution was
saturated with HCl. The mixture was heated at reflux for 12 hours
then was allowed to cool. The mixture was concentrated to provide
crude lactam which was purified by chromatography or
crystallization.
General Procedure 7-C
Resolution of
5-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2078] In a round bottom flask was added the racemic freebase amine
(1.0 eq.) in methanol followed by di-p-toluoyl-D-tartaric acid
monohydrate (1.0 eq.). The mixture was concentrated in vacuo to a
residue and redissolved in a moderate volume of methanol and
allowed to stir at room temperature open to the atmosphere (8-72
hours). The solid was removed by filtration. The enantiomeric
excess was determined by chiral HPLC (Chiracel ODR) using 15%
acetonitrile and 85% H.sub.2O with 0.1% trifluoroacetic acid and a
flow rate of 1.0 mL/min at 35.degree. C. The resolved
di-p-toluoyl-D-tartaric salt was then dissolved in EtOAc and
saturated NaHCO.sub.3 until pH 9-10 was reached. The layers were
separated and the organic layer was washed again with saturated
NaHCO.sub.3, H.sub.2O, and brine. The organic layer was dried over
MgSO.sub.4 and the drying agent was removed by filtration. The
filtrate was concentrated in vacuo. The free amine was dissolved in
MeOH and HCl (12M, 1.0 eq.) was added. The salt was concentrated in
vacuo and the resulting film was triturated with EtOAc. The HCl
salt was filtered and rinsed with EtOAc. The ee was determined by
chiral HPLC.
Example 7-A
Synthesis of
5-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Hydrochloride
Step A--Synthesis of
7-Methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2079] A round bottom flask was charged with sodium hydride (0.295
g, 7.46 mmol) in 9.0 ml of DMF and treated with
5,7-dihydro-6H-dibenz[b,d]azepin-- 6-one (1.3 g, 6.22 mmol) (CAS #
20011-90-9, prepared as described in Brown, et. al., Tetrahedron
Letters, No. 8, 667-670, (1971) and references cited therein).
After stirring at 60.degree. C. for 1 h, the solution was treated
with methyl iodide (1.16 ml, 18.6 mmol) and stirring continued for
17 h with the exclusion of light. After cooling, the reaction was
diluted with CH.sub.2Cl.sub.2/H.sub.2O, washed with NaHSO.sub.4
solution, H.sub.2O, and dried over Na.sub.2SO.sub.4. Evaporation
and flash chromatography (SiO.sub.2, CHCl.sub.3) gave 0.885 g (63%)
of the title compound as a colorless solid.
[2080] NMR data was as follows:
[2081] .sup.1H-nmr (CDCl.sub.3): .delta.=7.62 (d, 2H), 7.26-7.47
(m, 6H), 3.51 (m, 2H), 3.32 (s, 3H).
[2082] C.sub.15H.sub.13NO (MW=223.27); mass spectroscopy (MH+)
223.
[2083] Anal. Calcd for C.sub.15H.sub.13NO; C, 80.69 H, 5.87 N,
6.27. Found: C, 80.11 H, 5.95 N, 6.23.
Step B--Synthesis of
7-Methyl-5-oximo-5,7-dihydro-6H-dibenz[b,d]azepin-6-o- ne
[2084] The compound isolated above (0.700 g, 3.14 mmol) was
dissolved in 20 ml of toluene and treated with butyl nitrite (0.733
ml, 6.28 mmol). The reaction temperature was lowered to 0.degree.
C. and the solution was treated with KHMDS (9.42 ml, 0.5 M) under
N.sub.2 atmosphere. After stirring for 1 h the reaction was
quenched with a saturated solution of NaHSO.sub.4, diluted with
CH.sub.2Cl.sub.2 and separated. The organic layer was dried over
Na.sub.2SO.sub.4 and the title compound purified by chromatography
(SiO.sub.2, 98:2 CHCl.sub.3/MeOH) giving 0.59 g (80%) as a
colorless solid.
[2085] C.sub.15H.sub.12N.sub.2O.sub.2 (MW=252.275); mass
spectroscopy (MH+) 252.
[2086] Anal. Calcd for C.sub.15H.sub.12N.sub.2O.sub.2; C, 71.42 H,
4.79 N, 11.10. Found: C, 71.24 H, 4.69 N, 10.87.
Step C--Synthesis of
5-Amino-7-Methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-o- ne
Hydrochloride
[2087] The oxime isolated above (0.99 g, 3.92 mmol) was
hydrogenated in a Parr apparatus at 35 psi over 10% Pd/C (0.46 g)
in 3A ethanol. After 32 h the reaction mixture was filtered through
a plug of celite, the filtrate evaporated to a foam and treated
with a saturated solution of HCl (g) in Et.sub.2O. The resulting
colorless solid was filtered, rinsed with cold Et.sub.2O and vacuum
dried to give 0.66 g (61%) of the title compound.
[2088] NMR data was as follows:
[2089] .sup.1H-nmr (DMSOd6): .delta.=9.11 (bs, 3H), 7.78-7.41(m,
8H), 4.83 (s, 1H), 3.25 (s, 3H).
[2090] C.sub.15H.sub.14N.sub.2O HCl (MW=274.753); mass spectroscopy
(MH+free base) 238.
[2091] Anal. Calcd for C.sub.15H.sub.14N.sub.2O HCl; C, 65.57 H,
5.50 N, 10.19 Found: C, 65.27 H, 5.67 N, 10.13.
Example 7-B
Synthesis of (S)- and
(R)-5-(L-Alaninyl)-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
Step A--Synthesis of (S)- and
(R)-5-(N-Boc-L-Alaninyl)-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[2092] Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved
in THF and treated with HOBt hydrate (0.305 g, 2.26 mmol), and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.45 g,
1.89 mmol) (Example 7-A). The temperature was lowered to 0.degree.
C. and the reaction mixture treated with EDC (0.449 g, 2.26 mmol)
(Alrich) and stirred 17 hours under N.sub.2. The reaction mixture
was evaporated, the residue diluted with EtOAc/H.sub.2O, washed 1.0
N HCl, sat. NaHCO.sub.3, brine and dried over Na.sub.2SO4. The
diastereomers were separated on a Chiralcel OD column using 10%
IPA/heptane at 1.5 ml/minute.
[2093] Isomer 1: Retention time 3.37 minutes.
[2094] NMR data was as follows:
[2095] .sup.1H-nmr (CDCl.sub.3): .delta.=7.62-7.33 (m, 9H), 5.26
(d, 1H), 5.08 (m, 1H), 4.34 (m, 1H), 3.35 (s, 3H), 1.49 (s, 9H),
1.40 (d, 3H).
[2096] Optical Rotation: [.alpha.].sub.20=-96 @589 nm (c=1,
MeOH).
[2097] C.sub.23H.sub.27N.sub.3O.sub.4 (MW=409.489); mass
spectroscopy (MH+) 409.
[2098] Anal. Calcd for C.sub.23H.sub.27N.sub.3O.sub.4; C, 67.46 H,
6.64 N, 10.26. Found: C, 68.42 H, 7.02 N, 9.81.
[2099] Isomer 2: Retention time 6.08 minutes.
[2100] NMR data was as follows:
[2101] .sup.1H-nmr (CDCl.sub.3): .delta.=7.74 (bd, 1H), 7.62-7.32
(m, 8H), 5.28 (d, 1H), 4.99 (m, 1H), 4.36 (m, 1H), 3.35 (s, 3H),
1.49 (s, 9H), 1.46 (d, 3H).
[2102] Optical Rotation: [.alpha.].sub.20=69 @589 n (c=1,
MeOH).
[2103] C.sub.23H.sub.27N.sub.3O.sub.4 (MW=409.489); mass
spectroscopy (MH+) 409.
[2104] Anal. Calcd for C.sub.23H.sub.27N.sub.3O.sub.4; C, 67.46 H,
6.64 N, 10.26. Found: C, 67.40 H, 6.62 N, 10.02
Step B--Synthesis of (S)- and
(R)-5-(L-Alaninyl)-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one Hydrochloride
[2105] The compounds isolated in Part A (each isomer separately)
were dissolved in dioxane and treated with excess HCl (g). After
stirring for 17 hours, the title compounds were isolated as
colorless solids after evaporation and vacuum drying.
[2106] Isomer 1:
[2107] C.sub.18H.sub.19N.sub.3O.sub.2.HCl (MW=345.832); mass
spectroscopy (MH+free base) 309.
[2108] Optical Rotation: [.alpha.].sub.20=-55 @589 nm (c=1,
MeOH).
[2109] Isomer 2:
[2110] C.sub.18H.sub.19N.sub.3O.sub.2.HCl (MW=345.832); mass
spectroscopy (MH+free base) 309.
[2111] Optical Rotation: [.alpha.].sub.20=80 @589 nm (c=1,
MeOH).
Example 7-C
Synthesis of (S)- and
(R)-5-(L-Valinyl)-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
Step A--Synthesis of (S)- and
(R)-5-(N-Boc-L-Valinyl)-amino-7-methyl-S
7-dihydro-6H-dibenz[b,d]azepin-6-one
[2112] Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in
THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05
ml, 6.05 mmol) and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature was
lowered to 0.degree. C. and the reaction mixture treated with EDC
(0.601 g, 3.02 mmol)(Alrich) and stirred 17 hours under N.sub.2.
The reaction mixture was evaporated, the residue diluted with
EtOAc/H.sub.2O, washed 1.0 N HCl, sat. NaHCO.sub.3, brine and dried
over Na.sub.2SO.sub.4. The diastereomers were separated on a
Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.
[2113] Isomer 1: Retention time 3.23 minutes.
[2114] Optical Rotation: [.alpha.].sub.20=-120 @589 nm (c=1,
MeOH).
[2115] C.sub.25H.sub.31N.sub.3O.sub.4 (MW=437.544); mass
spectroscopy (MH+) 438
[2116] Isomer 2: Retention time 6.64 minutes.
[2117] Optical Rotation: [.alpha.].sub.20=50 @589 nm (c=1,
MeOH).
[2118] C.sub.25H.sub.31N.sub.3O.sub.4 (MW=437.544); mass
spectroscopy (MH+) 438
Step B--Synthesis of (S)- and
(R)-5-(L-Valinyl)-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one Hydrochloride
[2119] The compounds isolated in Part A (each isomer separately)
were dissolved in dioxane and treated with excess HCl (g). After
stirring for 17 hours, the title compounds were isolated as
colorless solids after evaporation and vacuum drying.
[2120] Isomer 1:
[2121] C.sub.20H.sub.23N.sub.3O.sub.2.HCl (MW=373.88); mass
spectroscopy (MH+free base) 338.
[2122] Optical Rotation: [.alpha.].sub.20=-38 @589 nm (c=1,
MeOH).
[2123] Isomer 2:
[2124] C.sub.20H.sub.23N.sub.3O.sub.2.HCl (MW=373.88); mass
spectroscopy (MH+free base) 338.
[2125] Optical Rotation: [.alpha.].sub.20=97 @589 nm (c=1,
MeOH).
Example 7-D
Synthesis of (S)- and
(R)-5-(L-tert-Leucine)-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
Step A--Synthesis of (S)- and
(R)-5-(N-Boc-L-tert-Leucinyl)-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2126] Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was
dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol),
Dipea (1.05 ml, 6.05 mmol) and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature was
lowered to 0.degree. C. and the reaction mixture treated with EDC
(0.601 g, 3.02 mmol) (Alrich) and stirred 17 hours under N.sub.2.
The reaction mixture was evaporated, the residue diluted with
EtOAc/H.sub.2O, washed 1.0 N HCl, sat. NaHCO.sub.3, brine and dried
over Na.sub.2SO.sub.4. The diastereomers were separated on a
Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.
[2127] Isomer 1: Retention time 3.28minutes.
[2128] Optical Rotation: [.alpha.].sub.20=-128 @589 nm (c=1,
MeOH).
[2129] C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451.571); mass
spectroscopy (MH+) 452
[2130] Isomer 2: Retention time 5.52 minutes.
[2131] Optical Rotation: [.alpha.].sub.20=26 @589 nm (c=1,
MeOH).
[2132] C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451.571); mass
spectroscopy (MH+) 452
Step B--Synthesis of (S)- and
(R)-5-(L-tert-Leucinyl)-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
[2133] The compounds isolated in Part A (each isomer separately)
were dissolved in dioxane and treated with excess HCl (g). After
stirring for 17 hours, the title compounds were isolated as
colorless solids after evaporation and vacuum drying.
[2134] Isomer 1:
[2135] C.sub.21H.sub.25N.sub.3O.sub.2.HCl (MW=387.91); mass
spectroscopy (MH+free base) 352.
[2136] Optical Rotation: [.alpha.].sub.20=-34 @589 nm (c=1,
MeOH).
[2137] Isomer 2:
[2138] C.sub.21H.sub.25N.sub.3O.sub.2.HCl (MW=387.91); mass
spectroscopy (MH+free base) 352.
[2139] Optical Rotation: [.alpha.].sub.20=108 @589 nm (c=1,
MeOH).
Example 7-E
Synthesis of
5-(N-Boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one
Step A--Synthesis of
5-Iodo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2140] A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g,
4.77 mmol) (Example 7-A) and Et.sub.3N (2.66 ml, 19.12 mmol) were
stirred for 5.0 minutes at -15.degree. C. in CH.sub.2Cl.sub.2and
treated with TMSI (1.36 ml, 9.54 mmol). After stirring for 15
minutes I.sub.2 (1.81 g, 7.16 mmol) was added in a single portion
and the reaction allowed to warm to 5-10.degree. C. over 3 h. The
reaction was quenched with sat. Na.sub.2SO.sub.3, diluted with
CH.sub.2Cl.sub.2 and separated. The organics were washed with
Na.sub.2SO.sub.3 and NaHSO.sub.3 and dried over MgSO.sub.4. After
filtration, the organics were concentrated to approximately 20 ml
and diluted with an additional 20 ml of hexanes. The title compound
was isolated as a tan precipitate by filtration.
Step B--Synthesis of
5-Azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2141] The iodide isolate above was dissolved in DMF and treated
with 1.2 equivalents of NaN.sub.3. After stirring 17 h at
23.degree. C. the mixture was diluted with EtOAc/H.sub.2O,
separated, washed with brine and dried over MgSO.sub.4. The title
compound was triturated from hot EtOAc as a tan powder.
Step C--Synthesis of
5-(N-Boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6- -one
[2142] The azide was dissolved in THF/H.sub.2O and stirred at
23.degree. C. for 17 h in the presence of 3.0 equivalents of
Ph.sub.3P. The reaction was diluted with 50% HOAc/toluene,
separated, the aqueous layer extracted with toluene and evaporated
to an oily residue. This was taken to pH 7.0 by the addition of 1 N
NaOH, the resulting HOAc salt was collected and vacuum dried.
Finally, the compound was treated with Boc anhydride (1.05
equivalents) and Et.sub.3N (2.1 equivalents) in THF. After stirring
for 5 h at 23.degree. C. the reaction was filtered and the title
compound isolated as a colorless powder.
Example 7-F
Synthesis of
5-Amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6- -one
Hydrochloride
Step A--Synthesis of
5-(N-Boc-Amino)-7-(2-methylpropyl)-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[2143] A solution of
5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-on- e (0.2 g,
0.617 mmol) (Example 7-E) in DMF was treated with Cs.sub.2CO.sub.3
(0.22 g, 0.678 mmol) and warmed to 60.degree. C. To the reaction
mixture was added 1-iodo-2-methylpropane (0.078 ml, 0.678 mmol) and
stirring continued for 17 h. After cooling to 23.degree. C. the
mixture was diluted with CH.sub.2Cl.sub.2, washed with several
portions of brine and dried over Na.sub.2SO.sub.4. The title
compound was purified by chromatography (SiO.sub.2, CHCl.sub.3/MeOH
9:1).
[2144] C.sub.23H.sub.28N.sub.2O.sub.3 (MW=380.41); mass
spectroscopy (MH+) 381
[2145] Anal. Calcd for C.sub.23H.sub.28N.sub.2O.sub.3; C, 72.61 H,
7.42 N, 7.36. Found: C, 72.31 H, 7.64 N, 7.17.
Step B--Synthesis of
5-Amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]- azepin-6-one
Hydrochloride
[2146] The compound isolated in Part A was deprotected in dioxane
saturated with gaseous HCl. The title compound was isolated as a
slightly colored solid after evaporation and vacuum drying.
Example 7-G
Synthesis of
5-Amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-- one
Hydrochloride
Step A--Synthesis of
5-(N-Boc-Amino)-7-(methoxyacetyl)-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[2147] A solution of
5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-on- e (1.03,
3.08 mmol) (Example 7-E) in DMF was treated with Cs.sub.2CO.sub.3
(1.10 g, 3.39 mmol) and warmed to 60.degree. C. To the reaction
mixture was added bromomethyl acetate (0.321 ml, 3.39 mmol)
(Aldrich) and stirring continued for 17 h. After cooling to
23.degree. C. the mixture was diluted with CH.sub.2Cl.sub.2, washed
with several portions of brine and dried over Na.sub.2SO.sub.4. The
title compound was purified by chromatography (SiO.sub.2,
CHCl.sub.3).
[2148] C.sub.22H.sub.24N.sub.2O.sub.5 (MW=396.44); mass
spectroscopy (MH+) 397
[2149] Anal. Calcd for C.sub.22H.sub.24N.sub.2O.sub.5; C, 66.65 H,
6.10 N, 7.07. Found: C, 66.28 H, 5.72 N, 6.50.
Step B--Synthesis of
5-Amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]a- zepin-6-one
Hydrochloride
[2150] The compound isolated in Part A was deprotected in dioxane
saturated with gaseous HCl. The title compound was isolated as-a
colorless solid after evaporation and vacuum drying.
[2151] C.sub.17H.sub.16N.sub.2O.sub.3 HCl (MW=332.78); mass
spectroscopy (MH+free base) 297.
Example 7-H
Synthesis of
5-Amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,-
d]azepin-6-one Hydrochloride
Step A--Synthesis of
5-(N-Boc-Amino)-7-(3,3-dimethyl-butanonyl)-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[2152] A solution of
5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-on- e (0.2 g,
0.617 mmol) (Example 7-E) in. DMF was treated with Cs.sub.2CO.sub.3
(0.3 g, 0.925 mmol) and warmed to 60.degree. C. To the reaction
mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 ml, 0.74
mmol) (Aldrich) and stirring continued for 17 h. After cooling to
23.degree. C., the mixture was diluted with CH.sub.2Cl.sub.2,
washed with several portions of brine and dried over
Na.sub.2SO.sub.4. The title compound was isolated as a colorless
solid.
[2153] C.sub.25H.sub.30N.sub.2O.sub.4 (MW=422.522); mass
spectroscopy (MH+) 423
Step B--Synthesis of
5-Amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one Hydrochloride
[2154] The compound isolated in Part A was deprotected in dioxane
saturated with gaseous HCl. The title compound was isolated as a
colorless solid after evaporation and vacuum drying.
Example 7-1
Synthesis of
L-Alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin--
6-one Hydrochloride
[2155] Step A: Following General Procedure D and using
N-t-Boc-L-alanine and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e was prepared.
[2156] Step B: Following General Procedure 8-N and using the
N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e, the title compound was prepared. Other substituted
N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
es can also be prepared by this procedure.
Example 7-J
Synthesis of
L-Valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- -one
Hydrochloride
[2157] Step A: Following General Procedure D and using
N-t-Boc-L-valine and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
was prepared.
[2158] Step B: Following General Procedure 8-N and using the
N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one-
, the title compound was prepared. Other substituted
N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one-
s can also be prepared by this procedure.
Example 7-K
Synthesis of
5-Amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2159] Following General Procedure 7-A and using
5,7-dihydro-6H-dibenz[b,d- ]azepin-6-one (prepared as described in
Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and
references cited therein) and 1-chloro-4-phenylbutane (Aldrich),
the title compound was prepared.
Example 7-L
Synthesis of
5-Amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one
[2160] Following General Procedure 7-A and using
5,7-dihydro-6H-dibenz[b,d- ]azepin-6-one (prepared as described in
Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and
references cited therein) and (bromomethyl)cyclopropane (Aldrich),
the title compound was prepared.
Example 7-M
Synthesis of
5-Amino-7-(2',2',2'-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d-
]azepin-6-one
[2161] Following General Procedure 7-A and using
5,7-dihydro-6H-dibenz[b,d- ]azepin-6-one (prepared as described in
Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and
references cited therein) and 1-bromo-2,2,2-trifluoroethane
(Aldrich), the title compound was prepared.
Example 7-N
Synthesis of
5-Amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2162] Following General Procedure 7-A and using
5,7-dihydro-6H-dibenz[b,d- ]azepin-6-one (prepared as described in
Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and
references cited therein) and bromocyclohexane (Aldrich), the title
compound was prepared.
Example 7-O
Synthesis of
5-(L-Alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b-
,d]azepin-6-one Hydrochloride
[2163] Step 1: 2-Bromo-5-fluorotoluene was stirred in THF at -78C.
s-BuLi (1.05 eq., 1.3 M in cyclohexane) was slowly added and the
mixture was stirred for 45 minutes. Trimethylborate (1.5 eq) was
added and the mixture was allowed to warm to ambient temperature.
After stirring for 1 hour, pinacol (2 eq.) was added. The mixture
was stirred for 16 hours then was concentrated under reduced
pressure. The resulting residue was slurried in CH.sub.2Cl.sub.2
and filtered through Celite. The filtrate was concentrated to yield
an oil which was purified by chromatography on deactivated silica
gel (Et.sub.3N) to yield the arylboronate ester.
[2164] Step 2: 2-Bromoaniline (1 eq.) and di-t-butyl-dicarbonate
(1.1 eq.) were stirred at 80.degree. C. for 20 hours. The resulting
mixture was allowed to cool and was directly distilled using house
vacuum to provide N-t-Boc-2-bromoaniline.
[2165] Step 3: N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the
arylboronate ester (Step 1, 1.1 eq.), K.sub.2CO.sub.3 (1.1 eq.) and
tetrakis(triphenylphosphine)palladium(0) (0.02 eq) were stirred in
20% water/dioxane under nitrogen. The solution was heated at reflux
for 10 hours. The mixture was allowed to cool then was
concentrated. The resulting residue was partitioned between water
and chloroform. The organic portion was dried and concentrated to
yield an oil which was purified by silica gel chromatography using
1:1 CH.sub.2Cl.sub.2/hexanes.
[2166] Step 4: Following General Procedure 7-B and using the
substituted biphenyl from step 3, the
9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
[2167] Step 5: 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1
eq., Step 4), cesium carbonate (1.1 eq., Aldrich) and methyl iodide
(1.1 eq., Aldrich) were stirred in dry DMF at ambient temperature
for 16 hours. The mixture was concentrated under reduced pressure
to provide a residue which was partitioned between EtOAc and water.
The organic portion was dried and concentrated to yield an oil
which was purified by silica gel chromatography to
9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on- e.
[2168] Step 6: Following General Procedure 7-A, Step B and
9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step
5, 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
was prepared.
[2169] Step 7: Following the procedure of Example 7-I and using
5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
from Step 6, the title compound was prepared.
Example 7-P
Synthesis of
5-(L-Alaninyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one Hydrochloride
[2170] Following the procedure of Example 7-O and using
2-bromo-4-fluoroaniline (Step 2, Lancaster) and o-tolylboronic acid
(Step 3, Aldrich), the title compound was prepared.
Example 7-Q
Synthesis of
5-(L-Alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one Hydrochloride
[2171] Following the procedure of Example 7-O and using
2-bromo-4-fluorotoluene (Step 1), the title compound was
prepared.
Example 7-R
Synthesis of
5-(L-Alanyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one Hydrochloride
[2172] Following the procedure of Example 7-I and using
5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(Example 7-L), the title compound was prepared.
Example 7-S
Synthesis of
5-(L-Alaninyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]aze-
pin-6-one Hydrochloride
[2173] Following the procedure of Example 7-I and using
5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example
7-K), the title compound was prepared.
Example 7-T
Synthesis of
5-(L-Valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[-
b,d]azepin-6-one Hydrochloride
[2174] Following the procedure of Example 7-J and using
5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(Example 7-L), the title compound was prepared.
Example 7-U
Synthesis of
5-(L-Valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azep-
in-6-one Hydrochloride
[2175] Following the procedure of Example 7-J and using
5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example
7-U), the title compound was prepared.
Example 7-V
Synthesis of
5-(L-Valinyl)amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- -one
Hydrochloride
[2176] Step A: Following General Procedure 7-A and using
5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in
Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and
references cited therein) and 1-bromohexane (Aldrich),
5-amino-7-hexyl-5,7-dihydro-6H-dibe- nz[b,d]azepin-6-one was
prepared.
[2177] Step B: Following the procedure of Example 7-J and using
5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title
compound was. prepared.
Example 7-W
Synthesis of
5-(L-Valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b-
,d]azepin-6-one Hydrochloride
[2178] Following the procedure of Example 7-J and using
5-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(as prepared in Example 7-Q, the title compound was prepared.
Example 7-X
Synthesis of
5-(L-Valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b-
,d]azepin-6-one Hydrochloride
[2179] Following the procedure of Example 7-J and using the
5-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(as prepared in Example 7-P), the title compound was prepared.
Example 7-Y
Synthesis of
5-(L-Valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b-
,d]azepin-6-one Hydrochloride
[2180] Following the procedure of Example 7-J and using the
5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(as prepared in Example 7-O), the title compound was prepared.
Example 7-Z
Synthesis of
(5-Amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]a-
zepin-6-one
[2181] The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7-A) was dissolved in a 1:1 mixture of
EtOAc/HOAc. 5% Rh/C was added and the mixture was stirred at
60.degree. C. under 60 psi of hydrogen. After 3 days, the mixture
was filtered and the filtrate was concentrated to provide an oil
which was purified by SCX-cation exchange chromatography to yield
the title compound.
Example 7-AA
Synthesis of
5-(S)-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Hydrochloride
[2182] Following General Procedure 7-C using racemic
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.)
and di-p-toluoyl-D-tartaric acid monohydrate (1.0 eq.) in methanol,
the title compound was prepared as a solid. The product was
collected by filtration. Enantiomeric excess was determined by
chiral HPLC.
[2183] Desired enantiomer 1: retention time of 9.97 minutes.
[2184] Undesired enantiomer 2: retention time of 8.62 minutes.
[2185] NMR data was as follows:
[2186] .sup.1H-nmr (CDCl.sub.3): .delta.=9.39 (s, 2H), 7.75-7.42
(m, 8H), 4.80 (s, 1H), 3.30 (s, 3H).
[2187] C.sub.15H.sub.15ClN.sub.2O (MW=274.75); mass spectroscopy
(MH.sup.+) 239.1.
[2188] Anal Calcd for C.sub.15H.sub.15ClN.sub.2O.sub.3; C, 65.57;
H, 5.50; N, 10.20; Found: C, 65.51, H, 5.61; N, 10.01.
Example 7-1
Synthesis of 5-(S)-
[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2189] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]a- zepin-6-one
hydrochloride (Example 7-A), the title compound was prepared as a
colorless solid. The diastereomers were purified by HPLC (Bulk
OD-25) using 15% EtOH in heptane as eluent and a flow rate of 1.5
ml/min.
[2190] Isomer 1: retention time of 11.4 minutes.
[2191] NMR data was as follows:
[2192] .sup.1H-nmr (CDCl.sub.3): .delta.=7.62-7.33 (m, 8H), 6.79
(m, 2H), 6.71 (m, 1H), 6.47 (m, 1H), 5.24 (d 1H), 4.70 (m, 1H),
3.48 (s, 2H), 3.34 (s, 3H), 1.42 (d, 3H).
[2193] Optical Rotation: [.alpha.].sub.20=-125 @589 nm (c=1,
MeOH).
[2194] C.sub.26H.sub.23F.sub.2N.sub.3O.sub.3 (MW=463.49); mass
spectroscopy (MH+) 463.
[2195] Anal. Calcd for C.sub.26H.sub.23F.sub.2N.sub.3O.sub.3; C,
67.38 H, 5.00 N, 9.06. Found: C, 67.49 H, 5.06 N, 8.93.
Example 7-2
Synthesis of
5-(S)-[N'-((S)-3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-al-
aninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
and
5-(S)-[N'-((R)-3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2196] Following General Procedure D above using
3,5-difluoromandelic acid and
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6--
one hydrochloride (Example 7-B), the title compound was prepared as
a colorless solid. The diastereomers were purified by flash
chromatography using 98:2 CHCl.sub.3/MeOH.
[2197] Isomer 1:
[2198] NMR data was as follows:
[2199] .sup.1H-nmr (CDCl.sub.3): .delta.=7.67 (d, 1H), 7.60-7.28
(m, 8H), 7.15 (d, 1H), 6.98 (m, 2H), 6.74 (m, 1H), 5.21 (d, 1H),
4.94 (d, 1H), 4.61 (m, 1H), 4.56 (m, 1H), 3.34 (s, 3H), 1.42 (d,
3H).
[2200] Optical Rotation: [.alpha.].sub.20=-121 @589 nm (c=1,
MeOH).
[2201] C.sub.26H.sub.23F.sub.2N.sub.3O.sub.4 (MW=479.488); mass
spectroscopy (MH+) 479.
[2202] Anal. Calcd for C.sub.26H.sub.23F.sub.2N.sub.3O.sub.4; C,
65.13 H, 4.83 N, 8.76. Found: C, 65.42 H, 4.73 N, 8.65.
[2203] Isomer 2:
[2204] NMR data was as follows:
[2205] .sup.1H-nmr (CDCl.sub.3): .delta.=7.78 (d, 1H), 7.66 (d,
1H), 7.54-7.28 (m, 8H), 6.89 (m, 2H), 6.71 (m, 2H), 5.22 (d 1H),
4.92 (m, 1H), 4.65 (m, 1H), 4.01 (m, 1H), 3.37 (s, 3H), 1.39 (d,
3H).
[2206] Optical Rotation: [.alpha.].sub.20=-146 589 nm (c=1,
MeOH).
[2207] C.sub.26H.sub.23F.sub.2N.sub.3O.sub.4 (MW=479.488); mass
spectroscopy (MH+) 479.
[2208] Anal. Calcd for C.sub.26H.sub.23F.sub.2N.sub.3O.sub.4; C,
65.13 H, 4.83 N, 8.76. Found: C, 65.18, 4.82, 8.65.
Example 7-3
Synthesis of 5-(S)-
[N'-(3,5-Difluorophenyl-.alpha.-ketoacetyl)-L-alaninyl
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2209] Following the Jones oxidation procedure (Fieser and Fieser,
Reagents for Organic Synthesis, Vol. 1, p. 142) using
5-(S)-[((SIR)-3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-2), the
title compound was prepared as a colorless solid.
[2210] NMR data was as follows:
[2211] .sup.1H-nmr (CDCl.sub.3): .delta.=7.92 (m, 2H), 7.61-7.35
(m, 8H), 7.08 (m, 1H), 5.31 (d, 1H), 4.74 (m, 1H), 3.38 (s, 3H),
1.56 (d, 3H).
[2212] C.sub.26H.sub.21F.sub.2N.sub.3O.sub.4 (MW=477.472); mass
spectroscopy (MH+) 477.
[2213] Anal. Calcd for C.sub.26H.sub.21F.sub.2N.sub.3O.sub.4; C,
65.40 H, 4.43 N, 8.80. Found: C, 65.66 H, 4.71 N, 8.54.
Example 7-4
Synthesis of
5-(S)-[N'-(3,5-difluorophenylacetyl)-L-valinyl]amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2214] Following General Procedure D above using
3,5-difluorophenylacetic acid and
5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepi-
n-6-one hydrochloride (Example 7-C), the title compound was
prepared as a colorless solid. The product was purified by flash
chromatography using 98:2 CHCl.sub.3/MeOH.
[2215] NMR data was as follows:
[2216] .sup.1H-nmr (CDCl.sub.3): .delta.=7.54-7.25 (m, 8H), 6.74
(m, 2H), 6.74 (m, 2H), 6.70 (m, 1H), 6.49 (d, 1H), 5.26 (d, 1H),
4.49 (m,1H), 3.43 (s, 2H), 3.35 (s, 3H), 2.06 (m, 1H), 0.91 (m,
6H).
[2217] Optical Rotation: [.alpha.].sub.20=-144 @589 nm (c=1,
MeOH).
[2218] C.sub.28H.sub.27F.sub.2N.sub.3O.sub.3 (MW=491.543); mass
spectroscopy (MH+) 490.9
[2219] Anal. Calcd for C.sub.28H.sub.27F.sub.2N.sub.3O.sub.3; C,
68.42 H, 5.54 N, 8.55. Found: C, 68.51 H, 5.82, N, 8.61.
Example 7-5
Synthesis of
5-(S)-[N'-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2220] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood) and
5-(S)-[L-tert-leucinyl]-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one hydrochloride (Example 7-D), the title
compound was prepared as a colorless solid. The product was
purified by flash chromatography using 98:2 CHCl.sub.3/MeOH.
[2221] NMR data was as follows:
[2222] .sup.1H-nmr (CDCl.sub.3): .delta.=7.58-7.36 (m, 9H), 6.80
(m, 2H), 6.72 (m, 1H), 6.25 (d, 1H), 5.27 (d, 1H), 4.52 (d, 1H),
3.53 (s, 2H), 3.35 (s, 3H), 0.97 (m, 9H).
[2223] Optical Rotation: [.alpha.].sub.20=-137 @589 nm (c=1,
MeOH).
[2224] C.sub.29H.sub.29F.sub.2N.sub.3O.sub.4 (MW=505.57); mass
spectroscopy (MH+) 504.9
[2225] Anal. Calcd for
C.sub.28H.sub.27F.sub.2N.sub.3O.sub.4.H.sub.2O; C, 66.52 H, 5.92 N,
8.02. Found: C, 66.39 H, 5.76, N, 7.79.
Example 7-6
Synthesis of
5-(S)-[N'-((S)-3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-va-
linyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2226] Following General Procedure D above using
(S)-3,5-difluoromandelic acid and
5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepi-
n-6-one hydrochloride (Example 7-C), the title compound was
prepared as a colorless solid. The product was purified by flash
chromatography using 98:2 CHCl.sub.3/MeOH.
[2227] NMR data was as follows:
[2228] .sup.1H-nmr (CDCl.sub.3): .delta.=7.78 (d, 1H), 7.53-7.25
(m, 8H), 6.86 (m, 2H), 6.71 (m, 2H), 5.22 (d, 1H), 4.76 (s, 1H)
4.43 (m,1H), 3.34 (s, 3H), 2.08 (m, 1H), 0.91 (m, 6H).
[2229] C.sub.28H.sub.27F.sub.2N.sub.3O.sub.4 (MW=507.542); mass
spectroscopy (MH+) 506.9
[2230] Anal. Calcd for C.sub.28H.sub.27F.sub.2N.sub.3O.sub.4; C,
66.26 H, 5.32 N, 8.27. Found: C, 66.08 H, 5.62, N, 7.97.
Example 7-7
Synthesis of
5-(S)-[N'-((S)-3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-te-
rt-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2231] Following General Procedure D above using
(S)-3,5-difluoromandelic acid and
5-(S)-[L-tert-leucinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d-
]azepin-6-one hydrochloride (Example 7-D), the title compound was
prepared as a colorless solid. The product was purified by flash
chromatography using 98:2 CHCl.sub.3/MeOH.
[2232] NMR data was as follows:
[2233] .sup.1H-nmr (CDCl.sub.3): .delta.=7.67 (d, 1H), 7.54-7.25
(m, 8H), 6.83 (m, 2H), 6.69 (m, 2H), 5.22 (d, 1H), 4.74 (s, 1H)
4.44 (d, 1H), 3.35 (s, 3H), 0.97 (m, 9H).
[2234] C.sub.29H.sub.29F.sub.2N.sub.3O.sub.4 (MW=521.569); mass
spectroscopy (MH+) 520.9
[2235] Anal. Calcd for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.4; C,
66.78 H, 5.60 N, 8.06. Found: C, 66.56 H, 5.85, N, 7.83.
Example 7-8
Synthesis of
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methoxya-
cetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2236] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Example B) and
5-amino-7-(methoxyacetyl)-5,7-dihydro-6H-diben- z[b,d]azepin-6-one
hydrochloride (Example 7-G), the title compound was prepared as a
colorless solid. The product was purified by flash
chromatography.
[2237] NMR data was as follows:
[2238] .sup.1H-nmr (CDCl.sub.3): .delta.=7.61-7.215 (m, 8H), 6.76
(m, 2H), 6.68 (m, 1H), 6.53 and 6.40 (two d, 1H), 5.32 (d, 1H),
4.71 (m, 1H) 4.37 (m, 2H), 3.69 (s, 3H), 1.49 and 1.39 (two d,
3H).
[2239] C.sub.28H.sub.25F.sub.2N.sub.3O.sub.5 (MW=521.518); mass
spectroscopy (MH+) 522
[2240] Anal. Calcd for C.sub.28H.sub.25F.sub.2N.sub.3O.sub.5.1.5
mol H.sub.2O; C, 61.30 H, 4.55 N, 7.65. Found: C, 61.30 H, 4.53, N,
7.68.
Example 7-9
Synthesis of
5-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-7-(methylca-
rboxylate)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2241] Following General Procedure II-A, Method B and using
5-[(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-(methoxyacetyl)-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one (Example 7-8), the title compound
was prepared as a colorless solid. The product was purified by
flash chromatography.
[2242] C.sub.27H.sub.23F.sub.2N.sub.3O.sub.5 (MW=507.49); mass
spectroscopy (MH+) 508
[2243] Anal. Calcd for C.sub.27H.sub.23F.sub.2N.sub.3O.sub.5.2 mol
H.sub.2O; C, 59.66 H, 4.23 N, 7.72. Found: C, 59.88 H, 4.29, N,
7.66.
Example 7-10
Synthesis of
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(3,3-dime-
thyl-2-butanoyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2244] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Example B) and
5-amino-7-(3,3-dimethyl-2-butanoyl)-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-H), the title
compound was prepared as a colorless solid. The product was
purified by flash chromatography.
[2245] NMR data was as follows:
[2246] .sup.1H-nmr (CDCl.sub.3): .delta.=7.57 (m, 3H), 7.41 (m,
5H), 7.14 (m, 1H), 6.78 (m, 2H), 6.68 (m, 1H), 6.44 and 6.26 (two
d, 1H), 5.34(d, 1H), 4.68 (m, 1H) 4.59 (m, 2H), 3.52 and 3.47 (two
s, 2H), 1.52 and 1.42 (two d, 3H), 1.23 (s, 9H).
[2247] C.sub.31H.sub.31F.sub.2N.sub.3O.sub.4 (MW=547.599); mass
spectroscopy (MH+) 548
[2248] Anal. Calcd for C.sub.31H.sub.31F.sub.2N.sub.3O.sub.4.0.5
mol H.sub.2O; C, 66.89 H, 5.59 N, 7.54. Found: C, 66.52 H, 5.73, N,
7.18.
Example 7-11
Synthesis of
5-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(morpholi-
nylacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2249] Following General Procedure D using
5-[N'-(3,5-difluorophenylacetyl-
)-L-alaninyl]-amino-7-(methylcarboxylate)-5,7-dihydro-6H-dibenz[b,d]azepin-
-6-one (Example 7-9) and morpholine (Aldrich), the title compound
was prepared as a colorless foam. The product was purified by flash
chromatography.
[2250] NMR data was as follows:
[2251] .sup.1H-nmr (CDCl.sub.3): .delta.=7.57-7.37 (m, 8H),
6.81-6.69 (m, 3H), 5.35 (m, 1H), 4.73-4.67 (m, 2H), 4.17 (m, 1H),
3.66-3.26 (m, 10 H), 1.46 and 1.40 (two d, 3H).
[2252] C.sub.31H.sub.30F.sub.2N.sub.4O.sub.5 (MW=576.592); mass
spectroscopy (MH+) 577
[2253] Anal. Calcd for C.sub.31H.sub.30F.sub.2N.sub.4O.sub.5.0.5
mol H.sub.2O; C, 63.57 H, 5.12 N, 9.56. Found: C, 63.41 H, 5.51, N,
8.92.
Example 7-12
Synthesis of
5-(S)-(N'-((S)-(+)-2-Hydroxy-3-methylbutyryl)-L-alaninyl)amin-
o-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2254] Following General Procedure H using
(S)-(+)-2-hydroxy-3-methylbutyr- ic acid (Aldrich) and
5-5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one (Example 7-B), the title compound was prepared
as a white solid. The product was purified by silica gel
chromatography using gradient elution of MeOH/CH.sub.2Cl.sub.2
(1:99-3:97).
[2255] NMR data was as follows:
[2256] .sup.1H-nmr (CDCl.sub.3): .delta.=7.94 (d, J=7.0 Hz, 1H),
7.55-7.22 (m, 9H), 5.25 (d, J=7.5 Hz, 1H), 4.79-4.75 (m, 1H), 3.83
(d, J=3.1 Hz, 1H), 3.78 (br s, 1H), 3.32 (s, 3H), 2.08-2.01 (m,
1H), 1.36 (d, J=7.0 Hz, 3H), 0.83 (d, J=7.0 Hz, 3H), 0.76 (d, J=6.5
Hz, 3H).
[2257] C.sub.23H.sub.27N.sub.3O.sub.4 (MW=409.48); mass
spectroscopy (MH.sup.+) 410.4.
[2258] Anal Calcd for C.sub.23H.sub.27N.sub.3O.sub.4, C, 67.46; H,
6.65, N, 10.26; Found: C, 67.59; H, 6.66; N, 10.34.
Example 7-13
Synthesis of
5-[N'-Cyclopentyl-.alpha.-hydroxyacetyl)-L-valinyl]amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2259] Following General Procedure D above using
cyclopentyl-.alpha.-hydro- xyacetic acid (Example P) and
5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-C), the title
compound was prepared as a colorless solid. The product was
purified by flash chromatography using 98:2 CHCl.sub.3/MeOH.
[2260] C.sub.27H.sub.33N.sub.3O.sub.4 (MW=463.5); mass spectroscopy
(MH+) 464.
[2261] Anal. Calcd for C.sub.27H.sub.33N.sub.3O.sub.4; C, 69.96 H,
7.18 N, 9.06. Found: C, 69.72 H, 6.99, N, 8.91.
Example 7-14
Synthesis of
5-(S)-(N'-((S)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amin-
o-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
and
5-(S)-(N'-((R)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[2262] Following General Procedure H using
2-hydroxy-3,3-dimethylbutyric acid (Aldrich) and
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one (Example 7-B), the title compound was prepared
as a white solid. The product was purified by silica gel
chromatography using gradient elution of MeOH/CH.sub.2Cl.sub.2
(1:99-3:97).
[2263] NMR data for isomer 1 was as follows:
[2264] .sup.1H-nmr (CDCl.sub.3): .delta.=7.90 (d, J=6.6 Hz, 1H),
7.57-7.24 (m, 8H), 6.99 (d, J=7.5 Hz, 1H), 5.24 (d, J=6.5 Hz, 1H),
4.83-4.76 (m, 1H), 3.69 (s, 1H), 3.32 (s, 3H), 3.19 (br s, 1H),
1.39 (d, J=7.0 Hz, 3H), 0.96 (s, 9H).
[2265] C.sub.24H.sub.29N.sub.3O.sub.4 (MW=423.51); mass
spectroscopy (MH.sup.+) 424.1.
[2266] Anal Calcd for C.sub.24H.sub.29N.sub.3O.sub.4(isomer 1), C,
68.07; H, 6.90; N, 9.92; Found: C, 68.22, H, 7.04; N, 9.91.
[2267] NMR data for isomer 2 was as follows:
[2268] .sup.1H-nmr (CDCl.sub.3): .delta.=8.00-7.99 (m, 1H),
7.97-7.30 (m, 8H), 7.03-7.00 (m, 1H), 5.25 (d, J=7.0 Hz, 1H),
4.82-4.75 (m, 1H), 3.69 (s, 1H), 3.33 (s, 3H), 2.66 (br s, 1H),
1.48 (d, J=7.0 Hz, 3H), 0.98 (s, 9H).
[2269] C.sub.24H.sub.29N.sub.3O.sub.4 (MW=423.51); mass
spectroscopy (MH.sup.+) 424.1.
[2270] Anal Calcd for C.sub.24H.sub.29N.sub.3O.sub.4(isomer 2), C,
68.07; H, 6.90; N, 9.92; Found: C, 67.77, H, 7.08; N, 9.66.
Example 7-15
Synthesis of
5-[N'-Cyclopentyl-.alpha.-hydroxyacetyl)-L-tert-leucinyl]amin-
o-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2271] Following General Procedure D above using
cyclopentyl-.alpha.-hydro- xyacetic acid (Example P) and
5-(S)-[L-tert-leucinyl]-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-D), the
title compound was prepared as a colorless solid. The product was
purified by flash chromatography using 98:2 CHCl.sub.3/MeOH.
[2272] C.sub.28H.sub.35N.sub.3O.sub.4.(477.6); mass spectroscopy
(MH+) 478.
[2273] Anal. Calcd for C.sub.28H.sub.35N.sub.3O.sub.4; C, 66.39 H,
5.57 N, 11.06. Found: C, 66.33 H, 5.67, N, 10.89.
Example 7-16
Synthesis of
5-[N'-Cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2274] Following General Procedure D above using
cyclopentyl-.alpha.-hydro- xyacetic acid (Example P) and
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-B), the title
compound was prepared as a colorless solid. The product was
purified by flash chromatography using 99:1 CHCl.sub.3/MeOH.
[2275] NMR data was as follows:
[2276] .sup.1H-nmr (CDCl.sub.3): .delta.=7.78 (m, 2H), 7.62-7.28
(m, 8H), 7.08 and 6.99 (two d, 1H), 5.27 (d, 1H), 4.78 (m, 1H),
4.06 (m, 1H), 3.34 (s, 3H), 2.54 (m, 2H), 2.29 (m, 1H), 1.76-1.48
(m, 6H)1.43 (d, 3H).
[2277] C.sub.25H.sub.29N.sub.3O.sub.4.(435.52); mass spectroscopy
(MH+) 436
[2278] Anal. Calcd for C.sub.25H.sub.29N.sub.3O.sub.4; C, 68.95 H,
6.71 N, 9.65. Found: C, 69.06 H, 6.89, N, 9.51.
Example 7-17
Synthesis of
5-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-
-6H,7H-dibenz[b,d]azepin-6-one
[2279] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
5-amino-5,7-dihydro-6H,7H-dibenz[b,d]azepin-- 6-one hydrochloride
(prepared using the compound of Example 7-E, followed by Boc
removal as in Example 7-B, Step B), the title compound was prepared
as a colorless solid. The product was purified by flash
chromatography using 95:5 CHCl.sub.3/MeOH.
[2280] NMR data was as follows:
[2281] .sup.1H-nmr (DMSO.sub.d6): .delta.=8.86 (m, 1H), 8.75 (m,
1H), 8.49 (m, 1H), 7.78-7.23 (m, 8H), 7.09 (m, 1H), 7.03 (m, 2H),
5.07 (m, 1H), 4.60 (m, 1H), 3.55 (s, 2H), 1.32 (d, 3H).
[2282] C.sub.25H.sub.21F.sub.2N.sub.3O.sub.3.(449.45); mass
spectroscopy (MH+) 450.
[2283] Anal. Calcd for C.sub.25H.sub.21F.sub.2N.sub.3O.sub.3; C,
66.81 H, 4.71 N, 9.35. Found: C, 67.11 H, 4.84, N, 9.09.
Example 7-18
Synthesis of
5-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-7-(2-methyl-
propyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2284] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
5-amino-7-(2-methylpropyl)-5,7-dihydro-6H-di- benz[b,d]azepin-6-one
hydrochloride (Example 7-F), the title compound was prepared as a
colorless solid. The product was purified by flash chromatography
using 99:1 CHCl.sub.3/MeOH.
[2285] NMR data was as follows:
[2286] .sup.1H-nmr (CDCl.sub.3): .delta.=7.58-7.33 (m, 4H), 7.40
(m, 4H), 6.81 (m, 2H), 6.71 (m, 1H), 6.34 and 6.27 (two d, 1H),
5.22 (d 1H), 4.69 (m, 1H), 4.27 (m, 1H), 3.52 (s, 2H), 3.33 (m,
1H), 1.52 and 1.42 (two d, 3H), 0.57 and 0.29 (two d, 3H).
[2287] C.sub.29H.sub.29F.sub.2N.sub.3O.sub.3 (MW=505.562); mass
spectroscopy (MH+) 505.
[2288] Anal. Calcd for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.3; C,
68.89 H, 5.78 N, 8.31. Found: C, 69.01 H, 6.02 N, 8.33.
Example 7-19
Synthesis of
5-[N'-(2-Hydroxy-3-methylbutyryl)-L-valinyl]amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[2289] Following General Procedure D above using
2-hydroxy-3-methylbutyric acid (Aldrich) and
5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz-
[b,d]azepin-6-one hydrochloride (Example 7-C), the title compound
was prepared as a colorless solid. The product was purified by
flash chromatography using 98:2 CHCl.sub.3/MeOH.
[2290] NMR data was as follows:
[2291] .sup.1H-nmr (CDCl.sub.3): .delta.=7.69-7.25 (m, 8H), 7.08
and 6.92 (two d, 1H), 5.29 (d, 1H), 4.54 (m, 1H), 4.01 (m, 1H),
3.36 (s, 3H), 2.12 (m, 2H), 0.99 (m, 6H) 0.83 (m, 6H).
[2292] C.sub.25H.sub.31N.sub.3O.sub.4.(437.537); mass spectroscopy
(MH+) 438.
[2293] Anal. Calcd for C.sub.25H.sub.31N.sub.3O.sub.4; C, 68.63 H,
7.14 N, 9.60. Found: C, 68.71 H, 6.99, N, 9.42.
Example 7-20
Synthesis of 5-(S)-[N'-((S or
R)-2-Hydroxy-3,3-dimethylbutyryl)-L-valinyl]-
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
and
5-(S)-[N'-((S or
R)-2-Hydroxy-3,3-dimethylbutyryl)-L-valinyl]amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2294] Following General Procedure D above using
2-hydroxy-3,3-dimethylbut- yric acid (Aldrich) and
5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one hydrochloride (Example 7-C), the title
compound was prepared as a colorless solid. The diastereomers were
purified by flash chromatography using 99:1 CHCl.sub.3/MeOH.
[2295] Isomer 1:
[2296] NMR data was as follows:
[2297] .sup.1H-nmr (CDCl.sub.3): .delta.=7.60-7.28 (m, 8H), 6.63
(d, 1H), 5.26 (d, 1H), 4.53 (m, 1H), 3.74 (s, 1H), 3.35 (s, 3H),
2.12 (m, 1H), 0.998 (m, 15H).
[2298] C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451); mass spectroscopy
(MH+) 452.
[2299] Anal. Calcd for C.sub.26H.sub.33N.sub.3O.sub.4.0.5 mol
H.sub.2O; C, 67.80 H, 7.16 N, 9.11. Found: C, 68.32 H, 7.06 N,
8.91.
[2300] Isomer 2:
[2301] NMR data was as follows:
[2302] .sup.1H-nmr (CDCl.sub.3): .delta.=7.59-7.28 (m, 8H), 6.82
(d, 1H), 5.25 (d, 1H), 4.52(m, 1H), 3.74 (s, 1H), 3.33 (s, 3H),
2.16 (m, 1H), 0.997 (m, 15H).
[2303] C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451); mass spectroscopy
(MH+) 452
[2304] Anal. Calcd for C.sub.26H.sub.33N.sub.3O.sub.4; C, 69.16 H,
7.37 N, 9.31. Found: C, 69.33 H, 7.49 N, 9.22.
Example 7-22
Synthesis of
5-{N'-(4-Phenyl-furazan-3-yl)alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[2305] Following General Procedure D and using
N-(4-phenyl-furazan-3-yl)al- anine (Example I) and
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-- one (Example
7-A), the title compound was prepared. The reaction was monitored
by tlc (Rf=0.75, 5% MeOH/CHCl.sub.3) and product was purified by
chromatography (silica, CHCl.sub.3).
[2306] NMR data was as follows:
[2307] .sup.1H-nmr (CDCl.sub.3): .delta.=4.52 (m, 1H); 4.87 (t,
1H).
[2308] MW=453.50; mass spectroscopy (M+) 454.
Example 7-23
Synthesis of
5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-methyl-1,-
2,3,4,5,7-hexahydro-6H-dibenz[b,d]azepin-6-one
[2309] Following Procedure D and using
N-(3,5-difluorophenylacetyl)-L-alan- ine (Ex. B) and
5-amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d-
]azepin-6-one (Example 7-Z), the title compound was prepared. The
reaction was monitored by tlc (Rf=0.3, 4% MeOH/CHCl.sub.3) and
product was purified by chromatography (silica, 4%
MeOH/CHCl.sub.3).
[2310] NMR data was as follows:
[2311] .sup.1H-nmr (CDCl.sub.3): .delta.=3.54 (s, 2H); 1.36 (m,
3H).
[2312] MW=475.58; mass spectroscopy (MH+) 476.
Example 7-24
Synthesis of
5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-phenbutyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2313] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Ex. B) and
5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azep- in-6-one
(Example 7-K), the title compound was prepared. The reaction was
monitored by tlc (Rf=0.35, 3% MeOH/CHCl.sub.3) and product was
purified by chromatography (silica, 3% MeOH/CHCl.sub.3).
[2314] NMR data was as follows:
[2315] .sup.1H-nmr (CDCl.sub.3): .delta.=4.68 (m, 1H); 6.32 (dd,
1H). MW=581.66; mass spectroscopy (M+) 582.
Example 7-25
Synthesis of
5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-cycloprop-
ymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2316] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Ex. B) and
5-amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b- ,d]azepin-6-one
(Example 7-L), the title compound was prepared. The reaction was
monitored by tlc (Rf=0.30, 5% MeOH/CHCl.sub.3) and product was
purified by chromatography (silica, 3% MeOH/CHCl.sub.3).
[2317] NMR data was as follows:
[2318] .sup.1H-nmr (CDCl.sub.3): .delta.=4.07 (m, 1H); 4.70 (m,
1H); 5.24 (d, 1H).
[2319] MW=503.55; mass spectroscopy (M+) 504.
Example 7-26
Synthesis of
5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-(2',2',2'-
-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2320] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Ex. B) and
5-amino-7-(2',2',2'-trifluoroethyl)-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one (Example 7-M), the title compound was
prepared. The reaction was monitored by tlc (Rf=0.15, 5%
MeOH/CHCl.sub.3) and product was purified by chromatography
(silica, 5% MeOH/CHCl.sub.3).
[2321] NMR data was as follows:
[2322] .sup.1H-nmr (CDCl.sub.3): .delta.=4.07 (m, 1H); 4.69 (m,
1H); 5.02 (m, 1H); 5.37 (d, 1H).
[2323] MW=531.48; mass spectroscopy (MH+) 530.
Example 7-27
Synthesis of
5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-cyclohexy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2324] Following General Procedure D and using
N-(3,5-difluorophenylacetyl- )-L-alanine (Ex. B) and
5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]aze- pin-6-one
(Example 7-N), the title compound was prepared. The reaction was
monitored by tlc (Rf=0.35, 5% MeOH/CHCl.sub.3) and product was
purified by chromatography (silica, 5% MeOH/CHCl.sub.3).
[2325] NMR data was as follows:
[2326] .sup.1H-nmr (CDCl.sub.3): .delta.=1.43 (dd, 3H); 3.94 (m,
1H); 4.68 (m, 1H); 5.18 (d, 1H).
[2327] MW=531.60); mass spectroscopy (M+) 533.
Example 7-28
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-9-fluoro-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2328] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-alaninyl)-amino-9-fluoro-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-O), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.4,
10% MeOH/CHCl.sub.3) and product was purified by chromatography
(silica, 2.5% MeOH/CHCl.sub.3).
[2329] NMR data was as follows:
[2330] .sup.1H-nmr (CDCl.sub.3): .delta.=3.36 (s, 3H); 4.67 (m,
1H); 5.05 (s, 1H); 5.21 (m, 1H).
[2331] MW=497.47; mass spectroscopy (M+) 498.
Example 7-29
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-alaninyl}-amino-13-fluoro--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2332] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-alaninyl)-amino-13-fluoro-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-P), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.4,
10% MeOH/CHCl.sub.3) and product was purified by 2.5%
chromatography (silica, MeOH/CHCl.sub.3).
[2333] NMR data was as follows:
[2334] .sup.1H-nmr (CDCl.sub.3): .delta.=1.45 (dd, 3H); 3.31 (d,
3H).
[2335] MW=497.47; mass spectroscopy (MH+) 498.
Example 7-30
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-10-fluoro-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2336] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-alaninyl)-amino-10-fluoro-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-Q), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.4,
10% MeOH/CHCl.sub.3) and product was purified by chromatography
(silica, 2.5% MeOH/CHCl.sub.3).
[2337] NMR data was as follows:
[2338] .sup.1H-nmr (CDCl.sub.3): .delta.=1.44 (dd, 3H); 3.35 (d,
3H).
[2339] MW=497.47; mass spectroscopy (M+) 498.
Example 7-31
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-7-cycloprop-
ylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2340] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-alaninyl)-amino-7-cyclopropylmethyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-R), the title
compound was prepared. The product was purified by chromatography
(silica, 2.5% MeOH/CHCl.sub.3).
[2341] NMR data was as follows:
[2342] .sup.1H-nmr (CDCl.sub.3): .delta.=1.48 (dd, 3H); 3.45 (m,
1H).
[2343] MW=519.55; mass spectroscopy (M+) 520.
Example 7-32
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-7-phenbutyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2344] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-alaninyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one hydrochloride (Example 7-S), the title compound
was prepared. The product was purified by chromatography (silica,
1-2% MeOH/CHCl.sub.3).
[2345] NMR data was as follows:
[2346] .sup.1H-nmr (CDCl.sub.3): .delta.=1.48 (dd, 3H); 5.04 (d,
1H).
[2347] MW=597.66; mass spectroscopy (M+) 599.
Example 7-33
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-7-cyclopropy-
lmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2348] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-valinyl)-amino-7-cyclopropylmethyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-T), the title
compound was prepared. The reaction was monitored by tlc (Rf=0.3,
2.5% MeOH/CHCl.sub.3) and product was purified by chromatography
(silica, 2.5% MeOH/CHCl.sub.3).
[2349] NMR data was as follows:
[2350] .sup.1H-nmr (CDCl.sub.3): .delta.=3.42 (m, 1H); 4.07 (m,
1H); 5.03 (d, 1H).
Example 7-34
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-7-phenbutyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2351] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-valinyl)-amino-7-phenbutyl-5,7-dihydro-6H-diben-
z[b,d]azepin-6-one hydrochloride (Example 7-U), the title compound
was prepared. The product was purified by chromatography (silica,
1-2% MeOH/CHCl.sub.3).
[2352] NMR data was as follows:
[2353] .sup.1H-nmr (CDCl.sub.3): .delta.=3.54 (m, 1H); 4.35 (m,
1H); 5.03 (d, 1H).
[2354] MW=625.71; mass spectroscopy (M+) 625.
Example 7-35
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-7-hexyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[2355] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-valinyl)-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,-
d]azepin-6-one hydrochloride (Example 7-V), the title compound was
prepared. The product was purified by chromatography (silica, 5%
MeOH/CHCl.sub.3).
[2356] NMR data was as follows:
[2357] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.25 (m, 1H); 4.52 (m,
1H); 5.05 (t, 1H); 5.24 (2 doublets, 1H).
[2358] MW=577.67; mass spectroscopy (M+) 578.
Example 7-36
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-10-fluoro-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2359] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-valinyl)-amino-10-fluoro-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-W), the title
compound was prepared. The product was purified by chromatography
(silica, 2.5% MeOH/CHCl.sub.3).
[2360] Anal. Calc.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H,
6.12, N, 6.63.
Example 7-37
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-13-fluoro-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2361] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-valinyl)-amino-13-fluoro-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-X), the title
compound was prepared. The product was purified by chromatography
(silica, 2.5% MeOH/CHCl.sub.3).
[2362] Anal. Calc.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H,
6.12, N, 6.63.
Example 7-38
Synthesis of
5-{N'-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-9-fluoro-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[2363] Following General Procedure D and using
(S)-3,5-difluoromandelic acid (Example L) and
5-(L-valinyl)-amino-9-fluoro-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one hydrochloride (Example 7-Y), the title
compound was prepared. The product was purified by chromatography
(silica, 2.5% MeOH/CHCl.sub.3).
[2364] Anal. Calc.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H,
6.12, N, 6.63.
[2365] 8. Benzodiazepine Derivatives and Related Compounds
General Procedure 8-A
N-1-Methylation of Benzodiazepines
[2366] A solution of benzodiazepine (1 eq.) in DMF (0.1 M
concentration) at 0.degree. C. was treated with potassium
tert-butoxide (1.0 eq., 1.0 M solution in THF). After stirring for
30 minutes at 0.degree. C., iodomethane (1.3 eq.) was added and
stirring continued for 25 minutes. The mixture was diluted with
methylene chloride and washed with water and brine. The organic
phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The crude product was then either purified by trituration with 1:1
ether/hexanes or chromatographed via HPLC using ethyl
acetate/hexanes as the eluent.
General Procedure 8-B
Cbz Removal Procedure
[2367] A flask was charged with the Cbz-protected
3-aminobenzodiazepine (1 eq.). To this was added HBr (34 eq.; 30%
solution in acetic acid). Within 20 minutes all of the starting
material dissolves. The reaction was stirred for 5 hours at ambient
temperature. Ether was added to the orange solution causing the
HBr.amine salt to precipitate. The mixture was decanted. This
process of adding ether and decanting was repeated thrice in an
effort to remove acetic acid and benzyl bromide. Toluene was added
and the mixture concentrated in vacuo. This step was also repeated.
The HBr salt was partitioned between ethyl acetate and 1 M
K.sub.2CO.sub.3. The aqueous layer was back-extracted with ethyl
acetate. The combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated.
General Procedure 8-C
Boc Removal Procedure
[2368] A solution of Boc-protected amine (1 eq.) in methylene
chloride (0.15 M concentration) was cooled to 0.degree. C. and
treated with trifluoroacetic acid (30 eq.). After 10 minutes at
0.degree. C., the cooling bath was removed and stirring continued
at ambient for 20 minutes to 1 hour. The mixture was concentrated
in vacuo to remove excess trifluoroacetic acid. The residue was
dissolved in methylene chloride and washed with saturated aqueous
NaHCO.sub.3 or 1 M K.sub.2CO.sub.3 and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
General Procedure 8-D
Azide Transfer Reaction Using KHMDS
[2369] The azido derivative was prepared using the procedure
described in John W. Butcher et al., Tet. Lett., 37, 6685-6688
(1996).
General Procedure 8-E
Azide Transfer Reaction Using LDA
[2370] To a solution of diisopropylamine (1.1 eq.) in 1 mL of dry
THF cooled to -78.degree. C. was added n-butyl lithium (1.6M in
hexane) (1.1 eq.) dropwise maintaining the reaction temperature at
-78.degree. C. The reaction mixture was stirred for 30 min. at
-78.degree. C. and then the lactam (0.471 mM) was added dropwise as
a solution in 1 mL of dry THF. The reaction mixture was stirred at
-78.degree. C. for 30 min. and then a pre-cooled solution of trisyl
azide (1.2 eq.) was added as a solution in 1 mL of dry THF. The
reaction mixture was stirred at -78.degree. C. for 20 min. and then
quenched with acetic acid (4.0 eq.). The reaction mixture was then
stirred at 40.degree. C. for 2 hrs. The reaction was then poured
into EtOAc and washed with water, sodium bicarbonate and brine, and
then dried over sodium sulfate, filtered and concentrated. The
residue was purified by LC 2000 chromatography.
General Procedure 8-F
Azido Group Reduction
[2371] The azido group was reduced to the corresponding primary
amine using the procedure described in John W. Butcher et al., Tet.
Lett., 37, 6685-6688 (1996).
General Procedure 8-G
N-Alkylation of Amides or Lactams Using Sodium Hydride or Potassium
tert-Butoxide
[2372] To a slurry of sodium hydride or potassium tert-butoxide
(1.1 eq) in 15 mL of dry DMF was added the appropriate amide
(0.0042 moles) as a solution in 10 mL of DMF. The alkyl iodide was
then added and a thick slurry resulted. The reaction became less
thick as time elapsed and when complete by TLC the reaction had
become homogeneous. The reaction mixture was poured over ice and
extracted into ethyl acetate. The organic layer was washed with
water, followed by brine. The organic layer was then dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by HPLC (LC 2000), eluting with an ethyl
acetate/hexane system.
General Procedure 8-H
N-Alkylation of Amides or Lactams Using KHMDS
[2373] To the appropriate amide or lactam in THF cooled to
-78.degree. C. was added KHMDS dropwise and the reaction mixture
was stirred for 30 min. at -78.degree. C. The alkyl iodide was then
added dropwise while maintaining the temperature at -70.degree. C.
The cooling bath was then removed and reaction was allowed to warm
to room temperature and stirring was continued for 2 hours. The
reaction mixture was then poured over ice and extracted into ethyl
acetate. The organic extracts were washed with water, followed by
brine. The organic layer was then dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane
system.
General Procedure 8-I
N-Alkylation of Amides or Lactams Using Cesium Carbonate
[2374] To a solution of the amide or lactam in DMF was added cesium
carbonate (1.05 eq) and an alkyl iodide (1.1 eq). The mixture was
allowed to stir overnight at room temperature and then the reaction
mixture was dilluted with ethyl acetate and washed with water,
followed by brine. The organic layer was dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane
system.
General Procedure 8-J
BOC Removal Procedure
[2375] To an N-Boc protected compound was added
CH.sub.2Cl.sub.2/TFA (4:1) at room temperature. The reaction
mixture was stirred at room temperature for 3 hours and then
concentrated. The residue was extracted into dichloromethane and
washed with water, saturated sodium bicarbonate, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the free
amine.
General Procedure 8-K
Azide Transfer Procedure
[2376] This azide transfer procedure is a modification of the
procedure described in Evans, D. A.; Britton, T. C.; Ellman, J. A.;
Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011-4030. To a solution
of the lactam substrate (1.0 eq.) in THF (.about.0.1 M) under
N.sub.2 at -78.degree. C. was added a solution of KN(TMS).sub.2
(1.1 eq. of 0.5 M in Toluene, Aldrich) dropwise over a period of
2-10 minutes. A slight exotherm was often observed by an internal
thermometer, and the resulting solution was stirred for 5-15
minutes, while re-cooling to -78.degree. C. Then, trisyl azide
(1.1-1.5 eq., CAS No. 36982-84-0, prepared as described by
references in the Evans reference above) in THF (.about.-0.5 M),
either precooled to -78.degree. C. or at room temperature, was
added via cannula over a period of 0.5-5 minutes. Again, a slight
exotherm was generally noted. The resulting solution was stirred
for from 5-10 minutes, while re-cooling to -78.degree. C. Then,
AcOH (4.5-4.6 eq., glacial) was added, the cooling bath removed and
the mixture allowed to warm to room temperature with stirring for
12-16 hours. The mixture was diluted with EtOAc, in a 2-5 volume
multiple of the initial THF volume, and washed with dilute aq.
NaHCO.sub.3 (1-2.times.), 0.1-1.0 M aq. HCl (0-2.times.), and brine
(1.times.). The organic phase was then dried over MgSO.sub.4,
filtered, concentrated to provide the crude product.
General Procedure 8-L
Azide Reduction to an Amine
[2377] A mixture of the azide in absolute EtOH (0.03-0.07 M) and
10% Pd/C (.about.1/3 by weight of the azide) was shaken in a Parr
apparatus under H.sub.2 (35-45 psi) at room temperature for 3-6
hours. The catalyst was removed by filtration through a plug of
Celite, rinsing with absolute EtOH, and the filtrate concentrated
to provide the crude amine product.
General Procedure 8-M
Amide Alkylation Using Cesium Carbonate
[2378] This procedure is a modification of the procedure described
in Claremon, D. A.; et al, PCT Application: WO 96-US8400 960603. To
a mixture of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
(CAS No. 49799-48-6) in DMF (1.0 eq., 0.7 M) under N.sub.2 at room
temperature was added Cs.sub.2CO.sub.3 (2.2 eq.) and the
appropriate alkyl halide (2.2 eq.). The mixture was stirred at room
temperature for 5.5-16 hours. The mixture was partitioned between
EtOAc and sat. NaHCO.sub.3. The aqueous layer was extracted with
EtOAc (1-2.times.) and the combined EtOAc extracts were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide the crude
product.
General Procedure 8-N
BOC Removal Procedure
[2379] A stream of anhydrous HCl gas was passed through a stirred
solution of the N-t-Boc protected amino acid in 1,4-dioxane
(0.03-0.09 M), chilled in a ice bath to .about.10.degree. C. under
N.sub.2, for 10-15 minutes. The solution was capped, the cooling
bath removed, and the solution was allowed to warm to room
temperature with stirring for 2-8 hours, monitoring by TLC for the
consumption of starting material. The solution was concentrated
(and in some instances dissolved in CH.sub.2Cl.sub.2 then
re-concentrated and placed in vacuum oven at 60-70.degree. C. to
remove most of the residual dioxane) and used without further
purification.
Example 8-A
Synthesis of
3-Amino-1,3-dihydro-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2--
one
Step A--Preparation of
1.2-Dihydro-3H-1-methyl-5-(1-piperidinyl)-1.4-benzo-
diazepin-2-one
[2380] A solution of phosphorous pentachloride (1.2 eq) in
methylene chloride was added dropwise to a solution of
1-methyl-1,2,3,4-tetrahydro-- 3H-1,4-benzodiazepin-2,5-dione
(Showell, G. A.; Bourrain, S.; Neduvelil, J. G.; Fletcher, S. R.;
Baker, R.; Watt, A. P.; Fletcher, A. E.; Freedman, S. B.; Kemp, J.
A.; Marshall, G. R.; Patel, S.; Smith, A. J.; Matassa, V. G. J.
Med. Chem. 1994, 37, 719.) in methylene chloride. The resultant
yellowish-orange solution was stirred at ambient temperature for
2.5 hours; the solvent was removed in vacuo. The orange residue was
redissolved in methylene chloride, cooled to 0.degree. C., and
treated with a solution of piperidine (2 eq) and triethylamine (2
eq) in methylene chloride. The cooling bath was removed and the
reaction stirred for 18 hours. The reaction mixture was washed with
saturated aqueous NaHCO.sub.3 (back-extracted with methylene
chloride) and brine. The organic phase was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified via HPLC eluting with a gradient of 4 to 10%
methanol/methylene chloride affording the title intermediate as a
yellow solid having a melting point of 103-105.degree. C.
[2381] C.sub.15H.sub.19N.sub.3O (MW 257.37); mass spectroscopy
257.
[2382] Anal. Calcd for C.sub.15H.sub.19N.sub.3O: C, 70.01; H, 7.44;
N, 16.33. Found: C, 69.94; H, 7.58; N, 16.23.
Step B--Preparation of
1,2-Dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)- -1
4-benzodiazep in-2-one
[2383] Potassium tert-butoxide (2.5 eq) was added in two portions
to a -20.degree. C. solution of
1,2-dihydro-3H-1-methyl-5-(1-piperidinyl)-1,4-- benzodiazepin-2-one
(1 eq) in toluene). After stirring at -20.degree. C. for 20 min,
isoamyl nitrite (1.2 eq.; Aldrich) was added to the red reaction
mixture. The reaction was stirred at -20 .degree. C. for 5 hours at
which time the reaction was done by TLC. The cooling bath was
removed and the reaction quenched with 0.5 M citric acid. After
stirring for 10 minutes, diethyl ether was added. The suspension
was stirred at ambient temperature overnight then filtered washing
with ether. The resultant cream colored solid had a melting point
of 197-200.degree. C.
[2384] .sup.1H NMR data of the E/Z isomers was as follows:
[2385] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.64 (1H, bs),
7.48 (2H, d, J=7.4 Hz), 7.35-7.20 (6H, m), 6.75 (1H, bs), 3.8-3.2
(8H, m), 3.46 (3H, s), 3.42 (3H, s) 1.90-1.40 (12H, m).
[2386] C.sub.15H.sub.18N.sub.4O.sub.2 (MW=286.37); mass
spectroscopy 286.
Step C--Preparation of
1,2-dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)ox-
imidol-5-(1-piperidinyl)-1,4-benzodiazepin-2-one
[2387] A mixture of
1,2-dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)-1,-
4-benzodiazepin-2-one (1 eq) in THF was treated with ethyl
isocyanate (1.7 eq) and triethylamine (0.6 eq). The mixture was
heated to 64.degree. C. for 4 hours. The mixture was concentrated
and the residue purified, by HPLC eluting with 5%
methanol/methylene chloride.
[2388] .sup.1H NMR data of the E/Z isomers was as follows:
[2389] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.50 (2H, dd,
J=8.4, 1.5 Hz), 7.35-7.22 (6H, m), 6.42 (1H, bt), 6.20 (1H, bt),
3.7-3.4 (8H, m), 3.46 (3H, s), 3.44 (3H), s), 3.25 (4H, m), 1.9-1.4
(12H, m), 1.12 (3H, t, J=6.3 Hz), 1.10 (3H, t, J=6.3 Hz).
[2390] C.sub.18H.sub.23N.sub.5O.sub.3 (MW=357.46); mass
spectroscopy 357.
Step D--Preparation of
3-Amino-1,3-dihydro-2H-1-methyl-5-(1-piperidinyl)-1-
.4-benzodiazepin-2-one
[2391] The
1,2-dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)oximido]-5-(1--
piperidinyl)-1,4-benzodiazepin-2-one (1 eq) was hydrogenated in
methanol over 5% palladium on carbon (0.15 eq) at 43 psi for 3.25
hours. The reaction was filtered through celite and concentrated in
vacuo. The residue was taken up in methylene chloride and filtered
a second time through celite. The filtrate was concentrated and the
resultant foam was used immediately.
Example 8-B
Synthesis of
3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-ben-
zodiazepin-2-one
Step A--Preparation of
(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-be-
nzodiazepin-2-one.
(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanes-
ulfonate
[2392] The title intermediate was prepared according to Reider, P.
J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem.
1987, 52, 955 using
3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one
(Bock M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D.
F.; Freidinger, R. M.; Hirshfield, J.; Springer, J. P. J. Org.
Chem. 1987, 52, 3232.) as the starting material.
Step B--Preparation of
3-[N'-(tert-Butylcarbamate)-L-alaninyl]-amino-2.3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2393]
(S)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-on-
e, (1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate
was free based by partitioning between methylene chloride and 1M
potassium carbonate. The free amine was then coupled with
N-Boc-alanine following General Procedure D.
[2394] C.sub.24H.sub.28N.sub.4O.sub.4 (MW=436.56); mass
spectroscopy 436.
[2395] Anal. Calc. for C.sub.24H.sub.28N.sub.4O.sub.4: C, 66.03; H,
6.47; N, 12.84. Found: C, 65.79; H, 6.68; N, 12.80.
[2396] Step C--Preparation of
3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
[2397] Following General Procedure 8-C using
3-[N'-(tert-butylcarbamate)-L-
-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,
the title compound was prepared as a white foam.
[2398] Anal. Calc. for C.sub.19H.sub.19N.sub.4O.sub.2: C, 69.21; H,
6.64; N, 15.37. Found: C, 70.11; H, 6.85; N, 15.01.
Example 8-C
Synthesis of
3-(L-Alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1-
H-1,4-benzodiazepin-2-one
Step A--Preparation of
3-(Benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2399] A solution of
3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-ph-
enyl-1H-1,4-Benzodiazepin-2-one (1 eq; Neosystem) in DMF was cooled
to 0.degree. C. and treated with potassium tert-butoxide (1 eq;
1.0M solution in THF). The resultant yellow solution was stirred at
0.degree. C. for 30 minutes then quenched with methyl iodide (1.3
eq). After stirring an addition 25 minutes the reaction was diluted
with methylene chloride and washed with water and brine. The
organic phase was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified via HPLC chromatography
eluting with a gradient of 20.fwdarw.30% ethyl acetate/hexanes.
[2400] C.sub.24H.sub.20ClN.sub.3O.sub.3 (MW=433.92); mass
spectroscopy 433.
[2401] Anal. calcd for C.sub.24H.sub.20ClN.sub.3O.sub.3: C, 66.44;
H, 4.65; N, 9.68. Found: C, 66.16; H, 4.50; N, 9.46.
Step B--Preparation of
3-Amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1-
,4-benzodiazepin-2-one
[2402] Following General Procedure 8-B using
3-(benzyloxycarbonyl)-amino-7-
-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,
the title intermediate was prepared as a white foam which was used
immediately in Step C.
Step C--Preparation of
3-[N'-tert-Butylcarbamate)-L-alaninyl]-amino-7-chlo-
ro-1.3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one
[2403] Following General Procedure D using N-Boc-L-alanine and
3-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one-
, the title intermediate was prepared as a white foam.
[2404] C.sub.24H.sub.28ClN.sub.4O.sub.4 (MW=471.18); mass
spectroscopy 471
[2405] Anal. calcd for C.sub.24H.sub.28ClN.sub.4O.sub.4: C, 61.21;
H, 5.78; N, 11.90. Found: C, 61.24; H, 5.59; N, 11.67.
Step D--Preparation of
3-(L-Alaninyl)amino-7-chloro-1,3-dihydro-1-methyl-5-
-phenyl-2H-1,4-benzodiazepin-2-one
[2406] Following General Procedure 8-C using
3-[N'-tert-butylcarbamate)-L--
alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepi-
n-2-one, the title intermediate was prepared as a white foam. The
crude material was used immediately.
Example 8-D
Synthesis of
3-(L-Alaninyl)amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorop-
henyl)-1H-1,4-benzodiazepin-2-one
Step A--Preparation of
3-(Benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-m-
ethyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[2407] Following General Procedure 8-A using
3-(benzyloxycarbonyl)-amino-7-
-bromo-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
(Neosystem), the title intermediate was prepared as a white
foam.
[2408] C.sub.24H,.sub.9BrFN.sub.3O.sub.3 (MW=496.36); mass
spectroscopy 497.
[2409] Anal. calcd for C.sub.24H.sub.19BrFN.sub.3O.sub.3: C, 58.08;
H, 3.86; N, 8.47. Found: C, 57.90; H, 4.15; N, 8.20.
Step B--Preparation of
3-Amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophe-
nyl)-2H-1,4-benzodiazepin-2-one
[2410] Following General Procedure 8-B using
3-(benzyloxycarbonyl)-amino-7-
-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one,
the title intermediate was prepared as a white foam which was used
immediately in Step C.
Step C--Preparation of
3-[N'-(tert-Butylcarbamate)-L-alaninyl]-amino-7-bro-
mo-1.3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one
[2411] Following General Procedure D using N-Boc-L-alanine (Novo)
and
3-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiaze-
pin-2-one, the title intermediate was prepared as a white foam.
[2412] C.sub.24H.sub.26BrFN.sub.4O.sub.4 (MW=533.12); mass
spectroscopy 533.2.
[2413] Anal. calcd for C.sub.24H.sub.26BrFN.sub.4O.sub.4: C, 54.04;
H, 4.91; N, 10.50. Found: C, 53.75; H, 4.92; N, 10.41.
Step D--Preparation of
3-(L-Alaninyl)-amino-7-bromo-13-dihydro-1-methyl-5--
(2-fluorophenyl)-2H-1.4-benzodiazepin-2-one
[2414] Following General Procedure 8-C using
3-[N'-(tert-butylcarbamate)-L-
-alaninyl]-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-be-
nzodiazepin-2-one, the title intermediate was prepared as a white
foam. The crude material was used immediately.
Example 8-E
Synthesis of
3-(N'-Methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one
Step A--Preparation of
3-[N'-(tert-Butylcarbamate)-N'-methyl-L-alaninyl]-a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2415] Following General Procedure D and using
(S)-3-amino-1,3-dihydro-1-m-
ethyl-5-phenyl-2H-1,4-benzodiazepin-2-one (Example 8-B) and
N-tert-Boc-N-methyl-alanine (Sigma), the title intermediate was
obtained as a white solid.
[2416] C.sub.25H.sub.30N.sub.4O.sub.4 (MW=450.2); mass spectroscopy
(M+1) 451.2.
[2417] Anal. calcd for C.sub.25H.sub.30N.sub.4O.sub.4: C, 66.65; H,
6.71; N, 12.44. Found: C, 66.66; H, 6.89; N, 12.21.
Step A--Preparation of
3-(N'-Methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[2418] Following General Procedure 8-C and using
3-[N'-(tert-butylcarbamat-
e)-N'-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzod-
iazepin-2-one, the title intermediate was prepared as a white
foam.
[2419] C.sub.20H.sub.22N.sub.4O.sub.2 (MW=350.46); mass
spectroscopy (M+1) 351.4.
[2420] Anal. calcd for C.sub.20H.sub.22N.sub.4O.sub.2: C, 68.55; H,
6.33; N, 15.99. Found, C, 68.36; H, 6.20; N, 15.79.
Example 8-F
Synthesis of
3-(L-Alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chloro-
phenyl)-1H-1,4-benzodiazepin-2-one
Step A--Preparation of
3-(Benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1--
methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazeipin-2-one
[2421] Following General Procedure 8-A using
3-(benzyloxycarbonyl)-amino-7-
-chloro-2,3-dihydro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one
(Neosystem), the title intermediate was prepared as a white solid
having a melting point of 232-233.degree. C.
[2422] C.sub.24H.sub.19Cl.sub.2N.sub.3O.sub.3 (MW=468.36); mass
spectroscopy 468.
[2423] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.67 (1H, m),
7.52 (1H, dd, J=2.4, 8.7 Hz), 7.42-7.26 (9H, m), 7.07 (1H, d, J=2.4
Hz), 6.70 (1H, d, J=8.3 Hz), 5.35 (1H, d, J=8.4 Hz), 5.14 (2H, ABq,
J=19.6 Hz), 3.47 (3H, s).
[2424] .sup.13C NMR (75 MHz, CDCl.sub.3): .delta.=166.66, 165.65,
155.72, 140.52, 136.99, 136.0, 132.87, 131.99, 131.47, 131.40,
131.38, 131.16, 130.54, 130.06, 128.45, 128.08, 128.03, 127.72,
127.22, 123.28, 122.01, 68.95, 67.02, 35.32.
Step B--Preparation of
3-Amino-7-chloro-1.3-dihydro-1-methyl-5-(2-chloroph-
enyl)-2H-1,4-benzodiazepin-2-one
[2425] Following General Procedure 8-B using
3-(benzyloxycarbonyl)-amino-7-
-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one-
, the title intermediate was prepared as a white foam which was
used immediately in Step C.
Step C--Preparation of
3-[N'-(tert-Butylcarbamate)-L-alaninyl]-amino-7-chl-
oro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one
[2426] Following General Procedure D using N-Boc-L-alanine and
3-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiaz-
epin-2-one, the title intermediate was prepared as a white
foam.
[2427] C.sub.24H.sub.26Cl.sub.2N.sub.4O.sub.4 (MW=505.44); mass
spectroscopy 505.2.
Step D--Preparation of
3-(L-Alaninyl)-amino-7-chloro-1,3-dihydro-1-methyl--
5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one
[2428] Following General Procedure 8-C using
3-[N'-(tert-butylcarbamate)-L-
-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-b-
enzodiazepin-2-one, the title intermediate was prepared as a white
foam. The crude material was used immediately.
Example 8-G
Synthesis of
3-(L-Alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4--
Benzodiazepin-2-one
Step A--Preparation of
3-(Benzyloxycarbonyl)-amino-5-cylclohexyl-2,3-dihyd-
ro-1-methyl-1H-1,4-benzodiazepin-2-one
[2429] Following General Procedure 8-A using
3-(benzyloxycarbonyl)-amino-5-
-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (Neosystem), the
title intermediate was prepared as a white solid having a melting
point of 205-206.degree. C.
[2430] C.sub.24H.sub.27N.sub.3O.sub.3 (MW=405.54); mass
spectroscopy 405.
[2431] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.54 (1H, d,
J=7.9 Hz), 7.48 (1H, d, J=7.7 Hz), 7.36-7.26 (7H, m), 6.54 (1H, d,
J=8.3 Hz), 5.15 (1H, d, J=8.0 Hz), 5.09 (2H, ABq, J=17.1 Hz), 3.39
(3H, s), 2.77 (1H, m), 2.01 (1H, bd, J=13.6 Hz), 1.85 (1H, bd,
J=12.4 Hz), 1.68-1.49 (4H, m), 1.34-1.02 (4H, m).
Step B--Preparation of
3-Amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-be-
nzodiazepin-2-one
[2432] Following General Procedure 8-B using
3-(benzyloxycarbonyl)-amino-5-
-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one, the
title intermediate was prepared as a white foam which was used
immediately in Step C.
[2433] C.sub.16H.sub.21N.sub.3O (MW+H=272.1763); mass spectroscopy
272.1766
Step C--Preparation of
3-[N'-(tert-Butylcarbamate)-L-alaninyl]-amino-5-cyc-
lohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one
[2434] Following General Procedure D using N-Boc-L-alanine and
3-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one,
the title intermediate was prepared as a white foam.
[2435] C.sub.24H.sub.34N.sub.4O.sub.4 (MW=442.62); mass
spectroscopy (M+H) 443.2.
Step D--Preparation of
3-(L-Alaninyl)amino-5-cyclohexyl-1,3-dihydro-1-meth-
yl-2H-1,4-benzodiazepin-2-one
[2436] Following General Procedure 8-C using
3-[N'-(tert-butylcarbamate)-L-
-alaninyl]-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2--
one, the title intermediate was prepared as a white foam. The crude
material was used immediately.
[2437] C.sub.19H.sub.26N.sub.4O.sub.2 (M+H=343.2136); mass
spectroscopy found 343.2139.
Example 8-H
Synthesis of
3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H--
1,4-benzodiazepin-2-one
Step A--Preparation of
2-[N-(.alpha.-Isopropylthio)-N'-(benzyloxycarbonyl)-
-glycinyl]-amino-5-nitrobenzophenone
[2438] A solution of
.alpha.-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq;
prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975,
31, 863.) in dry THF was cooled to 0.degree. C. and treated with
oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15
minutes at 0.degree. C., the cooling bath was removed and stirring
continued at ambient temperature for 40 minutes. The solution was
recooled to 0.degree. C. A solution of 2-amino-5-nitrobenzophenone
(0.9 eq.; Acros) and 4-methylmorpholine (2.0 eq.) in dry THF was
added via cannulation to the acid chloride. The cooling bath was
removed and the reaction stirred at ambient for 5 hours. The
reaction was diluted with methylene chloride and washed with 0.5 M
citric acid, saturated aqueous NaHCO.sub.3, and brine. The organic
phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The residue was purified via preparative LC2000 eluting with a
gradient of 15.fwdarw.20% ethyl acetate/hexanes giving an off-white
foam.
[2439] C.sub.26H.sub.25N.sub.3O.sub.6S (MW=507.61); mass
spectroscopy found 507.9.
[2440] Anal. calcd for C.sub.26H.sub.25N.sub.3O.sub.6S: C, 61.53;
H, 4.96; N, 8.28. Found: C, 61.70; H, 4.99; N, 8.22.
Step B--Preparation of
2-[N-(.alpha.-Amino)-N'-(benzyloxycarbonyl)-glyciny-
l]-amino-5-nitrobenzophenone
[2441] Ammonia gas was bubbled into a solution
2-[N-(.alpha.-isopropylthio-
)-N'-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone (1 eq)
in THF at 0.degree. C. After 35 minutes mercury(II) chloride (1.1
eq) was added. The ice bath was removed and ammonia gas was
continued to bubble through the suspension for 4 hours. The bubbler
was removed and the reaction continued to stir for 16 hours. The
mixture was filtered through celite washing with THF. The filtrate
was concentrated in vacuo. The crude solid was used in step C
without further purification.
Step C--Preparation of
3-(Benzyloxycarbonyl)-amino-2,3-dihydro-7-nitro-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[2442]
2-[N-(.alpha.-Amino)-N'-(benzyloxycarbonyl)-glycinyl]-amino-5-nitro-
benzophenone (1 eq) was treated with glacial acetic acid and
ammonium acetate (4.7 eq). The suspension was stirred at ambient
temperature for 21 hours. After concentrating the reaction in
vacuo, the residue was partitioned between ethyl acetate and 1 N
NaOH. The aqueous layer was back-extracted with ethyl acetate. The
combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified via flash chromatography eluting with a gradient of
2.fwdarw.3% isopropyl alcohol/methylene chloride.
[2443] C.sub.23H.sub.18N.sub.4O.sub.5 (MW=430.45); mass
spectroscopy found (M+H) 431.2.
[2444] Anal. calcd for C.sub.23H.sub.18N.sub.4O.sub.5: C, 64.18; H,
4.22; N, 13.02. Found: C, 64.39; H, 4.30; N, 13.07.
Step D--Preparation of
3-(Benzyloxycarbonyl)-amino-2.3-dihydro-1-methyl-7--
nitro-5-phenyl-1H-1,4-benzodiazepin-2-one
[2445] Following General Procedure 8-A and using
3-(benzyloxycarbonyl)-ami-
no-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one, the
title intermediate was prepared as a yellow foam.
[2446] C.sub.24H.sub.20N.sub.4O.sub.5 (MW=444.48); mass
spectroscopy found (M+H) 445.2.
[2447] Anal. calcd for C.sub.24H.sub.20N.sub.4O.sub.5: C, 64.86; H,
4.54; N, 12.60. Found: C, 65.07; H, 4.55; N, 12.46.
Step E--Preparation of
3-Amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,-
4-benzodiazepin-2-one
[2448] Following General Procedure 8-B and using
3-(benzyloxycarbonyl)-ami-
no-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one,
the title intermediate was prepared as a yellow foam which was used
immediately in Step F.
Step F--Preparation of
3-[N'-(tert-Butylcarbamate)-L-alaninyl]-amino-2.3-d-
ihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one
[2449] Following General Procedure D using N-Boc-L-alanine and
3-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one,
the title intermediate was prepared as a yellow solid.
[2450] C.sub.24H.sub.27N.sub.5O.sub.6 (MW=481.56); mass
spectroscopy found (M+H) 482.3.
[2451] Anal. calcd for C.sub.24H.sub.27N.sub.5O.sub.6: C, 59.88; H,
5.61; N, 14.55. Found: C, 60.22; H, 5.75; N, 13.91.
Step G--Preparation of
3-(L-Alaninyl)-amino-2.3-dihydro-1-methyl-7-nitro-5-
-phenyl-1H-1,4-benzodiazepin-2-one
[2452] Following General Procedure 8-C using
3-[N'-(tert-butylcarbamate)-L-
-alaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepi-
n-2-one, the title intermediate was prepared as a yellow foam. The
crude material was used immediately.
Example 8-I
Synthesis of
3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1-
H-1,4-benzodiazepin-2-one
Step A--Preparation of
3-Amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H--
1,4-benzodiazepin-2-one
[2453] A flask was charged with
3-(benzyloxycarbonyl)-amino-7-bromo-2,3-di-
hydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1
eq.; Example 8-D, Step A) and 10% palladium on carbon. Methanol was
added, and the flask was placed under a balloon of H.sub.2. The
reaction was stirred for 21 hours. The mixture was filtered through
celite washing with methanol. The filtrate was concentrated to a
white solid.
[2454] C.sub.16H.sub.14FN.sub.3O (MW=283.33); mass spectroscopy
found (M+H) 284.1.
Step B--Preparation of
3-[N'-(tert-Butylcarbamate)-L-alaninyl]-amino-1,3-d-
ihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one
[2455] Following General Procedure D using N-Boc-L-alanine and
3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-on-
e, the title intermediate was prepared as a white solid.
[2456] C.sub.24H.sub.27FN.sub.4O.sub.4 (MW=454.50); mass
spectroscopy found (M+H) 455.4.
[2457] Anal. calcd for C.sub.24H.sub.27FN.sub.4O.sub.4: C, 63.44;
H, 5.95; N, 12.33. Found: C, 63.64; H, 6.08; N, 12.16.
Step C--Preparation of
3-(L-Alaninyl)-amino-7-bromo-1,3-dihydro-1-methyl-5-
-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one
[2458] Following General Procedure 8-C using
3-[N'-(tert-butylcarbamate)-L-
-alaninyl]-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiaze-
pin-2-one, the title intermediate was prepared as a white foam. The
crude material was used immediately.
Example 8-J
Synthesis of
3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)--
1H-1,4-benzodiazepin-2-one
Step A--Preparation of 2-Amino-3'-fluorobenzophenone
[2459] A solution of 3-bromofluorobenzene (1 eq.) in THF was cooled
to -78.degree. C. under nitrogen and treated with tert-butyllithium
(2.05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The
internal temperature did not rise above -74.degree. C. The orange
solution was stirred at -78.degree. C. for 30 minutes prior to the
addition of anthranilonitrile (0.6 eq.) as a solution in THF. The
reaction was warmed to 0.degree. C. and stirred for 2 hours. 3N HCl
was added to the mixture and stirring continued for 30 minutes. The
reaction was diluted with ethyl acetate and the layers were
separated. The aqueous layer was back-extracted thrice with ethyl
acetate. The combined extracts were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified via HPLC eluting with 93:7 hexanes/ethyl acetate.
[2460] C.sub.13H.sub.10FNO (MW=215.24); mass spectroscopy found
(M+H) 216.3.
[2461] .sup.1H NMR (300 MHz, CDCl.sub.3) d 7.44-7.19 (6H, m), 6.74
(1H, d, J=8.0 Hz), 6.61 (1H, dd, J=0.94, 7.9 Hz), 6.10 (2H,
bs).
Step B--Preparation of
2-[N-(.alpha.-Isopropylthio)-N'-(benzyloxycarbonyl)-
-glycinyl]-amino-3'-fluorobenzophenone
[2462] A solution of
.alpha.-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq;
prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975,
31, 863.) in dry THF was cooled to 0.degree. C. and treated with
oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15
minutes at 0.degree. C., the cooling bath was removed and stirring
continued at ambient temperature for 40 minutes. The solution was
recooled to 0.degree. C. A solution of
2-amino-3'-fluorobenzophenone (0.9 eq.) and 4-methylmorpholine (2.0
eq.) in dry THF was added via cannulation to the acid chloride. The
cooling bath was removed and the reaction stirred at ambient for 5
hours. The reaction was diluted with methylene chloride and washed
with 0.5 M citric acid, saturated aqueous NaHCO.sub.3, and brine.
The organic phase was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified via preparative LC2000
eluting with a gradient of 15.fwdarw.20% ethyl acetate/hexanes
giving an off-white foam.
[2463] C.sub.26H.sub.25N.sub.2O.sub.4S (MW=480.60); mass
spectroscopy found (M+NH.sub.4.sup.+) 498.3.
[2464] .sup.1H NMR (300 MHz, CDCl.sub.3) d 11.39 (1H, s), 8.59 (1H,
d, J=6.0 Hz), 7.63-7.55 (2H, m), 7.48-7.27 (9H, m), 7.14 (1H, dt,
J=1.2, 8.4 Hz), 5.94 (1H, d, J=7.2 Hz), 5.58 (1H, d, J=8.7 Hz),
5.17 (2H, ABq, J=14.7 Hz), 3.25 (1H, sep, J=6.6 Hz), 1.44 (3H, d,
J=6.0 Hz), 1.28 (3H, d, J=6.6 Hz).
Step C--Preparation of
2-[N-(.alpha.-Amino)-N'-(benzyloxycarbonyl)-glyciny-
l]-amino-3'-fluorobenzophenone
[2465] Ammonia gas was bubbled into a solution
2-[N-(.alpha.-isopropylthio-
)-N'-(benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1
eq) in THF at 0.degree. C. After 35 minutes mercury(II) chloride
(1.1 eq) was added. The ice bath was removed and ammonia gas was
continued to bubble through the suspension for 4 hours. The bubbler
was removed and the reaction continued to stir for 16 hours. The
mixture was filtered through celite washing with THF. The filtrate
was concentrated in vacuo. The crude solid was used in step D
without further purification.
Step D--Preparation of
3-(Benzyloxycarbonyl)-amino-2,3-dihydro-5-(3-fluoro-
phenyl)-1H-1,4-benzodiazepin-2-one
[2466]
2-[N-(.alpha.-Amino)-N'-(benzyloxycarbonyl)-glycinyl]-amino-3'-fluo-
robenzophenone (1 eq) was treated with glacial acetic acid and
ammonium acetate (4.7 eq). The suspension was stirred at ambient
temperature for 21 hours. After concentrating the reaction in
vacuo, the residue was partitioned between ethyl acetate and 1 N
NaOH. The aqueous layer was back-extracted with ethyl acetate. The
combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified via flash chromatography eluting with a gradient of
2.fwdarw.3% isopropyl alcohol/methylene chloride.
[2467] C.sub.23H.sub.18FN.sub.3O.sub.3 (MW=403.44); mass
spectroscopy found (M+H) 404.4.
[2468] Anal. calcd for C.sub.23H.sub.18FN.sub.3O.sub.3.0.5H.sub.2O:
C, 66.98; H, 4.64; N, 10.18. Found: C, 67.20; H, 4.64; N, 9.77.
Step E--Preparation of
3-(Benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5--
(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[2469] Following General Procedure 8-A and using
3-(benzyloxycarbonyl)-ami-
no-2,3-dihydro-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one, the
title intermediate was prepared as a yellow foam.
[2470] C.sub.24H.sub.20FN.sub.3O.sub.3 (MW=417.47); mass
spectroscopy found (M+H) 418.3.
[2471] Anal. calcd for C.sub.24H.sub.20FN.sub.3O.sub.3: C, 69.06;
H, 4.83; N, 10.07. Found: C, 69.33; H, 4.95; N, 9.82.
Step F--Preparation of
3-Amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H--
1,4-benzodiazepin-2-one
[2472] Following General Procedure 8-B and using
3-(benzyloxycarbonyl)-ami-
no-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one,
the title intermediate was prepared as a yellow foam which was used
immediately in Step G.
Step G--Preparation of
3-[N'-(tert-Butylcarbamate)-L-alaninyl]-amino-2,3-d-
ihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[2473] Following General Procedure D using N-Boc-L-alanine and
3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-2-on-
e, the title intermediate was prepared as a yellow solid.
[2474] C.sub.24H.sub.27FN.sub.4O.sub.4 (MW=454.50); mass
spectroscopy found (M+H) 455.3.
[2475] Anal. calcd for C.sub.24H.sub.27FN.sub.4O.sub.4: C, 63.42;
H, 5.99; N, 12.33. Found: C, 63.34; H, 6.01; N, 12.08.
Step H--Preparation of
3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluo-
rophenyl)-1H-1,4-benzodiazepin-2-one
[2476] Following General Procedure 8-C using
3-[N'-(tert-butylcarbamate)-L-
-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiaze-
pin-2-one, the title intermediate was prepared as a yellow foam.
The crude material was used immediately.
Example 8-K
Synthesis of
3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1-
H-1,4-benzodiazepin-2-one
Step A--Preparation of 2-Amino-4'-fluorobenzophenone
[2477] A solution of 4-bromofluorobenzene (1 eq.) in THF was cooled
to -78.degree. C. under nitrogen and treated with tert-butyllithium
(2.05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The
internal temperature did not rise above -74.degree. C. The orange
solution was stirred at -78.degree. C. for 30 minutes prior to the
addition of anthranilonitrile (0.6 eq.) as a solution in THF. The
reaction was warmed to 0.degree. C. and stirred for 2 hours. 3N HCl
was added to the mixture and stirring continued for 30 minutes. The
reaction was diluted with ethyl acetate and the layers were
separated. The aqueous layer was back-extracted thrice with ethyl
acetate. The combined extracts were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified via HPLC eluting with 93:7 hexanes/ethyl acetate.
[2478] C.sub.13H.sub.10FNO (MW=215.24); mass spectroscopy found
(M+H) 216.3.
[2479] Anal. calcd for C.sub.13H.sub.10FNO: C, 72.55; H, 4.68; N,
6.51. Found: C, 72.80; H, 4.51; N, 6.74.
Step B--Preparation of
2-[N-(.alpha.-Isopropylthio)-N'-(benzyloxycarbonyl)-
-glycinyl]-amino-4'-fluorobenzophenone
[2480] A solution of
.alpha.-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq;
prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975,
31, 863.) in dry THF was cooled to 0.degree. C. and treated with
oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15
minutes at 0.degree. C., the cooling bath was removed and stirring
continued at ambient temperature for 40 minutes. The solution was
recooled to 0.degree. C. A solution of
2-amino-4'-fluorobenzophenone (0.9 eq.) and 4-methylmorpholine (2.0
eq.) in dry THF was added via cannulation to the acid chloride. The
cooling bath was removed and the reaction stirred at ambient for 5
hours. The reaction was diluted with methylene chloride and washed
with 0.5 M citric acid, saturated aqueous NaHCO.sub.3, and brine.
The organic phase was dried over Na2SO4, filtered, and
concentrated. The residue was purified via preparative LC2000
eluting with a gradient of 15.fwdarw.20% ethyl acetate/hexanes
giving an off-white foam.
[2481] C.sub.26H.sub.25N.sub.2O.sub.4S (MW=480.60); mass
spectroscopy found (M+NH.sub.4.sup.+) 498.2.
[2482] .sup.1H NMR (300 MHz, CDCl.sub.3) d 11.28 (1H, s), 8.56 (1H,
d, J=8.4 Hz), 7.78-7.73 (2H, m), 7.61-7.53 (2H, m), 7.36-7.32 (5H,
m), 7.20-7.14 (3H, m), 5.98 (1H, d, J=7.5 Hz), 5.57 (1H, d, J=7.8
Hz), 5.16 (2H, ABq, J=14.7 Hz), 3.25 (1H, sep, J=6.0 Hz), 1.43 (3H,
d, J=6.3 Hz), 1.27 (3H, d, J=6.6 Hz).
Step C--Preparation of
2-[N-(.alpha.-Amino)-N'-(benzyloxycarbonyl)-glyciny-
l]-amino-4'-fluorobenzophenone
[2483] Ammonia gas was bubbled into a solution
2-[N-(.alpha.-isopropylthio-
)-N'-(benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1
eq) in THF at 0.degree. C. After 35 minutes mercury(II) chloride
(1.1 eq) was added. The ice bath was removed and ammonia gas was
continued to bubble through the suspension for 4 hours. The bubbler
was removed and the reaction continued to stir for 16 hours. The
mixture was filtered through celite washing with THF. The filtrate
was concentrated in vacuo. The crude solid was used in step D
without further purification.
[2484] Step D--Preparation of
3-(Benzyloxycarbonyl)amino-2,3-dihydro-5-(4--
fluorophenyl)-1H-1,4-benzodiazepin-2-one
2-[N-(.alpha.-Amino)-N'-(benzylox-
ycarbonyl)-glycinyl]-amino-4'-fluorobenzophenone (1 eq) was treated
with glacial acetic acid and ammonium acetate (4.7 eq). The
suspension was stirred at ambient temperature for 21 hours. After
concentrating the reaction in vacuo, the residue was partitioned
between ethyl acetate and 1 N NaOH. The aqueous layer was
back-extracted with ethyl acetate. The combined organics were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified via flash chromatography
eluting with a gradient of 2.fwdarw.3% isopropyl alcohol/methylene
chloride.
[2485] C.sub.23H.sub.18FN.sub.3O.sub.3 (MW=403.44); mass
spectroscopy found (M+H) 404.4.
[2486] Anal. calcd for
C.sub.23H.sub.18FN.sub.3O.sub.3.1.25H.sub.2O: C, 64.85; H, 4.85.
Found: C, 64.80; H, 4.55.
[2487] Step E--Preparation of
3-(Benzyloxycarbonyl)-amino-2,3-dihydro-1-me-
thyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[2488] Following General Procedure 8-A and using
3-(benzyloxycarbonyl)-ami-
no-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one, the
title intermediate was prepared as a yellow foam.
[2489] C.sub.24H.sub.20FN.sub.3O.sub.3 (MW=417.47); mass
spectroscopy found (M+H) 418.2.
[2490] Anal. calcd for C.sub.24H.sub.20FN.sub.3O.sub.3: C, 69.06;
H, 4.83; N, 10.07. Found: C, 69.35; H, 4.93; N, 9.97.
Step F--Preparation of
3-Amino-1,3-dihydro-1-methyl-5-(4-fluorophenyl)-2H--
1,4-benzodiazepin-2-one
[2491] Following General Procedure 8-B and using
3-(benzyloxycarbonyl)-ami-
no-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one,
the title intermediate was prepared as a yellow foam which was used
immediately in Step G.
Step G--Preparation of
3-[N'-(tert-Butylcarbamate)-L-alaninyl]-amino-2,3-d-
ihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[2492] Following General Procedure D using N-Boc-L-alanine and
3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-2-on-
e, the title intermediate was prepared as a yellow solid.
[2493] C.sub.24H.sub.27FN.sub.4O.sub.4 (MW=454.50); mass
spectroscopy found (M+H) 455.4.
[2494] Anal. calcd for C.sub.24H.sub.27FN.sub.4O.sub.4.1.5H.sub.2O:
C, 59.86; H, 6.28; N, 11.64. Found: C, 60.04; H, 5.62; N,
11.27.
Step H--Preparation of
3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(4-fluo-
rophenyl)-1H-1,4-benzodiazepin-2-one
[2495] Following General Procedure 8-C using
3-[N'-(tert-butylcarbamate)-L-
-alaninyl]-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiaze-
pin-2-one, the title intermediate was prepared as a yellow foam.
The crude material was used immediately.
Example 8-L
Synthesis of
3-(N'-L-Alaninyl)amino-2,3-dihydro-1-isobutyl-5-phenyl-1H-1,4-
-benzodiazepin-2-one
[2496] Step A: 1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one
(prepared according to the procedure of M. G. Bock et al., J. Org.
Chem. 1987, 52, 3232-3239) was alkylated with isobutyl iodide using
General Procedure 8-G to afford
1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
[2497] Step B: Following General Procedures 8-D and 8-F and using
the product from Step A,
3-amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzo-
diazepin-2-one was prepared.
[2498] Step C: The product from Step B and N-Boc-L-alanine (Sigma)
were coupled using General Procedure D, followed by removal of the
Boc group using General Procedure 8-J, to afford
3-(N'-L-alaninyl)amino-1,3-dihydro-
-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one. By substituting
isopropyl iodide, n-propyl iodide, cyclopropylmethyl iodide and
ethyl iodide for isobutyl iodide in Step A above, the following
additional intermediates were prepared:
[2499]
3-(N'-L-alaninyl)amino-1,3-dihydro-1-isopropyl-5-phenyl-2H-1,4-benz-
odiazepin-2-one
[2500]
3-(N'-L-alaninyl)amino-1,3-dihydro-1-propyl-5-phenyl-2H-1,4-benzodi-
azepin-2-one
[2501]
3-(N'-L-alaninyl)amino-1,3-dihydro-1-cyclopropylmethyl-5-phenyl-2H--
1,4-benzodiazepin-2-one
[2502]
3-(N'-L-alaninyl)amino-1,3-dihydro-1-ethyl-5-phenyl-2H-1,4-benzodia-
zepin-2-one.
Example 8-M
Synthesis of
3-(N'-L-Alaninyl)amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2-
H-1,5-benzodiazepin-2-one
[2503] Step A:
1,3,4,5-Tetrahydro-5-phenyl-2H-1,5-benzodiazepin-2-one (CAS No.
32900-17-7) was methylated using General Procedure 8-I to afford
1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one.
[2504] Step B: Following General Procedures 8-E and 8-F and using
the product from Step A,
3-amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5--
benzodiazepin-2-one was prepared.
[2505] Step C: The product from Step B and N-Boc-L-alanine (Sigma)
were coupled using General Procedure D, followed by removal of the
Boc group using General Procedure 8-N, to afford
3-(N'-L-alaninyl)amino-1-methyl-5--
phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one.
Example 8-N
Synthesis of
3-(N'-L-Alaninyl)amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-te-
trahydro-1H-1,5-benzodiazepine
[2506]
3-Amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepine (CAS No. 131604-75-6) was coupled with N-Boc-L-alanine
(Sigma) using General Procedure D, followed by removal of the Boc
group using General Procedure 8-N, to afford the title
compound.
Example 8-O
Synthesis of
3-((R)-Hydrazinopropionyl)amino-2,3-dihydro-1-methyl-5-phenyl-
)-1H-1,4-benzodiazepin-2-one
[2507]
3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
was coupled to (R)-N,N'-di-BOC-2-hydrazinopropionic acid (Example
N) using General Procedure D. Removal of the Boc group using
General Procedure 5-B afforded the title compound.
Example 8-P
Synthesis of
3-Amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro--
1H-1,5-benzodiazepine
Step A:--Synthesis of
2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2508] 2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No.
49799-48-6) was prepared from 1,2-phenylenediamine (Aldrich) and
malonic acid (Aldrich) using the procedure of Claremon, D. A.; et
al, PCT Application: WO 96-US8400 960603.
Step B:--Synthesis of
2,4-Dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-
-1H-1,5-benzodiazepine
[2509]
2,4-Dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodi-
azepine (CAS No. 113021-84-4) was prepared following General
Procedure 8-M using the product from Step A and 2-iodopropane
(Aldrich). Purification was by flash chromatography eluting with
EtOAc/hexanes (3:7 gradient to 1:1), then recrystalization from
EtOAc/hexanes.
Step C:--Synthesis of
3-Azido-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-te-
trahydro-1H-1,5-benzodiazepine
[2510] Following General Procedure 8-K using the product from Step
B, 3-azido-2,4-dioxo-1,5-bis-(
1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benz- odiazepine (CAS No.
186490-50-6) was prepared as a white solid. The product was
purified by flash chromatography eluting with hexanes/EtOAc (4:1)
to provide a separable 23:1 mixture of
pseudo-axial/pseudo-equatori- al azides. The pure pseudo-axial
azide was used in the next step.
Step D:--Synthesis of
3-Amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-te-
trahydro-1H-1,5-benzodiazepine
[2511] Following General Procedure 8-L using the product from Step
C,
3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepine (CAS No. 186490-51-7) was prepared as a white solid.
Purification was by flash chromatography eluting with
CH.sub.2Cl.sub.2/MeOH (98:2 gradient to 95:5). The isolated
pseudo-axial amine atropisomer was completely converted to the
pseudo-equatorial amine atropisomer by heating in toluene to
100-105.degree. C. for 15 minutes, and the pseudo-equatorial amine
atropisomer was used in the next step. The isomers were
distinguished by .sup.1H-NMR in CDCl.sub.3. Selected .sup.1H-NMR
(CDCl.sub.3): Pseudo-axial amine 4.40 (s, 1H); Pseudo-equatorial
amine 3.96 (s, 1H).
Example 8-Q
Synthesis of
3-(R-2-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(1-methylethyl-
)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
Step A:--Synthesis of N-(t-Butoxycarbonyl)-R-2-thienylglycine
[2512] N-(t-Butoxycarbonyl)-R-2-thienylglycine (CAS No. 74462-03-1)
was prepared from L-.alpha.-(2-thienyl)glycine (Sigma) by the
procedure described in Bodansky, M. et al; The Practice of Peptide
Synthesis; Springer Verlag; 1994, p. 17.
Step B:--Synthesis of
3-[N'-(t-Butoxycarbonyl)-R-2-thienylglycinyl]-amino--
2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2513] Following General Procedure J above using the product from
Example 8-P and the product from Step A above,
3-[N'-(t-butoxycarbonyl)-R-2-thien-
ylglycinyl]-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H--
1,5-benzodiazepine was prepared as a white foam. Purification was
by flash chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (9:1
gradient to 5:1).
Step C:--Synthesis of
3-(R-2-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(1-me-
thylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
Hydrochloride
[2514] Following General Procedure 8-N above using the product from
Step B, the title compound was prepared as a white solid.
Example 8-R
Synthesis of
3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahy-
dro-1H-1,5-benzodiazepine Hydrochloride
Step A:--Synthesis of
2,4-Dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-b-
enzodiazepine
[2515]
2,4-Dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
(CAS No. 23954-54-3) was prepared following General Procedure 8-M
using the product from Example 8-P, Step A and iodomethane
(Aldrich). The white solid product precipitated during partial
concentration of the reaction after work-up, and was isolated by
filtration.
Step B:--Synthesis of
3-Azido-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro--
1H-1,5-benzodiazepine
[2516] For this substrate, General Procedure 8-K was modified in
the following manner. Initially the product from Step A was
suspended (not a solution) in THF at -78.degree. C., and following
addition of the KN(TMS).sub.2 solution, this suspension was allowed
to warm to -35.degree. C. over a period of 12 minutes, during which
the suspension became a solution, and was re-cooled to -78.degree.
C.; then treated as described in the General Procedure.
3-Azido-2,4-dioxo-1,5-bis-methyl-2,3,-
4,5-tetrahydro-1H-1,5-benzodiazepine was purified by flash
chromatography eluting with CHCl.sub.3/EtOAc (7:1), then
trituration from hot CHCl.sub.3 with hexanes and cooled to
-23.degree. C. The product was isolated as a white solid.
Step C:--Synthesis of
3-Amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro--
1H-1,5-benzodiazepine
[2517] Following General Procedure 8-L using the product from Step
B,
3-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
was prepared as a white solid. The crude product was used without
further purification.
Step D:-13 Synthesis of
3-[N'-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dio-
xo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2518] Following General Procedure I above using N-Boc-L-alanine
(Novabiochem) and the product from Step C,
3-[N'-(t-butoxycarbonyl)-L-ala-
ninyl]-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiaze-
pine was prepared as a white foam. Purification was by flash
chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (2:1 gradient to
1:1).
Step E:--Synthesis of
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,-
5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
[2519] Following General Procedure 8-N above using the product from
Step D, the title compound was prepared as an off-white amorphous
solid.
Example 8-S
Synthesis of
3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,-
5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
Step A:--Synthesis of
2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydr-
o-1H-1,5-benzodiazepine
[2520]
2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzod-
iazepine was prepared following General Procedure 8-M using the
product from Example 8-P, Step A and 1-iodo-2-methylpropane
(Aldrich). Purification was by flash chromatography eluting with
EtOAc/hexanes (3:7 gradient to 1:1), then recrystalization from
EtOAc/hexanes.
Step B:--Synthesis of
3-Azido-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-t-
etrahydro-1H-1,5-benzodiazepine
[2521] Following General Procedure 8-K (a precipitate formed during
the addition of the KN(TMS).sub.2, but dissolved upon addition of
the trisyl azide) using the product from Step A,
3-azido-2,4-dioxo-1,5-bis-(2-methyl-
propyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared as a
white solid. The product was purified by flash chromatography
eluting with hexanes/EtOAc (4:1) and a second flash chromatography
eluting with CH.sub.2Cl.sub.2/hexanes/EtOAc (10:10:1 gradient to
8:6:1).
Step C:--Synthesis of
3-Amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-t-
etrahydro-1H-1,5-benzodiazepine
[2522] Following General Procedure 8-L using the product from Step
B,
3-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benz-
odiazepine was prepared as a white solid. Purification was by flash
chromatography eluting with CH.sub.2Cl.sub.2/MeOH (98:2 gradient to
95:5, with 5% NH.sub.3 in the MeOH).
Step D:--Synthesis of
3-[N'-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-
-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2523] Following General Procedure I above using N-Boc-L-alanine
(Novabiochem) and the product from Step C,
3-[N'-(t-butoxycarbonyl)-L-ala-
ninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5--
benzodiazepine was prepared as a white foam. Purification was by
flash chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (3:1
gradient to 3:2).
Step E:--Synthesis of
3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2-methylprop-
yl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
[2524] Following General Procedure 8-N above using the product from
Step D, the title compound was prepared as an amorphous white
solid.
Example 8-T
Synthesis of
3-(S-Phenylglycinyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)--
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
Step A:--Synthesis of
3-[N'-(t-Butoxycarbonyl)-5-phenylglycinyl]-amino-2,4-
-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2525] Following General Procedure J above using the product from
Example 8-S, Step C and the Boc-L-phenylglycine (Novabiochem, CAS
No. 2900-27-8),
3-[N'-(t-butoxycarbonyl)-5-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-met-
hylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared as
a white foam. Purification was by flash chromatography eluting with
CH.sub.2Cl.sub.2/EtOAc (9:1 gradient to 5:1).
Step B:--Synthesis of
3-(S-Phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-meth-
ylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
Hydrochloride
[2526] Following General Procedure 8-N above using the product from
Step A,
3-(S-phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5--
tetrahydro-1H-1,5-benzodiazepine hydrochloride was prepared as an
off-white solid.
Example 8-U
Synthesis of
3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3-
,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
Step A:--Synthesis of
2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrah-
ydro-1H-1,5-benzodiazepine
[2527]
2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-ben-
zodiazepine was prepared following General Procedure 8-M using the
product from Example 8-P, Step A, and (bromomethyl)cyclopropane
(Lancaster). Purification was by flash chromatography eluting with
EtOAc/hexanes (3:7 gradient to straight EtOAc), then
recrystalization from EtOAc/hexanes.
Step B:--Synthesis of
3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,-
5-tetrahydro-1H-1,5-benzodiazepine
[2528] For this substrate General Procedure 8-K was modified in the
following manner. Initially the product from Step A was suspended
(not a solution) in THF at -78.degree. C., and following addition
of the KN(TMS).sub.2 solution, this suspension was allowed to warm
to -30.degree. C., during which the suspension became a solution,
and was re-cooled to -78.degree. C. Upon re-cooling to -78.degree.
C. a precipitate began to form, therefore the reaction flask
containing the mixture was partially raised above the cooling bath
until the internal temperature rose to -50.degree. C.; then the
trisyl azide solution was added. The cooling bath was removed and
the mixture allowed to warm to -20.degree. C. whereupon the mixture
had become a nearly homogenous solution, and the AcOH was added.
Then, treated as described in the general procedure.
3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5--
tetrahydro-1H-1,5-benzodiazepine was purified by trituration with
hot to room temperature EtOAc, followed by recrystalization from
hot to -23.degree. C. CHCl.sub.3/EtOAc/EtOH (5:5:1) and isolated as
a white solid.
Step C:--Synthesis of
3-Amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,-
5-tetrahydro-1H-1,5-benzodiazepine
[2529] Following General Procedure 8-L using the product from Step
B,
3-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-b-
enzodiazepine was prepared as a white solid. Purification was by
flash chromatography eluting with CH.sub.2Cl.sub.2/MeOH (98:2
gradient to 95:5, with 5% NH.sub.3 in the MeOH) followed by
recrystalization from warm CH.sub.2Cl.sub.2/hexanes (1:1) to
-23.degree. C.
Step D:--Synthesis of
3-[N'-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-
-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2530] Following General Procedure I above using N-Boc-L-alanine
(Novabiochem) and the product from Step C,
3-[N'-(t-butoxycarbonyl)-L-ala-
ninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1-
,5-benzodiazepine was prepared as a white foam. Purification was by
flash chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (3:1
gradient to 2:1).
Step E:--Synthesis of
3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylm-
ethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
[2531] Following General Procedure 8-N above using the product from
Step D, the title compound was prepared as an off-white solid.
Example 8-V
Synthesis of
3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2-
,3,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
Step A:--Synthesis of
2,4-Dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetra-
hydro-1H-1,5-benzodiazepine
[2532] To a stirred suspension of the product from Example 8-P,
Step A (1.0 eq., 17.08 g) in DMSO (500 mL) at room temperature was
added neopentyl iodide (43.01 g, 2.24 eq., Aldrich) and
Cs.sub.2CO.sub.3 (72.65 g, 2.3 eq., Aldrich). The resulting mixture
was heated to 75.degree. C. for 30 minutes, then additional
Cs.sub.2CO.sub.3 (31.59 g, 1.0 eq.) was added and the mixture
rapidly stirred at 75.degree. C. for 6 hours. The mixture was
allowed to cool and H.sub.2O (500 mL) and EtOAc (1000 mL) were
added. The phases were partitioned and the organic phase washed
with H.sub.2O (1.times.500 mL), 1 M aq. HCl (2.times.500 mL), and
brine (1.times.500 mL). Then, the organic phase was dried over
MgSO.sub.4, filtered, concentrated, and purified by flash
chromatography eluting with hexanes/EtOAc (3:2 gradient to 2:3) to
provide 2,4-dioxo-1,5-bis-(2,2-dim-
ethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine as a white
solid.
Step B:--Synthesis of
3-Azido-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4-
,5-tetrahydro-1H-1,5-benzodiazepine
[2533] Following General Procedure 8-K using the product from Step
A,
3-azido-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5--
benzodiazepine was prepared as a white solid. The product was
purified by flash chromatography eluting with
hexanes/CH.sub.2Cl.sub.2/EtOAc (10:5:1 gradient to 5:5:1) to
provide a separable 13:1 mixture of pseudo-axial/pseudo-equatorial
azides. The pure pseudo-axial azide was used in the next step.
Selected .sup.1H-NMR (CDCl.sub.3): Pseudo-axial azide 5.12 (s, 1H);
Pseudo-equatorial azide 4.03 (s, 1H).
Step C:--Synthesis of
3-Amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4-
,5-tetrahydro-1H-1,5-benzodiazepine
[2534] Following General Procedure 8-L using the product from Step
B,
3-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5--
benzodiazepine was prepared as a white solid. Purification was by
flash chromatography eluting with CH.sub.2Cl.sub.2/MeOH (98:2
gradient to 95:5, with 5% NH.sub.3 in the MeOH). The isolated white
solid product was identified as a .about.4:1 mixture of
pseudo-axial and pseudo-equatorial amines atropisomers by
.sup.1H-NMR. The mixture was heated in toluene to 100.degree. C.
for 20 minutes, then re-concentrated to provide the pure
pseudo-equatorial amine atropisomer, as a white solid, and this was
for the next step. Selected .sup.1H-NMR (CDCl.sub.3): Pseudo-axial
amine 4.59 (s, 1H); Pseudo-equatorial amine 4.03 (s, 1H).
Step D:--Synthesis of
3-[N'-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-
-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2535] Following General Procedure I above using N-Boc-L-alanine
(Novabiochem) and the product from Step C,
3-[N'-(t-butoxycarbonyl)-L-ala-
ninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H--
1,5-benzodiazepine was prepared as a white foam. Purification was
by flash chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (4:1
gradient to 5:2).
Step E:--Synthesis of
3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethyl-
propyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
[2536] Following General Procedure 8-N above using the product from
Step D, the title compound was prepared as an off-white solid.
Example 8-W
Synthesis of
3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahyd-
ro-1H-1,5-benzodiazepine hydrochloride
Step A:--Synthesis of
2,4-Dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-b-
enzodiazepine
[2537] This procedure is a modification of the procedure described
in Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016. A mixture
of the product from Example 8-P, Step A (1.0 eq., 7.50 g),
Ph.sub.3Bi (2.2 eq., 41.26 g, Aldrich), Cu(OAc).sub.2 (2.0 eq.,
15.48 g, Aldrich), Et.sub.3N (2.0 eq., 8.62 g) in CH.sub.2Cl.sub.2
(100 mL) was stirred under N.sub.2 at room temperature for 6 days
(monitoring by TLC). The solids were removed by filtration through
a plug of Celite rinsing with CH.sub.2Cl.sub.2/MeOH (3.times.75
mL). The filtrate was concentrated, dissolved in hot
CH.sub.2Cl.sub.2/MeOH (9:1) and filtered through a large plug of
silica gel eluting with CH.sub.2Cl.sub.2/MeOH (9:1, 2L). The
filtrate was concentrated and the residue purified by flash
chromatography eluting with straight CH.sub.2Cl.sub.2 gradient to
CH.sub.2Cl.sub.2/MeOH (9:1).
2,4-Dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-- 1H-1,5-benzodiazepine
crystallized during concentration of the fractions containing the
product, and was isolated by filtration as a white solid.
Step B:--Synthesis of
3-Azido-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro--
1H-1,5-benzodiazepine
[2538] For this substrate, General Procedure 8-K was modified in
the following manner. Initially the product from Step A was
suspended (not a solution) in THF at -70.degree. C., and following
addition of the KN(TMS).sub.2 solution, this suspension was allowed
to warm to -20.degree. C. over a period of 10 minutes, during which
the suspension became a solution, and was re-cooled to -70.degree.
C.; then treated as described in the general procedure. The title
compound was purified by trituration with hot CHCl.sub.3/hexanes
(1:1) to yield
3-azido-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
as a white solid.
Step C:--Synthesis of
3-Amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro--
1H-1,5-benzodiazepine
[2539] Following General Procedure 8-L using the product from Step
B,
3-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
was prepared as a white solid. Purification was by flash
chromatography eluting with CH.sub.2Cl.sub.2/MeOH (98:2 gradient to
95:5, with 5% NH.sub.3 in the MeOH).
Step D:--Synthesis of
3-[N'-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-
-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2540] Following General Procedure I above using N-Boc-L-alanine
(Novabiochem) and the product from Step C,
3-[N'-(t-butoxycarbonyl)-L-ala-
ninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiaze-
pine was prepared as a white foam. Purification was by flash
chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (4:1 gradient to
3:1).
Step E:--Synthesis of
3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,-
5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride
[2541] Following General Procedure 8-N above using the product from
Step D, the title compound was prepared as a white amorphous
solid.
Example 8-X
Synthesis of
3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2--
one
[2542] Following the method of R. G. Sherrill et al., J. Org.
Chem., 1995, 60, 730-734 and using glacial acetic acid and HBr gas,
the title compound was prepared.
Example 8-Y
Synthesis of
3-(L-Valinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benz-
odiazepin-2-one
Step A--Synthesis of
3-[N'-(tert-Butylcarbamate)-L-valinyl]-amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2543]
(S)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-on-
e, (1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate
(Example 8-B, Step A) was free based by partitioning between
methylene chloride and 1M potassium carbonate. The free amine was
then coupled with N-Boc-valine following General Procedure D to
give the title compound.
[2544] C.sub.26H.sub.32N.sub.4O.sub.4 (MW 464.62); mass
spectroscopy 464.3.
[2545] Anal. Calcd for C.sub.26H.sub.32N.sub.4O.sub.4: C, 67.22; H,
6.94; N, 12.06. Found: C, 67.29; H, 6.79; N, 11.20.
Step B--Synthesis of
3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H--
1,4-benzodiazepin-2-one
[2546] Following General Procedure 8-C and using
3-[N'-(tert-butylcarbamat-
e)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-
-one, the title compound was prepared as a white foam.
[2547] C.sub.21H.sub.23N.sub.4O.sub.2 (MW 363.48); mass
spectroscopy (M+H) 364.2.
Example 8-Z
Synthesis of
3-(L-tert-Leucinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,-
4-benzodiazepin-2-one
Step A--Synthesis of
3-[N'-(tert-Butylcarbamate)-L-tert-leucinyl]-amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2548]
(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-on-
e, (1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate
(Example 8-B, Step A) was free based by partitioning between
methylene chloride and 1M potassium carbonate. The free amine was
then coupled with N-Boc-tert-leucine following General Procedure D
to give the title compound.
[2549] C.sub.27H.sub.35N.sub.4O.sub.4 (MW 479.66); mass
spectroscopy 479.
Step B--Synthesis of
3-(L-tert-Leucinyl)-amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one
[2550] Following General Procedure 8-C and using
3-[N'-(tert-butylcarbamat-
e)-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazep-
ine-2-one, the title compound was prepared as a white foam.
[2551] Anal. Calcd for C.sub.22H.sub.25N.sub.4O.sub.2.0.5H.sub.2O:
C, 68.19; H, 7.02; N, 14.40. Found: C, 68.24; H, 7.00; N,
14.00.
Example 8-AA
Synthesis of
3-(L-Alaninyl)-amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodia-
zepine
[2552] 2,3-Dihydro-1,5-dimethyl-1H-1,4-benzodiazepine was prepared
following General Procedures 8-I (using methyl iodide), 8-D and
8-F. Coupling of this intermediate with Boc-L-alanine (Novo) using
General Procedure D, followed by deprotection using General
Procedure 5-B afforded the title compound which was used without
further purification.
Example 8-AB
Synthesis of
3-(L-3-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(2,2-dimethylp-
ropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
Step A:--Synthesis of N-(t-Butoxycarbonyl)-L-3-thienylglycine
[2553] N-(t-Butoxycarbonyl)-L-3-thienylglycine was prepared from
L-.alpha.-(3-thienyl)glycine (Sigma) by the procedure described in
Bodansky, M. et al; The Practice of Peptide Synthesis; Springer
Verlag; 1994, p. 17.
Step B:--Synthesis of
3-[N'-(t-Butoxycarbonyl)-L-3-thienylglycinyl]-amino--
2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiaz-
epine
[2554] Following General Procedure D above using the product from
Example 8-V, Step C and the product from Step A above,
3-[N'-(t-butoxycarbonyl)-L-
-3-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-t-
etrahydro-1H-1,5-benzodiazepine was prepared.
Step C:--Synthesis of
3-(L-3-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(2,2--
dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2555] Following General Procedure 8-N above using the product from
Step B, the title compound was prepared.
Example 8-1
Synthesis of
3-(3,5-Difluorophenylacetyl)amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one
[2556] Following General Procedure A above using
3,5-difluorophenylacetic acid (Oakwood) and
3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaz- epin-2-one
(Example 8-X), the title compound was prepared as a solid having a
melting point of 236-239.degree. C. The reaction was monitored by
tlc on silica gel (Rf=0.7 in 10% methanol/dichloromethane) and
purification was by silica gel chromatography using 10%
methanol/dichloromethane as the eluant.
[2557] NMR data was as follows:
[2558] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4 (m, 9H), 6.90 (dd,
J=6.0, 2.2, 2H), 6.73 (dt, J=6.6, 2.2, 2.2, 6.6, 1H), 5.50 (d,
J=7.7, 1H), 3.68 (s, 2H), 3.46 (s, 3H).
[2559] .sup.13C-nmr (CDCl.sub.3): .delta.=172.9, 165.2, 163.5,
138.3, 133.6, 127.7, 126.4, 125.4, 124.6, 123.9, 120.3, 117.2,
108.2, 107.9; 98.4, 62.8, 38.6, 30.9.
[2560] C.sub.24H.sub.19N.sub.3O.sub.2F (MW=419); mass spectroscopy
(MH.sup.+) 420.
Example 8-2
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydr-
o-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2561] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-- benzodiazepin-2-one
(prepared as described in Example 8-X using ethyl iodide), the
title compound was prepared as a solid having a melting point of
155-158.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.48 in 10% methanol/dichloromethane) and purification was by
silica gel chromatography using 10% methanol/dichloromethane as the
eluant, followed by recrystallization from diethyl ether.
[2562] NMR data was as follows:
[2563] .sup.1H-nmr (CDCl.sub.3): .delta.=7/73 (d, J=7.7, 1H), 7.4
(m, 9H), 6.86 (m, 2H), 6.68 (m, 1H), 6.58 (d, J=7.2, 1H), 5.43 (dd,
J=2.7, 4.9, 2.7, 1H), 4.67 (m, 1H), 4.3 (m, 1H), 3.7 (m, 1H), 3,52
(s, 2H), 1.46 (dd, J=6.6, 6.6, 3H), 1.10 (dt, J=7.1, 1.1, 6.0,
3H).
[2564] .sup.13C-nmr (CDCl.sub.3): .delta.=167.8, 164.8, 163.4,
161.3, 136.7, 133.6, 127.6, 126.4, 125.2, 124.0, 118.1, 107.8,
98.3, 95.5, 62.9, 44.7, 38.6, 14.5, 8.7.
[2565] C.sub.28H.sub.26N.sub.4O.sub.3F.sub.2 (MW=504); mass
spectroscopy (MH.sup.+) 505.
Example 8-3
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydr-
o-5-phenyl-1H-1,4benzodiazepin-2-one
[2566] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodia- zepin-2-one (CAS:
10334347-1. Sherrill, R. G.; Sugg, E. E. J. Org. Chem. 1995, 60,
730.), the title compound was prepared as a white solid.
Purification was by trituration with 1: 1 ether/hexanes.
[2567] C.sub.26H.sub.21F.sub.2N.sub.4O.sub.3 (MW=475.51); mass
spectroscopy (MH.sup.+) 476.
[2568] Anal. Calcd for C.sub.26H.sub.21F.sub.2N.sub.4O.sub.3: C,
65.54; H, 4.65; N, 11.76. Found: C, 65.37; H, 4.67; N, 11.63.
Example 8-4
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydr-
o-1-methyl-5-(1-piperidinyl)-1H-1,4-benzodiazepin-2-one
[2569] Following General Procedure D above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-1,3-dihydro-1-methyl-5-(1-piperidiny-
l)-2H-1,4-benzodiazepin-2-one (Example 8-A), the title compound was
prepared as a white solid having a melting point of 154-160.degree.
C.
[2570] C.sub.26H.sub.29F.sub.2N.sub.5O.sub.3 (MW=497.60); mass
spectroscopy 497.
[2571] Anal. Calcd for C.sub.26H.sub.29F.sub.2N.sub.5O.sub.3: C,
62.75; H, 5.89; N, 14.08. Found: C, 62.52; H, 5.81; N, 13.62.
Example 8-5
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2572] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-7-chloro-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-C), the
title compound was prepared as a white solid having a melting point
of 126.5-130.degree. C.
[2573] C.sub.27H.sub.23ClF.sub.2N.sub.4O.sub.3 (MW=524.1); mass
spectroscopy 523.7.
[2574] Anal. calcd for C.sub.27H.sub.23ClF.sub.2N.sub.4O.sub.3: C,
61.78; H, 4.42; N, 10.67. Found: C, 61.92; H, 4.52; N, 10.46.
Example 8-6
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-7-bromo-2,-
3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[2575] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-7-bromo-2,3-dihydr-
o-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example
8-D), the title compound was prepared as a white solid.
[2576] C.sub.27H.sub.22BrF.sub.3N.sub.4O.sub.3 (MW=587.43); mass
spectroscopy 587.
[2577] Anal calcd for C.sub.27H.sub.22BrF.sub.3N.sub.4O.sub.3: C,
55.21; H, 3.78; N, 9.54. Found: C, 55.25; H, 4.00; N, 9.72.
Example 8-7
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-N'-methyl-L-alaninyl]-amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2578] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(N'-methyl-L-alaninyl)-amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-E), the
title compound was prepared as a white solid.
[2579] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.65 (1H, d,
J=7.9 Hz), 7.59-7.34 (8H, m), 7.23 (1H, t, J=7.2 Hz), 6.84 (2H, d,
J=6.0 Hz), 6.65 (1H, t, J=7.2 Hz), 5.46 (1H, d, J=7.9 Hz), 5.42
(1H, d, J=7.2 Hz), 3.78 (2H, s), 3.47 (3H, s), 3.02 (3H, s), 1.42
(3H, d, J=7.1 Hz).
[2580] C.sub.28H.sub.26F.sub.2N.sub.4O.sub.3 (MW=505.2051); mass
spectroscopy 505.2046.
Example 8-8
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2-
,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one
[2581] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-7-chloro-2,3-dihyd-
ro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one (Example
8-F), the title compound was prepared as a white solid.
[2582] C.sub.27H.sub.22Cl.sub.2F.sub.2N.sub.4O.sub.3 (MW=559.43);
mass spectroscopy 559.2.
[2583] Anal. calcd for
C.sub.27H.sub.22Cl.sub.2F.sub.2N.sub.4O.sub.3: C, 57.97; H, 3.96;
N, 10.02. Found: C, 57.99; H, 3.98; N, 9.92.
Example 8-9
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-5-cyclohex-
yl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one
[2584] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-5-cylcohexyl-2,3-d-
ihydro-1-methyl-1H-1,4-benzodiazepin-2-one (Example 8-G), the title
compound was prepared as a white solid.
[2585] C.sub.27H.sub.30F.sub.2N.sub.4O.sub.3 (MW=497.2364); mass
spectroscopy 497.2370.
Example 8-10
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydr-
o-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one
[2586] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-2,3-dihydro-1-meth-
yl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-H), the
title compound was prepared as a yellow solid.
[2587] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.44 (1H, dd,
J=2.2, 9.0 Hz), 8.42 (1H, dd, J=2.3, 9.0 Hz), 8.23 (2H, d, J=2.6
Hz), 7.73 (2H, m), 7.56-7.40 (12H, m), 6.83 (4H, m), 6.69 (2H, m),
6.37 (2H, apt, J=7.8 Hz), 5.45 (1H, d, J=7.7 Hz), 5.44 (1H, d,
J=7.7 Hz), 4.71 (2H, m), 3.56 (2H, s), 3.55 (2H, s), 3.52 (3H, s),
3.51 (3H, s), 1.47 (3H, d, J=7.0 Hz), 1.46 (3H, d, J=7.0 Hz).
[2588] C.sub.27H.sub.23F.sub.2N.sub.5O.sub.5 (M+H=536.1747); mass
spectroscopy found 536.1749.
Example 8-11
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydr-
o-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[2589] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-2,3-dihydro-1-meth-
yl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-I), the
title compound was prepared as a white solid having a melting point
of 185-188.degree. C.
[2590] C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3 (MW=508.54); mass
spectroscopy found (M+H) 509.3.
[2591] Anal. calcd for C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3: C,
63.78; H, 4.53; N, 11.02. Found: C, 63.99; H, 4.49; N, 10.84.
Example 8-12
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-valinyl]-a- mino
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2592] Following General Procedure D above using
S-(+)-3,5-difluoromandeli- c acid (Example L) and
3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5-1H-1,4-b-
enzodiazepin-2-one (Example 8-Y), the title compound was prepared
as a white solid.
[2593] C.sub.29H.sub.28F.sub.2N.sub.4O.sub.4 (MW=534.61); mass
spectroscopy found (M+H) 535.3.
[2594] Anal. calcd for C.sub.29H.sub.28F.sub.2N.sub.4O.sub.4: C,
65.16; H, 5.28; N, 10.48. Found: C, 65.34; H, 5.43; N, 10.35.
Example 8-13
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-tert-leuciny-
l]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2595] Following General Procedure D above using
S-(+)-3,5-difluoromandeli- c acid (Example L) and
3-(ten-leucinyl)-amino-2,3-dihydro-1-methyl-5-1H-1,-
4-benzodiazepin-2-one (Example 8-Z), the title compound was
prepared as a white solid.
[2596] C.sub.30H.sub.30F.sub.2N.sub.4O.sub.4 (MW=548.64); mass
spectroscopy found (M+H) 549.3.
[2597] Anal. calcd for C.sub.30H.sub.30F.sub.2N.sub.4O.sub.4: C,
65.68; H, 5.51; N, 10.21. Found: C, 65.38; H, 5.44; N, 10.14.
Example 8-14
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydr-
o-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[2598] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-2,3-dihydro-1-meth-
yl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-J), the
title compound was prepared as an off white solid.
[2599] C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3 (MW=508.50); mass
spectroscopy found (M+H) 509.3.
[2600] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.65-7.53 (4H,
m), 7.42-7.24 (12H, m), 7.22-7.14 (2H, m), 6.87-6.81 (4H, m),
6.75-6.65 (2H, m), 6.29 (1H, d, J=6.6 Hz), 6.21 (1H, d, J=7.2 Hz),
5.45 (1H, d, J=7.8 Hz), 5.44 (1H, d, J=7.5 Hz), 4.67 (2H, m), 3.57
(2H, s), 3.55 (2H, s), 3.474 (3H, s), 3.468 (3H, s), 1.48 (3H, d,
J=7.2 Hz), 1.47 (3H, d, J=6.8 Hz).
Example 8-15
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-methyl-5-(4-fluorophenyl)-1H-1,4benzodiazepin-2-one
[2601] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-2,3-dihydro-1-meth-
yl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-K), the
title compound was prepared as an off-white solid.
[2602] C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3 (MW=508.50); mass
spectroscopy found (M+H) 509.7.
[2603] Anal. calcd for C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3: C,
63.78; H, 4.56; N, 11.01. Found: C, 64.09; H, 4.81; N, 10.40.
Example 8-16
Synthesis of
3-[N'-(Cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4benzodiazepin-2-one
[2604] Following General Procedure D above using
(.+-.)-.alpha.-hydroxy-cy- clopentylacetic acid (Example P) and
3-(L-alaninyl)-amino-2,3-dihydro-1-me-
thyl-5-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound
was prepared as a white solid.
[2605] Isomer 1:
[2606] C.sub.26H.sub.30N.sub.4O.sub.4 (MW=462.60); mass
spectroscopy found (M+H) 463.6.
[2607] Anal. calcd for C.sub.26H.sub.30N.sub.4O.sub.4: C, 67.51; H,
6.54; N, 12.11. Found: C, 67.78; H, 6.65; N, 12.29.
[2608] Isomer 2:
[2609] C.sub.26H.sub.30N.sub.4O.sub.4 (MW=462.60); mass
spectroscopy found (M+H) 463.4.
[2610] Anal. calcd for C.sub.26H.sub.30N.sub.4O.sub.4: C, 67.51; H,
6.54; N, 12.11. Found: C, 67.74; H, 6.56; N, 11.81.
Example 8-17
Synthesis of
3-[N'-(Cyclopentyl-.alpha.-hydroxyacetyl)-L-valinyl]-amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2611] Following General Procedure D above using
(.+-.)-.alpha.-hydroxy-cy- clopentylacetic acid (Example P) and
3-(L-valinyl)-amino-2,3-dihydro-1-met-
hyl-5-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound
was prepared as a white solid.
[2612] Isomer 1:
[2613] C.sub.28H.sub.34N.sub.4O.sub.4 (MW=490.66); mass
spectroscopy found (M+H) 491.4.
[2614] Isomer 2:
[2615] C.sub.28H.sub.34N.sub.4O.sub.4 (MW=490.66); mass
spectroscopy found (M+H) 491.4.
Example 8-18
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-
-1,5-dimethyl-1H-1,4-benzodiazepin-2-one
[2616] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-2,3-dihydro-1,5-di-
methyl-1H-1,4-benzodiazepin-2-one (Example 8-AA), the title
compound was prepared as a solid (mp.=222-223.degree. C.). The
product was purified by slurrying in ether.
[2617] MW=429; mass spectroscopy found (M+H) 429.
[2618] Anal. calcd: C, 61.67; H, 5.18; N, 13.08. Found: C, 61.43;
H, 5.17; N, 12.79.
Example 8-19
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-isobutyl-5-phenyl)-1H-1,4-benzodiazepin-2-one
[2619] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)-amino-2,3-dihydro-1-isob-
utyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-L), the title
compound was prepared as a solid (mp.=210-211.degree. C.). The
product was purified by tituration from ether/hexanes.
[2620] C.sub.30H.sub.30F.sub.2N.sub.4O.sub.3 (MW=532.23); mass
spectroscopy found (M+H) 532.
[2621] Anal. calcd: C, 67.66; H, 5.68; N, 10.52. Found: C, 67.67;
H, 5.55; N, 10.34.
[2622] Purification by C 2000 chromatography, eluting with
hexanes/ethyl acetate (20:80) afforded the following isomers:
[2623] Isomer 1:
[2624] Melting Point: 202-203.degree. C.
[2625] C.sub.30H.sub.30F.sub.2N.sub.4O.sub.3 (MW=532.23); mass
spectroscopy found (M+H) 532.23.
[2626] Isomer 2:
[2627] Melting Point: 211-212.degree. C.
[2628] C.sub.30H.sub.30F.sub.2N.sub.4O.sub.3 (MW=532.23); mass
spectroscopy found (M+H) 532.
Example 8-20
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2629] Following General Procedure D above using
3,5-difluoromandelic acid (Fluorochem) and
3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
-benzodiazepin-2-one (Example 8-B), the title compound was prepared
as a solid. The product was purified by LC 2000 chromatography,
eluting with hexanes/ethyl acetate (20:80).
[2630] Isomer 1:
[2631] Melting Point: 240-241.degree. C.
[2632] C.sub.27H.sub.24F.sub.2N.sub.4O.sub.4 (MW=506.51); mass
spectroscopy found (M+H) 506.
[2633] Anal. calcd for C.sub.27H.sub.24F.sub.3N.sub.4O.sub.4: C,
64.03; H, 4.78; N, 11.06. Found: C, 64.31; H, 4.86; N, 11.04.
[2634] Isomer 2:
[2635] Melting Point: 128.degree. C.
[2636] C.sub.27H.sub.24F.sub.2N.sub.4O.sub.4 (MW=506.51); mass
spectroscopy found (M+H) 506.
[2637] Anal. calcd for C.sub.27H.sub.24F.sub.3N.sub.4O.sub.4: C,
64.03; H, 4.78; N, 11.06. Found: C, 63.92; H, 5.00; N, 10.88.
Example 8-21
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-oxoacetyl)-L-alaninyl]amino-
-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2638] Following General Procedure D above using
3,5-difluoro-.alpha.-oxoa- cetic acid (Example O) and
3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound was
prepared as a solid (mp.=128-129.degree. C.). The product was
purified by LC 2000 chromatography, eluting with hexanes/ethyl
acetate (30:70).
[2639] C.sub.27H.sub.22F.sub.2N.sub.4O.sub.4 (MW=504); mass
spectroscopy found (M+H) 503.9.
[2640] Optical Rotation: [.alpha.]=-113.64 @589; -333.33 @365 (c 1,
MeOH).
[2641] Anal. calcd for C.sub.27H.sub.22F.sub.3N.sub.4O.sub.4: C,
64.28; H, 4.40; N, 11.11. Found: C, 64.51; H, 4.54; N, 11.04.
Example 8-22
Synthesis of
3-[N'-(2-Methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2642] Following General Procedure D above using 2-methylthioacetic
acid (Aldrich) and
3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-b-
enzodiazepin-2-one (Example 8-B), the title compound was prepared
as a solid (mp.=205-206.degree. C.). The product was purified by
slurrying in hexanes/ether (1:1).
[2643] C.sub.22H.sub.24N.sub.4O.sub.3S (MW=424); mass spectroscopy
found (M+H) 424.
[2644] Anal. calcd for C.sub.22H.sub.24N.sub.4O.sub.3S: C, 62.25;
H, 5.70; N, 13.20. Found: C, 62.11; H, 5.89; N, 13.02.
Example 8-23
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-valinyl]amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4benzodiazepin-2-one
[2645] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-valinyl)amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Y), the title
compound was prepared as a solid (mp.=228-229.degree. C.). The
product was purified by slurrying in ether/hexanes (80:20).
[2646] C.sub.29H.sub.28F.sub.2N.sub.4O.sub.3 (MW=518); mass
spectroscopy found (M+H) 518.
[2647] Optical Rotation: [.alpha.]=-117.96 @589; -341.55 @365 (c 1,
MeOH).
[2648] Anal. calcd for C.sub.29H.sub.28F.sub.2N.sub.4O.sub.3: C,
67.17; H, 5.44; N, 10.8. Found: C, 67.45; H, 5.49; N, 10.61.
Example 8-24
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-tert-leucinyl]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2649] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-tert-leucinyl)amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Z), the title
compound was prepared as a solid (mp.=221-222.degree. C.). The
product was purified by slurrying in ether.
[2650] C.sub.30H.sub.30F.sub.2N.sub.4O.sub.3 (MW=532); mass
spectroscopy found (M+H) 532.
[2651] Anal. calcd for C.sub.30H.sub.30F.sub.2N.sub.4O.sub.3: C,
67.66; H, 5.68; N, 10.52. Found: C, 67.93; H, 5.95; N, 10.25.
Example 8-25
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2652] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)amino-2,3-dihydro-1-isopr-
opyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-L), the title
compound was prepared as a solid (mp.=208-209.degree. C.). The
product was purified by slurrying in ether/hexanes (1:1).
[2653] MW=518; mass spectroscopy found (M+H) 518.
[2654] Anal. calcd: C, 67.17; H, 5.44; N, 10.80. Found: C, 67.39;
H, 5.62; N, 10.84.
Example 8-26
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-
-1-cyclopropylmethyl-5-phenyl-1H-1,4benzodiazepin-2-one
[2655] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)amino-2,3-dihydro-1-cyclo-
propylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-L), the
title compound was prepared as a solid (mp.=203-205.degree. C.).
The product was purified by slurrying in ether/hexanes.
[2656] C.sub.30H.sub.28F.sub.2N.sub.4O.sub.3 (MW=530.58); mass
spectroscopy found (M+H) 530.
[2657] Anal. calcd for C.sub.30H.sub.28F.sub.2N.sub.4O.sub.3: C,
67.91; H, 5.32; N, 10.56. Found: C, 68.14; H, 5.54; N, 10.62.
Example 8-27
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-fluoroacetyl)-L-alaninyl]am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2658] Following General Procedure D above using
3,5-difluorophenyl-.alpha- .-fluoroacetic acid (Example S) and
3-(L-alaninyl)amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Y), the title
compound was prepared as a solid. The product was purified by LC
2000 chromatography, eluting with hexanes/ethyl acetate
(35:65).
[2659] Isomer 1:
[2660] Melting Point: 119-120.degree. C.
[2661] C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3 (MW=508); mass
spectroscopy found (M+H) 508.
[2662] Optical Rotation: [.alpha.]=-115.62 @589; -292.09 @365 (c 1,
MeOH).
[2663] Anal. calcd for C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3: C,
62.66; H, 4.67; N, 10.82. Found: C, 62.55; H, 4.74; N, 10.51.
[2664] Isomer 2:
[2665] Melting Point: 198-199.degree. C.
[2666] C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3 (MW=508); mass
spectroscopy found (M+H) 508.
[2667] Optical Rotation: [.alpha.]=-99.65 @589; -279.72 @365 (c 1,
MeOH).
[2668] Anal. calcd for C.sub.27H.sub.23F.sub.3N.sub.4O.sub.3: C,
62.66; H, 4.67; N, 10.82. Found: C, 62.40; H, 4.62; N, 10.84.
Examples 8-28 to 8-139
[2669] By following the procedures set forth above, the following
additional compounds were prepared:
34 8-28 3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2- ,3-
dihydro-1-n-propyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-29
3-[N'-(3-methylbutyryl)-L-phenylglycinyl]amino-2,3-dihydro-
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-30
3-[N'-(3,5-difluorophenylacetyl)-L-phenylglycinyl]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-31
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-32
3-[N'-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-33
3-[N'-(2-phenylthioacetyl)-L-phenylglycinyl]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-34
3-[N'-(3-(4-methoxyphenyl)propionyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-35
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-36
3-[N'-(4-cyclohexylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-37
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-38
3-[N'-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-39
3-[N'-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-40
3-[N'-(3,3-dimethylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-41
3-[N'-(thien-2-yl-acetyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-42
3-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-43
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-44
3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-45
3-[N'-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-46
3-[N'-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-47
3-[N'-(3,5-di(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2- one 8-48
3-[N'-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-49
3-[N'-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-50
3-[N'-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-
alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-51 3-[N'-(thionaphth-3-ylacetyl)-L-alaninyl]-
amino-2,3-dihydro-1- methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-o-
ne 8-52 3-[N'-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-53
3-[N'-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-54
3-[N'-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-55
3-[N'-(4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-56
3-[N'-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-57
3-[N'-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-60
3-[N'-(2,6-difluorophenyl)-.alpha.-hydroxyacetyl)-L-
alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-61 3-[N'-(4-fluorophenyl)-.alpha.-hydroxyace-
tyl)-L-alaninyl]amino- 2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-b-
enzodiazepin-2- one 8-62 3-[N'-(2,5-difluorophenyl)-.alpha.-
-hydroxyacetyl)-L- alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridy-
l)-1H-1,4- benzodiazepin-2-one 8-63 3-[N'-(2,4,6-trifluorop-
henyl)acetyl)-L-alaninyl]amino-2,3- dihydro-1-methyl-5-(2-pyridyl)-
-1H-1,4-benzodiazepin-2-one 8-64
3-[N'-(2-trifluoromethyl-4-fluorop- henyl)acetyl)-L-
alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)- -1H-1,4-
benzodiazepin-2-one 8-65 3-[N'-(4,4,4-trifluorobut-
yryl)-L-alaninyl]amino-2,3-dihydro- 1-methyl-5-(2-pyridyl)-1H-1,4--
benzodiazepin-2-one 8-66
3-[N'-(4-iso-propylphenylacetyl)-L-alaniny- l]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2- -one 8-67
3-[N'-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-68
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-69
3-[N'-(4-chlorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2- one 8-70
3-[N'-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-71
3-[N'-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-72
3-[N'-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-
1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-73
3-[N'-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-
dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-74
3-[N'-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-
methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-75
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-
1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-76 3-[N'-(2-thienylacetyl)-L-alaninyl]amino--
2,3-dihydro-1-(tert- butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-ben-
zodiazepin-2- one 8-77 3-[N'-(3,5-difluorophenylacetyl)-L-a-
laninyl]amino-2,3- dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyrid-
yl)-1H-1,4- benzodiazepin-2-one 8-78
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-
(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-79 3-[N'-(2-phenylthioacetyl)-L-alaninyl]ami-
no-2,3-dihydro-1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-80 3-[N'-(4-ethoxyphenylacetyl)-L-al-
aninyl]amino-2,3-dihydro- 1-(tert-butylcarbonylmethyl)-5-(2-pyridy-
l)-1H-1,4- benzodiazepin-2-one 8-81 3-[N'-(4-trifluoromethy-
lphenylacetyl)-L-alaninyl]amino-2,3- dihydro-1-(tert-butylcarbonyl-
methyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-82
3-[N'-(3,5-di-(trifluoromethyl)phenylacetyl)-L-
alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-
pyridyl)-1H-1,4-benzodiazepin-2-one 8-83 3-[N'-(2-methylthioacetyl-
)-L-alaninyl]amino-2,3-dihydro-1- (tert-butylcarbonylmethyl)-5-(2--
pyridyl)-1H-1,4- benzodiazepin-2-one 8-84
3-[N'-(2-cyclomethylacetyl)-L-alaninyl]amino-2,3-dihydro-1-
(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-85 3-[N'-(2,3,4,5,6-pentafluorophenyloxyacet-
yl)-L- alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(-
2- pyridyl)-1H-1,4-benzodiazepin-2-one 8-86
3-[N'-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-
(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-87 3-[N'-(2,4,6-trimethylphenylacetyl)-L-ala-
ninyl]amino-2,3- dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl-
)-1H-1,4- benzodiazepin-2-one 8-88 3-[N'-((4-phenyl)phenyla-
cetyl)-L-alaninyl]amino-2,3-dihydro- 1-(tert-butylcarbonylmethyl)--
5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-89
3-[N'-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-
dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-90 3-[N'-(4-(2-thienyl)butyryl)-L-alaninyl]a-
mino-2,3-dihydro-1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,-
4- benzodiazepin-2-one 8-91 3-[N'-(5-methylhexanoyl)-L-alan-
inyl]amino-2,3-dihydro-1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)-
-1H-1,4- benzodiazepin-2-one 8-95 3-[N'-(2,6-difluorophenyl-
-.alpha.-hydroxyacetyl)-L- alaninyl]amino-2,3-dihydro-1-(tert-buty-
lcarbonylmethyl)-5-(2- pyridyl)-1H-1,4-benzodiazepin-2-one 8-96
3-[N'-(4-fluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-
2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-
1,4-benzodiazepin-2-one 8-97 3-[N'-(2,5-difluorophenyl-.alpha.-hyd-
roxyacetyl)-L- alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmet-
hyl)-5-(2- pyridyl)-1H-1,4-benzodiazepin-2-one 8-98
3-[N'-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3-
dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-99 3-[N'-(2-trifluoromethyl-4-fluorophenylac-
etyl)-L- alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-
-(2- pyridyl)-1H-1,4-benzodiazepin-2-one 8-100
3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-
1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-101 3-[N'-(4-iso-propylphenylacetyl)-L-alani-
nyl]amino-2,3- dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)--
1H-1,4- benzodiazepin-2-one 8-102 3-[N'-(3-phenyl-2-hydroxy-
propionyl)-L-alaninyl]amino-2,3- dihydro-1-(tert-butylcarbonylmeth-
yl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-103
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-
dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-104 3-[N'-(4-chlorophenylacetyl)-L-alaninyl]-
amino-2,3-dihydro-1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1-
,4- benzodiazepin-2-one 8-105 3-[N'-(3-methylbutyryl)-L-ala-
ninyl]amino-2,3-dihydro-1-(tert- butylcarbonylmethyl)-5-(2-pyridyl-
)-1H-1,4-benzodiazepin-2- one 8-106 3-[N'-(2,3,5-trifluorop-
henylacetyl)-L-alaninyl]amino-2,3- dihydro-1-(tert-butylcarbonylme-
thyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-107
3-[N'-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-
1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-108 3-[N'-(3-methyl-2-hydroxybutyryl)-L-alan-
inyl]amino-2,3- dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-
-1H-1,4- benzodiazepin-2-one 8-109 3-[N'-(3-nitrophenylacet-
yl)-L-alaninyl]amino-2,3-dihydro-1- (tert-butylcarbonylmethyl)-5-(-
2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-110
3-[N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-
1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-111 3-[N'-(2-thienylacetyl)-L-alaninyl]amino-
-2,3-dihydro-1-(2- (N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-112 3-[N'-(3,5-difluorophenylacetyl)-
-L-alaninyl]amino-2,3- dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2--
pyridyl)-1H-1,4- benzodiazepin-2-one 8-113
3-[N'-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-
(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-114 3-[N'-(2-phenylthioacetyl)-L-alaninyl]am-
ino-2,3-dihydro-1- (2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,-
4- benzodiazepin-2-one 8-117 3-[N'-(2-cyclohexylacetyl)-L-a-
laninyl]amino-2,3-dihydro-1- (2-(N,N-diethylamino)ethyl)-5-(2-pyri-
dyl)-1H-1,4- benzodiazepin-2-one 8-118
3-[N'-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-
alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-
(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-119
3-[N'-(2-thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-
1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-120 3-[N'-(2-phenyl-2-oxoacetyl)-L-alaninyl]-
amino-2,3-dihydro-1- (2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H--
1,4- benzodiazepin-2-one 8-123 3-[N'-((3,4-difluorophenyl)a-
cetyl)-L-alaninyl]amino-2,3- dihydro-1-(2-(N,N-diethylamino)ethyl)-
-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-124
3-[N'-((4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-
1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-125 3-[N'-(5-methylhexanoyl)-L-alaninyl]amin-
o-2,3-dihydro-1-(2- (N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-130 3-[N'-(4-fluorophenyl-.alpha.-hy-
droxyacetyl)-L-alaninyl]amino- 2,3-dihydro-1-(2-(N,N-diethylamino)-
ethyl)-5-(2-pyridyl)-1H- 1,4-benzodiazepin-2-one 8-131
3-[N'-(2,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-
alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-
(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-135
3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-
1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-136 3-[N'-(4-iso-propylphenylacetyl)-L-alani-
nyl]amino-2,3- dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-
-1H-1,4- benzodiazepin-2-one 8-137 3-[N'-(3-phenyl-2-hydrox-
ypropionyl)-L-alaninyl]amino-2,3- dihydro-1-(2-(N,N-diethylamino)e-
thyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-138
3-[N'-(phenyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,3-
dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-
benzodiazepin-2-one 8-139 3-[N'-(4-chlorophenyl-.alpha.-hydroxyace-
tyl)-L-alaninyl]amino- 2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-
-(2-pyridyl)-1H- 1,4-benzodiazepin-2-one
Example 8-140
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-3-thienylg-
lycinyl]amino-2,4-dioxo-1,5-bis(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H--
1,5-benzodiazepine
[2670] Following General Procedure D above using
3,5-difluoromandelic acid (Fluorochem) and
3-(L-3-thienylglycinyl]amino-2,4-dioxo-1,5-bis(2,2-dimet-
hylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (Example 8-AB),
the title compound was prepared as a solid. The product was
purified by LC 2000 chromatography, eluting with hexanes/ethyl
acetate (1:1).
[2671] Isomer 1:
[2672] Melting Point: 191-192.degree. C.
[2673] Optical Rotation: [.alpha.]=+21.47 @589; +52.17 @365 (c 1,
MeOH).
[2674] C.sub.33H.sub.38F.sub.2N.sub.4O.sub.5S (MW=640); mass
spectroscopy found (M+H) 639.1; 640.1.
[2675] Anal. calcd for C.sub.33H.sub.38F.sub.2N.sub.4O.sub.5S: C,
61.68; H, 5.89; N, 8.74. Found: C, 61.87; H, 6.08; N, 8.84.
[2676] Isomer 2:
[2677] Melting Point: 230-231.degree. C.
[2678] Optical Rotation: [.alpha.]=+59.26 @589; +200.0 @365 (c 1,
MeOH).
[2679] C.sub.33H.sub.38F.sub.2N.sub.4O.sub.5S (MW=640); mass
spectroscopy found (M+H) 639.4; 640.4.
[2680] Anal. calcd for C.sub.33H.sub.38F.sub.2N.sub.4O.sub.5S: C,
61.68; H, 5.89; N, 8.74. Found: C, 62.01; H, 6.07; N, 8.52.
Example 8-141
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]a-
mino-2,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2681] Following General Procedure D above using
3,5-difluoromandelic acid (Fluorochem) and
3-(L-alaninyl)amino-2,4-dioxo-1-phenyl-5-methyl-2,3,4,5--
tetrahydro-1H-1,5-benzodiazepine (Example 8-N), the title compound
was prepared as a solid. The product was purified by LC 2000
chromatography, eluting with hexanes/ethyl acetate (30:70).
[2682] Isomer 1:
[2683] Melting Point: 212-213.degree. C.
[2684] Optical Rotation: [.alpha.]=+101.34 @589; +491.4 @365 (c 1,
MeOH).
[2685] C.sub.27H.sub.24F.sub.2N.sub.4O.sub.5 (MW=522.17); mass
spectroscopy found (M+H) 523.3; 521.3.
[2686] Isomer 2:
[2687] Melting Point: 282-283.degree. C.
[2688] C.sub.27H.sub.24F.sub.2N.sub.4O.sub.5 (MW=522.1793); exact
mass spectroscopy found (M+) 523.1800.
[2689] Isomer 3:
[2690] Melting Point: 147-148.degree. C.
[2691] C.sub.27H.sub.24F.sub.2N.sub.4O.sub.5 (MW=522.1793); exact
mass spectroscopy found (M+) 523.1793.
[2692] Isomer 4:
[2693] Melting Point: 255-256.degree. C.
[2694] C.sub.27H.sub.24F.sub.2N.sub.4O.sub.5 (MW=522.17); mass
spectroscopy found (M+) 523.2.
[2695] Anal. calcd for C.sub.27H.sub.24F.sub.2N.sub.4O.sub.5: C,
62.07; H, 4.63; N, 10.72. Found: C, 62.18; H, 4.84; N, 10.74.
Example 8-142
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]a-
mino-2-oxo-1-methyl-5-phenyl-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2696] Following General Procedure D above using
3,5-difluoromandelic acid (Fluorochem) and
3-(L-alaninyl)amino-2-oxo-1-methyl-5-phenyl-1,3,4,5-tetr-
ahydro-1H-1,5-benzodiazepine (Example 8-M), the title compound was
prepared as a solid. The product was purified by LC 2000
chromatography, eluting with hexanes/ethyl acetate (40:60).
[2697] Isomer 1:
[2698] Melting Point: 258-259.degree. C.
[2699] C.sub.27H.sub.26F.sub.2N.sub.4O.sub.4 (MW=508); mass
spectroscopy found (M+H) 507; 508.
[2700] Anal. calcd for C.sub.27H.sub.26F.sub.2N.sub.4O.sub.4: C,
63.77; H, 5.16; N, 11.02. Found: C, 63.84; H, 5.34; N, 10.96.
[2701] Isomer 2:
[2702] C.sub.27H.sub.26F.sub.2N.sub.4O.sub.4 (MW=508); mass
spectroscopy found (M+H) 507; 508.
[2703] Anal. calcd for C.sub.27H.sub.26F.sub.2N.sub.4O.sub.4: C,
63.77; H, 5.16; N, 11.02. Found: C, 63.74; H, 5.38; N, 10.76.
[2704] Isomer 3:
[2705] Melting Point: 121-123.degree. C.
[2706] C.sub.27H.sub.26F.sub.2N.sub.4O.sub.4 (MW=508); mass
spectroscopy found (M+H) 507; 508.
[2707] Anal. calcd for C.sub.27H.sub.26F.sub.2N.sub.4O.sub.4: C,
63.77; H, 5.16; N, 11.02. Found: C, 63.55; H, 5.30; N, 10.74.
[2708] Isomer 4:
[2709] Melting Point: 204-205.degree. C.
[2710] C.sub.27H.sub.26F.sub.2N.sub.4O.sub.4 (MW=508); mass
spectroscopy found (M+H) 507; 508.
[2711] Anal. calcd for C.sub.27H.sub.26F.sub.2N.sub.4O.sub.4: C,
63.77; H, 5.16; N, 11.02. Found: C, 63.23; H, 5.24; N, 10.74.
Example 8-143
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-L-1H-imidaz-
ole[1,2-a]-6-phenyl-1,4-benzodiazepine
[2712] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)amino-L-1H-imidiazole[1,2-
-a]-6-phenyl-1,4-benzodiazepine (prepared by the methods described
in Bock et al., Bioorganic and Medicinal Chemistry, Vol. 2, 987-988
(1994); J. Med. Chem., 1988, 31, 176-181; and J. Org. Chem., 1987,
52, 3232), the title compound was prepared as a solid. The product
was purified by LC 2000 chromatography, eluting with
methanol/dichloromethane (5:95).
[2713] Isomer 1:
[2714] Melting Point: 205-206.degree. C.
[2715] Optical Rotation: [.alpha.]=-12.86 @589; -135.05 @365 (c 1,
MeOH).
[2716] C.sub.28H.sub.23F.sub.2N.sub.5O.sub.2 (MW=499); mass
spectroscopy found (M+H) 499.1.
[2717] Anal. calcd for C.sub.28H.sub.23F.sub.2N.sub.5O.sub.2: C,
67.33; H, 4.64; N, 14.02. Found: C, 67.49; H, 4.61; N, 13.77.
[2718] Isomer 2:
[2719] Melting Point: 151-153.degree. C.
[2720] Optical Rotation: [.alpha.]=-37.41 @589; -114.71 @365 (c 1,
MeOH).
[2721] C.sub.28H.sub.23F.sub.2N.sub.5O.sub.2 (MW=499.1894); exact
mass spectroscopy found (M+H) 499.1898.
[2722] Anal. calcd for C.sub.28H.sub.23F.sub.2N.sub.5O.sub.2: C,
67.33; H, 4.64; N, 14.02. Found: C, 63.43; H, 4.36; N, 13.10.
Example 8-144
Synthesis of
4-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-L-1H-imidaz-
ole[1,2-a]-2,4-dihydro-6-phenyl-1,4-benzodiazepine
[2723] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)amino-L-1H-imidazole[1,2--
a]-2,4-dihydro-6-phenyl-1,4-benzodiazepine (prepared by the methods
described in Bock et al., Bioorganic and Medicinal Chemistry, Vol.
2, 987-988 (1994); J. Med. Chem., 1988, 31, 176-181; and J. Org.
Chem., 1987, 52, 3232), the title compound was prepared as a solid.
The product was purified by LC 2000 chromatography, eluting with
methanol/dichloromethane (5:95).
[2724] Isomer 1:
[2725] Melting Point: 135-136.degree. C.
[2726] Optical Rotation: [.alpha.]=+15.63 @589; -162.5 @365 (c 1,
MeOH).
[2727] C.sub.28H.sub.25F.sub.2N.sub.5O.sub.2 (MW=501.2); mass
spectroscopy found (M+H) 501.1.
[2728] Anal. calcd for C.sub.28H.sub.25F.sub.2N.sub.5O.sub.2: C,
67.06; H, 5.02; N, 13.96. Found: C, 62.9; H, 4.93; N, 12.53.
[2729] Isomer 2:
[2730] Melting Point: 162-165.degree. C.
[2731] Optical Rotation: [.alpha.]=-28.66 @589; -76.43 @365 (c 1,
MeOH).
[2732] C.sub.28H.sub.25F.sub.2N.sub.5O.sub.2 (MW=502.2050); exact
mass spectroscopy found (M+H) 502.2050.
[2733] Anal. calcd for C.sub.28H.sub.25F.sub.2N.sub.5O.sub.2: C,
67.06; H, 5.02; N, 13.96. Found: C, 62.70; H, 4.78; N, 12.69.
Example 8-145
Synthesis of
4-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-L4H[1,2,4]t-
riazole[4,3-a]-6phenyl-1,4-benzodiazepine
[2734] Following General Procedure D above using
3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and
3-(L-alaninyl)amino-L-4H[1,2,4]triazole-
[4,3-a]-6-phenyl-1,4-benzodiazepine (prepared by the methods
described in Bock et al., Bioorganic and Medicinal Chemistry, Vol.
2, 987-988 (1994); J. Med. Chem., 1988, 31, 176-181; and J. Org.
Chem., 1987, 52, 3232), the title compound was prepared as a solid
(m.p.=165-167.degree. C.). The product was purified by LC 2000
chromatography, eluting with methanol/dichloromethane (4:96).
[2735] Optical Rotation: [.alpha.]=-34.63 @589; -138.53 @365 (c 1,
MeOH).
[2736] C.sub.27H.sub.22F.sub.2N.sub.6O.sub.2 (MW=500); mass
spectroscopy found (M+H) 500.1.
[2737] Anal. calcd for C.sub.27H.sub.22F.sub.2N.sub.6O.sub.2: C,
64.79; H, 4.43; N, 16.79. Found: C, 63.01; H, 4.73; N, 15.32.
Example 8-146
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,4dioxo-1,-
5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2738] Following General Procedure I above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,-
3,4,5-tetrahydro-1H-1,5-benzodiazepine (Example 8-P), the title
compound was prepared as a white solid (melting
point=232-233.degree. C.). Purification was by flash chromatography
eluting with EtOAc/hexanes (4:1 gradient to 6:1). R.sub.f=0.31 (4:1
EtOAc/hexanes).
[2739] C.sub.26H.sub.30F.sub.2N.sub.4O.sub.4 (MW 500.55); mass
spectroscopy (MH+) 500.2
[2740] Anal. Calcd. for C.sub.26H.sub.30F.sub.2N.sub.4O.sub.4: C,
62.39; H, 6.04; N, 11.19. Found: C, 62.62; H, 6.00; N, 11.21.
Example 8-147
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-(R)-2-thienylglycinyl]amino--
2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2741] Following General Procedure I above using
3,5-difluorophenylacetic acid (Lancaster) and
3-(R-2-thienylglycinyl)-amino-2,4-dioxo-1,5-bis-(1-m-
ethylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride
(Example 8-Q), the title compound was prepared as an amorphous
white solid. Purification was by flash chromatography eluting with
CH.sub.2Cl.sub.2/EtOAc (5:1 gradient to 4:1). R.sub.f=0.34 (4:1
CH.sub.2Cl.sub.2/EtOAc).
[2742] C.sub.29H.sub.30F.sub.2N.sub.4O.sub.4S (MW 568.65); mass
spectroscopy (MH+) 568.
[2743] Anal. Calcd. for C.sub.29H.sub.30F.sub.2N.sub.4O.sub.4S: C,
61.25; H, 5.32; N, 9.85. Found: C, 61.00; H, 5.42; N, 9.68.
Example 8-148
Synthesis of
3-[N'-(Cyclopropylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-
-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2744] Following General Procedure I above using cyclopropylacetic
acid (Lancaster) and the product from Example 8-Q, the title
compound was prepared as an amorphous white solid. Purification was
by flash chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (4:1
gradient to 5:2). R.sub.f=0.26 (4:1 CH.sub.2Cl.sub.2/EtOAc).
[2745] C.sub.26H.sub.32N.sub.4O.sub.4S (MW 496.63); mass
spectroscopy (MH+) 496.5
[2746] Anal. Calcd. for C.sub.26H.sub.32N.sub.4O.sub.4S: C, 62.88;
H, 6.49; N, 11.28. Found: C, 62.65; H, 6.57; N, 11.55.
Example 8-149
Synthesis of
3-[N'-(Cyclopentylacetyl)-R-2-thienylglycinyl]amino-2,4dioxo--
1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2747] Following General Procedure I above using cyclopentylacetic
acid (Aldrich) and the product from Example 8-Q, the title compound
was prepared as an amorphous white solid. Purification was by flash
chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (5:1 gradient to
4:1). R.sub.f=0.26 (4:1 CH.sub.2Cl.sub.2/EtOAc).
[2748] C.sub.28H.sub.36N.sub.4O.sub.4S (MW 524.69); mass
spectroscopy (MH+) 524.5
[2749] Anal. Calcd. for C.sub.28H.sub.36N.sub.4O.sub.4S: C, 64.10;
H, 6.92; N, 10.68. Found: C, 64.07; H, 6.91; N, 10.67.
Example 8-150
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1-
,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2750] Following General Procedure I above using
3,5-difluorophenylacetic acid (Lancaster) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,-
5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-R), the
title compound was prepared as a white solid (melting
point=206-207.degree. C.). Purification was by flash chromatography
eluting with straight EtOAc gradient to EtOAc/Acetone (95:5).
R.sub.f=0.32 (EtOAc).
[2751] C.sub.22H.sub.22F.sub.2N.sub.4O.sub.4 (MW 444.42); mass
spectroscopy (MH+) 444.
[2752] Anal. Calcd. for C.sub.22H.sub.22F.sub.2N.sub.4O.sub.4: C,
59.46; H, 4.99; N, 12.61. Found: C, 59.54; H, 5.09; N, 12.56.
Example 8-151
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]a-
mino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2753] Following General Procedure I above using
3,5-difluoromandelic acid (Lancaster) and the product from Example
8-R, the title compound was prepared as an amorphous white solid.
Purification was by L.C. 2000 eluting with straight EtOAc then
flash chromatography eluting with CH.sub.2Cl.sub.2/Acetone (4:1
gradient to 3:1). R.sub.f=0.39 and 0.34 (EtOAc).
[2754] C.sub.22H.sub.22F.sub.2N.sub.4O.sub.5 (MW 460.44); mass
spectroscopy (MH+) 461.0.
[2755] Anal. Calcd. for C.sub.22H.sub.22F.sub.2N.sub.4O.sub.5: C,
57.39; H, 4.82; N, 12.17. Found: C, 57.16; H, 4.88; N, 11.97.
Example 8-152
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1-
,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2756] Following General Procedure I above using
3,5-difluorophenylacetic acid (Lancaster) and
3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropy-
l)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example
8-S), the title compound was prepared as a white solid (melting
point=197-198.degree. C.). Purification was by flash chromatography
eluting with CH.sub.2Cl.sub.2/EtOAc (2:1 gradient to 3:4).
R.sub.f=0.23 (CH.sub.2Cl.sub.2/EtOAc, 1:1).
[2757] C.sub.28H.sub.34F.sub.2N.sub.4O.sub.4 (MW 528.60); mass
spectroscopy (MH+) 528.
[2758] Anal. Calcd. for C.sub.28H.sub.34F.sub.2N.sub.4O.sub.4: C,
63.62; H, 6.48; N, 10.60. Found: C, 63.75; H, 6.63; N, 10.67.
Example 8-153
Synthesis of
3-[N'-(Cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis--
(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2759] Following General Procedure I above using cyclopentylacetic
acid (Aldrich) and
3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,-
4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-S),
the title compound was prepared as an amorphous white solid.
Purification was by flash chromatography eluting with
CH.sub.2Cl.sub.2/EtOAc (1:1). R.sub.f=0.31 (CH.sub.2Cl.sub.2/EtOAc,
1:1).
[2760] C.sub.27H.sub.40N.sub.4O.sub.4 (MW 484.64); mass
spectroscopy (MH+) 484.
[2761] Anal. Calcd. for C.sub.27H.sub.40N.sub.4O.sub.4: C, 66.92;
H, 8.32; N, 11.56. Found: C, 66.86; H, 8.64; N, 11.41.
Example 8-154
Synthesis of
3-[N'-(Cyclopropylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-
-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2762] Following General Procedure I above using cyclopropylacetic
acid (Lancaster) and
3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,-
3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-S),
the title compound was prepared as a white solid (melting
point=190-191.degree. C.). Purification was by flash chromatography
eluting with CH.sub.2Cl.sub.2/EtOAc (1:1 gradient to 3:4) and a
second flash chromatography eluting with EtOAc/Toluene (7:3).
R.sub.f=0.28 (EtOAc/Toluene, 7:3).
[2763] C.sub.25H.sub.36N.sub.4O.sub.4 (MW 456.59); mass
spectroscopy (MH+) 456.1.
[2764] Anal. Calcd. for C.sub.25H.sub.36N.sub.4O.sub.4: C, 65.77;
H, 7.95; N, 12.27. Found: C, 66.01; H, 8.03; N, 12.35.
Example 8-155
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-5-phenylglycinyl]-amino-2,4--
dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2765] Following General Procedure I above using
3,5-difluorophenylacetic acid (Lancaster) and
3-(S-phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-meth-
ylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride
(Example 8-T), the title compound was prepared as a white solid
(melting point=186-187.degree. C.). Purification was by flash
chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (7:1 gradient to
4:1). R.sub.f=0.39 (CH.sub.2Cl.sub.2/EtOAc, 7:1).
[2766] C.sub.33H.sub.36F.sub.2N.sub.4O.sub.4 (MW 590.68); mass
spectroscopy (MH+) 590.0.
[2767] Anal. Calcd. for C.sub.33H.sub.36F.sub.2N.sub.4O.sub.4: C,
67.10; H, 6.14; N, 9.49. Found: C, 67.36; H, 6.38; N, 9.56.
Example 8-156
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,4dioxo-1-
,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2768] Following General Procedure I above using
3,5-difluorophenylacetic acid (Lancaster) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylm-
ethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride
(Example 8-U), the title compound was prepared as a white solid
(melting point=211-212.degree. C.). Purification was by flash
chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (1:1 gradient to
2:3). R.sub.f=0.44 (CH.sub.2Cl.sub.2IEtOAc, 1:1).
[2769] C.sub.28H.sub.30F.sub.2N.sub.4O.sub.4 (MW 524.57); mass
spectroscopy (MH+) 524.1.
[2770] Anal. Calcd. for C.sub.28H.sub.30F.sub.2N.sub.4O.sub.4: C,
64.11; H, 5.76; N, 10.68. Found: C, 64.07; H, 5.79; N, 10.49.
Example 8-157
Synthesis of
3-[N'-(Cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-
-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2771] Following General Procedure I above using cyclopentylacetic
acid (Aldrich) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)--
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example
8-U), the title compound was prepared as a white foam. Purification
was by flash chromatography eluting with CH.sub.2Cl.sub.2/EtOAc
(1:1 gradient to 2:3). R.sub.f=0.50 (CH.sub.2Cl.sub.2/EtOAc,
1:1).
[2772] C.sub.27H.sub.36N.sub.4O.sub.4 (MW 480.61); mass
spectroscopy (MH+) 481.2 and (MH-) 479.2.
[2773] Anal. Calcd. for C.sub.27H.sub.36N.sub.4O.sub.4: C, 67.48;
H, 7.55; N, 11.66. Found: C, 67.33; H, 7.57; N, 11.37.
Example 8-158
Synthesis of
3-[N'-(Cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino-2-
,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazep-
ine
[2774] Following General Procedure I above using
cyclopentyl-.alpha.-hydro- xyacetic acid (Example P) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cycl-
opropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
hydrochloride (Example 8-U), the title compound was prepared as a
white foam. Purification was by L.C. 2000 eluting with
CH.sub.2Cl.sub.2/EtOAc (1:1 gradient to 1:2) then flash
chromatography eluting with 2:1 EtOAc/CH.sub.2Cl.sub.2.
R.sub.f=0.47 and 0.37 (CH.sub.2Cl.sub.2/EtOAc, 1:2).
[2775] C.sub.27H.sub.36N.sub.4O.sub.5 (MW 496.61); mass
spectroscopy (MH+) 497.2 and (MH-) 495.2
[2776] Anal. Calcd. for C.sub.27H.sub.36N.sub.4O.sub.5: C, 65.30;
H, 7.31; N, 11.28. Found: C, 65.01; H, 7.35; N, 11.28.
Example 8-159
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo--
1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2777] Following General Procedure I above using
3,5-difluorophenylacetic acid (Lancaster) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethyl-
propyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride
(Example 8-V), the title compound was prepared as a white solid
(melting point=194-195.degree. C.). Purification was by flash
chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (2:1 gradient to
3:2). R.sub.f=0.46 (CH.sub.2Cl.sub.2/EtOAc, 2: 1).
[2778] C.sub.30H.sub.38F.sub.2N.sub.4O.sub.4 (MW 556.66); mass
spectroscopy (MH+) 557.0 (MH-) 555.4.
[2779] Anal. Calcd. for C.sub.30H.sub.38F.sub.2N.sub.4O.sub.4: C,
64.73; H, 6.88; N, 10.06. Found: C, 64.45; H, 6.82; N, 10.08.
Example 8-160
Synthesis of
3-[N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl]--
amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-ben-
zodiazepine
[2780] Following General Procedure I above using
3,5-difluoromandelic acid (Lancaster) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropy-
l)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example
8-V), the title compound was prepared as a white solid (melting
point=116-126.degree. C.). Purification was by flash chromatography
eluting with CH.sub.2Cl.sub.2/EtOAc (1:1 gradient to 2:3).
R.sub.f=0.54 and 0.40 (CH.sub.2Cl.sub.2/EtOAc, 1:1).
[2781] C.sub.30H.sub.38F.sub.2N.sub.4O.sub.5 (MW 572.66); mass
spectroscopy (MH+) 573.4 (MH-) 571.6.
[2782] Anal. Calcd. for C.sub.30H.sub.38F.sub.2N.sub.4O.sub.5: C,
62.92; H, 6.69; N, 9.78. Found: C, 62.86; H, 6.54; N, 9.65.
Example 8-161
Synthesis of
3-[N'-(Cyclopentylacetyl)-L-alaninyl]amino2,4-dioxo-1,5-bis-(-
2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2783] Following General Procedure I above using cyclopentylacetic
acid (Aldrich) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-
-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example
8-V), the title compound was prepared as a white amorphous solid.
Purification was by flash chromatography eluting with
CH.sub.2Cl.sub.2/EtOAc (2:1 gradient to 3:2). R.sub.f=0.29
(CH.sub.2Cl.sub.2/EtOAc, 2:1).
[2784] C.sub.29H.sub.44N.sub.4O.sub.4 (MW 512.70); mass
spectroscopy (MH+) 513.6 (MH-) 511.6.
[2785] Anal. Calcd. for C.sub.29H.sub.44N.sub.4O.sub.4: C, 67.94;
H, 8.65; N, 10.93. Found: C, 68.18; H, 8.60; N, 10.68.
Example 8-162
Synthesis of
3-[N'-(Cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]amino-2,-
4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazep-
ine
[2786] Following General Procedure I above using
cyclopentyl-.alpha.-hydro- xyacetic acid (Example P) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2--
dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
hydrochloride (Example 8-V), the title compound was prepared as a
white solid (melting point=119-129.degree. C.). Purification was by
flash chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (1:1
gradient to 2:3). R.sub.f=0.42 and 0.28 (CH.sub.2Cl.sub.2/EtOAc,
1:1).
[2787] C.sub.29H.sub.44N.sub.4O.sub.5 (MW 528.70); mass
spectroscopy (MH+) 529.2 (MH-) 527.4.
[2788] Anal. Calcd. for C.sub.29H.sub.44N.sub.4O.sub.5: C, 65.88;
H, 8.39; N, 10.60. Found: C, 65.56; H, 8.03; N, 10.35.
Example 8-163
Synthesis of
3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo--
1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2789] Following General Procedure I above using
3;5-difluorophenylacetic acid (Lancaster) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,-
5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the
title compound was prepared as a white solid (melting
point=139-141.degree. C.). Purification was by flash chromatography
eluting with CH.sub.2Cl.sub.2/EtOAc (1:1). R.sub.f=0.46
(CH.sub.2Cl.sub.2/EtOAc, 1:1).
[2790] C.sub.32H.sub.26F.sub.2N.sub.4O.sub.4 (MW 568.59); mass
spectroscopy (MH+) 569.2 (MH-) 567.4.
[2791] Anal. Calcd. for C.sub.32H.sub.26F.sub.2N.sub.4O.sub.4: C,
67.60; H, 4.61; N, 9.85. Found: C, 67.39; H, 4.66; N, 9.60.
Example 8-164
Synthesis of
3-[N'-(Cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis--
phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2792] Following General Procedure I above using cyclopentylacetic
acid (Aldrich) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetra-
hydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title
compound was prepared as an amorphous white solid. Purification was
by flash chromatography eluting with CH.sub.2Cl.sub.2/EtOAc (1:1).
R.sub.f=0.44 (CH.sub.2Cl.sub.2/EtOAc, 1:1).
[2793] C.sub.31H.sub.32N.sub.4O.sub.4 (MW 524.63); mass
spectroscopy (MH+) 525.2 (MH-) 523.2.
[2794] Anal. Calcd. for C.sub.31H.sub.32N.sub.4O.sub.4: C, 70.97;
H, 6.15; N, 10.68. Found: C, 70.67; H, 5.98; N, 10.43.
Example 8-165
Synthesis of
3-[N'-(Cyclopentyl-.alpha.-hydroxyacetyl)-L-alaninyl]-amino-2-
,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[2795] Following General Procedure I above using
cyclopentyl-.alpha.-hydro- xyacetic acid (Example P) and
3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-pheny-
l-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example
8-W), the title compound was prepared as a white solid (melting
point=139-149.degree. C.). Purification was by flash chromatography
eluting with CH.sub.2Cl.sub.2/EtOAc (1:2). R.sub.f=0.50 and 0.39
(CH.sub.2Cl.sub.2/EtOAc, 1:2).
[2796] C.sub.31H.sub.32N.sub.4O.sub.5 (MW 540.63); mass
spectroscopy (MH+) 541.2 (MH-) 539.6.
[2797] Anal. Calcd. for C.sub.31H.sub.32N.sub.4O.sub.5: C, 68.87;
H, 5.97; N, 10.36. Found: C, 68.87; H, 5.88; N, 10.15.
Example 8-166
Synthesis of
3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-
-1-methyl-5phenyl-1H-1,4-benzodiazepin-2-one
[2798] Following General Procedure A above using
N-(3,5-difluorophenylacet- yl)-L-alanine (Example B) and
3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4- -benzodiazepin-2-one
(prepared as described in Bock M. G.; DiPardo, R. M.; Evans, B. E.;
Rittle, K. E.; Veber, D. F.; Freidinger, R. M.; Hirshfield, J.;
Springer, J. P. J. Org. Chem. 1987, 52, 3232), the title compound
was prepared as a solid having a melting point of 152-160.degree.
C. The reaction was monitored by tlc on silica gel (Rf=0.15 in 50%
ethyl acetate/hexanes) and purification was by silica gel
chromatography.
[2799] NMR data was as follows:
[2800] .sup.1H-nmr (CDCl.sub.3): .delta.=7.70 (t, J=7.2, 7.2, 1H);
7.4 (m, 9H); 6.83 (d, J=5.5, 2H); 6.7 (m, 1H); 6.50 (d, J=7.1, 1H);
5.44 (dd, 2.8, 4.9, 2.8, 1H); 4.7 (m, 1H); 3.53 (s, 2H); 3.45 (s,
3H); 1.46 (dd, J=4.4, 2.2, 4.9, 3H).
[2801] .sup.13C-nmr (CDCl.sub.3): .delta.=172.9, 167.8, 138.3,
133.4, 127.7, 126.5, 126.3, 125.4, 123.9, 120.3, 117.2, 108.1,
107.8, 98.4, 63.0, 44.7, 40.1, 38.4, 30.9, 14.5, 14.1.
[2802] C.sub.27H.sub.24F.sub.2N.sub.4O.sub.3 (MW=490); mass
spectroscopy (MH.sup.+) 491.
[2803] The title compound was resolved using a Daicel chiral column
(2.times.25 cm, ID.times.L) (normal phase polysaccharide type; 10
micro particle size). Using a gradient of 40% isopropanol/hexanes
(4 mL/min flow rate for 35 minutes), followed by 20%
isopropanol/hexanes (3 mL/min), isomer 1 and isomer 2 had retention
times of 27.5 and 36.4 minutes, respectively.
Example 8-167
Synthesis of
3-(N'-(3,5-Difluorophenyl-.alpha.-hydroxyacetyl)-L-alaninyl)a-
mino-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6(7H)-one
[2804] 5H-Pyrrolo[1,2-a][1,5]benzodiazepin-6(7H)-one (CAS No.
63743-03-3) was methylated using General Procedure 8-I, aminated by
azide transfer using General Procedure 8-D and azide reduction
using General Procedure 8-F, and coupled to L-Boc-alanine (Sigma)
using General Procedure D. The Boc group was then removed using
General Procedure 8-N and the diastereomers were separated by LC
chromatography. Each isomer was separately coupled with
(S)-(+)-3,5-difluoromandelic acid (Example L) using General
Procedure D to give the title compound.
[2805] Isomer 1:
[2806] Melting point=239-240.degree. C.
[2807] MW=469.1687; exact mass spectroscopy (M+) 469.1693.
[2808] Optical rotation: [.alpha.]=-121.18.degree. @589 and
-540.33.degree. @365 (c=1, MeOH).
[2809] Isomer 2:
[2810] Melting point=144-145.degree. C.
[2811] MW=469.1687; exact mass spectroscopy (M.sup.+) 469.1687.
[2812] Optical rotation: [.alpha.]=+64.66.degree. @589 and
+255.03.degree. @365 (c=1, MeOH).
[2813] Using the following combinatorial procedures, the following
additional intermediates and examples were prepared.
General Procedure C-A
[2814] To a 4 mL vial containing 60-100 mg (0.06-0.1 mmol) of
polymer bound 1-(1-pyrrolidinyl propyl)-3-ethyl carbodiimide was
added 2 mL of a 0.015 mM stock solution of starting material 1 in
DMF/chloroform and 1 mL of a 0.0148 mM stock solution of starting
material 2 in chloroform. The resulting slurry were shaken for 48 h
and filtered. The filtered resin was washed with chloroform and the
filtrate was concentrated to dryness under vacuum. All product
structures and purities were confirmed by HPLC using UV detection
and IEX MS. Samples were submitted for testing with out any further
purification.
General Procedure C-B
[2815] To a 4 mL vial was added 840 uL of 0.05 mM stock solution of
starting material 1 in DMF/chloroform, 100 uL of a 0.21 mM stock
solution of starting material 2 in chloroform and 100 uL of a 0.63
mM stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
in chloroform. After allowing to stand undisturbed for 48 h, the
reaction mixture was concentrated and the residue redissolved in 2
mL of a 10% methanol/methylene chloride solution. This solution was
then filtered through a pre-washed (methanol) 500 mg SCX column
(Varian Sample Preparation; Harbor City Calif.) using an additional
8 mL of the same solvent. The filtrate was concentrated under
reduced pressure and the residue was dissolved in 20%
methanol/methylene chloride and passed through a plug of silica gel
(100 mg, Varian Sample Preparation). The collected filtrate was
concentrated under reduced pressure and the crude products were
submitted for testing without further purification. Product
structure and purity were confirmed by HPLC and IEX MS.
General Procedure C-C
[2816] To a 4 mL vial was added 540 uL of 0.05 mM stock solution of
starting material 1 in DMF/chloroform, 100 uL of a 0.44 mM stock
solution of starting material 2 in chloroform and 100 uL of a 0.38
mM stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
in chloroform. After standing undisturbed for 48 h, the reaction
mixture was concentrated and the residue redissolved in 2 mL of a
10% methanol/methylene chloride solution. This solution was then
filtered through a pre-washed (methanol) 500 mg SCX column using an
additional 8 mL of the same solvent. The filtrate was concentrated
under reduced pressure and the residue was dissolved in 20%
methanol/methylene chloride and passed through a plug of silica gel
(100 mg, Varian Sample Preparation). The collected filtrate was
concentrated under reduced pressure and the crude products were
submitted for testing without further purification. Product
structure and purity were confirmed by HPLC and IEX MS.
General Procedure C-D
[2817] To a 4 mL vial was added 540 uL of 0.05 mM stock solution of
starting material 1 in DMF / chloroform, 100 uL of a 0.44 mM stock
solution of starting material 2 in chloroform, 100 uL of a 0.38 mM
stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in
chloroform and 100 uL of a 0.38 mM stock solution of PP-HOBt in
DMF. After standing undisturbed for 48 h, the reaction mixture was
concentrated and the residue redissolved in 2 mL of a 10%
methanol/methylene chloride solution. This solution was then
filtered through a pre-washed (methanol) 500 mg SCX column using an
additional 8 mL of the same solvent. The filtrate was concentrated
under reduced pressure and the residue was dissolved in 20%
methanol/methylene chloride and passed through a plug of silica gel
(100 mg, Varian Sample Preparation). The collected filtrate was
concentrated under reduced pressure and the crude products were
submitted for testing without further purification. Product
structure and purity were confirmed by HPLC and IEX MS.
General Procedure C-E
[2818] To a 4 mL vial was added 870 uL of 0.05 mM stock solution of
starting material 1 in DMF/chloroform, 1000 uL of a 0.05 mM stock
solution of starting material 2 in chloroform, 1000 uL of a 0.05 mM
stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in
chloroform and 100 uL of a 0.48 mM stock solution of HOBt in DMF.
After standing undisturbed for 48 h, the reaction mixture was
concentrated and the residue redissolved in 2 mL of a 10%
methanol/methylene chloride solution. This solution was then
filtered through a pre-washed (methanol) 500 mg SCX column using an
additional 8 mL of the same solvent. The filtrate was concentrated
under a stream of nitrogen to approximately 1/3 its original volume
and then passed over a plug (200 mg) of AG 1-8.times.anion exchange
resin (BioRad; Hercules, Calif.; Columns were pre-washed with 1N
NaOH, water and methanol) using an additional 6 mL of 10%
methanol/methylene chloride solution. The resulting filtrate was
concentrated under vacuum and the crude products were submitted for
testing without further purification. Product structure and purity
were confirmed by HPLC and IEX MS.
General Procedure C-F
[2819] Starting material 1 (9.1 uL, 0.109 mmol) was added neat to a
mixture of starting material 2 (22.5 mg, 0.054 mmol) and
piperidinylmethyl polystyrene (45 mg, 3.6 mmol/g (Fluka)) in 1 mL
of methylene. The mixture was shaken for 80 h at ambient
temperatures and then treated with methylisocyanate polystyrene
(100 mg, 1.0 mmol/g (Novabiochem)) for 24 h with shaking. The
reaction mixture was filtered and the resin washed with methylene
chloride. The crude product was loaded onto a 500 mg SCX ion
exchange column (Varian Sample Preparation), washed 3.times. with 3
mL of methanol and then eluted with 4 mL of 2 M ammonia methanol.
Further purification of the final product was achieved using
semi-preparative HPLC (0-100% acetonitrile (0.08 % TFA)/water (0.1%
TFA); 25 mL/min.; 20.times.50 ODS-A column) to give 17 mg of the
final product as an off white foam.
[2820] NMR data was as follows:
[2821] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.45-1.65 (m, 3H),
1.70-2.00 (m, 4H), 2.55-2.80 (m, 4H), 3.25 (s, 2H), 3.50 (s, 3H),
4.654.80 (m, 1H), 5.45-5.55 (m, 1H), 7.20-7.80 (m, 11H).
General Procedure C-G
[2822] To a 4 mL vial containing 0.03 mmol of starting material 2
was added 100 uL of 0.25 mM stock solution of starting material 1
in chloroform, 100 uL of a 0.3 mM stock solution of
1-(3-dimethylaminopropyl- )-3-ethyl carbodiimide in chloroform and
100 uL of a 0.3 mM stock solution of HOBt in DMF. After standing
undisturbed for 48 h, the reaction mixture was concentrated and the
residue redissolved in 2 mL of a 10% methanol/methylene chloride
solution. This solution was then filtered through a pre-washed
(methanol) 500 mg SCX column using an additional 8 mL of the same
solvent. The filtrate was concentrated under a stream of nitrogen
to approximately 1/3 its original volume and then passed over a
plug (200 mg) of AG 1-8.times.anion exchange resin (BioRad;
Hercules, Calif.; Columns were pre-washed with 1N NaOH, water and
methanol) using an additional 6 mL of 10% methanol/methylene
chloride solution. The resulting filtrate was concentrated under
vacuum and the crude products were submitted for testing without
further purification. Product structure and purity were confirmed
by HPLC and IEX MS.
General Procedure C-H
[2823] The intermediates shown in Table C-1 (i.e., Starting
material 2) were synthesized in parallel in using the following
procedure:
[2824] Step A: To a solution of
3-(tert-butoxycarbonyl)amino-2,3-dihydro-5-
-phenyl-1H-1,4-benzodiazepin-2-one (CA No. 125:33692: 100 mg, 0.28
mmol) in 1 mL of anhydrous DMF was added 600 uL of a solution of
0.5 M potassium bis(trimethylsilyl)amide (0.30 mmol) in toluene.
Neat alkyl halide (0.56 mmol; as indicated in Table C-1) was added
immediately in one portion and the reaction mixture was left
undisturbed overnight. When an alkyl chloride was used, 1
equivalent of sodium iodide was added to the reaction mixture.
After concentration under reduced pressure, the crude reaction
residue was partitioned between methylene chloride (2 mL) and
aqueous saturated bicarbonate (2 mL) and then passed through a 5 g
Extralut QE cartridge (EM Science; Gibbstown, N.J.) using 10 mL of
methylene chloride. The resulting filtrate was concentrated under
reduced pressure and the crude product was further purified using
automated semi-preparative HPLC (YMC 20.times.50 mm Silica column;
gradient elution; 0-5% (5.5 min.), 5-20% (3.5 min.), 20-100% (2
min.), 100% (4 min.) ethyl acetate/methylene chloride, flow rate of
25 mL/min.). Product provided the expected M+1 peak by IEX MS and
were carried on without further purification and
characterization.
[2825] Step B: The product obtained from Step A was dissolved in 5
mL of a 15% TFA/methylene chloride solution and allowed to stand
undisturbed for 16 h. After concentration under reduced pressure,
the TFA salt was dissolved in methanol and loaded directly onto a 1
g SCX column. The column was washed 3.times. with 2 mL portions of
methanol and the product was eluted from the column using 6 mL of
2.0 M solution of ammonia/methanol. After concentration under
reduced pressure, the product were characterized by IEX MS and
carried on without further purification.
[2826] Step C: To the crude product obtained from Step B (1.05
equiv.) was added sequentially a 0.3 mM stock solution of
HOBt.H.sub.2O (1.05 equiv.) in DMF, a 0.3 mM stock solution of
N-t-BOC-L-alanine (1.0 equiv.) in THF and 0.3 mM stock solution of
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.05 equiv.) in
THF. After standing undisturbed for 24 h, the reaction mixture was
concentrated and the residue redissolved in 2 mL of a 10%
methanol/methylene chloride solution. This solution was then
filtered through a pre-washed (methanol) 1 g SCX (Varian Sample
Preparation) column using an additional 8 mL of the same solvent.
For Example C-V a 1 g Si column (Varian Sample Preparation) was
used). The filtrate was concentrated under a stream of nitrogen to
approximately 1/3 its original volume and then passed over a plug
(500 mg) of AG 1-8.times.anion exchange resin (BioRad; Hercules,
Calif.; Columns were pre-washed with 1N NaOH, water and methanol)
using an additional 10 mL of methanol. The resulting filtrate was
concentrated under reduced pressure and the crude product was
carried on without further purification after characterization by
IEX MS.
[2827] Step D: The crude product obtained from Step C was dissolved
in 5 mL of a 15% TFA/methylene chloride solution and allowed to
stand undisturbed for 16 h. After concentration under reduced
pressure, the TFA salt was dissolved in methanol and loaded
directly onto a 1 g SCX column. The column was washed 3.times. with
2 mL portions of methanol and the product were eluted from the
column using 6 mL of 2.0 M solution of ammonia/methanol. After
concentration under reduced pressure, the product were
characterized by IEX MS and carried on without further
purification. The intermediates prepared by this method are shown
in Table C-A.
35TABLE C-A Intermediates Ex. Alkyl Halide Intermediate MS C-A
3-Fluorobenzyl 3-(L-alaninyl)amino-5-p- henyl- 431.1 bromide
2,3-dihydro-1-(3-fluorobenzyl)- (Aldrich)
1H-1,4-benzodiazepin-2-one C-B Benzyl bromide
3-(L-alaninyl)amino-5-phenyl- 513.2 (Aldrich)
2,3-dihydro-1-(benzyl)-1H-1,4- benzodiazepin-2-one C-C
tert-Butylbenzyl 3-(L-alaninyl)amino-5-phenyl- 469.2 bromide
2,3-dihydro-1-(4-tert- (Aldrich) butylbenzyl)-1H-1,4-
benzodiazepin-2-one C-D 2-Bromoethylcyclo- 3-(L-alaninyl)amino-5-p-
henyl- 433.2 hexane 2,3-dihydro-1-(2- (Fairfield)
cyclohexylethyl)-1H-1,4- benzodiazepin-2-one C-E 1-Bromo-3,3-di-
3-(L-alaninyl)amino-5-phenyl- 407.2 methylbutane
2,3-dihydro-1-(3,3- (Wiley) dimethylbutyl)-1H-1,4-
benzodiazepin-2-one C-F Methyl alpha- 3-(L-alaninyl)amino-5-phenyl-
- 471.2 bromophenylacetate 2,3-dihydro-1-(1- (Aldrich)
methoxycarbonyl-1- phenylmethyl)-1H-1,4- benzodiazepin-2-one C-G
1-bromo-2-ethylbutane 3-(L-alaninyl)amino-5-phenyl- 407.2 (Aldrich)
2,3-dihydro-1-(2-ethylbutyl)-1H- 1,4-benzodiazepin-2-one C-H
Bromomethyl- 3-(L-alaninyl)amino-5-phenyl- 419.2 cyclohexane
2,3-dihydro-1- (Aldrich) (cyclohexylmethyl)-1H-1,4-
benzodiazepin-2-one C-I 2-(Bromoethyl)ben- 3-(L-alaninyl)amino-5-p-
henyl- 427.2 zene 2,3-dihydro-1-(2-phenylethyl)- (Aldrich)
1H-1,4-benzodiazepin-2-one C-J 3-(Bromopropyl)ben-
3-(L-alaninyl)amino-5-phenyl- 441.2 zene 2,3-dihydro-1-(3-phenylp-
ropyl)- (K and K 1H-1,4-benzodiazepin-2-one Laboratories) C-K
N-(2-Bromo- 3-(L-alaninyl)amino-5-phenyl- 496.2 ethyl)phthalimide
2,3-dihydro-1-(2-(N- (Aldrich) phthalimidyl)ethyl)-1H-1,4-
benzodiazepin-2-one C-L 2-Phenylbenzyl
3-(L-alaninyl)amino-5-phenyl- 489.2 bromide 2,3-dihydro-1-(2-
(Aldrich) biphenylmethyl)-1H-1,4- benzodiazepin-2-one C-M
Tetrahydrofurfuryl 3-(L-alaninyl)amino-5-p- henyl- 407.2 bromide
2,3-dihydro-1-((2- (Lancaster) tetrahydrofuranyl)methyl)-1H-
1,4-benzodiazepin-2-one C-N 2-Bromomethyl-1,4-
3-(L-alaninyl)amino-5-phenyl- 471.2 benzodioxane
2,3-dihydro-1-(2-(1,4- (Acros) benzodioxanyl)methyl)-1H-1,4-
benzodiazepin-2-one C-O 3-Bromomethyl-5-
3-(L-alaninyl)amino-5-phenyl- 503.1 phene
chlorobenzo[b]thienyl))methyl)- (Maybridge)
1H-1,4-benzodiazepin-2-one C-P 1-Bromopinacolone
3-(L-alaninyl)amino-5-phenyl- 421.1 (Lancaster)
2,3-dihydro-1-(3,3-dimethyl-2- oxo-propyl)-1H-1,4-
benzodiazepin-2-one C-Q 5-(Bromo- 3-(L-alaninyl)amino-5-phenyl-
455.2 methyl)benzofurazan 2,3-dihydro-1-(5- (Maybridge)
benzofurazanylmethyl)-1H-1,4- benzodiazepin-2-one C-R
3-Phenoxypropyl 3-(L-alaninyl)amino-5-phenyl- 457.2 bromide
2,3-dihydro-1-(3-phenoxypropyl)- (Aldrich)
1H-1,4-benzodiazepin-2-one C-S 6-(Bromomethyl)-2-
3-(L-alaninyl)amino-5-phenyl- 533.2 (trifluoro-
2,3-dihydro-1-(6-(2- methyl)quinoline trifluoromethylquinolinyl)m-
ethyl)- (Maybridge) 1H-1,4-benzodiazepin-2-one C-T 1-bromo-2-
3-(L-alaninyl)amino-5-phenyl- 393.2 methylbutane
2,3-dihydro-1-(2-methylbutyl)- (Aldrich) 1H-1,4-benzodiazepin-2-o-
ne C-U Ethyl bromide 3-(L-alaninyl)amino-5-phenyl- 351.2 (Aldrich)
2,3-dihydro-1-(ethyl)-1H-1,4- benzodiazepin-2-one C-V 3-Picolyl
chloride 3-(L-alaninyl)amino-5-phenyl- 414.1 hydrochloride
2,3-dihydro-1-(3-pyridylmethyl)- (Aldrich)
1H-1,4-benzodiazepin-2-one C-W 1-(2-Chloro-
3-(L-alaninyl)amino-5-phenyl- 482.2 acetyl)indoline
2,3-dihydro-1-(2-oxo-2-(N- (Maybridge) indolinyl)ethyl)-1H-1,4-
benzodiazepin-2-one C-Y 4-(Chloromethyl)-3,5-
3-(L-alaninyl)amino-5-phenyl- 432.2 dimethylisoxazole
2,3-dihydro-1-((4-(3,5- (Aldrich) dimethyl)isoxazolyl)methyl)-1H-
1,4-benzodiazepin-2-one. C-Z 2-Bromoethyl
3-(L-alaninyl)amino-5-phenyl- 381.2 methyl ether
2,3-dihydro-1-(2-methoxyethyl)- (Aldrich) 1H-1,4-benzodiazepin-2--
one
General Procedure C-I
[2828] To a 4 mL vial containing 0.03 mmol of starting material 2
(from General Procedure C-H) was added 100 uL of 0.25 mM stock
solution of starting material 1 in chloroform, 100 uL of a 0.3 mM
stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in
chloroform and 100 uL of a 0.3 mM stock solution of HOBt in DMF.
After standing undisturbed for 48 h, the reaction mixture was
concentrated and the residue redissolved in 2 mL of a 10%
methanol/methylene chloride solution. This solution was then
filtered through a pre-washed (methanol) 500 mg Si column using an
additional 8 mL of the same solvent. The filtrate was concentrated
under a stream of nitrogen to approximately 1/3 its original volume
and then passed over a plug (200 mg) of AG 1-8.times.anion exchange
resin (Columns were pre-washed with 1N NaOH, water and methanol)
using an additional 6 mL of 10% methanol/methylene chloride
solution. The resulting filtrate was concentrated under vacuum and
the crude products were submitted for testing without further
purification. Product structure and purity were confirmed by HPLC
and IEX MS.
Example C-AA
Synthesis of
(S)-3-(L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1-
H-1,4-benzodiazepin-2-one
Step A: Synthesis of
(S)-3-(N'-(tert-Butoxycarbonyl)-L-phenylglycinyl)amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[2829] To a solution of triethyl amine (519 uL, 3.8 mmol) and
(S)-3-amino-5-phenyl-2-oxo-1,4-benzodiazepine (1.0 g, 3.8 mmol)
(prepared according to the procedure of M. G. Bock et al., J. Org.
Chem. 1987, 52, 3232-3239) in 100 mL of anhydrous methylene
chloride at -20.degree. C. was added N-Boc-L-phenylglycine fluoride
(Carpino et al, J. Org. Chem. 1991, 56, 2611-2614) in one portion.
The reaction mixture was stirred for 15 min. and quenched with
saturated aqueous bicarbonate (10 mL). The layers were separated,
the organic layer washed sequentially with saturated aqueous
bicarbonate, water and brine and then dried over sodium sulfate.
Purification of the crude product using silica gel chromatography
(10-50% ethyl acetate/hexane) gave 1.3 g (69%) of a hydroscopic
white foam.
[2830] NMR data was as follows:
[2831] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.35 (br s, 9H),
3.41 (s, 3H), 5.30-5.45 (m, 2H), 5.75-5.95 (m, 1H), 7.15-7.75 (m,
15H).
[2832] IR (CDCl.sub.3): 1709.7, 1676.6, 1489, 1166.3 cm.sup.-1.
[2833] IEX MS (M+1): 498.0.
Step B: Synthesis of
(S)-3-(L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
[2834]
(S)-3-(N'-(tert-Butoxycarbonyl)-L-phenylglycinyl)amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (1.27 g, 2.55 mmol)
was added to 50 mL of a stirring solution of 15% TFA in methylene
chloride in one portion. After stirring 1 h, the reaction mixture
was concentrated under reduced pressure and the residue dissolved
in 100 mL of methylene chloride. This solution was washed twice
with saturated sodium bicarbonate, once with brine and then dried
over sodium sulfate. Purification of the crude product using silica
gel column chromatography (5-10% methanol/methylene chloride) gave
743 mg (73%) of a very light green foam.
[2835] NMR data was as follows:
[2836] .sup.1H NMR (CDCl.sub.3): .delta.=2.05 (br s, 1H), 3.45 (s,
3H), 5.51 (d, J=8.39 Hz, 1H), 7.15-7.70 (m, 14H), 8.60 (d, J=830
Hz, 1H).
[2837] IR (CDCl.sub.3): 1673.3, 1601.1, 1506.1 cm.sup.-1.
[2838] IEX MS (M+1): 399.2.
Example C-AB
Synthesis of
3-(L-Alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
Step A: Synthesis of
3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(2-oxo-2-pheny-
lethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one
[2839] To a solution of
3-(Benzoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1-
,4-benzodiazepin-2-one (Bock, M. G. et al, Tetrahedron Lett. 1987,
28, 939; 4.0 g, 10.4 mmol) in 40 mL of anhydrous DMF at 0.degree.
C. was added potassium tert-butoxide (1.51 g, 13.5 mmol) in one
portion. The reaction mixture was stirred 20 min. and
.alpha.-bromoacetophenone (Lancaster; Windham, N.H.; 2.9 g, 14.6
mmol) was added. The reaction mixture was warmed to room
temperature over 30 min. and then diluted with 100 mL of water and
200 mL of methylene chloride. The layers were separated. The
organic layer was extracted with water and dried over sodium
sulfate. Purification of the crude product by silica gel column
chromatography (0-5% ethyl acetate/methylene chloride) gave 4.2 g
(81%) of an off white foam.
[2840] NMR data was as follows:
[2841] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=5.16 (s, 2H),
5.34 (s, 2H), 5.50 (d, J=8.33 Hz, 1H), 6.70 (d, J=8.28 Hz, 1H),
7.20-7.70 (m, 12H), 7.91 (d, J=7.54 Hz, 2H).
[2842] IR (CHCl.sub.3): 1706.04, 1685.3, 1505.9, 1489.1, 1450.3,
1244.7 cm.sup.-1.
[2843] IEX MS (M+1): 504.3.
Step B: Synthesis of
3-Amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl--
1H-1,4-benzodiazepin-2-one
[2844] A solution of
3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(2-oxo-2-pheny-
lethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (3.7 g, 7.36 mmol) in
100 mL of anhydrous methylene chloride was cooled to 0.degree. C.
under nitrogen. A stream of anhydrous HBr gas was then bubbled
through this solution for 1 h. The bubbler was removed and the
reaction was warmed to room temperature under nitrogen. After
stirring 1 h the reaction was concentrated under vacuum and the
residue was redissolved in 20 mL of methylene chloride. The crude
HBr salt of the product was precipitated from solution using 300 mL
of anhydrous ether and collected by filtration as a light yellow
solid. After washing with ether , the solid was dissolved in
methylene chloride and saturated sodium bicarbonate. The layers
were separated and the organic layer was extracted with saturated
sodium bicarbonate. The combined aqueous layers were then back
extracted twice with methylene chloride. The combined organic
layers were extracted once with water and dried over sodium
sulfate. After concentration under vacuum, 2.27 g of the product
was obtained as an orange foam which was carried on without further
purification.
[2845] NMR data was as follows:
[2846] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=2.60 (br s, 2H),
4.72 (s, 1H), 5.34 (s, 2H), 7.10-7.70 (m, 12H), 7.91 (d, J=7.60 Hz,
2H).
[2847] IEX MS (M+1): 370.2
Step C: Synthesis of
3-(N'-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihy-
dro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one
[2848] To a solution of HOBt-H.sub.2O (697 mg, 5.16 mmol),
N,N-diisopropylethylamine (900 uL, 5.16 mmol) and N-t-BOC-L-alanine
(975 mg, 5.16 mmol) in 20 mL of anhydrous THF at 0.degree. C. was
added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride
(EDCl; 986 mg, 5.16 mmol) in one portion. After stirring 5 min., a
solution of
3-amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-
-2-one (2.0 g, 5.43 mmol) in 20 mL of anhydrous THF was added via
syringe and the reaction mixture was warmed to room temperature and
stirred overnight. The reaction mixture was diluted with 200 mL
methylene chloride, extracted sequentially with 10% citric acid,
saturated sodium bicarbonate, water and brine and then dried over
sodium sulfate. Purification of the crude product using silica gel
chromatography (10%-30% ethyl acetate/methylene chloride) gave 2.59
g (93%) of a white foam.
[2849] NMR data was as follows:
[2850] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.30-1.60 (m,
12H), 4.35 (br s,1H), 5.00-5.50 (m, 3H), 5.65-5.70 (m, 1H),
7.15-7.65 (m, 12H), 7.70-7.80 (m, 1H), 7.85-7.95 (m, 1H).
[2851] IR (CHCl.sub.3): 1705.8, 1678.8, 1488.7, 1450.2, 1230.4,
1164.4 cm.sup.-1.
[2852] IEX MS (M+1): 541.2.
Step D: Synthesis of
3-(L-Alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethy-
l)-5-phenyl-1H-1,4-benzodiazepin-2-one
[2853]
3-(N'-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(2-oxo-2-
-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (2.5 g, 4.63
mmol) was added to 100 mL of a stirring solution of 15%
TFA/methylene chloride in one portion. After stirring 2 h, the
reaction mixture was concentrated under reduced pressure and the
residue was dissolved in 150 mL of methylene chloride. This
solution was washed twice with saturated sodium bicarbonate, once
with brine and then dried over sodium sulfate. Purification of the
crude product using silica gel column chromatography (1-10%
methanol/methylene chloride) gave 1.91 g (94%) of the title
compound as a white foam.
[2854] NMR data was as follows:
[2855] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.30-1.50 (m,
3H), 1.80-2.20 (br s, 2 H), 3.55-3.75 (m, 1H), 5.20-5.45 (m, 2H),
5.67 (t, J=7.48 Hz, 1H), 7.20-7.65 (m, 12H), 7.90 (d, J=7.7 Hz,
2H), 8.80 (dd, J.sub.1=25.09 Hz, J.sub.2=8.33 Hz, 1H).
[2856] EX MS (M+1): 441.2.
Example C-AC
Synthesis of
3-(L-Alaninyl)amino-2,3-dihydro-1-(4,4,4trifluorobutyl)-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
Step A: Synthesis of
3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(4,4,4-trifluo-
robutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one
[2857] To a solution of
3-(benzoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1-
,4-benzodiazepin-2-one (3.7 g, 9.61 mmol) in 40 mL of anhydrous DMF
at 0.degree. C. was added potassium tert-butoxide (1.6 g, 14.4
mmol) in one portion. The reaction mixture was stirred 20 min. and
4,4,4-trifluoro-1-bromobutane (Lancaster; Windham, N.H.; 2.6 g,
13.4 mmol) was added. The reaction mixture was warmed to room
temperature over 30 min. and then diluted with 100 mL of water and
200 mL of methylene chloride. The layers were separated. The
organic layer was extracted with water and dried over sodium
sulfate. Purification of the crude product by silica gel column
chromatography (0-3% ethyl acetate/methylene chloride) gave 1.52 g
(32%) of an off white foam.
[2858] NMR data was as follows:
[2859] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.50-2.10 (m,
4H), 3.70-3.90 (m, 1 H), 4.354.55 (m, 1H), 5.15 (s, 2H), 5.33 (d,
J=8.47 Hz, 1H), 6.67 (d, J=8.40 Hz, 1H), 7.2-7.70 (m, 14H).
[2860] IR (CHCl.sub.3): 1720.4, 1683.0, 1604.8, 1505.5, 1451.1,
1323.9, 1254.5, 1148.4 cm.sup.-1.
[2861] IEX MS (M+1): 496.3.
Step B: Synthesis of
3-Amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-
-1H-1,4benzodiazepin-2-one
[2862] A solution of
3-(benzoxycarbonyl)amino-2,3-dihydro-1-(4,4,4-trifluo-
robutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (1.42 g, 2.87 mmol) in
50 mL of anhydrous methylene chloride was cooled to 0.degree. C.
under nitrogen. A stream of anhydrous HBr gas was slowly bubbled
through the solution for 1 h. The bubbler was removed and the
reaction was warmed to room temperature under nitrogen. After
stirring for 1 h, the reaction was concentrated under vacuum and
the residue was redissolved in 10 mL of methylene chloride. The
crude HBr salt of the product was precipitated from solution using
90 mL of anhydrous ether and collected by filtration. After washing
with ether, the HBr salt was dissolved in methylene chloride and
saturated sodium bicarbonate. The layers were separated and the
organic layer was extracted with saturated sodium bicarbonate. The
combined aqueous layers were then back extracted twice with
methylene chloride. The combined organic layers were extracted once
with water and dried over sodium sulfate. After concentration under
vacuum, 1.06 g (100%) of the product was obtained as a white foam
which was carried on without further purification.
[2863] NMR data was as follows:
[2864] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.60-2.10 (m,
4H), 2.76 (br s, 2H), 3.75-3.85 (m, 1H), 4.40-4.60 (m, 2H),
7.20-7.70 (m, 9H).
[2865] IEX MS (M+1): 362.1.
Step C: Synthesis of
3-(N'-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihy-
dro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one
[2866] To a solution of HOBt-H.sub.2O (373 mg, 2.76 mmol),
N,N-diisopropylethylamine (481 uL, 2.76 mmol) and N-t-BOC-L-alanine
(522 mg, 2.76 mmol) in 10 mL of anhydrous THF at 0.degree. C. was
added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride
(EDCl; 527 mg, 2.76 mmol) in one portion. After stirring 5 min., a
solution of
3-amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepi-
n-2-one (1.05 g, 2.91 mmol) in 10 mL of anhydrous THF was added via
syringe and the reaction mixture was warmed to room temperature and
stirred overnight. The reaction mixture was diluted with 100 mL
methylene chloride, extracted sequentially with 10% citric acid,
saturated sodium bicarbonate, water and brine and then dried over
sodium sulfate. Purification of the crude product using silica gel
chromatography (10%-30% ethyl acetate/methylene chloride) gave 1.28
g (83%) of a white foam.
[2867] NMR data was as follows:
[2868] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.40-2.10 (m,
16H), 3.70-3.85 (m, 1 H), 4.304.55 (m, 2H), 5.10 (br s, 1H),
5.45-5.55 (m, 1H), 7.25-7.80 (m, 10H).
[2869] IR (CDCl.sub.3): 1676.6, 1605.2, 1488.6, 1450.9, 1393.2,
1338.7, 1324.9, 1253.8, 1150.4 cm.sup.-1.
[2870] IEX MS (M+1): 533.1.
Step D: Synthesis of
3-(L-Alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobut-
yl)-5-phenyl-1H-1,4-benzodiazepin-2-one
[2871]
3-(N'-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(4,4,4-t-
rifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (1.21 g, 2.27
mmol) was added to 50 mL of a stirring solution of 15%
TFA/methylene chloride in one portion. After stirring 2 h, the
reaction mixture was concentrated under reduced pressure and the
residue was dissolved in 100 mL of methylene chloride. This
solution was washed twice with saturated sodium bicarbonate, once
with brine and then dried over sodium sulfate. Purification of the
crude product using silica gel column chromatography (1-5%
methanol/methylene chloride) gave 670 mg (68%) of a light pink
foam.
[2872] NMR data was as follows:
[2873] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.43 (t, J=7.0
Hz, 3H), 1.60-2.20 (m, 7H), 3.60-3.85 (m, 2H), 4.35-4.55 (m, 1H),
5.51 (dd, J.sub.1=8.36 Hz, J.sub.2=2.48 Hz, 1H), 7.20-7.70 (m, 9H),
8.80 (dd, J.sub.1=27.73 Hz, J.sub.2=8.34 Hz, 1H).
[2874] IEX MS (M+1): 433.2.
Example C-AD
Synthesis of
3-(N'-(Chloroacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
[2875] A solution of
3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H--
1,4-benzodiazepin-2-one (20.0 mg, 0.0595 mmol),
.alpha.-chloroacetyl chloride (5.9 uL, 0.0744 mmol) and
piperidinylmethyl polystyrene (59.5 mg, 3.6 mmol/g (Fluka)) in 1 mL
of methylene chloride were shaken for 20 min. Aminomethyl
polystyrene (58 mg, 3.0 mmol/g (Advanced Chemtech)) was then added
and the reaction mixture was shaken for an additional 15 min. and
filtered. Removal of the solvent under reduced pressure provided
23.9 mg (98%) of the crude product which was used without further
purification.
[2876] NMR data was as follows:
[2877] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.40-1.60 (m,
3H), 3.40-3.6 (m, 3H), 4.1 (s, 2H), 4.60-4.80 (m, 1H), 5.45-5.50
(m, 1H), 7.20-7.90 (m, 11H). Using the procedures indicated, the
compounds shown in Table C-1 were prepared.
36TABLE C-1 Example General No. Compound Starting Material 1
Starting Material 2 Procedure MS 8C-1 3-(N'-(3,4- 3,4-Methylene-
3-(L-alaninyl)amino-2,3- C-A 498.8 Methylenedioxyphenylacetyl)-L-
dioxyphenylacetic dihydro-1-methyl-5-pheny- l-1H-
alaninyl)amino-2,3-dihydro-1- acid 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B) benzodiazepin-2-one
8C-2 3-(N'-(2-Methoxyphenoxyacetyl)- 2-Methoxyphenoxyacetic
3-(L-alaninyl)amino-2,3- C-A 500.8 L-alaninyl)amino-2,3-dihydro-1-
acid dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
(Lancaster) 1,4-benzodiazepin-2-one benzodiazepin-2-one (Example
8-B) 8C-3 3-(N'-(4- 4-Isopropylphenoxyacetic
3-(L-alaninyl)amino-2,3- C-A 513.0 Isopropylphenoxyacetyl)-L- acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Lancaster) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Example 8-B) benzodiazepin-2-one 8C-4 3-(N'-(Ethoxyacetyl)-L-
Ethoxyacetic acid 3-(L-alaninyl)amino-2,3- C-A 422.6
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-5
3-(N'-(4-Phenoxyphenylacetyl)- 4-Phenoxyphenylacetic acid
3-(L-alaninyl)amino-2,3- C-A 547.0 L-alaninyl)amino-2,3-dihydro-1-
- (Trans World) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-6 3-(N'-(4-Ethoxyphenylacet- yl)-L-
4-Ethoxyphenylacetic acid 3-(L-alaninyl)amino-2,3- C-A 501.1
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-7
3-(N'-(2,5- 2,5-Dimethoxyphenylacetic 3-(L-alaninyl)amino-2,3- C-A
514.8 Dimethoxyphenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-8
3-(N'-(3,5-Difluorobenzoyl)-L- 3,5-Difluorobenzoic acid
3-(L-alaninyl)amino-2,3- C-A 476.8 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-9
3-(N'-(o-Tolylacetyl)-L- o-Tolylacetic acid
3-(L-alaninyl)amino-2,3- - C-A 470.0 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-10
3-(N'-(3,3-Diphenylpropionyl)- 3,3-Diphenylpropionic acid
3-(L-alaninyl)amino-2,3- C-A 545.0 L-alaninyl)amino-2,3-dihydro-1-
- (Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-11
3-(N'-(3-Phenoxypropionyl)-L- 3-Phenoxypropionic acid
3-(L-alaninyl)amino-2,3- C-A 485.0 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-12
3-(N'-(Indole-3-acetyl)-L- Indole-3-acetic acid
3-(L-alaninyl)amino-2,3- C-A 494.0 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-13
3-(N'-(4- 4- 3-(L-alaninyl)amino-2,3- C-A 523.0
(Trifluoromethyl)phenylacetyl)- (Trifluoromethyl)phenyl-
dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1-
acetic acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Maybridge) (Example 8-B) benzodiazepin-2-one 8C-14
3-(N'-((4-Methylphenoxy)acetyl)- (4-Methylphenoxy)acetic
3-(L-alaninyl)amino-2,3- C-A 485.0 L-alaninyl)amino-2,3-dihydro-1-
- acid dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
(Aldrich) 1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B)
8C-16 3-(N'-(4- 4- 3-(L-alaninyl)amino-2,3- C-A 500.8
(Hydroxymethyl)phenoxyacetyl)- (Hydroxymethyl)phenoxy-
dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1-
acetic acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Sigma)
(Example 8-B) benzodiazepin-2-one 8C-17
3-(N'-(2-Phenoxyphenylacetyl)- 2-Phenoxyphenylacetic acid
3-(L-alaninyl)amino-2,3- C-A 546.8 L-alaninyl)amino-2,3-dihydro-1-
- (Trans World) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-18 3-(N'-(3-Phenoxyphenylac- etyl)-
3-Phenoxyphenylacetic acid 3-(L-alaninyl)amino-2,3- C-A 547.0
L-alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-19
3-(N'-(3,4- 3,4-dichlorophenoxyacetic 3-(L-alaninyl)amino-2,3- C-A
539.2 dichlorophenoxyacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-20
3-(N'-(4-Fluorophenoxyacetyl)- 4-Fluorophenoxyacetic acid
3-(L-alaninyl)amino-2,3- C-A 489.0 L-alaninyl)amino-2,3-dihydro-1-
- (Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-21
3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid
3-(L-alaninyl)amino-2,3- C-A 424.8 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-22
3-(N'-(Methoxyacetyl)-L- Methoxyacetic acid
3-(L-alaninyl)amino-2,3- C-A 409.0 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-23
(S)-3-(N'-(Phenoxyacetyl)-L- Phenoxyacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 471.0 alaninyl)amino-2,3-dihydro-
-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-24
(S)-3-(N'-(Phenylacetyl)- -L- Phenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 455.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-25
(S)-3-(N'-(2-Phenoxybuty- ryl)-L- 2-Phenoxybutyric acid
(S)-3-(L-alaninyl)amino-2,3- C-B 498.8
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-26
(S)-3-(N'-(3- 3-Methoxyphenoxyacetic (S)-3-(L-alaninyl)amino-2,3-
C-B 501.0 Methoxyphenoxyacetyl)-L- acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example
8-B) benzodiazepin-2-one 8C-28 (S)-3-(N'-(4- 4-Butoxyphenylacetic
acid (S)-3-(L-alaninyl)amino-2,- 3- C-B 526.8
Butoxyphenylacetyl)-L- (Lancaster) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-29
(S)-3-(N'-(3-(2- 3-(2- (S)-3-(L-alaninyl)amino-2,3- C-B 498.8
Methoxyphenyl)propionyl)-L- - Methoxyphenyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example
8-B) benzodiazepin-2-one 8C-30 (S)-3-(N'-(4-Fluorophenylacetyl)-
4-Fluorophenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-B 472.8
L-alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-31
(S)-3-(N'-(Isopropoxylac- etyl)-L- Isopropoxylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 436.8
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-32
(S)-3-(N'-(1-Phenyl-1H-t- etrazole- 1-Phenyl-1H-tetrazole-5-
(S)-3-(L-alaninyl)amino-2,3- C-B 523.0
5-acetyl)-L-alaninyl)amino-2,3- acetic acid
dihydro-1-methyl-5-phenyl-1H- dihydro-1-methyl-5-phenyl-1H- (Raap,
R. Can. J. Chem. 1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one
1968, 46(13), 2255-61) (Example 8-B) 8C-33 (S)-3-(N'-(3-(3,4-
3-(3,4- (S)-3-(L-alaninyl)amino-2,3- C-B 513.2
methylenedioxyphenyl)propionyl)- methylenedioxyphenyl)
dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-
propionic acid 1,4-benzodiazepin-2-one 1-methyl-5-phenyl-1H-1,4-
(Apin) (Example 8-B) benzodiazepin-2-one 8C-34 (S)-3-(N'-(3-
3-Cyclopentylpropionic acid (S)-3-(L-alaninyl)amino-2,3- C-B 461.0
Cyclopentylpropionyl)-L- (Aldrich) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-35
(S)-3-(N'-(2-Cyclopentene-1- 2-Cyclopentene-1-acetic
(S)-3-(L-alaninyl)amino-2,3- C-B 445.0
acetyl)-L-alaninyl)amino-2,3- acid dihydro-1-methyl-5-phenyl-1H-
dihydro-1-methyl-5-phenyl-1H- (Aldrich) 1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example 8-B) 8C-36 (S)-3-(N'-(2-Chloro-6-
2-Chloro-6- (S)-3-(L-alaninyl)amino-2,3- C-B 507.0
fluorophenylacetyl)-L- fluorophenylacetic acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example
8-B) benzodiazepin-2-one 8C-37 (S)-3-(N'-(Cyclohexylacetyl)-L-
Cyclohexylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-B 461.0
alaninyl)amino-2,3-dihydro- -1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-38
(S)-3-(N'-(2,5- 2,5-Difluorophenylacetic
(S)-3-(L-alaninyl)amino-2,3- C-B 491.2 Difluorophenylacetyl)-L-
acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example
8-B) benzodiazepin-2-one 8C-39 (S)-3-(N'- Pentafluorophenoxyacetic
(S)-3-(L-alaninyl)amino-2,3- C-B 561.0
(Pentafluorophenoxyacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-40
(S)-3-(N'-(3,5- 3,5-Dimethylphenoxyacetic
(S)-3-(L-alaninyl)amino-2,3- C-B 498.8 Dimethylphenoxyacetyl)-L-
acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Sigma-Aldrich Rare 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
Chemicals) (Example 8-B) benzodiazepin-2-one 8C-41
(S)-3-(N'-(4-Chlorophenylacetyl)- 4-Chlorophenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 489.2
L-alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-42
(S)-3-(N'-(3- 3-Chlorophenoxyacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 505.0 Chlorophenoxyacetyl)-L-
(Lancaster) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-43
(S)-3-(N'-(Benzo[b]thiophene-3- Benzo[b]thiophene-3-
(S)-3-(L-alaninyl)amino-2,3- C-B 511.2 acetyl)-L-alaninyl)amino-2-
,3- acetic acid dihydro-1-methyl-5-phenyl-1H-
dihydro-1-methyl-5-phenyl-1H- (Lancaster) 1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example 8-B) 8C-44
(S)-3-(N'-(Benzoylformyl)-L- Benzoylformic acid
(S)-3-(L-alaninyl)amino-2- ,3- C-B 468.8
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-45
(S)-3-(N'-(3,5- 3,5-Dimethoxyphenylacetic (S)-3-(L-alaninyl)amino--
2,3- C-B 515.0 Dimethoxyphenylacetyl)-L- acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example
8-B) benzodiazepin-2-one 8C-46 (S)-3-(N'-(2,5-
2,5-Dimethylphenylacetic (S)-3-(L-alaninyl)amino-2,3- C-B 483.2
Dimethylphenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Lancaster) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-47
(S)-3-(N'-(2,6- 2,6-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2-
,3- C-B 491.2 Difluorophenylacetyl)-L- acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example
8-B) benzodiazepin-2-one 8C-48 (S)-3-(N'-(2,4-
2,4-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2,3- C-B 491.0
Difluorophenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-49
(S)-3-(N'-(Mesitylacetyl)-L- Mesitylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 497.0 alaninyl)amino-2,3-dihydro-
-1- (Lancaster) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-50 (S)-3-(N'-(4-Biphenylace- tyl)-L-
4-Biphenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-B 531.2
alaninyl)amino-2,3-dihydro-1- (Lancaster)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-51
(S)-3-(N'-(3,4- 3,4-Difluorophenylacetic
(S)-3-(L-alaninyl)amino-2,3- C-B 491.2 Difluorophenylacetyl)-L-
acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example
8-B) benzodiazepin-2-one 8C-52 (S)-3-(N'-(trans-Styrylacetyl)-L-
trans-Styrylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-B 481.2
alaninyl)amino-2,3-dihydro- -1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-53
(S)-3-(N'-(3-Benzoylprop- ionyl)- 3-Benzoylpropionic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 497.0
L-alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1- H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-54
(S)-3-(N'-(trans-3-Hexen- oyl)-L- trans-3-Hexenoic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 433.2
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-55
(S)-3-(N'-(Heptanoyl)-L- Heptanoic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 449.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-56
(S)-3-(N'-(3-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-B 483.2
Methylphenyl)propionyl)-L- Methylphenyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Lancaster)
(Example 8-B) benzodiazepin-2-one 8C-57 (S)-3-(N'-(3-(4- 3-(4-
(S)-3-(L-alaninyl)amino-2,3- C-B 503.0 Chlorophenyl)propionyl)-L-
Chlorophenyl)propionic dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- acid 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Trans World) (Example 8-B)
benzodiazepin-2-one 8C-58 (S)-3-(N'-(3-Phenylbutyryl)-L-
3-Phenylbutyric acid (S)-3-(L-alaninyl)amino-2,3- C-B 483.2
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-59
(S)-3-(N'-(4-(4- 4-(4-Methoxyphenyl)butyric
(S)-3-(L-alaninyl)amino-2,3- C-B 513.2 Methoxyphenyl)butyryl)-L-
acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Aldrich) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-60
(S)-3-(N'-(3- mono-Methyl succinate (S)-3-(L-alaninyl)amino-2,3-
C-B 451.0 Methoxycarbonylpropionyl)-L- (3-
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
Methoxycarbonylpropionic 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- acid) (Example 8-B) benzodiazepin-2-one
(Aldrich) 8C-61 (S)-3-(N'-(4-Phenylbutyryl)-L- 4-Phenylbutyric acid
(S)-3-(L-alaninyl)amino-2,3- C-B 483.2
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-62
(S)-3-(N'-(3- 3-(Benzylthio)propionic (S)-3-(L-alaninyl)amino-2,3-
C-B 515.2 (Benzylthio)propionyl)-L- acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Sigma-Aldrich Rare 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
Chemicals) (Example 8-B) benzodiazepin-2-one 8C-63
(S)-3-(N'-(3-Methylpentanoyl)-L- 3-Methylpentanoic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 435.2
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-64
(S)-3-(N'-(6- Suberic acid monomethyl (S)-3-(L-alaninyl)amino-2,3-
C-B 507.0 Methoxycarbonylheptanoyl)-L- ester(6-
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
Methoxycarbonylheptanoic 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- acid) (Example 8-B) benzodiazepin-2-one
8C-65 (S)-3-(N'-(2-Indanylacetyl- )-L- 2-Indanylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-B 495.0
alaninyl)amino-2,3-dihydro-1- (Lancaster)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-66
(S)-3-(N'-(4- 4-Methoxyphenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 485.2 Methoxyphenylacetyl)-L-
(Aldrich) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-67
(S)-3-(N'-(o- o-Chlorophenoxyacetic acid (S)-3-(L-alaninyl)amino-2-
,3- C-C 505.0 Chlorophenoxyacetyl)-L- (Lancaster)
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)
benzodiazepin-2-one 8C-68 (S)-3-(N'-(2-Thiopheneacetyl)-L-
2-Thiopheneacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 461.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-69
(S)-3-(N'-(3- 3- (S)-3-(L-alaninyl)amino-2,3- C-C 523.0
(Trifluoromethyl)phenylace- tyl)- (Trifluoromethyl)phenylacet-
dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1- ic
acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Marshallton)
(Example 8-B) benzodiazepin-2-one 8C-70
(S)-3-(N'-(p-Tolylacetyl)-L- p-Tolylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 469.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-71
(S)-3-(N'-(2,6- 2,6-Difluoromandelic acid
(S)-3-(L-alaninyl)amino-2,3- C-D 448.0 Difluoromandelyl)-L-
(Fluorochem) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-72
(S)-3-(N'-(-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-C 499.0
Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example
8-B) benzodiazepin-2-one 8C-73 (S)-3-(N'-(3,5-
3,5-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2,3- C-C 491.0
Difluorophenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-74
(S)-3-(N'-(m-Tolylacetyl)-L- m-Tolylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 469.0 alaninyl)amino-2,3-dihydro-
-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-75
(S)-3-(N'-(3-Fluoropheny- lacetyl)- 3-Fluorophenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 473.0
L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phen-
yl-1H- methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example 8-B) 8C-76 (S)-3-(N'-(4-
4-Chlorophenoxyacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 505.0
Chlorophenoxyacetyl)-L- (Grand Island Biological
dihydro-1-methyl-5-pheny- l-1H- alaninyl)amino-2,3-dihydro-1-
Company) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example
8-B) benzodiazepin-2-one 8C-77 (S)-3-(N'-(2-Naphthylacetyl)-L-
2-Naphthylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 505.2
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-78
(S)-3-(N'-(3-Chloropheny- lacetyl)- 3-Chlorophenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 489.2
L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phen-
yl-1H- methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example 8-B) 8C-79 (S)-3-(N'-(3-
3-Methylphenoxyacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 485.2
Methylphenoxyacetyl)-L- (Lancaster) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-80
(S)-3-(N'-(3,4- 3,4- (S)-3-(L-alaninyl)amino-2,3- C-C 499.0
Methylenedioxyphenylacetyl)-L- Methylenedioxyphenylacetic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example
8-B) benzodiazepin-2-one 8C-81 (S)-3-(N'-(2- 2-Methoxyphenoxyacetic
(S)-3-(L-alaninyl)amino-2,3- C-C 501.0 Methoxyphenoxyacetyl)-L-
acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Lancaster) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Example 8-B) benzodiazepin-2-one 8C-82 (S)-3-(N'-(4-
4-Isopropylphenoxyacetic (S)-3-(L-alaninyl)amino-2,3- - C-C 513.2
Isopropylphenoxyacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Lancaster) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-83
(S)-3-(N'-(4- 4-Phenoxyphenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 547.0 Phenoxyphenylacetyl)-L-
(Trans World) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-84
(S)-3-(N'- Phenylmercaptoacetic acid (S)-3-(L-alaninyl)amino-2,3-
C-C 487.2 (Phenylmercaptoacetyl)-L- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)
benzodiazepin-2-one 8C-85 (S)-3-(N'-(4- 4-Ethoxyphenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 499.0 Ethoxyphenylacetyl)-L-
(Aldrich) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-86
(S)-3-(N'-(2,5- 2,5-Dimethoxyphenylacetic (S)-3-(L-alaninyl)amino--
2,3- C-C 515.0 Dimethoxyphenylacetyl)-L- acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example
8-B) benzodiazepin-2-one 8C-87 (S)-3-(N'-(o-Tolylacetyl)-L-
o-Tolylacetic acid (S)-3-(L-alaninyl)amino-2- ,3- C-C 469.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-88
(S)-3-(N'-(3,3- 3,3-Diphenylpropionic acid (S)-3-(L-alaninyl)amino-
-2,3- C-C 545.3 Diphenylpropionyl)-L- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)
benzodiazepin-2-one 8C-89 (S)-3-(N'-(3-Phenoxypropionyl)-
3-Phenoxypropionic acid (S)-3-(L-alaninyl)amino-2,3- C-C 485.4
L-alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-90
(S)-3-(N'-(Indole-3-acet- yl)-L- Indole-3-acetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 494.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-91
(S)-3-(N'-(4- 4- (S)-3-(L-alaninyl)amino-2,3- C-C 523.0
(Trifluoromethyl)phenylace- tyl)- (Trifluoromethyl)phenylacet-
dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1- ic
acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Maybridge)
(Example 8-B) benzodiazepin-2-one 8C-92 (S)-3-(N'-(3,5- 3,5-
(S)-3-(L-alaninyl)amino-2,3- C-C 591.0 Bis(trifluoromethyl)phenyl-
acetyl)- Bis(trifluoromethyl)phenyl- dihydro-1-methyl-5-phenyl-1H-
L-alaninyl)amino-2,3-dihydro- acetic acid 1,4-benzodiazepin-2-one
1-methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B)
benzodiazepin-2-one 8C-93 (S)-3-(N'-(2- 2-Phenoxyphenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 547.0 Phenoxyphenylacetyl)-L-
(Trans World) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-94
(S)-3-(N'-(3- 3-Phenoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2-
,3- C-D 547.0 Phenoxyphenylacetyl)-L- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)
benzodiazepin-2-one 8C-95 (S)-3-(N'-(4- 4-Fluorophenoxyacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 489.2 Fluorophenoxyacetyl)-L-
(Aldrich) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-96
(S)-3-(N'-(2,4- 2,4-Dichlorophenylacetic (S)-3-(L-alaninyl)amino-2-
,3- C-C 523.0 Dichlorophenylacetyl)-L- acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Fairfield) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Example 8-B) benzodiazepin-2-one 8C-97
(S)-3-(N'-((Methylthio)acetyl)-L- (Methylthio)acetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 425.0 alaninyl)amino-2,3-dihydro-
-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-98
(S)-3-(N'-(4-Fluoromande- lyl)-L- 4-Fluoromandelic acid
(S)-3-(L-alaninyl)amino-2,3- C-D 489.0
alaninyl)amino-2,3-dihydro-1- (Lancaster)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-99
(S)-3-(N'-(4- 4-Thionaphthenacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 511.2 Thionaphthenacetyl)-L-
(Aldrich) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-100
(S)-3-(N'-(Methoxyacetyl)-L- Methoxyacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 409.0 alaninyl)amino-2,3-dihydro-
-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-101
(S)-3-(N'-(Ethoxyacetyl)- -L- Ethoxyacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 422.8
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-102
(S)-3-(N'-(3-Indolepropi- onyl)-L- 3-Indolepropionic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 508.2
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-103
(S)-3-(N'-(3-(2- 3-(2- (S)-3-(L-alaninyl)amino-2,3- C-C 503.0
Chlorophenyl)propionyl)-L- Chlorophenyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Trans World)
(Example 8-B) benzodiazepin-2-one 8C-104 (S)-3-(N'-(Butyryl)-L-
Butyric acid (S)-3-(L-alaninyl)amino-2,3- C-C 407.2
alaninyl)amino-2,3-dihydro- -1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-105
(S)-3-(N'-(Hexanoyl)-L- Hexanoic acid (S)-3-(L-alaninyl)amino-2,3-
C-C 435.0 alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-106
(S)-3-(N'-(5-Phenylpenta- noyl)-L- 5-Phenylvaleric acid
(S)-3-(L-alaninyl)amino-2,3- C-C 497.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-107
(S)-3-(N'-(4-(2-Thienyl)- butyryl)- 4-(2-Thienyl)butyric acid
(S)-3-(L-alaninyl)amino-2,3- C-C 489.2
L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phen-
yl-1H- methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example 8-B) 8C-108 (S)-3-(N'-(4-
4-Nitrophenoxyacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 516.2
Nitrophenoxyacetyl)-L- (Apin) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-109
(S)-3-(N'-(3-(3- 3-(3- (S)-3-(L-alaninyl)amino-2,3- C-C 499.0
Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Lancaster)
(Example 8-B) benzodiazepin-2-one 8C-110
(S)-3-(N'-(5-Methylhexanoyl)-L- 5-Methylhexanoic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 449.0 alaninyl)amino-2,3-dihydro-
-1- (Pfalz and Bauer) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-111 (S)-3-(N'-(Hydrocinnamyl- )-L- Hydrocinnamic
acid (S)-3-(L-alaninyl)amino-2,3- C-C 469.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-112
(S)-3-(N'-(Octanoyl)-L- Octanoic acid (S)-3-(L-alaninyl)amino-2,3-
C-C 463.2 alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-113
(S)-3-(N'-(3-(3- 3-(3- (S)-3-(L-alaninyl)amino-2,3- C-D 485.2
Hydroxyphenyl)propionyl)-L- - Hydroxyphenyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Lancaster)
(Example 8-B) benzodiazepin-2-one 8C-114 (S)-3-(N'-(3-(4- 3-(4-
(S)-3-(L-alaninyl)amino-2,3- C-D 485.2 Hydroxyphenyl)propionyl)-L-
- Hydroxyphenyl)propionic dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- acid 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B) benzodiazepin-2-one
8C-115 (S)-3-(N'-(3,4,5- 3,4,5-Trifluorophenylacetic
(S)-3-(L-alaninyl)amino-2,3- C-C 509.0 Trifluorophenylacetyl)-L-
acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Fluorochem) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Example 8-B) benzodiazepin-2-one 8C-116
(S)-3-(N'-(5-Hydantoinacetyl)-L- 5-Hydantoinacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 477.0 alaninyl)amino-2,3-dihydro-
-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-117
(S)-3-(N'-(Cyclopentylac- etyl)-L- Cyclopentylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 447.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-118
(S)-3-(N'-(3- 3-(Trifluoromethyl)butyric
(S)-3-(L-alaninyl)amino-2,3- C-C 475.0 (Trifluoromethyl)butyryl)-L-
acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Fluorochem) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Example 8-B) benzodiazepin-2-one 8C-119 (S)-3-(N'-(2-Methyl-3-
2-Methyl-3- (S)-3-(L-alaninyl)amino-2,3- C-C 509.2
Benzofuranacetyl)-L- Benzofuranacetic acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Maybridge) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Example 8-B) benzodiazepin-2-one 8C-120 (S)-3-(N'-(Propionyl)-L-
Propionic acid (S)-3-(L-alaninyl)amino-2,3- C-C 393.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-121
(S)-3-(N'-(Cyclopropylacetyl)-L- Cyclopropylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 419.0 alaninyl)amino-2,3-dihydro-
-1- (Lancaster) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-122 (S)-3-(N'-(3-Methoxyprop- ionyl)-
3-Methoxypropionic acid (S)-3-(L-alaninyl)amino-2,3- C-C 423.2
L-alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1- H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-123
(S)-3-(N'-(5-(Thienyl)pe- ntanoyl)- 5-(Thienyl)pentanoic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 503.0
L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phen-
yl-1H- methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example 8-B) 8C-124 (S)-3-(N'-(3-(4- 3-(4-
(S)-3-(L-alaninyl)amino-2,3- C-C 487.2 Fluorophenyl)propionyl)-L-
Fluorophenyl)propionic acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Trans World) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-125
(S)-3-(N'-(3-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-C 503.0
Fluorophenoxy)propionyl)-L- Fluorophenoxy)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Maybridge)
(Example 8-B) benzodiazepin-2-one 8C-126
(S)-3-(N'-(2-Norbornaneacetyl)- 2-Norbornaneacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 473.0 L-alaninyl)amino-2,3-dihyd-
ro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-128 (S)-3-(N'-(2,3- 2,3-Difluoromandelic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 507.0 Difluoromandelyl)-L-
(Fluorochem) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-129
(S)-3-(N'-(3-Pentenoyl)-L- 3-Pentenoic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 419.0 alaninyl)amino-2,3-dihydro-
-1- (Fluka) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-130
(S)-3-(N'-(4-(2,4- 4-(2,4- (S)-3-(L-alaninyl)amino-2,3- C-C 567.2
dichlorophenoxy)butyryl)-L- dichlorophenoxy)butyric
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example
8-B) benzodiazepin-2-one 8C-131 (S)-3-(N'-(2,3-
2,3-Dichlorophenoxyacetic (S)-3-(L-alaninyl)amino-2,3- C-C 539.2
Dichlorophenoxyacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-133
(S)-3-(N'-(2-Fluorophenylacetyl)- 2-Fluorophenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 473.0 L-alaninyl)amino-2,3-dihyd-
ro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-135 (S)-3-(N'-(2-Nitrophenyl- acetyl)-
2-Nitrophenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 499.8
L-alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl- -1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-136
(S)-3-(N'-(4- 4- (S)-3-(L-alaninyl)amino-2,3- C-C 501.0
(Hydroxymethyl)phenoxyacet- yl)- (Hydroxymethyl)phenoxy-
dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1-
acetic acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Sigma)
(Example 8-B) benzodiazepin-2-one 8C-137 (S)-3-(N'-(2-Fluoro-3-
2-Fluoro-3- (S)-3-(L-alaninyl)amino-2,3- C-C 541.0
(trifluoromethyl)phenylace- tyl)-L- (trifluoromethyl)phenyl-
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acetic
acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Fluorochem)
(Example 8-B) benzodiazepin-2-one 8C-138 (S)-3-(N'-(2,4,6-
2,4,6-Trifluorophenylacetic (S)-3-(L-alaninyl)amino-2,3- C-C 509.0
Trifluorophenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Fluorochem) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-139
(S)-3-(N'-(4-Fluoro-2- 4-Fluoro-2- (S)-3-(L-alaninyl)amino-2,3- C-C
541.0 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenyl-
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acetic
acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Fluorochem)
(Example 8-B) benzodiazepin-2-one 8C-140 (S)-3-(N'-(4,4,4-
4,4,4-Trifluorobutyric acid (S)-3-(L-alaninyl)amino-2,3- C-C 461.0
Trifluorobutyryl)-L- (Fluorochem) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-141
(S)-3-(N'-(2-Fluoro-4- 2-Fluoro-4- (S)-3-(L-alaninyl)amino-2,3- C-C
541.0 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenyl-
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acetic
acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Fluorochem)
(Example 8-B) benzodiazepin-2-one 8C-142
(S)-3-(N'-(4-Bromophenylacetyl)- 4-Bromophenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 533.0
L-alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-143
(S)-3-(N'-(3-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-C 515.0
Fluorobenzoyl)propionyl)-L- - Fluorobenzoyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example
8-B) benzodiazepin-2-one 8C-144 (S)-3-(N'-((2-
(2-Methylphenoxy)acetic (S)-3-(L-alaninyl)amino-2,3- C-C 485.2
Methylphenoxy)acetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Lancaster) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-145
(S)-3-(N'-(4- 4-Methoxyphenoxyacetic (S)-3-(L-alaninyl)amino-2,3-
C-C 501.0 Methoxyphenoxyacetyl)-L- acid
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Lancaster) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Example 8-B) benzodiazepin-2-one 8C-146 (S)-3-(N'-(3-
3-(Phenylsulfonyl)propionic (S)-3-(L-alaninyl)amino-- 2,3- C-C 531
(Phenylsulfonyl)propionyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
(M-1) alaninyl)amino-2,3-dihydro-1- - (Aldrich)
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)
benzodiazepin-2-one 8C-147 (S)-3-(N'-(2- 2-Methoxyphenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 485.2 Methoxyphenylacetyl)-L-
(Aldrich) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-148
(S)-3-(N'-(2-Bromophenylacetyl)- 2-Bromophenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 535.0 L-alaninyl)amino-2,3-dihyd-
ro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-149 (S)-3-(N'-(p-Isopropyl p-Isopropyl
phenylacetic (S)-3-(L-alaninyl)amino-2,3- C-C 497.0
phenylacetyl)-L-alaninyl)amino- acid dihydro-1-methyl-5-phenyl-1H-
2,3-dihydro-1-methyl-5-phenyl- (Lancaster) 1,4-benzodiazepin-2-one
1H-1,4-benzodiazepin-2-one (Example 8-B) 8C-150
(S)-3-(N'-(4-Pentenoyl)-L- 4-Pentenoic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 419.0
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-151
(S)-3-(N'-(4- 4-Hydroxyphenoxyacetic (S)-3-(L-alaninyl)amino-2,3-
C-D 487.2 Hydroxyphenoxyacetyl)-L- acid dihydro-1-methyl-5-phenyl-
-1H- alaninyl)amino-2,3-dihydro-1- (Acros) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-152
(S)-3-(N'-(4-Oxopentanoyl)-L- Levulinic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 433.1
alaninyl)amino-2,3-dihydro-1- (4-Oxopentanoic acid)
dihydro-1-methyl-5-phenyl-1H- (M-1) methyl-5-phenyl-1H-1,4-
(Aldrich) 1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B)
8C-153 (S)-3-(N'-(2- 2-Hydroxyphenylacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-D 471.0 Hydroxyphenylacetyl)-L-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydr-
o-1- 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)
benzodiazepin-2-one 8C-154 (S)-3-(N'-(3,4-
3,4-Dimethoxyphenylacetic (S)-3-(L-alaninyl)amino-2,3- C-C 515.0
Dimethoxyphenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-155
(S)-3-(N'-(3-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-C 527.0
Methoxybenzoyl)propionyl)-L- Methoxybenzoyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example
8-B) benzodiazepin-2-one 8C-156 (S)-3-(N'-(Thiophene-3-acetyl)-
Thiophene-3-acetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 461.0
L-alaninyl)amino-2,3-dihyd- ro-1- (Acros)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-157
(S)-3-(N'-(6-Phenylhexan- oyl)-L- 6-Phenylhexanoic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 511.2
alaninyl)amino-2,3-dihydro-1- (Avocado)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-158
(S)-3-(N'-(Isovaleryl)-L- - Isovaleric acid
(S)-3-(L-alaninyl)amino-2,3- C-C 420.8
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-159
(S)-3-(N'-(2,3,5- 2,3,5-Trifluorophenylacetic
(S)-3-(L-alaninyl)amino-2,3- C-C 508.8 Trifluorophenylacetyl)-L-
acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-
(Fluorochem) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Example 8-B) benzodiazepin-2-one 8C-160 (S)-3-(N'-(2,4,5-
2,4,5-Trifluorophenylacetic (S)-3-(L-alaninyl)amino-2,3- C-C 509.0
Trifluorophenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- (Fluorochem) 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-161
(S)-3-(N'-(1-Adamantaneacetyl)- 1-Adamantaneacetic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 513.2 L-alaninyl)amino-2,3-dihyd-
ro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example 8-B) 8C-162 (S)-3-(N'- Cyclohexanepentanoic acid
(S)-3-(L-alaninyl)amino-2,3- C-C 503.0 (Cyclohexanepentanoyl)-L-
(Aldrich) dihydro-1-methyl-5-phenyl-1H-
alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-one
methyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-163
(S)-3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 523.0 phenylglycinyl)amino-2,3-
- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phen-
yl-1H- 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example
C-AA) 8C-164 (S)-3-(N'-(3- 3- (S)-3-(L-phenylglycinyl)ami- no- C-C
585.0 (Trifluoromethyl)phenylacetyl)- (Trifluoromethyl)phenyl-
2,3-dihydro-1-methyl-5-phenyl- L-phenylglycinyl)amino-2,3- acetic
acid 1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H-
(Marshallton) (Example C-AA) 1,4-benzodiazepin-2-one 8C-165
(S)-3-(N'-(3,5- 3,5-Difluorophenylacetic
(S)-3-(L-phenylglycinyl)amino- C-C 553.0 Difluorophenylacetyl)-L-
acid 2,3-dihydro-1-methyl-5-phenyl- phenylglycinyl)amino-2,3-
(Aldrich) 1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H-
(Example C-AA) 1,4-benzodiazepin-2-one 8C-166
(S)-3-(N'-(m-Tolylacetyl)-L- m-Tolylacetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 531.2 phenylglycinyl)amino-2,3-
(Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-167
(S)-3-(N'-(3-Fluorophenylacetyl)- 3-Fluorophenylacetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 535.2 L-phenylglycinyl)amino-2-
,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-168
(S)-3-(N'-(3-Bromophenylacetyl)- 3-Bromophenylacetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 595.2 L-phenylglycinyl)amino-2-
,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-169
(S)-3-(N'-(3-Chlorophenylacetyl)- 3-Chlorophenylacetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 551.2 L-phenylglycinyl)amino-2-
,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-170 (S)-3-(N'-(3,4- 3,4-
(S)-3-(L-phenylglycinyl)amino- C-C 561.2
Methylenedioxyphenylacetyl)-L- Methylenedioxyphenylacetic
2,3-dihydro-1-methyl-5-phenyl- phenylglycinyl)amino-2,3- acid
1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H- (Aldrich)
(Example C-AA) 1,4-benzodiazepin-2-one 8C-171 (S)-3-(N'-
Phenylmercaptoacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 549.0
(Phenylmercaptoacetyl)-L- (Aldrich) 2,3-dihydro-1-methyl-5--
phenyl- phenylglycinyl)amino-2,3- 1H-1,4-benzodiazepin-2-one
dihydro-1-methyl-5-phenyl-1H- (Example C-AA)
1,4-benzodiazepin-2-one 8C-173 (S)-3-(N'-(3,5- 3,5-
(S)-3-(L-phenylglycinyl)amino- C-C 653.0 Bis(trifluoromethyl)phen-
ylacetyl)- Bis(trifluoromethyl)phenyl-
2,3-dihydro-1-methyl-5-phenyl- L-phenylglycinyl)amino-2,3- acetic
acid 1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H-
(Aldrich) (Example C-AA) 1,4-benzodiazepin-2-one 8C-174
(S)-3-(N'-((Methylthio)acetyl)-L- (Methylthio)acetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 487.2 phenylglycinyl)amino-2,3-
(Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-175
(S)-3-(N'-(Phenoxyacetyl)-L- Phenoxyacetic acid
(S)-3-(L-phenylglycinyl)a-
mino- C-C 533.0 phenylglycinyl)amino-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA)
8C-176 (S)-3-(N'-(Phenylacetyl)-L- Phenylacetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 517.2 phenylglycinyl)amino-2,3-
- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phen-
yl-1H- 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example
C-AA) 8C-177 (S)-3-(N'-(Cyclohexylacetyl)-L- Cyclohexylacetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 523.2 phenylglycinyl)amino-2,3-
(Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-178 (S)-3-(N'-(2,5-
2,5-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C-C 553.0
Difluorophenylacetyl)-L- acid 2,3-dihydro-1-methyl-5-phenyl-
phenylglycinyl)amino-2,3- (Aldrich) 1H-1,4-benzodiazepin-2-one
dihydro-1-methyl-5-phenyl-1H- (Example C-AA)
1,4-benzodiazepin-2-one 8C-179 (S)-3-(N'-(Benzo[b]thiophene-3-
Benzo[b]thiophene-3- (S)-3-(L-phenylglycinyl)amino- C-C 573.2
acetyl)-L-phenylglycinyl)amino- acetic acid
2,3-dihydro-1-methyl-5-phenyl- - 2,3-dihydro-1-methyl-5-phenyl-
(Aldrich) 1H-1,4-benzodiazepin-2-- one 1H-1,4-benzodiazepin-2-one
(Example C-AA) 8C-180 (S)-3-(N'-(benzoylformyl)-L- Benzoylformic
acid (S)-3-(L-phenylglycinyl)a- mino- C-C 531.2
phenylglycinyl)amino-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-181 (S)-3-(N'-(2,6-
2,6-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C-C 553.0
Difluorophenylacetyl)-L- acid 2,3-dihydro-1-methyl-5-phenyl-
phenylglycinyl)amino-2,3- (Aldrich) 1H-1,4-benzodiazepin-2-one
dihydro-1-methyl-5-phenyl-1H- - (Example C-AA)
1,4-benzodiazepin-2-one 8C-182 (S)-3-(N'-(2,4-
2,4-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C-C 553.0
Difluorophenylacetyl)-L- acid 2,3-dihydro-1-methyl-5-ph- enyl-
phenylglycinyl)amino-2,3- (Aldrich) 1H-1,4-benzodiazepin-2-o- ne
dihydro-1-methyl-5-phenyl-1H- (Example C-AA)
1,4-benzodiazepin-2-one 8C-183 (S)-3-(N'-(3,4-
3,4-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C-C 553.0
Difluorophenylacetyl)-L- acid 2,3-dihydro-1-methyl-5-phenyl-
phenylglycinyl)amino-2,3- (Aldrich) 1H-1,4-benzodiazepin-2-one
dihydro-1-methyl-5-phenyl-1H- (Example C-AA)
1,4-benzodiazepin-2-one 8C-184 (S)-3-(N'-(Butyryl)-L- Butyric acid
(S)-3-(L-phenylglycinyl)amino- C-C 469.0 phenylglycinyl)amino-2,3-
- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phen-
yl-1H- 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example
C-AA) 8C-185 (S)-3-(N'-(Heptanoyl)-L- Heptanoic acid
(S)-3-(L-phenylglycinyl)amino- C-C 511.2 phenylglycinyl)amino-2,3-
- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phen-
yl-1H- 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example
C-AA) 8C-186 (S)-3-(N'-(4-(2-Thienyl)butyryl)- 4-(2-Thienyl)butyric
acid (S)-3-(L-phenylglycinyl)amino- C-C 551.0
L-phenylglycinyl)amino-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA)
8C-187 (S)-3-(N'-(5-Methylhexanoyl)-L- 5-Methylhexanoic acid
(S)-3-(L-phenylglycinyl)amino- C-C 511.2 phenylglycinyl)amino-2,3-
- (Pfaltz and Bauer) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-188
(S)-3-(N'-(Hydrocinnamyl)-L- Hydrocinnamic acid
(S)-3-(L-phenylglycinyl)a- mino- C-C 531.2
phenylglycinyl)amino-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-189
(S)-3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
(S)-3-(L-phenylglycinyl)amino- C-C 509.2 phenylglycinyl)amino-2,3-
(Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-190
(S)-3-(N'-(Propionyl)-L- Propionic acid
(S)-3-(L-phenylglycinyl)amino- C-C 455.0 phenylglycinyl)amino-2,3-
(Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-AA) 8C-191 (S)-3-(N'-(3,4,5-
3,4,5-Trifluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C-C
571.0 Trifluorophenylacetyl)-L- - acid
2,3-dihydro-1-methyl-5-phenyl- phenylglycinyl)amino-2,3-
(Fluorochem) 1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-
-1H- (Example C-AA) 1,4-benzodiazepin-2-one 8C-192
(S)-3-(N'-(4-Phenylbutyryl)-L- 4-Phenylbutyric acid
(S)-3-(L-phenylglycinyl)amino- C-C 545.2 phenylglycinyl)amino-2,3-
- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phen-
yl-1H- 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example
C-AA) 8C-193 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid
3-(L-alaninyl)amino-2,3- C-E 557.2 alaninyl)amino-2,3-dihydro-5-
(Aldrich) dihydro-5-phenyl-1-(4,4,4-
phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC)
8C-194 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid
3-(L-alaninyl)amino-1-(2-oxo-2- C-E 565.2 alaninyl)amino-1-(2-oxo-
-2- (Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-
-5- phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2-
one one (Example C-AB) 8C-195 3-(N'-(2-Thiopheneacetyl)-- L-
2-Thiopheneacetic acid 3-(L-alaninyl)amino-1-methyl- C-E 468.1
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-196
3-(N'-(2-Thiopheneacety- l)-L- 2-Thiopheneacetic acid
3-(L-alaninyl)amino-7-chloro- C-E 495.1
alaninyl)amino-7-chloro-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C)
8C-197 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid
3-(L-alaninyl)amino-7-chloro-5- C-E 529.1 alaninyl)amino-7-chloro-
-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 531.1
chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-198
3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid
3-(L-alaninyl)amino-5-(2- C-E 467.1 alaninyl)amino-5-(2-thienyl)--
2,3- (Aldrich) thienyl)-2,3-dihydro-1-methyl-
dihydro-1-methyl-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AI) 8C-199 3-(N'-(2-Thiopheneacety-
l)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-5- C-E 467.2
alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)
cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-200 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid
3-(L-alaninyl)amino-7-bromo-5- C-E 557.1 alaninyl)amino-7-bromo-5-
-(2- (Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 559.1
fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-201
3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid
3-(L-alaninyl)-amino-)-2,4- C-E 527.3 alaninyl)-amino-)-2,4-dioxo-
-1,5- (Aldrich) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4-
,5- dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-
benzodiazepine benzodiazepine (Example 8-V) 8C-202
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-2,3- C-E 587.2 L-alaninyl)amino-2,3-dihydro-5-
acid dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-
(Aldrich) trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AC) 8C-203
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-1-(2-oxo-2- C-E 595.2 L-alaninyl)amino-1-(2-o-
xo-2- acid phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-
(Aldrich) phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiaze-
pin-2- one one (Example C-AB) 8C-204
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-1-methyl- C-E 498.1 L-alaninyl)amino-1-methyl-
-2,3- acid 2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-
-1H-1,4- (Aldrich) 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example C-AH) 8C-205 3-(N'-(3,5-Difluorophenylacetyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-7-chloro- C-E 525.2
L-alaninyl)amino-7-chloro-2,3- acid 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- (Aldrich) 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example 8-C) 8C-206
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-7-chloro-5- C-E 559.1 L-alaninyl)amino-7-chlo-
ro-5-(2- acid (2-chlorophenyl)-2,3-dihydro-1- 561.1
chlorophenyl)-2,3-dihydro-1- (Aldrich)
methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2- one
one (Example 8-F) 8C-207 3-(N'-(3,5-Difluorophenylacetyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-(2- C-E 497.1
L-alaninyl)amino-5-(2-thienyl- )- acid
thienyl)-2,3-dihydro-1-methyl- 2,3-dihydro-1-methyl-1H-1,4- -
(Aldrich) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example
C-AI) 8C-208 3-(N'-(3,5-Difluorophenylacetyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5- C-E 497.2
L-alaninyl)amino-5-cyclohexyl- acid cyclohexyl-2,3-dihydro-1-
2,3-dihydro-1-methyl-1H-1,4- (Aldrich)
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-209 3-(N'-(3,5-Difluorophenylacetyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-7-bromo-5- C-E 587.1
L-alaninyl)amino-7-bromo- -5-(2- acid
(2-fluorophenyl)-2,3-dihydro-1- 590.1 fluorophenyl)-2,3-dihydro-1-
(Aldrich) methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-210
3-(N'-(3,5- 3,5-Difluorophenylacetic 3-(L-alaninyl)-amino-)-2,4-
C-E 557.3 Difluorophenylacetyl)-L- acid dioxo-1,5-bis-(2,2-
alaninyl)-amino-)-2,4-dioxo-1,5- (Aldrich) dimethylpropyl)-2,3,4,5-
bis-(2,2-dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5-
tetrahydro-1H-1,5- benzodiazepine benzodiazepine (Example 8-V)
8C-211 3-(N'-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid
3-(L-alaninyl)amino-2,3- C-E 569.2 alaninyl)amino-2,3-dihydro-5-
(Aldrich) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobut-
yl)- trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AC) 8C-212
3-(N'-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid
3-(L-alaninyl)amino-1-(2-oxo-2- C-E 577.2 alaninyl)amino-1-(2-oxo-
-2- (Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-
-5- phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2-
one one (Example C-AB) 8C-213 3-(N'-(3-Fluorophenylacety- l)-L-
3-Fluorophenylacetic acid 3-(L-alaninyl)amino-1-methyl- C-E 480.1
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1- H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-214
3-(N'-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid
3-(L-alaninyl)amino-7-chloro- C-E 507.2 alaninyl)amino-7-chloro-2-
,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example 8-C) 8C-215
3-(N'-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid
3-(L-alaninyl)amino-7-chloro-5- C-E 541.1 alaninyl)amino-7-chloro-
-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 543.1
chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-216
3-(N'-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid
3-(L-alaninyl)amino-5-(2- C-E 479.1 alaninyl)amino-5-(2-thienyl)--
2,3- (Aldrich) thienyl)-2,3-dihydro-1-methyl-
dihydro-1-methyl-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AI) 8C-217 3-(N'-(3-Fluorophenylac-
etyl)-L- 3-Fluorophenylacetic acid 3-(L-alaninyl)amino-5- C-E 479.2
alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)
cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-218 3-(N'-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic
acid 3-(L-alaninyl)amino-7-bromo-5- C-E 571.1
alaninyl)amino-7-bromo-5- -(2- (Aldrich)
(2-fluorophenyl)-2,3-dihydro-1- 573.1 fluorophenyl)-2,3-dihydro-1-
methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2- one
one (Example 8-D) 8C-219 3-(N'-(3-Fluorophenylacetyl)-L-
3-Fluorophenylacetic acid 3-(L-alaninyl)-amino-)-2,4- C-E 539.3
alaninyl)-amino-)-2,4-dioxo- -1,5- (Aldrich) dioxo-1,5-bis-(2,2-
bis-(2,2-dimethylpropyl)-2,3,4- ,5- dimethylpropyl)-2,3,4,5-
tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine
(Example 8-V) 8C-220 3-(N'-(Methylthio)acetyl)-L-
(Methylthio)acetic acid 3-(L-alaninyl)amino-2,3- C-E 521.2
alaninyl)amino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-1-(4,4,4-
phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC)
8C-221 3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid
3-(L-alaninyl)amino-1-(2-oxo-2- C-E 529.2 alaninyl)amino-1-(2-oxo-
-2- (Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-
-5- phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2-
one one (Example C-AB) 8C-222 3-(N'-(Methylthio)acetyl)-- L-
(Methylthio)acetic acid 3-(L-alaninyl)amino-1-methyl- C-E 432.1
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-223
3-(N'-(Methylthio)acety- l)-L- (Methylthio)acetic acid
3-(L-alaninyl)amino-7-chloro- C-E 459.1
alaninyl)amino-7-chloro-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C)
8C-224 3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid
3-(L-alaninyl)amino-7-chloro-5- C-E 493.1 alaninyl)amino-7-chloro-
-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 495.1
chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-225
3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid
3-(L-alaninyl)amino-5-(2- C-E 431.1 alaninyl)amino-5-(2-thienyl)--
2,3- (Aldrich) thienyl)-2,3-dihydro-1-methyl-
dihydro-1-methyl-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AI) 8C-226 3-(N'-(Methylthio)acety-
l)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino-5- C-E 431.2
alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)
cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-227 3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid
3-(L-alaninyl)amino-7-bromo-5- C-E 521.1 alaninyl)amino-7-bromo-5-
-(2- (Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 523.1
fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-228
3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid
3-(L-alaninyl)-amino-)-2,4- C-E 491.3 alaninyl)-amino-)-2,4-dioxo-
-1,5- (Aldrich) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4-
,5- dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-
benzodiazepine benzodiazepine (Example 8-V) 8C-229
3-(N'-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino-2,3-
C-E 551.2 alaninyl)amino-2,3-dihydro-5-
(Aldrich) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobut-
yl)- trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AC) 8C-230 3-(N'-(Phenylacetyl)-L-
Phenylacetic acid 3-(L-alaninyl)amino-1-(2-oxo-2- C-E 559.5
alaninyl)amino-1-(2-oxo-2- (Aldrich) phenylethyl)-2,3-dihydro-5-
phenylethyl)-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-
phenyl-1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-231
3-(N'-(Phenylacetyl)-L- Phenylacetic acid
3-(L-alaninyl)amino-1-methyl- C-E 462.2
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-232
3-(N'-(Phenylacetyl)-L- Phenylacetic acid
3-(L-alaninyl)amino-7-chloro- C-E 489.2
alaninyl)amino-7-chloro-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C)
8C-233 3-(N'-(Phenylacetyl)-L- Phenylacetic acid
3-(L-alaninyl)amino-7-chloro-5- C-E 523.1
alaninyl)amino-7-chloro-5-(2- (Aldrich)
(2-chlorophenyl)-2,3-dihydro-1- 525.1 chlorophenyl)-2,3-dihydro--
1- methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-
one one (Example 8-F) 8C-234 3-(N'-(Phenylacetyl)-L- Phenylacetic
acid 3-(L-alaninyl)amino-5-(2- C-E 461.1
alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich)
thienyl)-2,3-dihydro-1-methyl- - dihydro-1-methyl-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI)
8C-235 3-(N'-(Phenylacetyl)-L- Phenylacetic acid
3-(L-alaninyl)amino-5- C-E 461.2 alaninyl)amino-5-cyclohexyl-2,3-
(Aldrich) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-236 3-(N'-(Phenylacetyl)-L- Phenylacetic acid
3-(L-alaninyl)amino-7-bromo-5- C-E 553.1
alaninyl)amino-7-bromo-5-(2- (Aldrich)
(2-fluorophenyl)-2,3-dihydro-1- 554.1 fluorophenyl)-2,3-dihydro--
1- methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-
one one (Example 8-D) 8C-237 3-(N'-(Phenylacetyl)-L- Phenylacetic
acid 3-(L-alaninyl)-amino-)2,4- C-E 521.3
alaninyl)-amino-)2,4-dioxo-1,5- (Aldrich) dioxo-1,5-bis-(2,2-
bis-(2,2-dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5-
tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine
(Example 8-V) 8C-238 3-(N'-(Benzoylformyl)-L- Benzoylformic acid
3-(L-alaninyl)amino-2,3- C-E 565.2 alaninyl)amino-2,3-dihydro-5-
(Aldrich) dihydro-5-phenyl-1-(4,4,4-
phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC)
8C-239 3-(N'-(Benzoylformyl)-L- Benzoylformic acid
3-(L-alaninyl)amino-1-(2-oxo-- 2- C-E 573.2
alaninyl)amino-1-(2-oxo-2- (Aldrich) phenylethyl)-2,3-dihydro-5-
phenylethyl)-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-
phenyl-1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-240
3-(N'-(Benzoylformyl)-L- Benzoylformic acid
3-(L-alaninyl)amino-1-methyl- C-E 476.1
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-241
3-(N'-(Benzoylformyl)-L- - Benzoylformic acid
3-(L-alaninyl)amino-7-chloro- C-E 503.1
alaninyl)amino-7-chloro-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C)
8C-242 3-(N'-(Benzoylformyl)-L- Benzoylformic acid
3-(L-alaninyl)amino-7-chloro-- 5- C-E 537.1
alaninyl)amino-7-chloro-5-(2- (Aldrich)
(2-chlorophenyl)-2,3-dihydro-1- 539.1 chlorophenyl)-2,3-dihydro--
1- methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-
one one (Example 8-F) 8C-243 3-(N'-(Benzoylformyl)-L- Benzoylformic
acid 3-(L-alaninyl)amino-5-(2- C-E 475.1
alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich)
thienyl)-2,3-dihydro-1-methyl- - dihydro-1-methyl-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI)
8C-244 3-(N'-(Benzoylformyl)-L- - Benzoylformic acid
3-(L-alaninyl)amino-5- C-E 475.2 alaninyl)amino-5-cyclohexyl-2,3-
(Aldrich) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-245 3-(N'-(Benzoylformyl)-L- Benzoylformic acid
3-(L-alaninyl)amino-7-bromo-5- - C-E 567.1
alaninyl)amino-7-bromo-5-(2- (Aldrich)
(2-fluorophenyl)-2,3-dihydro-1- 568.1 fluorophenyl)-2,3-dihydro--
1- methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-
one one (Example 8-D) 8C-246 3-(N'-(Benzoylformyl)-L- Benzoylformic
acid 3-(L-alaninyl)-amino-)-2,4- C-E 535.3
alaninyl)-amino-)-2,4-dioxo-1,5- (Aldrich) dioxo-1,5-bis-(2,2-
bis-(2,2-dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5-
tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine
(Example 8-V) 8C-247 3-(N'-(Butyryl)-L- Butyric acid
3-(L-alaninyl)amino-2,3- C-E 503.2 alaninyl)amino-2,3-dihydro-5-
(Aldrich) dihydro-5-phenyl-1-(4,4,4-
phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC)
8C-248 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-1-(2-ox-
o-2- C-E 511.2 alaninyl)amino-1-(2-oxo-2- (Aldrich)
phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-
phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2- one
one (Example C-AB) 8C-249 3-(N'-(Butyryl)-L- Butyric acid
3-(L-alaninyl)amino-1-methyl- C-E 414.1
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-250
3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-7-chloro- C-E
441.2 alaninyl)amino-7-chloro-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C)
8C-251 3-(N'-(Butyryl)-L- Butyric acid
3-(L-alaninyl)amino-7-chloro-5- C-E 475.1
alaninyl)amino-7-chloro-5-(2- (Aldrich)
(2-chlorophenyl)-2,3-dihydro-1- 477.1 chlorophenyl)-2,3-dihydro-1-
methyl-1H-1,4-benzodiazepin-2- - methyl-1H-1,4-benzodiazepin-2- one
one (Example 8-F) 8C-252 3-(N'-(Butyryl)-L- Butyric acid
3-(L-alaninyl)amino-5-(2- C-E 413.1
alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich)
thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI)
8C-253 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-5- C-E
413.2 alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)
cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-254 3-(N'-(Butyryl)-L- Butyric acid
3-(L-alaninyl)amino-7-bromo-5- C-E 503.1 alaninyl)amino-7-bromo-5-
-(2- (Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 506.1
fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-255
3-(N'-(Butyryl)-L-alaninyl)- Butyric acid 3-(L-alaninyl)-amino-)-2-
,4- C-E 473.3 amino-)-2,4-dioxo-1,5-bis-(2,2- (Aldrich)
dioxo-1,5-bis-(2,2- dimethylpropyl)-2,3,4,5-
dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-
benzodiazepine benzodiazepine (Example 8-V) 8C-256
3-(N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid
3-(L-alaninyl)amino-2,3- C-E 585.2 alaninyl)amino-2,3-dihydro-5-
(Aldrich) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobut-
yl)- trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AC) 8C-257
3-(N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid
3-(L-alaninyl)amino-1-(2-oxo-2- C-E 593.2 alaninyl)amino-1-(2-oxo-
-2- (Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-
-5- phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2-
one one (Example C-AB) 8C-258 3-(N'-(4-(2-Thienyl)butyry- l)-L-
4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-1-methyl- C-E 496.1
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1- H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-259
3-(N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid
3-(L-alaninyl)amino-7-chloro- C-E 523.2 alaninyl)amino-7-chloro-2-
,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example 8-C) 8C-260
3-(N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid
3-(L-alaninyl)amino-7-chloro-5- C-E 557.1 alaninyl)amino-7-chloro-
-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 559.1
chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-261
3-(N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid
3-(L-alaninyl)amino-5-(2- C-E 495.1 alaninyl)amino-5-(2-thienyl)--
2,3- (Aldrich) thienyl)-2,3-dihydro-1-methyl-
dihydro-1-methyl-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AI) 8C-262 3-(N'-(4-(2-Thienyl)but-
yryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-5- C-E 495.2
alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)
cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-263 3-(N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric
acid 3-(L-alaninyl)amino-7-bromo-5- C-E 585.1
alaninyl)amino-7-bromo-5- -(2- (Aldrich)
(2-fluorophenyl)-2,3-dihydro-1- 587.1 fluorophenyl)-2,3-dihydro-1-
methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2- one
one (Example 8-D) 8C-264 3-(N'-(4-(2-Thienyl)butyryl)-L-
4-(2-Thienyl)butyric acid 3-(L-alaninyl)-amino-)-2,4- C-E 555.3
alaninyl)-amino-)-2,4-dioxo- -1,5- (Aldrich) dioxo-1,5-bis-(2,2-
bis-(2,2-dimethylpropyl)-2,3,4- ,5- dimethylpropyl)-2,3,4,5-
tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine
(Example 8-V) 8C-265 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic
acid 3-(L-alaninyl)amino-2,3- C-E 543.3
alaninyl)amino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-1-(4,4,4-
phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC)
8C-266 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-1-(2-oxo-2- C-E 551.3 alaninyl)amino-1-(2-oxo-
-2- (Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-
-5- phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2-
one one (Example C-AB) 8C-267 3-(N'-(Cyclopentylacetyl)-- L-
Cyclopentylacetic acid 3-(L-alaninyl)amino-1-methyl- C-E 454.2
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-268
3-(N'-(Cyclopentylacety- l)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-7-chloro- C-E 481.2
alaninyl)amino-7-chloro-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C)
8C-269 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-7-chloro-5- C-E 515.2 alaninyl)amino-7-chloro-
-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 517.2
chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-270
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-(2- C-E 453.1 alaninyl)amino-5-(2-thienyl)--
2,3- (Aldrich) thienyl)-2,3-dihydro-1-methyl-
dihydro-1-methyl-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AI) 8C-271 3-(N'-(Cyclopentylacety-
l)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5- C-E 453.3
alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)
cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-272 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-7-bromo-5- C-E 543.1 alaninyl)amino-7-bromo-5-
-(2- (Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 546.1
fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-273
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)-amino-)-2,4- C-E 513.3 alaninyl)-amino-)-2,4-dioxo-
-1,5- (Aldrich) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4-
,5- dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-
benzodiazepine benzodiazepine (Example 8-F) 8C-274 3-(N'-(3-
3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-2,3- C-E 571.2
(Trifluoromethyl)butyryl)-L- acid dihydro-5-phenyl-1-(4,4,4-
alaninyl)amino-2,3-dihydro-5- (Fluorochem) trifluorobutyl)-1H-1,4-
phenyl-1-(4,4,4-trifluorobut- yl)- benzodiazepin-2-one
1H-1,4-benzodiazepin-2-one (Example C-AC) 8C-275 3-(N'-(3-
3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-1-(2-oxo-2- C-E
579.2 (Trifluoromethyl)butyry- l)-L- acid
phenylethyl)-2,3-dihydro-5- alaninyl)amino-1-(2-oxo-2- (Fluorochem)
phenyl-1H-1,4-benzodiazepin-2- phenylethyl)-2,3-dihydro-5- one
phenyl-1H-1,4-benzodiazepin-2- (Example C-AB) one 8C-276 3-(N'-(3-
3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-1-methyl- C-E 482.1
(Trifluoromethyl)butyryl)-L- acid 2,3-dihydro-5-(2-thiazolyl)-1H-
alaninyl)amino-1-methyl-2,3- (Fluorochem) 1,4-benzodiazepin-2-one
dihydro-5-(2-thiazolyl)-1H-1,4- (Example C-AH) benzodiazepin-2-one
8C-277 3-(N'-(3- 3-(Trifluoromethyl)butyric
3-(L-alaninyl)amino-7-chloro- C-E 509.1 (Trifluoromethyl)butyryl)-
-L- acid 2,3-dihydro-1-methyl-5-phenyl- alaninyl)amino-7-chloro-2,-
3- (Fluorochem) 1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phen-
yl-1H- (Example 8-C) 1,4-benzodiazepin-2-one 8C-278 3-(N'-(3-
3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-7-chloro-5- C-E
543.1 (Trifluoromethyl)butyryl)-L- acid (2-chlorophenyl)-2,3-dihy-
dro-1- 545.1 alaninyl)amino-7-chloro-5-(2- (Fluorochem)
methyl-1H-1,4-benzodiazepin-2- chlorophenyl)-2,3-dihydro-1- one
methyl-1H-1,4-benzodiazepin-2- (Example 8-F) one 8C-279 3-(N'-(3-
3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-5-(2- C-E 481.1
(Trifluoromethyl)butyryl)-L- acid thienyl)-2,3-dihydro-1-me- thyl-
alaninyl)amino-5-(2-thienyl)-2,3- (Fluorochem)
1H-1,4-benzodiazepin-2-one dihydro-1-methyl-1H-1,4- (Example C-AI)
benzodiazepin-2-one 8C-280 3-(N'-(3- 3-(Trifluoromethyl)butyric
3-(L-alaninyl)amino-5- C-E 481.2 (Trifluoromethyl)butyryl)-L- acid
cyclohexyl-2,3-dihydro-1- alaninyl)amino-5-cyclohexyl-2,3-
(Fluorochem) methyl-1H-1,4-benzodiazepin- -2-
dihydro-1-methyl-1H-1,4- one benzodiazepin-2-one (Example 8-G)
8C-281 3-(N'-(3- 3-(Trifluoromethyl)butyric
3-(L-alaninyl)amino-7-bromo-5- C-E 573.1 (Trifluoromethyl)butyryl-
)-L- acid (2-fluorophenyl)-2,3-dihydro-1- 574.1
alaninyl)amino-7-bromo-5-(2- (Fluorochem)
methyl-1H-1,4-benzodiazepin-2- fluorophenyl)-2,3-dihydro-1- one
methyl-1H-1,4-benzodiaz- epin-2- (Example 8-D) one 8C-282 3-(N'-(3-
3-(Trifluoromethyl)butyric 3-(L-alaninyl)-amino-)2,4- C-E 541.3
(Trifluoromethyl)butyryl)-L- acid dioxo-1,5-bis-(2,2-
alaninyl)-amino-)2,4-dioxo-1,5- (Fluorochem)
dimethylpropyl)-2,3,4,5- bis-(2,2-dimethylpropyl)-2,3,4,5-
tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine
(Example 8-V) 8C-283 3-(N'-(4,4,4-Trifluorobutyryl)-L-
4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-2,3- C-E 557.2
alaninyl)amino-2,3-dihydr-
o-5- (Fluorochem) dihydro-5-phenyl-1-(4,4,4-
phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC)
8C-284 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric
acid 3-(L-alaninyl)amino-1-(2-oxo-2- C-E 565.2
alaninyl)amino-1-(2-oxo-2- (Fluorochem) phenylethyl)-2,3-dihydro-5-
phenylethyl)-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-
phenyl-1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-285
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-1-methyl- C-E 468.1 alaninyl)amino-1-methyl-2-
,3- (Fluorochem) 2,3-dihydro-5-(2-thiazolyl)-1H-
dihydro-5-(2-thiazolyl)-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AH) 8C-286 3-(N'-(4,4,4-Trifluorob-
utyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-7-chloro- C-E 495.1
alaninyl)amino-7-chloro-2,3- (Fluorochem)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C)
8C-287 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric
acid 3-(L-alaninyl)amino-7-chloro-5- C-E 529.1
alaninyl)amino-7-chloro-5-(2- (Fluorochem)
(2-chlorophenyl)-2,3-dihydro-1- - 531.1
chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin- -2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-288
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-(2- C-E 467.1 alaninyl)amino-5-(2-thie-
nyl)-2,3- (Fluorochem) thienyl)-2,3-dihydro-1-methyl-
dihydro-1-methyl-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AI) 8C-289 3-(N'-(4,4,4-Trifluorob-
utyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5- C-E
467.2 alaninyl)amino-5-cyclohexyl-2,3- (Fluorochem)
cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-290 3-(N'-(4,4,4-Trifluorobutyryl)-L-
4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-7-bromo-5- C-E
559.1 alaninyl)amino-7-bromo-5-(2- (Fluorochem)
(2-fluorophenyl)-2,3-dihydro- -1- 560.1
fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazep- in-2-
methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-291
3-(N'-(4,4,4-Trifluorobutyryl)- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)-amino-)-2,4- C-E 527.3
L-alaninyl)-amino-)-2,4-dioxo- (Fluorochem) dioxo-1,5-bis-(2,2-
1,5-bis-(2,2-dimethylpropyl)- dimethylpropyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine (Example 8-V) 8C-292 3-(N'-(Isovaleryl)-L-
Isovaleric acid 3-(L-alaninyl)amino-2,3- C-E 517.2
alaninyl)amino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-1-(4,4,4-
- phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC)
8C-293 3-(N'-(Isovaleryl)-L- Isovaleric acid
3-(L-alaninyl)amino-1-(2-oxo-2- C-E 525.3 alaninyl)amino-1-(2-oxo-
-2- (Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-
-5- phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2-
one one (Example C-AB) 8C-294 3-(N'-(Isovaleryl)-L- Isovaleric acid
3-(L-alaninyl)amino-1-methyl- C-E 428.2
alaninyl)amino-1-methyl-2,3- (Aldrich)
2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-295
3-(N'-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-7-chloro-
C-E 455.2 alaninyl)amino-7-chloro-2,3- (Aldrich)
2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C)
8C-296 3-(N'-(Isovaleryl)-L- Isovaleric acid
3-(L-alaninyl)amino-7-chloro-5- C-E 489.1
alaninyl)amino-7-chloro-5-(2- (Aldrich)
(2-chlorophenyl)-2,3-dihydro-1- 491.1 chlorophenyl)-2,3-dihydro--
1- methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-
one one (Example 8-F) 8C-297 3-(N'-(Isovaleryl)-L- Isovaleric acid
3-(L-alaninyl)amino-5-(2- C-E 427.1
alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich)
thienyl)-2,3-dihydro-1-methyl- - dihydro-1-methyl-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI)
8C-298 3-(N'-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-5-
C-E 427.2 alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)
cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-299 3-(N'-(Isovaleryl)-L- Isovaleric acid
3-(L-alaninyl)amino-7-bromo-5- C-E 519.1
alaninyl)amino-7-bromo-5-(2- (Aldrich)
(2-fluorophenyl)-2,3-dihydro-1- 520.1 fluorophenyl)-2,3-dihydro--
1- methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-
one one (Example 8-D) 8C-300 3-(N'-(Isovaleryl)-L-alaniny- l)-
Isovaleric acid 3-(L-alaninyl)-amino-)-2,4- C-E 487.3
amino-)-2,4-dioxo-1,5-bis-(2,2- (Aldrich) dioxo-1,5-bis-(2,2-
dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5-
tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine
(Example 8-V) 8C-301 3-(N'-(L-alpha- L-alpha-Hydroxyisocaproic
3-(L-alaninyl)amino-2,3- C-E 547.3 Hydroxyisocaproyl)-L- acid
dihydro-5-phenyl-1-(4,4,4- alaninyl)amino-2,3-dihydro-5- (Aldrich)
trifluorobutyl)-1H-1,4- phenyl-1-(4,4,4-trifluorobutyl)-
benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one (Example C-AC)
8C-302 3-(N'-(L-alpha- L-alpha-Hydroxyisocaproic
3-(L-alaninyl)amino-1-(2-oxo-2- C-E 555.3 Hydroxyisocaproyl)-L-
acid phenylethyl)-2,3-dihydro-5- alaninyl)amino-1-(2-oxo-2-
(Aldrich) phenyl-1H-1,4-benzodiazepin-2-
phenylethyl)-2,3-dihydro-5- one phenyl-1H-1,4-benzodiazepin-2-
(Example C-AB) one 8C-303 3-(N'-(L-alpha- L-alpha-Hydroxyisocaproic
3-(L-alaninyl)amino-1-methyl- C-E 458.2 Hydroxyisocaproyl)-L- acid
2,3-dihydro-5-(2-thiazolyl)-1H- alaninyl)amino-1-methyl-2,3-
(Aldrich) 1,4-benzodiazepin-2-one dihydro-5-(2-thiazolyl)-1H-1,4-
(Example C-AH) benzodiazepin-2-one 8C-304 3-(N'-(L-alpha-
L-alpha-Hydroxyisocapro- ic 3-(L-alaninyl)amino-7-chloro- C-E 485.2
Hydroxyisocaproyl)-L- acid 2,3-dihydro-1-methyl-5-phenyl-
alaninyl)amino-7-chloro-2,3- (Aldrich) 1H-1,4-benzodiazepin-2-one
dihydro-1-methyl-5-phenyl-1H- - (Example 8-C)
1,4-benzodiazepin-2-one 8C-305 3-(N'-(L-alpha-
L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-7-chloro-5- C-E 519.1
Hydroxyisocaproyl)-L- acid (2-chlorophenyl)-2,3-dihydro- -1- 521.1
alaninyl)amino-7-chloro-5-(2- (Aldrich)
methyl-1H-1,4-benzodiazepin-2- chlorophenyl)-2,3-dihydro-1- one
methyl-1H-1,4-benzodiazepin-2- (Example 8-F) one 8C-306
3-(N'-(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-5-(2-
- C-E 457.1 Hydroxyisocaproyl)-L- acid thienyl)-2,3-dihydro-1-meth-
yl- alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich)
1H-1,4-benzodiazepin-2-one dihydro-1-methyl-1H-1,4- (Example C-AI)
benzodiazepin-2-one 8C-307 3-(N'-(L-alpha-
L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-5- C-E 457.3
Hydroxyisocaproyl)-L- acid cyclohexyl-2,3-dihydro-1-
alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)
methyl-1H-1,4-benzodiazepin-2- dihydro-1-methyl-1H-1,4- one
benzodiazepin-2-one (Example 8-G) 8C-308 3-(N'-(L-alpha-
L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-7-bromo-5- C-E 549.1
Hydroxyisocaproyl)-L- acid (2-fluorophenyl)-2,3-dihydro-1- 550.2
alaninyl)amino-7-bromo-5-(2- (Aldrich)
methyl-1H-1,4-benzodiazepin-2- fluorophenyl)-2,3-dihydro-1- one
methyl-1H-1,4-benzodiazepin- -2- (Example 8-D) one 8C-309
3-(N'-(L-alpha- L-alpha-Hydroxyisocaproic
3-(L-alaninyl)-amino-)-2,4- C-E 517.3
Hydroxyisocaproyl)-L-alaninyl)- acid dioxo-1,5-bis-(2,2-
amino-)-2,4-dioxo-1,5-bis-(2,2- (Aldrich) dimethylpropyl)-2,3,4,5-
dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-
benzodiazepine benzodiazepine (Example 8-V) 8C-310
3-(N'-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid
3-(L-alaninyl)amino-2,3- C-E 567.2 alaninyl)amino-2,3-dihydro-5-
(Sigma) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-
trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AC) 8C-311 3-(N'-(L-(+)-Mandelyl)-L-
L-(+)-Mandelic acid 3-(L-alaninyl)amino-1-(2-ox- o-2- C-E 575.2
alaninyl)amino-1-(2-oxo-2- (Sigma) phenylethyl)-2,3-dihydro-5-
phenylethyl)-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-
phenyl-1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-312
3-(N'-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid
3-(L-alaninyl)amino-1-methyl- C-E 478.1
alaninyl)amino-1-methyl-2,3- (Sigma)
2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-313
3-(N'-(L-(+)-Mandelyl)-- L- L-(+)-Mandelic acid
3-(L-alaninyl)amino-7-chloro- C-E 505.2
alaninyl)amino-7-chloro-2,3- (Sigma) 2,3-dihydro-1-methyl-5-phenyl-
dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example 8-C) 8C-314
3-(N'-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid
3-(L-alaninyl)amino-7-chlor- o-5- C-E 539.1
alaninyl)amino-7-chloro-5-(2- (Sigma)
(2-chlorophenyl)-2,3-dihydro-1- 541.1 chlorophenyl)-2,3-dihydro--
1- methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-
one one (Example 8-F) 8C-315 3-(N'-(L-(+)-Mandelyl)-L-
L-(+)-Mandelic acid 3-(N'-(L-alaninyl)amino-5-(2- C-E 477.1
alaninyl)amino-5-(2-thienyl)-2,3- (Sigma)
thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI)
8C-316 3-(N'-(L-(+)-Mandelyl)-- L- L-(+)-Mandelic acid
3-(L-alaninyl)amino-5- C-E 477.2 alaninyl)amino-5-cyclohexyl-2,3-
(Sigma) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-
methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
8-G) 8C-317 3-(N'-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid
3-(L-alaninyl)amino-7-bromo- -5- C-E 567.1
alaninyl)amino-7-bromo-5-(2- (Sigma)
(2-fluorophenyl)-2,3-dihydro-1- 569.1 fluorophenyl)-2,3-dihydro--
1- methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-
one one (Example 8-D) 8C-318 3-(N'-(3,5-Difluorophenylace- tyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 585.1
L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(3-fluorobenzyl)-
dihydro-1-(3-fluorobenzyl)-1H- (Aldrich) 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-A) 8C-319
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 567.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(benzyl)-1H-1,4- dihydro-1-(benzyl)-1H-1,-
4- (Aldrich) benzodiazepin-2-one benzodiazepin-2-one (Example C-B)
8C-320 3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- 11 623.2
L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(4-tert-
dihydro-1-(4-tert-butylbenzyl)- (Aldrich) butylbenzyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-C) 8C-321
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 587.2 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(2- dihydro-1-(2-cyclohexylethyl)-
(Aldrich) cyclohexylethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-D) 8C-322
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 561.2 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(3,3- dihydro-1-(3,3-dimethylbutyl)-
(Aldrich) dimethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-E) 8C-323
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 625.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(1- dihydro-1-(1-methoxycarbonyl-1-
(Aldrich) methoxycarbonyl-1- phenylmethyl)-1H-1,4-
phenylmethyl)-1H-1,4- benzodiazepin-2-one benzodiazepin-2-one
(Example C-F) 8C-324 3-(N'-(3,5-Difluorophenylacetyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 561.2
L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(2-ethylbutyl)-
dihydro-1-(2-ethylbutyl)-1H-1,4- (Aldrich)
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-G) 8C-325
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 573.2 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1- dihydro-1-(cyclohexylmethyl)- (Aldrich)
(cyclohexylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-H) 8C-326
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 581.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(2-phenylethyl)- dihydro-1-(2-phenylethyl-
)-1H- (Aldrich) 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one
(Example C-I) 8C-327 3-(N'-(3,5-Difluorophenylacetyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 595.2
L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(3-phenylpropyl)-
dihydro-1-(3-phenylpropyl)-1H- (Aldrich) 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-J) 8C-328
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 650.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(2-(N- dihydro-1-(2-(N- (Aldrich)
phthalimidyl)ethyl)-1H-1,4- phthalimidyl)ethyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-K) 8C-329
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 643.2 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(2- dihydro-1-(2-biphenylmethyl)-
(Aldrich) biphenylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-L) 8C-330
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 561.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-((2- dihydro-1-((2- (Aldrich)
tetrahydrofuranyl)methyl)-1H- tetrahydrofuranyl)methyl)-1H-
1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-M)
8C-331 3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 625.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(2-(1,4- dihydro-1-(2-(1,4- (Aldrich)
benzodioxanyl)methyl)-1H-1,4- benzodioxanyl)methyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-N) 8C-332
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 657.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-((3-(5- dihydro-1-(3-(5-chlorobenzo[b]
(Aldrich) chlorobenzo[b]thienyl))methyl)- thienyl)methyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-O) 8C-333
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 575.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(3,3-dimethyl-2- dihydro-1-(3,3-dimethyl--
2-oxo- (Aldrich) oxo-propyl)-1H-1,4- propyl)-1H-1,4-benzodiazepin--
2- benzodiazepin-2-one one (Example C-P) 8C-334
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 609.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(5- dihydro-1-(5- (Aldrich)
benzofurazanylmethyl)-1H-1,4- benzofurazanylmethyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-Q) 8C-335
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 611.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(3- dihydro-1-(3-phenoxypropyl)-1H-
(Aldrich) phenoxypropyl)-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-R) 8C-336
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 686.1
L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(6-(2- dihydro-1-(6-(2- (Aldrich)
trifluoromethylquinolinyl)methyl)- trifluoromethylquinolinyl)meth-
yl)- 1H-1,4-benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one (Example
C-S) 8C-337 3-(N'-(3,5-Difluorophenylacetyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 547.2
L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(2-methylbutyl)-
dihydro-1-(2-methylbutyl)-1H- (Aldrich) 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-T) 8C-338
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 505.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(ethyl)-1H-1,4- dihydro-1-(ethyl)-1H-1,4-
(Aldrich) benzodiazepin-2-one benzodiazepin-2-one (Example C-U)
8C-339 3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-I 568.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(3- dihydro-1-(3-pyridylmethyl)-1H-
(Aldrich) pyridylmethyl)-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-V) 8C-340
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 676.2 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-(2-oxo-2-(N- dihydro-1-(2-oxo-2-(N-
(Aldrich) indolinyl)ethyl)-1H-1,4- indolinyl)ethyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-W) 8C-341
3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- C-G 586.1 L-alaninyl)amino-5-phenyl-
-2,3- acid 2,3-dihydro-1-((4-(3,5- dihydro-1-(4-(3,5- (Aldrich)
dimethyl)isoxazolyl)methyl)-1H- dimethylisoxazolyl)methyl)-1H-
1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-Y)
8C-342 3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic
3-(L-alaninyl)amino-5-phenyl- L-alaninyl)amino-5-phenyl-2,3- acid
2,3-dihydro-1-(2-methoxyethyl)- dihydro-1-(2-methoxyethyl)-1H-
(Aldrich) 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one
(Example C-Z) 8C-343 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic
acid 3-(L-alaninyl)amino-5-phenyl- C-G 523.2
alaninyl)amino-5-phenyl-2,3- (Aldrich)
2,3-dihydro-1-(benzyl)-1H-1,4- dihydro-1-(benzyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-B) 8C-344
3-(N'-(Cyclopentylacetyl- )-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 579.2
alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1-(4-tert-
dihydro-1-(4-tert-butylbenzyl)- butylbenzyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-C) 8C-345
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 543.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(2- dihydro-1-(2-cyclohexylethyl)-
cyclohexylethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-D) 8C-346
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 517.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(3,3- dihydro-1-(3,3-dimethylbutyl)-
dimethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-E) 8C-347
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 475.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(isopropyl)-1H-
dihydro-1-(isopropyl)-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example 8-L) 8C-348 3-(N'-(Cyclopentylacetyl-
)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 581.2
alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1-(1-
dihydro-1-(1-methoxycarbonyl-1- methoxycarbonyl-1-
phenylmethyl)-1H-1,4- phenylmethyl)-1H-1,4- benzodiazepin-2-one
benzodiazepin-2-one (Example C-F) 8C-349
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 517.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(2-ethylbutyl)-
dihydro-1-(2-ethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-G) 8C-350 3-(N'-(Cyclopentylacetyl-
)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 529.2
alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1-
dihydro-1-(cyclohexylmethyl)- (cyclohexylmethyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-H) 8C-351
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 537.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(2-phenylethyl)-
dihydro-1-(2-phenylethyl)-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-I) 8C-352
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 551.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(3-phenylpropyl)-
dihydro-1-(3-phenylpropyl)-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-J) 8C-353
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 606.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(2-(N- dihydro-1-(2-(N-
phthalimidyl)ethyl)-1H-1,4- phthalimidyl)ethyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-K) 8C-354
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 599.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(2- dihydro-1-(2-biphenylmethyl)-
biphenylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-L) 8C-355
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 613.1 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(3-(5- dihydro-1-(3-(5-chlorobenzo[b]
chlorobenzo[b]thienyl)methyl)- thienyl)methyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-O) 8C-356
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(3,3-dimethyl-2-
dihydro-1-(3,3-dimethyl-2-oxo- oxo-butyl)-1H-1,4-
butyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
C-P) 8C-357 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 565.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(5- dihydro-1-(5-
benzofurazanylmethyl)-1H-1,4- benzofurazanylmethyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-Q) 8C-358
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 567.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(3- dihydro-1-(3-phenoxypropyl)-1H-
phenoxypropyl)-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example C-R) 8C-359 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic
acid 3-(L-alaninyl)amino-5-phenyl- C-G 642.2
alaninyl)amino-5-phenyl-2- ,3- (Aldrich) 2,3-dihydro-1-(6-(2-
dihydro-1-(6-(2- trifluoromethylquinolinyl)methyl)-
trifluoromethylquinolinyl)meth- yl)- 1H-1,4-benzodiazepin-2-one
1H-1,4-benzodiazepin-2-one (Example C-S) 8C-360
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 487.2
alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1-
dihydro-1-(cyclopropylmethyl)- (cyclopropylmethyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-L) 8C-361
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 503.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(2-methylbutyl)-
dihydro-1-(2-methylbutyl)-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-T) 8C-362
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 461.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(ethyl)-1H-1,4-
dihydro-1-(ethyl)-1H-1,4- benzodiazepin-2-one benzodiazepin-2-one
(Example C-U) 8C-363 3-(N'-(Cyclopentylacetyl- )-L-
Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 542.2
alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1-(4-(3,5-
dihydro-1-(4-(3,5- dimethylisoxazolyl)methyl)-1H-
dimethylisoxazolyl)methyl)-1H- 1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-Y) 8C-364
3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid
3-(L-alaninyl)amino-5-phenyl- C-G 475.2 alaninyl)amino-5-phenyl-2-
,3- (Aldrich) 2,3-dihydro-1-(propyl)-1H-1,4-
dihydro-1-(propyl)-1H-1,4- benzodiazepin-2-one benzodiazepin-2-one
(Example 8-L) 8C-365 3-(N'-(Cyclopentylacetyl- )-L-
Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 491.2
alaninyl)amino-5-phenyl-2,3- (Aldrich)
2,3-dihydro-1-(methoxyethyl)- dihydro-1-(2-methoxyethyl)-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-Z)
8C-366 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric
acid 3-(L-alaninyl)amino-5-phenyl- C-G 537.1
alaninyl)amino-5-phenyl-2- ,3- (Fluorochem)
2,3-dihydro-1-(benzyl)-1H-1,4- dihydro-1-(benzyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-B) 8C-367
3-(N'-(4,4,4-Trifluorobu- tyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 593.2
alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-(4-tert-
dihydro-1-(4-tert-butylbenzyl)- butylbenzyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-C) 8C-368
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 557.2 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(2- dihydro-1-(2-cyclohexylethyl)-
cyclohexylethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-D) 8C-369
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(3,3- dihydro-1-(3,3-dimethylbutyl)-
- dimethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-E) 8C-370
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 489.1 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(isopropyl)-1H-
dihydro-1-(isopropyl)-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example 8-L) 8C-371 3-(N'-(4,4,4-Trifluorobu-
tyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl-
C-G 595.1 alaninyl)amino-5-phenyl-2,3- (Fluorochem)
2,3-dihydro-1-(1- dihydro-1-(1-methoxycarbonyl-1-
methoxycarbonyl-1- phenylmethyl)-1H-1,4- phenylmethyl)-1H-1,4-
benzodiazepin-2-one benzodiazepin-2-one (Example C-F) 8C-372
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(2-ethylbutyl)-
dihydro-1-(2-ethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-G) 8C-373 3-(N'-(4,4,4-Trifluorobu-
tyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl-
C-G 543.2 alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-
dihydro-1-(cyclohexylmethyl)- (cyclohexylmethyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-H) 8C-374
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 565.1 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(3-phenylpropyl)-
dihydro-1-(3-phenylpropyl)-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-J) 8C-375
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 613.2 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(2- dihydro-1-(2-biphenylmethyl)-
biphenylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-L) 8C-376
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 627.1 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(3-(5- dihydro-1-(3-(5-chlorobenzo[-
b] chlorobenzo[b]thienyl)methyl)- thienyl)methyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-O) 8C-377
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 545.2 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(3,3-dimethyl-2-
dihydro-1-(3,3-dimethyl-2-oxo- oxo-butyl)-1H-1,4-
butyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
C-P) 8C-378 3-(N'-(4,4,4-Trifluorobutyryl)-L-
4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 579.1
alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-(5-
dihydro-1-(5- benzofurazanylmethyl)-1H-1,4-
benzofurazanylmethyl)-1H-1,4- benzodiazepin-2-one
benzodiazepin-2-one (Example C-Q) 8C-379 3-(N'-(4,4,4-Trifluorobu-
tyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl-
C-G 581.1 alaninyl)amino-5-phenyl-2,3- (Fluorochem)
2,3-dihydro-1-(3- dihydro-1-(3-phenoxypropyl)-1H-
phenoxypropyl)-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example C-R) 8C-380 3-(N'-(4,4,4-Trifluorobutyryl)-L-
4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 656.1
alaninyl)amino-5-phenyl-2- ,3- (Fluorochem) 2,3-dihydro-1-(6-(2-
dihydro-1-(6-(2- trifluoromethylquinolinyl)methyl)-
trifluoromethylquinolinyl)meth- yl)- 1H-1,4-benzodiazepin-2-one
1H-1,4-benzodiazepin-2-one (Example C-S) 8C-381
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 501.1
alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-
dihydro-1-(cyclopropylmethyl)- (cyclopropylmethyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-L) 8C-382
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 517.2 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(2-methylbutyl)-
dihydro-1-(2-methylbutyl)-1H- 1H-1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-T) 8C-383
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 475.1 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(ethyl)-1H-1,4-
dihydro-1-(ethyl)-1H-1,4- benzodiazepin-2-one benzodiazepin-2-one
(Example C-U) 8C-384 3-(N'-(4,4,4-Trifluorobu- tyryl)-L-
4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 556.1
alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-(4-(3,5-
dihydro-1-(4-(3,5- dimethylisoxazolyl)methyl)-1H-
dimethylisoxazolyl)methyl)-1H- 1,4-benzodiazepin-2-one
1,4-benzodiazepin-2-one (Example C-Y) 8C-385
3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid
3-(L-alaninyl)amino-5-phenyl- C-G 489.1 alaninyl)amino-5-phenyl-2-
,3- (Fluorochem) 2,3-dihydro-1-(propyl)-1H-1,4-
dihydro-1-(propyl)-1H-1,4- benzodiazepin-2-one benzodiazepin-2-one
(Example 8-L) 8C-386 3-(N'-(4,4,4-Trifluorobu- tyryl)-L-
4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 505.1
alaninyl)amino-5-phenyl-2,3- (Fluorochem)
2,3-dihydro-1-(2-methoxyethyl)- dihydro-1-(2-methoxyethyl)-1H-
1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-Z)
8C-387 3-(N'-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid
3-(L-alaninyl)-amino-)-2,4- C-E 537.3 alaninyl)-amino-)-2,4-dioxo-
-1,5- (Sigma) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4,5-
- dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-
benzodiazepine benzodiazepine (Example 8-L)
8C-388 (S)-3-(N'-(N-pyrrolidinylacetyl)- Pyrrolidine
(S)-3-(N'-(chloroacetyl)-L- C-F L-alaninyl)amino-2,3-dihydro-1-
(Aldrich) alaninyl)amino-2,3-dihydro-1- methyl-5-phenyl-1H-1,4-
methyl-5-phenyl-1H-1,4- benzodiazepin-2-one benzodiazepin-2-one
(Example C-AD) 8C-389 3-(N'-(o-Chlorophenoxyacetyl)-
o-Chlorophenoxyacetic acid 3-(L-alaninyl)amino-2,3- C-A 504.8
L-alaninyl)amino-2,3-dihydro-1- (Lancaster)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-390
3-(N'-(2-Thiopheneacetyl- )-L- 2-Thiopheneacetic acid
3-(L-alaninyl)amino-2,3- C-A 460.8 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-391
3-(N'-(3- 3- 3-(L-alaninyl)amino-2,3- C-A 523.1
(Trifluoromethyl)phenylacetic)- - (Trifluoromethyl)phenyl-
dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1-
acetic acid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-
(Marshallton) (Example 8-B) benzodiazepin-2-one 8C-392
3-(N'-(p-Tolylacetyl)-L- p-Tolylacetic acid
3-(L-alaninyl)amino-2,3- C-A 468.8 alaninyl)amino-2,3-dihydr- o-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-393
3-(N'-(3-(4- 3-(4- 3-(L-alaninyl)amino-2,3- C-A 498.8
Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionic
dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid
1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example
8-B) benzodiazepin-2-one 8C-394 3-(N'-(3,5-Difluorophenylacetyl)-
3,5-Difluorophenylacetic 3-(L-alaninyl)amino-2,3- C-A 491.0
L-alaninyl)amino-2,3-dihydro-1- acid dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- (Aldrich) 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example 8-B) 8C-395 3-(N'-(m-Tolylacetyl)-L-
m-Tolylacetic acid 3-(L-alaninyl)amino-2,3- C-A 468.6
alaninyl)amino-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-396
3-(N'-(3-Fluorophenylace- tyl)-L- 3-Fluorophenylacetic acid
3-(L-alaninyl)amino-2,3- C-A 472.8 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-397
3-(N'-(3-Bromophenylacet- yl)-L- 3-Bromophenylacetic acid
3-(L-alaninyl)amino-2,3- C-A 535.0 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-398
3-(N'-(4-Chlorophenoxyac- etyl)- 4-Chlorophenoxyacetic acid
3-(L-alaninyl)amino-2,3- C-A 505.0 L-alaninyl)amino-2,3-dihydro-1-
(Grand Island Biological dihydro-1-methyl-5-phenyl-1H-
methyl-5-phenyl-1H-1,4- Company) 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example 8-B) 8C-399
3-(N'-(2-Naphthylacetyl)-L- 2-Naphthylacetic acid
3-(L-alaninyl)amino-2,3- C-A 505.0 alaninyl)amino-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-400
3-(N'-(3-Methylphenoxyacetyl)- 3-Methylphenoxyacetic acid
3-(L-alaninyl)amino-2,3- C-A 489.0 L-alaninyl)amino-2,3-dihydro-1-
- (Lancaster) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-
1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B)
General Procedure C-J
[2878] A vial was charged with a CHCl.sub.3 solution of Starting
material 1 (71 umol), a DMF solution of HOBt monohydrate (71 umol),
a CHCl.sub.3 solution of diisopropylcarbodiimide (71 umol), and a
CHCl.sub.3 solution of starting material 2 (60 umol). The vial was
capped and the solution allowed to stand at room temperature for
two days. The reaction mixture was loaded onto a cation exchange
column, washed with MeOH and eluted with 2 N NH.sub.3/MeOH. The
eluents were concentrated and dried to give the desired product as
determined by MS (IS) and HPLC.
General Procedure C-K
[2879] To a 4 mL vial was added 870 uL of 0.05 mM stock solution of
starting material 1 in DMF/chloroform, 1000 uL of a 0.05 mM stock
solution of starting material 2 in chloroform, 1000 uL of a 0.05 mM
stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in
chloroform and 100 uL of a 0.48 mM stock solution of HOBt in DMF.
After standing undisturbed for 48 h, the reaction mixture was
concentrated and the residue redissolved in 2 mL of a 10%
methanol/methylene chloride solution. This solution was then
filtered through a pre-washed (methanol) 500 mg SCX column using an
additional 8 mL of the same solvent. The filtrate was concentrated
under a stream of nitrogen to approximately 1/3 its original volume
and then passed over a plug (200 mg) of AG 1-8x anion exchange
resin (BioRad; Hercules, California; Columns were pre-washed with
1N NaOH, water and methanol) using an additional 6 mL of 10%
methanol/methylene chloride solution. The resulting filtrate was
concentrated under vacuum and the crude products were submitted for
testing without further purification. Product structure and purity
were confirmed by HPLC and IEX MS.
Example C-AE
Synthesis of
3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1-
,4-benzodiazepin-2-one
Step A: Synthesis of
3-Amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-ben-
zodiazepin-2-one
[2880] The title compound was synthesized as described in Synth.
Commun., 26(4), 721-727 (1996).
Step B: Synthesis of
3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihyd-
ro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[2881] A solution of L-Boc-alanine (1.74 g, 9.20 mmol), HOBt
monohydrate (1.24 g, 9.20 mmol), diisopropylethylamime (1.6 mL,
9.20 mmol) and CH.sub.2Cl.sub.2 (30 mL) was purged with nitrogen
and cooled in an ice bath. To the cold solution was added
1-(3-dimethylaminopropyl)-3-ethylcar- bodimide hydrochloride (1.76
g, 9.20 mmol) followed by a solution of
3-amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
(2.45 g, 9.20 mmol) dissolved in CH.sub.2Cl.sub.2 (15 mL). The cold
bath was removed and the solution stirred overnight at room
temperature. The reaction mixture was extracted with H.sub.2O, 0,
0.1 N aq. citric acid, 5% aq. NaHCO.sub.3, and brine. The remaining
CH.sub.2Cl.sub.2 solution was dried (MgSO.sub.4) and concentrated
to a tan foam. The title compound was crystallized from
CH.sub.2Cl.sub.2/EtOAc to give 3.47 g (86% yield) of white
crystals, mp. 228-229.degree. C.
[2882] Anal. Calcd for C.sub.23H.sub.27N.sub.5O.sub.4: C, 63.14; H,
6.22; N, 16.01. Found: C, 63.25; H, 6.15; N, 15.95. MS (FD.sup.+)
437 m/z.
Step C: Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[2883] A solution of
3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihyd-
ro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (3.42 g, 7.82
mmol) in CH.sub.2Cl.sub.2 (90 mL) was cooled in an ice bath and
treated with TFA (13.2 mL, 172 mmol). The cold bath was removed and
the solution stirred at room temperature for four hours. The
reaction mixture was washed with 1 M aq. K.sub.2CO.sub.3 and the
aqueous back-extracted with CH.sub.2Cl.sub.2. The combined extracts
were washed with H.sub.2O, dried (MgSO.sub.4) and concentrated to
obtain 1.75 g (66% yield) of the title compound as an off-white
foam. MS (IS.sup.+) 338 (m/e).
[2884] .sub.1HNMR (CDCl.sub.3): .delta.=8.76-8.86 (1H, m), 8.63
(1H, m), 8.17 (1H, m), 7.82 (2H, m), 7.60 (1H, m), 7.41 (3H, m),
5.60 (1H, m), 3.63 (1H, m), 3.49 (3H, s), 1.66 (2H, broad), 1.45
(3H, m).
Example C-AF
Synthesis of
3-[(L-Alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)- -5
-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
Step A: Synthesis of 3-Amino-2,3-dihydro-1-(2-N,N
-diethylaminoethyl)-5-(2- -pyridyl)-1H-1,4-benzodiazepin-2-one
[2885] The title compound was synthesized as described in Synth.
Commun., 26(4), 721-727 (1996).
Step B: Synthesis of
3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihyd-
ro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[2886] A solution of L-Boc-alanine (1.80 g, 9.50 mmol), HOBt
monohydrate (1.28 g, 9.50 mmol), diisopropylethylamime (1.65 mL,
9.50 mmol) and CH.sub.2Cl.sub.2 (40 mL) was purged with nitrogen
and cooled in an ice bath. To the cold solution was added
1-(3-dimethylaminopropyl)-3-ethylcar- bodimide hydrochloride (1.82
g, 9.50 mmol) followed by a solution of
3-amino-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benz-
odiazepin-2-one (3.34 g, 9.50 mmol) dissolved in CH.sub.2Cl.sub.2
(25 mL). The cold bath was removed and the solution stirred
overnight at room temperature. The reaction mixture was extracted
with H.sub.2O, 5% aq. NaHCO.sub.3, and brine. The remaining
CH.sub.2Cl.sub.2 solution was dried (MgSO.sub.4) and concentrated
to a tan foam. The title compound was isolated via column
chromatography (2% MeOH/CH.sub.2Cl.sub.2 to 10%
MeOH/CH.sub.2Cl.sub.2) to give 3.53 g (71% yield) of yellow
foam.
[2887] MS (FD.sup.+) 522 (m/z).
[2888] .sup.1HNMR (CDCl.sub.3): .delta.=8.62 (1H, d), 8.11 (1H, m),
7.80 (2H, m), 7.59 (2H, m), 7.32-7.45 (2H, m), 5.54 (1H, m),
5.02-5.18 (1H, m), 4.38 (1H, m), 4.20 (1H, m), 3.83 (1H, m), 2.62
(2H, t), 2.44 (4H, m), 1.40-1.56 (12H, m), 0.88 (6H, m).
Step C: Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-1-(2-N,N
-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[2889] The title compound was synthesized using the procedure
described in Example C-AE, Step C. A solution of
3-[(N-tert-butoxycarbonyl-L-alaninyl)-
amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzod-
iazepin-2-one (3.52 g, 6.73 mmol) was treated with TFA (11.4 mL,
148 mmol) to give 2.61 g (92% yield) the title compound as a light
yellow foam.
[2890] MS (IS.sup.+) 423 (m/e).
[2891] .sup.1HNMR (CDCl.sub.3): .delta.=8.78-8.93 (1H, m), 8.62
(1H,d), 8.11 (1H, m), 7.80 (2H, m), 7.58 (2H, m), 7.39 (2H, m),
5.58 (1H, m), 4.22 (1H, m), 3.88 (1H, m), 3.61 (1H, m), 2.67 (2H,
t), 2.49 (4H, m), 1.73 (2H, broad), 1.42 (3H, m), 0.91 (6H, m).
Example C-AG
Synthesis of
3-[(L-Alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-
-5-(2-pyridyl)-1H-1,4benzodiazepin-2-one
Step A: Synthesis of
3-Amino-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-- pyridyl)-1H
1,4-benzodiazepin-2-one
[2892] The title compound was synthesized as described in Synth.
Commun., 26(4), 721-727 (1996).
Step B: Synthesis of
3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihyd-
ro-1-(3,3-dimethyl-2-oxobutyl)
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[2893] A solution of L-Boc-alanine (1.57 g, 8.33 mmol), HOBt
monohydrate (1.13 g, 8.33 mmol), diisopropylethylamime (1.45 mL,
8.33 mmol) and CH.sub.2Cl.sub.2 (40 mL) was purged with nitrogen
and cooled in an ice bath. To the cold solution was added
1-(3-dimethylaminopropyl)-3-ethylcar- bodimide hydrochloride (1.60
g, 8.33 mmol) followed by a solution of
3-amino-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benz-
odiazepin-2-one (2.92 g, 8.33 mmol) dissolved in CH.sub.2Cl.sub.2
(25 mL). The cold bath was removed and the solution stirred
overnight at room temperature. The reaction mixture was extracted
with H.sub.2O, 0.1 N aq. citric acid, 5% aq. NaHCO.sub.3, and
brine. The remaining CH.sub.2Cl.sub.2 solution was dried
(MgSO.sub.4) and concentrated to a yellow foam. The title compound
was isolated via column chromatography (20% EtOAc/hexanes to 60%
EtOAc/hexanes) to give 4.19 g (96% yield) of light yellow foam.
[2894] MS (FD.sup.30 ) 521 (m/z).
[2895] .sup.1HNMR (CDCl.sub.3): .delta.=8.65 (1H, t), 8.17 (1H, t),
7.90 (1H, t), 7.71-7.85 (1H, m), 7.54 (1H, m), 7.44 (1H, t), 7.37
(1H, d), 7.24-7.32 (1H, m), 7.14 (1H, m), 5.67 (1H, dd), 5.18 (1H,
broad), 4.93-5.07 (1H, m), 4.504.64 (1H, m), 4.38 (1H, broad),
1.42-1.51 (12H, m), 1.26 (9H, d).
Step C: Synthesis of
3-[(L-Alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-o-
xobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[2896] The title compound was synthesized using the procedure
described in Example C-AE, Step C. A solution of
3-[(N-tert-butoxycarbonyl-L-alaninyl)-
amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxbutyl)-5-(2-pyridyl)-1H-1,4-benzodi-
azepin-2 -one (4.18 g, 8.01 mmol) was treated with TFA (13.6 mL,
176 mmol) to give 3.14 g (93% yield) the title compound as an
off-white foam.
[2897] MS (IS.sup.30 ) 422 (m/e).
[2898] .sup.1HNMR (CDCl.sub.3) .delta.8.85-8.99 (1H, m), 8.68 (1H,
d), 8.20 (1H, t), 7.87 (1H, t), 7.58 (1H, t), 7.42 ( 2H, m), 7.30
(1H, t), 7.17 (1H, d), 5.72 (1H, m 5.08 (1H, d), 4.60 (1H, d), 3.66
(1H, m), 1.47 (3H, m), 1.28 (9H, m).
Example C-AH
Synthesis of
3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1-
,4benzodiazepin-2-one
Step A: Synthesis of
3-Amino-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-ben-
zodiazepin-2-one
[2899] The title compound was synthesized in a manner similar to
the procedure described in Synth. Commun., 26(4), 721-727 (1996),
starting with 2-(2-aminobenzoyl)thiazole (prepared as described in
Tetrahedron, 51(3), 773-786, (1995)).
[2900] MS (IS.sup.30 ) 273 (m/e).
[2901] .sup.1HNMR (CDCl.sub.3): .delta.=7.83-7.94 (2H, m), 7.61
(1H, t), 7.50 (1H, d), 7.34 (2H, m), 4.60 (1H, s), 3.46 (3H, s),
1.97 (2H, broad).
Set B: Synthesis of
3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydr-
o-1-methyl-5-(2-thiazyl) -1H-1,4-benzodiazepin-2-one
[2902] A solution of L-Boc-alanine (1.85 g, 9.77 mmol), HOBt
monohydrate (1.32 g, 9.77 mmol), diisopropylethylamime (1.70 mL,
9.77 mmol) and CH.sub.2Cl.sub.2 (30 mL) was purged with nitrogen
and cooled in an ice bath. To the cold solution was added
1-(3-dimethylaminopropyl)-3-ethylcar- bodimide hydrochloride (1.87
g, 9.77 mmol) followed by a solution of
3-amino-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one
(2.66 g, 9.77 mmol) dissolved in CH.sub.2Cl.sub.2 (20 mL). The cold
bath was removed and the solution stirred overnight at room
temperature. The reaction mixture was extracted with H.sub.2O, 0.1
N aq. citric acid, 5% aq. NaHCO.sub.3, and brine. The remaining
CH.sub.2Cl.sub.2 solution was dried (MgSO.sub.4) and concentrated
to a light yellow foam. The title compound was crystallized from
EtOAc/hexane to give 3.22 g (74% yield) of white crystals, mp.
196-197.degree. C. Anal. Calcd for C.sub.21H.sub.25N.sub.5O.sub.4S:
C, 56.87; H, 5.68; N, 15.79. Found: C, 56.74; H, 5.75; N,
15.55.
[2903] MS (IS.sup.30 ) 444 m/e.
Step C: Synthesis of
3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiaz- yl)-1H-1
,4-benzodiazepin-2-one
[2904] The title compound was synthesized using the procedure
described in Example C-AE, Step C.
Example C-AI
Synthesis of
3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(thiophen-2-yl)--
1H-1,4benzodiazepin-2-one
Step A: Synthesis of
3-Amino-2,3-dihydro-1-methyl-5-(2-thiophen-2-yl)-1H-1-
,4-benzodiazepin-2-one
[2905] The title compound was synthesized in a manner similar to
the procedure described in
Synth. Commun., 26(4), 721-727 (1996), starting with
2-(2-aminobenzoyl)thiophene (prepared as described in Collect.
Czech. Chem. Commun., 34(2), 468-478, (1969)).
[2906] MS (IS.sup.+) 272 (m/e).
[2907] .sup.1HNMR (CDCl.sub.3): .delta.=7.68 (1H, d), 7.60 (1H, t),
7.48 (1H, m), 7.35 (2H, d), 7.28 (1H, m), 7.15 (1H, d), 7.05 (1H,
d), 4.50 (1H, broad), 3.45 (3H, s), 2.26 (2H, broad).
Step B: Synthesis of
3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihyd-
ro-1-methyl-5-(2-thiophenyl) -1H-1,4-benzodiazepin-2-one
[2908] The title compound was synthesized in a manner similar to
the procedure described in Example C-AH, Step B.
[2909] MS (IS.sup.30 ) 443 (m/e).
[2910] .sup.1HNMR (CDCl.sub.3): .delta.=7.69 (1H, d), 7.61 (2H, m),
7.48 (1H, d), 7.27-7.42 (2H, m), 7.18 (1H, m), 7.05 (1H, m), 5.51
(1H, d), 5.13 (1H, broad), 4.36 (1H, broad), 3.44 (3H, s),
1.38-1.57 (12H, m).
Step C: Synthesis of
3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiop-
henyl)-1H-1,4-benzodiazepin-2-one
[2911] The title compound was synthesized in a manner similar to
the procedure described in Example C-AE, Step C.
[2912] MS (IS.sup.30 ) 343 (m/e).
[2913] .sup.1HNMR (CDCl.sub.3): .delta.=8.55 (1H, d), 7.68 (1H, d),
7.59 (1H, m), 7.48 (1H, d), 7.36 (1H, d), 7.31 ( 1H, d), 7.16 (1H,
m), 7.04 (1H, t), 5.54 (1H, d 3.58 (1H, m), 3.45 (3H, s), 1.41 (3H,
d).
[2914] Using the procedures indicated, the compounds shown in Table
C-2 were prepared.
37TABLE C-2 Example General No. Compound Starting Material 1
Starting Material 2 Procedure MS 8C-401
3-[(N'-(4-methoxyphenylacetyl)-L- 4-Methoxyphenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 485.5 alaninyl)amino]-2,3-dihydro--
1- acid dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,-
4- (Aldrich) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example C-AE) 8C-402 3-[(N'-(2-thiopheneacetyl)-L-
2-Thiopheneacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 461.5
alaninyl)amino]-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-403 3-[(N'-(3,5-difluorophe- nylacetyl)-L-
3,5-Difluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 491.5
alaninyl)amino]-2,3-dihydro-1- acid dihydro-1-methyl-5-(2-p-
yridyl)- methyl-5-(2-pyridyl)-1H-1,4- (Aldrich)
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-404 3-[(N'-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 534.4 alaninyl)amino]-2,3-dihydro--
1- (Aldrich) dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-405 3-[(N'-(phenylmercaptoa-
cetyl)-L- Phenylmercaptoacetic acid 3-[(L-alaninyl)amino]-2,3- C-J
487.6 alaninyl)amino]-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-(2-pyri- dyl)- methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-406 3-[(N'-(4-ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 499.6 alaninyl)amino]-2,3-dihydro--
1- (Aldrich) dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-407 3-[(N'-(4- 4-
3-[(L-alaninyl)amino]-2,3- C-J 523.5 (trifluoromethyl)phenylacety-
l)-L- (trifluoromethyl)phenyl- dihydro-1-methyl-5-(2-pyridyl)-
alaninyl)amino]-2,3-dihydro-1- acetic acid
1H-1,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-1H-1,4- (Aldrich)
(Example C-AE) benzodiazepin-2-one 8C-408 3-[(N'-(3,5-
3,5-bis(trifluoromethyl) 3-[(L-alaninyl)amino]-2,3- C-J 591.5
bis(trifluoromethyl)phenylac- etyl)-L- phenylacetic acid
dihydro-1-methyl-5-(2-pyridyl)- alaninyl)amino]-2,3-dihydro-1-
(Aldrich) 1H-1,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-1H-1,4-
(Example C-AE) benzodiazepin-2-one 8C-409
3-[(N'-((methylthio)acetyl)-L- (methylthio)acetic acid
3-[(L-alaninyl)amino]-2,3- C-J 425.5 alaninyl)amino]-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-410 3-[(N'-(cyclohexylacety-
l)-L- cyclohexylacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 461.6
alaninyl)amino]-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-411 3-[(N'-(pentafluorophen- oxyacetyl)-
pentafluorophenoxyacetic 3-[(L-alaninyl)amino]-2,3- C-J 561.5
L-alaninyl)amino]-2,3-dihydro-1- acid dihydro-1-methyl-5-(2-pyrid-
yl)- methyl-5-(2-pyridyl)-1H-1,4- (Aldrich)
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-412 3-[(N'-(benzo[b]thiophene-3-acetyl)- benzo[b]thiophene-3-
3-[(L-alaninyl)amino]-2,3- C-J 511.6 L-alaninyl)amino]-2,3-dihydr-
o-1- acetic acid dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- (Lancaster) 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-413 3-[(N'-(2,4,6-
2,4,6-trimethylphenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 497.6
trimethylphenylacetyl)-L- acid dihydro-1-methyl-5-(2-pyridyl)-
alaninyl)amino]-2,3-dihydro-1- (Lancaster)
1H-1,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-1H-1,4- (Example
C-AE) benzodiazepin-2-one 8C-414 3-[(N'-(4-biphenylacetyl)-L-
4-biphenylacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 531.6
alaninyl)amino]-2,3-dihydro-1- (Lancaster)
dihydro-1-methyl-5-(2-pyridyl)- - methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-415 3-[(N'-(3,4-difluorophe- nylacetyl)-L-
3,4-difluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 491.5
alaninyl)amino]-2,3-dihydro-1- acid dihydro-1-methyl-5-(2-p-
yridyl)- methyl-5-(2-pyridyl)-1H-1,4- (Aldrich)
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-416 3-[(N'-(4-(2-thienyl)butyryl)-L- 4-(2-thienyl)butyric acid
3-[(L-alaninyl)amino]-2,3- C-J 489.6 alaninyl)amino]-2,3-dihydro--
1- (Aldrich) dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-417 3-[(N'-(5-methylhexanoy-
l)-L- 5-methylhexanoic acid 3-[(L-alaninyl)amino]-2,3- C-J 449.5
alaninyl)amino]-2,3-dihydro-1- (P&B)
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-418 3-[(N'-(3- mono-methyl succinate 3-[(L-alaninyl)amino]-2,3-
C-J 451.5 methoxycarbonylpropionyl)-L- (Aldrich)
dihydro-1-methyl-5-(2-pyridyl)- alaninyl)amino]-2,3-dihydro-1-
1H-1,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-1H-1,4- (Example
C-AE) benzodiazepin-2-one 8C-419 3-[(N'-(methanesulfonylacetyl)-L-
methanesulfonylacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 457.5
alaninyl)amino]-2,3-dih- ydro-1- (Lancaster)
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-420 3-[(N'-(4-toluenesulfon- ylacetyl)-L-
4-toluenesulfonylacetic 3-[(L-alaninyl)amino]-2,3- C-J 533.6
alaninyl)amino]-2,3-dihydro-1- acid dihydro-1-methyl-5-(2-pyridyl-
)- methyl-5-(2-pyridyl)-1H-1,4- (Lancaster)
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-421 3-[(N'-(2,6-difluoromandelyl)-L- 2,6-difluoromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 507.5 alaninyl)amino]-2,3-dihydro--
1- (Fluorochem) dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-422 3-[(N'-(4-fluoromandely-
l)-L- 4-fluoromandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 489.5
alaninyl)amino]-2,3-dihydro-1- (Lancaster)
dihydro-1-methyl-5-(2-pyridyl)- - methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-423 3-[(N'-(2,5-difluoroman- delyl)-L- 2,5-difluoromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 507.5 alaninyl)amino]-2,3-dihydro-1-
(Fluorochem) dihydro-1-methyl-5-(2-p- yridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-424
3-[(N'-(2,4,6-trifluorophenylacetyl)- 2,4,6-trifluorophenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 509.5 L-alaninyl)amino]-2,3-dihydr-
o-1- acid dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H--
1,4- (Fluorochem) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example C-AE) 8C-425 3-[(N'-(4-fluoro-2- 4-fluoro-2-
3-[(L-alaninyl)amino]-2,3- C-J 541.5 (trifluoromethyl)phenylacety-
l)-L- (trifluoromethyl) dihydro-1-methyl-5-(2-pyridyl)-
alaninyl)amino]-2,3-dihydro-1- phenylacetic acid
1H-1,4-benzodiazepin-2-o- ne methyl-5-(2-pyridyl)-1H-1,4-
(Fluorochem) (Example C-AE) benzodiazepin-2-one 8C-426
3-[(N'-(4,4,4-trifluorobutyryl)-L- 4,4,4-trifluorobutyric acid
3-[(L-alaninyl)amino]-2,3- C-J 461.4 alaninyl)amino]-2,3-dihydro-1-
(Fluorochem) dihydro-1-methyl-5-(2-pyridyl- )-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-427
3-[(N'-(4-isopropylphenylacetyl)-L- 4-isopropylphenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 497.6 alaninyl)amino]-2,3-dihydro--
1- acid dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,-
4- (Lancaster) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example C-AE) 8C-428 3-[(N'-(beta-phenyllactyl)-L-
beta-phenyllactic acid 3-[(L-alaninyl)amino]-2,3- C-J 485.5
alaninyl)amino]-2,3-dihydro-1- (Sigma)
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-429 3-[(N'-(mandelyl)-L- mandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 471.5 alaninyl)amino]-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-430 3-[(N'-(4-chloromandely-
l)-L- p-chloromandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 506.0
alaninyl)amino]-2,3-dihydro-1- (Acros)
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-431 3-[(N'-(isovaleryl)-L- isovaleric acid
3-[(L-alaninyl)amino]-2,3- C-J 421.5 alaninyl)amino]-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-432 3-[(N'-(2,3,5-trifluoro-
phenylacetyl)- 2,3,5-trifluorophenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 509.5
L-alaninyl)amino]-2,3-dihydro-1- acid
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
(Fluorochem) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one
(Example C-AE) 8C-433 3-[(N'-(3-methylthiopropionyl)-L-
3-methylthiopropionic acid 3-[(L-alaninyl)amino]-2,3- C-J 439.5
alaninyl)amino]-2,3-dihydro-1- (Lancaster)
dihydro-1-methyl-5-(2-pyridyl)- - methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-434 3-[(N'-(L-alpha-hydroxy- isocaproyl)-
L-alpha-hydroxyisocaproic 3-[(L-alaninyl)amino]-2,3- C-J 451.5
L-alaninyl)amino]-2,3-dihydro-1- acid
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
(Aldrich) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example
C-AE) 8C-435 3-[(N'-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic
acid 3-[(L-alaninyl)amino]-2,3- C-J 500.5
alaninyl)amino]-2,3-dihydro-1- (Aldrich)
dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)
8C-436 3-[(N'-(D-3-phenylacety- l)-L- D-3-phenyllactic acid
3-[(L-alaninyl)amino]-2,3- C-J 485.5 alaninyl)amino]-2,3-dihydro-1-
(Aldrich) dihydro-1-methyl-5-(2-pyridyl)-
methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AE) 8C-437 3-[(N'-(4-methocyphenyl-
acetyl)-L- 4-Methoxyphenylacetic 3-[(L-alaninyl)amino]-2,3- C-J
569.6 alaninyl)amino]-2,3-dihydro-1-(3,3- acid
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
(Aldrich) oxobutyl)-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG)
8C-438 3-[(N'-(2-thiopheneacetyl)-L- 2-Thiopheneacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 545.6 alaninyl)amino]-2,3-dihydro--
1-(3,3- (Aldrich) dihydro-1-(3,3-dimethyl-2-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG)
8C-439 3-[(N'-(3,5-difluorophenylacetyl)-L-
3,5-Difluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 575.6
alaninyl)amino]-2,3-dihydro-1-(3,3- acid dihydro-1-(3,3-dimethyl-2-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- (Aldrich)
oxobutyl)-5-(2-pyridyl)-1- H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-440
3-[(N'-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 618.5
alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-441
3-[(N'-(phenylmercaptoacetyl)-L- Phenylmercaptoacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 571.7
alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-442
3-[(N'-(4-ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 583.7
alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-443 3-[(N'-(4- 4-
3-[(L-alaninyl)amino]-2,3- C-J 607.6
(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenyl-
dihydro-1-(3,3-dimethyl-2- alaninyl)amino]-2,3-dihydro-1-(3,3-
acetic acid oxobutyl)-5-(2-pyridyl)-1H-1,4-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- (Aldrich) benzodiazepin-2-one
1H-1,4-benzodiazepin-2-one (Example C-AG) 8C-444 3-[(N'-(3,5-
3,5-Bis(trifluoromethyl) 3-[(L-alaninyl)amino]-2,3- C-J 675.6
bis(trifluoromethyl)phenylacetyl)-L- phenylacetic acid
dihydro-1-(3,3-dimethyl-2- alaninyl)amino]-2,3-dihydro-1-(3,3-
(Aldrich) oxobutyl)-5-(2-pyridyl)-1H-1,4- dimethyl-2-oxobutyl)-5--
(2-pyridyl)- benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one
(Example C-AG) 8C-445 3-[(N'-((methylthio)acetyl)-L-
(methylthio)acetic acid 3-[(L-aladinyl)amino]-2,3- C-J 509.6
alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-446
3-[(N'-(cyclohexylacetyl)-L- cyclohexylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 545.7
alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-447
3-[(N'-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic
3-[(L-alaninyl)amino]-2,3- C-J 645.6
L-alaninyl)amino]-2,3-dihydro-1- acid dihydro-1-(3,3-dimethyl-2-
(3,3-dimethyl-2-oxobutyl)-5-(2- (Aldrich)
oxobutyl)-5-(2-pyridyl)-1H-1,4- pyridyl)-1H-1,4-benzodiazepin-2-
benzodiazepin-2-one one (Example C-AG) 8C-448
3-[(N'-(benzol[b]thiophene-3-acetyl)- benzo[b]thiophene-3-
3-[(L-alaninyl)amino]-2,3- C-J 595.7
L-alaninyl)amino]-2,3-dihydro-1- acetic acid
dihydro-1-(3,3-dimethyl-2- (3,3-dimethyl-2-oxobutyl)-5-(2-
(Lancaster) oxobutyl)-5-(2-pyridyl)- -1H-1,4-
pyridyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example
C-AG) 8C-449 3-[(N'-(2,4,6- 2,4,6-trimethylphenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 581.7 trimethylphenylacetyl)-L- acid
dihydro-1-(3,3-dimethyl-2- alaninyl)amino]-2,3-dihydro-1-(3,3-
(Lancaster) oxobutyl)-5-(2-pyridyl)-1- H-1,4-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- benzodiazepin-2-one
1H-1,4-benzodiazepin-2-one (Example C-AG) 8C-450
3-[(N'-(4-biphenylacetyl)-L- 4-biphenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 615.7 alaninyl)amino]-2,3-dihydro--
1-(3,3- (Lancaster) dihydro-1-(3,3-dimethyl-2-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG)
8C-451 3-[(N'-(3,4-difluorophenylacetyl)-L-
3,4-difluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 575.6
alaninyl)amino]-2,3-dihydro-1-(3,3- acid dihydro-1-(3,3-dimelhyl-2-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- (Aldrich)
oxobutyl)-5-(2-pyridyl)-1- H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-452
3-[(N'-(4-(2-thienyl)butyl)-L- 4-(2-thienyl)butyric acid
3-[(L-alaninyl)amino]-2,3- C-J 573.7
alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethhyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-- 1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-453
3-[(N'-(5-methylhexanoyl)-L- 5-methylhexanoic acid
3-[(L-alaninyl)amino]-2,3- C-J 533.7
alaninyl)amino]-2,3-dihydro-1-(3,3- (P&B)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-454 3-[(N'-(3- mono-methyl
succinate 3-[(L-alaninyl)amino]-2,3- C-J 535.6
methoxycarbonylpropionyl)-L- (Aldrich) dihydro-1-(3,3-dimethyl-2-
alaninyl)amino]-2,3-dihydro--
1-(3,3- oxobutyl)-5-(2-pyridyl)-1H-1,4- dimethyl-2-oxobutyl)-5-(2-
-pyridyl)- benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one 8C-455
3-[(N'-(methanesulfonylacetyl)-L- methanesulfonylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 541.6 alaninyl)amino]-2,3-dihydro--
1-(3,3- (Lancaster) dihydro-1-(3,3-dimethyl-2-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG)
8C-456 3-[(N'-(4-toluenesulfonylacetyl)-L- 4-toluenesulfonylacetic
3-[(L-alaninyl)amino]-2,3- C-J 617.7
alaninyl)amino]-2,3-dihydro-1-(3,3- acid dihydro-1-(3,3-dimethyl-2-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- (Lancaster)
oxobutyl)-5-(2-pyridyl)- -1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-457
3-[(N'-(2,6-difluoromandelyl)-L- 2,6-difluoromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 591.6
alaninyl)amino]-2,3-dihydro-1-(3,3- (Fluorochem)
dihydro-1-(3,3-dimethyl-- 2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H- -1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-458
3-[(N'-(4-fluoromandelyl)-L- 4-fluoromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 573.6
alaninyl)amino]-2,3-dihydro-1-(3,3- (Lancaster)
dihydro-1-(3,3-dimethyl-2- - dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-- 1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-459
3-[(N'-(2,5-difluoromandelyl)-L- 2,5-difluoromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 591.6
alaninyl)amino]-2,3-dihydro-1-(3,3- (Fluorochem)
dihydro-1-(3,3-dimethyl-- 2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H- -1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-460
3-[(N'-(2,4,6-trifluorophenylacetyl)- 2,4,6-trifluorophenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 593.6
L-alaninyl)amino]-2,3-dihydro-1- acid dihydro-1-(3,3-dimethyl-2-
(3,3-dimethyl-2-oxobutyl)-5-(2- (Fluorochem)
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- pyridyl)-1H-1,4-benzodiazepin-2-
benzodiazepin-2-one one (Example C-AG) 8C-461 3-[(N'-(4-fluoro-2-
4-fluoro-2- 3-[(L-alaninyl)amino]-2,3- C-J 625.6
(trifluoromethyl)phenylacety- l)-L- (trifluoromethyl)
dihydro-1-(3,3-dimethyl-2- alaninyl)amino]-2,3-dihydro-1-(3,3-
phenylacetic acid oxobutyl)-5-(2-pyridyl)-1H-1,4-
dimethyl-2-oxobutyl)-5-(2-pyridyl- )- (Fluorochem)
benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one (Example C-AG)
8C-462 3-[(N'-(4,4,4-trifluorobutyryl)-L- 4,4,4-trifluorobutyric
acid 3-[(L-alaninyl)amino]-2,3- C-J 545.5
alaninyl)amino]-2,3-dihydro-1-(3,3- (Fluorochem)
dihydro-1-(3,3-dimethyl-- 2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H- -1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-463
3-[(N'-(4-isopropylphenylacetyl)-L- 4-isopropylphenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 581.7
alaninyl)amino]-2,3-dihydro-1-(3,3- acid dihydro-1-(3,3-dimethyl-2-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- (Lancaster)
oxobutyl)-5-(2-pyridyl)- -1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-464
3-[(N'-(beta-phenyllactyl)-L- beta-phenyllactic acid
3-[(L-alaninyl)amino]-2,3- C-J 569.6
alaninyl)amino]-2,3-dihydro-1-(3,3- (Sigma)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-465 3-[(N'-(mandelyl)-L-
mandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 555.6
alaninyl)amino]-2,3-dihydro-- 1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-466
3-[(N'-(4-chloromandelyl)-L- p-chloromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 590.1 alaninyl)amino]-2,3-dihydro--
1-(3,3- (Acros) dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5--
(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG)
8C-467 3-[(N'-(isovaleryl)-L- isovaleric acid
3-[(L-alaninyl)amino]-2,3- C-J 505.6 alaninyl)amino]-2,3-dihydro--
1-(3,3- (Aldrich) dihydro-1-(3,3-dimethyl-2-
dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-
1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG)
8C-468 3-[(N'-(2,3,5-trifluorophenylacetyl)-
2,3,5-trifluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 593.6
L-alaninyl)amino]-2,3-dihydro-1- acid dihydro-1-(3,3-dimethyl-2-
(3,3-dimethyl-2-oxobutyl)-5-(2- (Fluorochem)
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- pyridyl)-1H-1,4-benzodiazepin-2-
benzodiazepin-2-one one (Example C-AG) 8C-469
3-[(N'-(3-methylthiopropionyl)-L- 3-methylthiopropionic acid
3-[(L-alaninyl)amino]-2,3- C-J 523.6
alaninyl)amino]-2,3-dihydro-1-(3,3- (Lancaster)
dihydro-1-(3,3-dimethyl-2- - dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-- 1,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-470
3-[(N'-(L-alpha-hydroxyisocaproyl)- L-alpha-hydroxyisocaproic
3-[(L-alaninyl)amino]-2,3- C-J 535.6
L-alaninyl)amino]-2,3-dihydro-1- acid dihydro-1-(3,3-dimethyl-2-
(3,3-dimethyl-2-oxobutyl)-5-(2- (Aldrich)
oxobutyl)-5-(2-pyridyl)-1H-1,4- pyridyl)-1H-1,4-benzodiazepin-2-
benzodiazepin-2-one one (Example C-AG) 8C-471
3-[(N'-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 584.6
alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-472
3-[(N'-(D-3-phenyllactyl)-L- D-3-phenyllactic acid
3-[(L-alaninyl)amino]-2,3- C-J 569.6
alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)
dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-
oxobutyl)-5-(2-pyridyl)-1H-1- ,4- 1H-1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AG) 8C-473
3-[(N'-(4-methoxyphenylacetyl)-L- 4-Methoxyphenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 570.7
alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethyl
N,N-diethyl aminoethyl)-5-(2- (Aldrich)
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-474
3-[(N'-(2-thiopheneacetyl)-L- 2-Thiopheneacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 546.7
alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-475
3-[(N'-(N"-acetyl-N"- N-acetyl-N-phenylglycine
3-[(L-alaninyl)amino]-2,3- C-J 597.7
phenylglycinyl)L-alaninyl)amino]- (Kodak) dihydro-1-(2-N,N-diethyl
2,3-dihydro-1-(2-N,N-diethyl aminoethyl)-5-(2-pyridyl)-1H-
aminoethyl)-5-(2-pyridyl)-1H-1,4- 1,4-benzodiazepin-2-one
benzodiazepin-2-one (Example C-AF) 8C-476 3-[(N'-(3,5-difluorophe-
nylacetyl)-L- 3,5-Difluorophenylacetic 3-[(L-alaninyl)amino]-2,3-
C-J 576.6 alaninyl)amino]-2,3-dihydro-1-(2- acid
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Aldrich)
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-477
3-[(N'-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 619.6 alaninyl)amino]-2,3-dihydro--
1-(2- (Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl
aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-
pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one
(Example C-AF) 8C-478 3-[(N'-(phenylmercaptoacetyl)-L-
Phenylmercaptoacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 572.7
alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-479
3-[(N'-(4-ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 584.7
alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-480 3-[(N'-(4- 4-
3-[(L-alaninyl)amino]-2,3- C-J 608.7
(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenyl-
dihydro-1-(2-N,N-diethyl alaninyl)amino]-2,3-dihydro-1-(2- acetic
acid aminoethyl)-5-(2-pyridyl)-1H- N,N-diethyl aminoethyl)-5-(2-
(Aldrich) 1,4-benzodiazepin-2-one pyridyl)-1H-1,4-benzodiazepin-2-
- (Example C-AF) one 8C-481 3-[(N'-(3,5- 3,5-Bis(trifluoromethyl)
3-[(L-alaninyl)amino]-2,3- C-J 676.7
bis(trifluoromethyl)phenylacetyl)-L- phenylacetic acid
dihydro-1-(2-N,N-diethyl alaninyl)amino]-2,3-dihydro-1-(2-
(Aldrich) aminoethyl)-5-(2-pyridyl)-1H- N,N-diethyl
aminoethyl)-5-(2- 1,4-benzodiazepin-2-one
pyridyl)-1H-1,4-benzodiazepin-2- (Example C-AF) one 8C-482
3-[(N'-((methylthio)acetyl)-L- (methylthio)acetic acid
3-[(L-alaninyl)amino]-2,3- C-J 510.6 alaninyl)amino]-2,3-dihydro--
1-(2- (Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl
aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-
pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one
(Example C-AF) 8C-483 3-[(N'-(cyclohexylacetyl)-L- cyclohexylacetic
acid 3-[(L-alaninyl)amino]-2,3- C-J 546.7
alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-484
3-[(N'-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic
3-[(L-alaninyl)amino]-2,3- C-J 646.6
L-alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethyl
N,N-diethyl aminoethyl)-5-(2- (Aldrich)
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-485
3-[(N'-(benzo[b]thiophene-3-acetyl)- benzo[b]thiophene-3-
3-[(L-alaninyl)amino]-2,3- C-J 596.7
L-alaninyl)amino]-2,3-dihydro-1-(2- acetic acid
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Lancaster)
aminoethyl)-5-(2-pyridy- l)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-486
3-[(N'-(benzoylformyl)-L- benzoylformic acid
3-[(L-alaninyl)amino]-2,3- C-J 554.6
alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-487 3-[(N'-(2,4,6-
2,4,6-trimethylphenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 582.7
trimethylphenylacetyl)-L- acid dihydro-1-(2-N,N-diethyl
alaninyl)amino]-2,3-dihydro-1-(2- (Lancaster)
aminoethyl)-5-(2-pyridyl)-1H- N,N-diethyl aminoethyl)-5-(2-
1,4-benzodiazepin-2-one pyridyl)-1H-1,4-benzodiazepin-2- (Example
C-AF) one 8C-488 3-[(N'-(4-biphenylacetyl)-L- 4-biphenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 616.8 alaninyl)amino]-2,3-dihydro--
1-(2- (Lancaster) dihydro-1-(2-N,N-diethyl N,N-diethyl
aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-
pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one
(Example C-AF) 8C-489 3-[(N'-(3,4-difluorophenylacetyl)-L-
3,4-difluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 576.6
alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethyl
N,N-diethyl aminoethyl)-5-(2- (Aldrich)
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-490
3-[(N'-(4-(2-thienyl)butyryl)-L- 4-(2-thienyl)butyric acid
3-[(L-alaninyl)amino]-2,3- C-J 574.7
alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-491
3-[(N'-(5-methylhexanoyl)-L- 5-methylhexanoic acid
3-[(L-alaninyl)amino]-2,3- C-J 534.7
alaninyl)amino]-2,3-dihydro-1-(2- (P&B)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-492 3-[(N'-(3-
mono-methyl succinate 3-[(L-alaninyl)amino]-2,3- C-J 536.6
methoxycarbonylpropionyl)-L- (Aldrich) dihydro-1-(2-N,N-diethyl
alaninyl)amino]-2,3-dihydro-1-- (2- aminoethyl)-5-(2-pyridyl)-1H-
N,N-diethyl aminoethyl)-5-(2- 1,4-benzodiazepin-2-one
pyridyl)-1H-1,4-benzodiazepin-2- (Example C-AF) one 8C-493
3-[(N'-(methanesulfonylacetyl)-L- - methanesulfonylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 542.6
alaninyl)amino]-2,3-dihydro-1-(2- (Lancaster)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-494
3-[(N'-(4-toluenesulfonylacetyl)-L- 4-toluenesulfonylacetic
3-[(L-alaninyl)amino]-2,3- C-J 618.7
alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethyl
N,N-diethyl aminoethyl)-5-(2- (Lancaster)
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-495
3-[(N'-(2,6-difluoromandelyl)-L- 2,6-difluoromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 592.6
alaninyl)amino]-2,3-dihydro-1-(2- (Fluorochem)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-496
3-[(N'-(4-fluoromandelyl)-L- 4-fluoromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 574.6
alaninyl)amino]-2,3-dihydro-1-(2- (Lancaster)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-497
3-[(N'-(2,5-difluoromandelyl)-L- 2,5-difluoromandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 592.6
alaninyl)amino]-2,3-dihydro-1-(2- (Fluorochem)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-498 3-[(N'-(4- 4-
3-[(L-alaninyl)amino]-2,3- C-J 586.7
(hydroxymethyl)phenoxyacetyl)-L- (hydroxymethyl)phenoxy-
dihydro-1-(2-N,N-diethyl alaninyl)amino]-2,3-dihydro-1-(2- acetic
acid aminoethyl)-5-(2-pyridyl)-1H- N,N-diethyl aminoethyl)-5-(2-
(Sigma) 1,4-benzodiazepin-2-one pyridyl)-1H-1,4-benzodiazepin-2-
(Example C-AF) one 8C-499 3-[(N'-(2.4.6-trifluorophenylace- tyl)-
2,4,6-trifluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 594.6
L-alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethyl
N,N-diethyl aminoethyl)-5-(2- (Fluorochem)
aminoethyl)-5-(2-pyridyl)-- 1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-500
3-[(N'-(4-fluoro-2- 4-fluoro-2- 3-[(L-alaninyl)amino]-2,3- C-J
626.6 (trifluoromethyl)phenylacety- l)-L- (trifluoromethyl)
dihydro-1-(2-N,N-diethyl alaninyl)amino]-2,3-dihydro-1-(2-
phenylacetic acid aminoethyl)-5-(2-pyridyl)-1H- N,N-diethyl
aminoethyl)-5-(2- (Fluorochem) 1,4-benzodiazepin-2-one
pyridyl)-1H-1,4-benzodiazepi- n-2- (Example C-AF) one 8C-501
3-[(N'-(4,4,4-trifluorobuty- ryl)-L- 4,4,4-trifluorobutyric acid
3-[(L-alaninyl)amino]-2,3- C-J 546.6
alaninyl)amino]-2,3-dihydro-1-(2- (Fluorochem)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-502
3-[(N'-(4-isopropylphenylacetyl)-L- 4-isopropylphenylacetic
3-[(L-alaninyl)amino]-2,3- C-J 582.7 alaninyl)amino]-2,3-dihydro--
1-(2- acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
(Lancaster) aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodi-
azepin-2- 1,4-benzodiazepin-2-one one (Example C-AF) 8C-503
3-[(N'-(beta-phenyllactyl)-L- beta-phenyllactic acid
3-[(L-alaninyl)amino]-2,3- C-J 570.7
alaninyl)amino]-2,3-dihydro--
1-(2- (Sigma) dihydro-1-(2-N,N-diethyl N,N-diethyl
aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-
pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one
(Example C-AF) 8C-504 3-[(N'-(mandelyl)-L- mandelic acid
3-[(L-alaninyl)amino]-2,3- C-J 556.7 alaninyl)amino]-2,3-dihydro--
1-(2- (Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl
aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-
pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one
(Example C-AF) 8C-505 3-[(N'-(4-chloromandelyl)-L- p-chloromandelic
acid 3-[(L-alaninyl)amino]-2,3- C-J 591.1
alaninyl)amino]-2,3-dihydro-1-(2- (Acros) dihydro-1-(2-N,N-diethyl
N,N-diethyl aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-
pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one
(Example C-AF) 8C-506 3-[(N'-(isovaleryl)-L- isovaleric acid
3-[(L-alaninyl)amino]-2,3- C-J 506.6 alaninyl)amino]-2,3-dihydro--
1-(2- (Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl
aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-
pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one
(Example C-AF) 8C-507 3-[(N'-(2,3,5-trifluorophenylacetyl)-
2,3,5-trifluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 594.6
L-alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethyl
N,N-diethyl aminoethyl)-5-(2- (Fluorochem)
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-508
3-[(N'-(3-methylthiopropionyl)-L- 3-methylthiopropionic acid
3-[(L-alaninyl)amino]-2,3- C-J 524.7
alaninyl)amino]-2,3-dihydro-1-(2- (Lancaster)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-509
3-[(N'-(L-alpha-hydroxyisocaproyl)- L-alpha-hydroxyisocaproic
3-[(L-alaninyl)amino]-2,3- C-J 536.7
L-alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethyl
N,N-diethyl aminoethyl)-5-(2- (Aldrich)
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-510
3-[(N'-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid
3-[(L-alaninyl)amino]-2,3- C-J 585.7
alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF) 8C-511
3-[(N'-(D-3-phenyllactyl)-L- D-3-phenyllactic acid
3-[(L-alaninyl)amino]-2,3- C-J 570.7
alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)
dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-
aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-
1,4-benzodiazepin-2-one one (Example C-AF)
General Procedure C-L
[2915] The following amino acids were employed in this procedure:
L-alanine (Aldrich), L-valine (Aldrich), L-norvaline (Aldrich),
L-methione (Aldrich), L-phenylalanine (Aldrich),
L-(+)-.alpha.-phenylglyc- ine (Aldrich),
L-.alpha.-(2-thienyl)glycine (Sigma), L-.alpha.-(3-thienyl)glycine
(Sigma), L-cyclohexylglycine hydrochloride (Senn Chemical AG),
O-tert-butyl-L-serine (Sigma), O-tert-butyl-L-threonine (Bachem)
and O-tert-butyl-L-tyrosine (Bachem).
[2916] The amino acid (60 .mu.moles), 305 mg (150 .mu.moles) of
N,O-bistrimethylsilylacetamaide and 1.5 mL of DMF were introduced
into separate fritted screw capped vials. The mixtures were heated
mildly and upon cooling 132 mg (15 .mu.moles) of
p-nitrophenylcarbonate Wang resin (actual load of 1.14 mmole/g)
(Novabiochem) was added to the individual vials. In addition, 73 mg
(60 mmoles) of dimethylaminopyridine was introduced into vials
containing L-cyclohexylglycine hydrochloride. The vials were shaken
at room temperature for 48 hours. Each reaction mixture was
filtered through the internal frit and the resulting resin was
washed with (9.times.1.0 mL) of DMF, (9.times.1.0 mL) of methanol
and (6.times.1.0 mL) of diethyl ether. Each reaction vial
containing the resin bound amino acid was then dried in a vacuum
oven at 30.degree. C.
General Procedure C-M
[2917] Into each fritted screw capped vial containing a resin bound
amino acid (from General Procedure C-L) was introduced 81 mg (60
.mu.moles) of 1-hydroxybenzotriazole hydrate (HOBT H.sub.2O), 115
mg (60 .mu.moles) of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride (EDC HCl), and 2 mL of THF. A
3-amino-2,4-dioxo-1,5-bis-(alkyl)-2,3,4,5-tetrahydro-1-
H-1,5-benzodiazepin (30 .mu.moles) selected from
3-amino-2,4-dioxo-1,5-bis-
(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin (Example
8S, Step C), 3-amino-2,4-dioxo-1,5-bis(methyl)-2,3
,4,5-tetrahydro-1H-1,5-benzodia- zepin (Example 8-R, Step C) and
3-amino-2,4-dioxo-1,5-bis(cyclopropylmethy-
l)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin (Example 8-U, Step C)
was added to the vials. Each vial was then capped and shaken at
room temperature for 4 days. Each reaction mixture was filtered
through the internal frit and the resulting resin was washed with
(3.times.2.0 mL) of DMF, (3.times.2.0 mL) of a 10% solution of
acetic acid in methanol, (3.times.2.0 mL) of a 10% solution of
acetic acid in THF, and (3.times.2.0 mL) of a 10% solution of
acetic acid in dichloromethane.
General Procedure C-N
[2918] Each resin from General Procedure C-M was suspended in 2.0
mL of trifluoroacetic acid for 30 minutes. Each reaction was
filtered through the internal frit into a 10 mL vial and the resin
was washed with (3.times.1.0 mL) of methanol. The filtrate was
concentrated under a flow of nitrogen at 30.degree. C. The
concentrated residue was dissolved in 1.5 mL of methanol and
partitioned into 3 portions. Each portion was subjected to affinity
chromatography on a pretreated SCX column (pretreatment consisted
of flushing with 2 mL of a 10% solution of acetic acid in methanol
followed by 2 mL of methanol). Once loaded, all columns were
flushed with 5 nL of methanol, discarding each wash. Each compound
was liberated from the column with 5 mL of a 1 N solution of
ammonia in a 1/1 solution of methanol and chloroform. Each solution
was transferred to a tarred vial followed by concentration under a
stream of nitrogen, followed by final concentration under
vacuum.
General Procedure C-O
[2919] To each vial containing a specific amino acid benzodiazepine
(from General Procedure C-N) was added 1 mL of a 0.4 M solution of
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC) and 0.9
equivalents of a carboxylic acid selected from
3,5-difluorophenylacetic acid, cyclopentylacetic acid and
4,4,4-trifluorophenylacetic acid. The vials were capped and shaken
for 4 days. Each reaction was then concentrated under a continuous
flow of nitrogen. The residue was subjected to affinity
chromatography on a pretreated SCX column (pretreatment consisted
of flushing with 2 mL of a 10% solution of acetic acid in methanol
followed by 2 mL of methanol). Once loaded, all columns were eluted
with 5 mL of methanol. Each solution was transferred to a tarred
vial followed by concentration under a stream of nitrogen with
final concentration under vacuum.
[2920] Using the procedures indicated, the compounds shown in Table
C-3 were prepared. In this table, Starting Material 1 was prepared
using General Procedures C-L, C-M and C-N. 3,5-Difluorophenylacetic
acid and cyclopenylacetic acid are available from Aldrich, and
4,4,4-trifluorobutyric acid is available from Fluorochem.
38TABLE C-3 Example General No. Compound Starting Material 1
Starting Material 2 Procedure MS 8C-512
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Alaninyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 529.2 alaninyl]-amino-2,4-dioxo-1,5--
bis- dioxo-1,5-bis-(2- Acid (2-methylpropyl)-2,3,4,5-tetrahydro-
methylpropyl)-2,3,4,5- 1H-1,5-benzodiazepine tetrahydro-1H-1,5-
benzodiazepine 8C-513 3-[N-(3,5-Difluorophenylacetyl)-L-
3-(L-Alaninyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 445.1
alaninyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(methyl)- Acid
(methyl)-2,3,4,5-tetrahydro-1H-1,5- 2,3,4,5-tetrahydro-1H-1,5-
benzodiazepine benzodiazepine 8C-514 3-[N-(3,5-Difluorophenylacety-
l)-L- 3-(L-Alaninyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 525.2
alaninyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis- Acid
(cyclopropylmethyl)-2,3,4,5-tetrahy- (cyclopropylmethyl)-
dro-1H-1,5-benzodiazepine 2,3,4,5-tetrahydro-1H-1,5- benzodiazepine
8C-515 3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Valinyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 557.3
valinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2- Acid
(2-methylpropyl)-2,3,4,5-tetrahydro- methylpropyl)-2,3,4,5-
1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine 8C-516
3-[N-(3,5-Difluorophenylacetyly-L- 3-(L-Valinyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 473.2 valinyl]-amino-2,4-dioxo-1,5-b-
is- dioxo-1,5-bis-(methyl)- Acid (methyl)-2,3,4,5-tetrahydro-1H-1,-
5- 2,3,4,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-517
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Valinyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 553.2 valinyl]-amino-2,4-dioxo-1,5-b-
is- dioxo-1,5-bis-(cyclopropyl- Acid (cyclopropylmethyl)-2,3,4,5-t-
etrahy- methyl)-2,3,4,5-tetrahydro- dro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-518 3-[N-(3,5-Difluorophenylacetyl)-L-
3-(L-Norvalinyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 557.3
norvalinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl- Acid
bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-519
3-[(N-(3,5-Difluorophenylacetyl)-L- 3-(L-Norvalinyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 473.2 norvalinyl]-amino-2,4-dioxo-1,-
5- dioxo-1,5-bis-(methyl)- Acid bis-(methyl)-2,3,4,5-tetrahydro-1H-
- 2,3,4,5-tetrahydro-1H-1,5- 1,5-benzodiazepine benzodiazepine
8C-520 3-[N-(3,5-Difluorophenylacetyl)-L-
3-(L-Norvalinyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 553.2
norvalinyl]-amino-2,4-dioxo-1,- 5- dioxo-1,5-bis-(cyclopropyl- Acid
bis-(cyclopropylmethyl)-2,3,4,- 5- methyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-521
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Methioninyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 587.3
methioninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl- Acid
bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-522
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Methioninyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 503.2 methioninyl]-amino-2,4-dioxo-1-
,5- dioxo-1,5-bis-(methyl)- Acid bis-(methyl)-2,3,4,5-tetrahydro-1-
H- 2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine 1,5-benzodiazepine
8C-523 3-(N-(3,5-Difluorophenylacetyl)-L-
3-(L-Methioninyl)-amino-2,4- - 3,5-Difluorophenylacetic C-O 583.2
methioninyl]-amino-2,4-dioxo-- 1,5- dioxo-1,5-bis-(cyclopropyl-
Acid bis-(cyclopropylmethyl)-2,3,- 4,5- methyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-524
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Phenylalaninyl)-amino-
3,5-Difluorophenylacetic C-O 603.3 phenylalaninyl]-amino-2,4-dioxo-
2,4-dioxo-1,5-bis-(2-methyl- Acid 1,5-bis-(2-methylpropyl)-2,3,4,5-
propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-525 3-[N-(3,5-Difluorophenylacetyl)-L-
3-(L-Phenylalaninyl)-amino- 3,5-Difluorophenylacetic C-O 519.2
phenylalaninyl]-amino-2,4-diox- o- 2,4-dioxo-1,5-bis-(methyl)- Acid
1,5-bis-(methyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-
tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-526
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Phenylalaninyl)-amino-
3,5-Difluorophenylacetic C-O 601.2 phenylalaninyl]-amino-2,4-dioxo-
2,4-dioxo-1,5-bis-(cyclo- Acid 1,5-bis-(cyclopropylmethyl)-
propylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-
tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-527
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Phenylglycinyl)-amino-
3,5-Difluorophenylacetic C-O 591.3 phenylglycinyl]-amino-2,4-dioxo-
2,4-dioxo-1,5-bis-(2-methyl- Acid 1,5-bis-(2-methylpropyl)-2,3,4,5-
propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-528 3-[N-(3,5-Difluorophenylacetyl)-L-
3-(L-Phenylglycinyl)-amino- 3,5-Difluorophenylacetic C-O 507.2
phenylglycinyl]-amino-2,4-diox- o- 2,4-dioxo-1,5-bis-(methyl)- Acid
1,5-bis-(methyl)-2,3,4,5- 2,3,4,5-terahydro-1H-
tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-529
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Phenylglycinyl)-amino-
3,5-Difluorophenylacetic C-O 587.2 phenylglycinyl]-amino-2,4-dioxo-
2,4-dioxo-1,5-bis-(cyclo- Acid 1,5-bis-(cyclopropylmethyl)-
propylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-
tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-530
3-[N-(3,5-Difluorophenylacetyl)-(2- 3-[(2-Thienyl)glycine]-amino-
3,5-Difluorophenylacetic C-O 597.2
thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl- Acid
1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-531
3-[N-(3,5-Difluorophenylacetyl)-(2- 3-[(2-Thienyl)glycine]-amino-
3,5-Difluorophenylacetic C-O 513.1 thienyl)glycine]-amino-2,4-dio-
xo- 2,4-dioxo-1,5-bis-(methyl)- Acid 1,5-bis-(methyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine
1,5-benzodiazepine 8C-532 3-[N-(3,5-Difluorophenylacetyl)-(2-
3-[(2-Thienyl)glycine]-amino- 3,5-Difluorophenylacetic C-O 593.2
thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis- Acid
1,5-bis-(cyclopropylmethyl)- (cyclopropylmethyl)-
2,3,4,5-tetrahydro-1H-1,5- 2,3,4,5-tetrahydro-1H- benzodiazepine
1,5-benzodiazepine 8C-533 3-[(N-(3,5-Difluorophenylacetyl)-(3-
3-[(3-Thienyl)glycine]-amino- 3,5-Difluorophenylacetic C-O 597.2
thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl- Acid
1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-534
3-[N-(3,5-Difluorophenylacetyl)-(3- 3-[(3-Thienyl)glycine]-amino-
3,5-Difluorophenylacetic C-O 513.1 thienyl)glycinel]-amino-2,4-di-
oxo- 2,4-dioxo-1,5-bis-(methyl)- Acid 1,5-bis-(methyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine
1,5-benzodiazepine 8C-535 3-[N-(3,5-Difluorophenylacetyl)-(3-
3-[(3-Thienyl)glycine]-amino- 3,5-Difluorophenylacetic C-O 593.2
thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo- Acid
1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-536 3-[N-(3,5-Difluorophenylacetyl)-L-
3-(L-Threoninyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 559.3
threoninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl- Acid
bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-537
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Threoninyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 475.2 threoninyl]-amino-2,4-dioxo-
dioxo-1,5-bis-(methyl)- Acid 1,5-bis-(methyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine
1,5-benzodiazepine 8C-538 3-[N-(3,5-Difluorophenylacetyl)-L-
3-(L-Threoninyl)-amino- 3,5-Difluorophenylacetic C-O 555.2
threoninyl]-amino-2,4-dioxo-1,5- 2,4-dioxo-1,5-bis-(cyclo- Acid
bis-(cyclopropylmethyl)-2,3,4,5- propylmethyl)-2,3,4,5-
tetrahydro-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine
8C-539 3-[N-(3,5-Difluorophenylacetyl)-L-
3-(L-Tyrosinyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 621.3
tyrosinyl]-amino-2,4-dioxo-1,5-bis dioxo-1,5-bis-(2-methyl- Acid
(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-540
3-[(N-(3,5-Difluorophenylacetyl)-L- 3-(L-Tyrosinyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 537.2 tyrosinyl]-amino-2,4-dioxo-1,5-
-bis dioxo-1,5-bis-(methyl)- Acid (methyl)-2,3,4,5-tetrahydro-1H-
2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine 1,5-benzodiazepine 8C-541
3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Tyrosinyl)-amino-2,4-
3,5-Difluorophenylacetic C-O 617.3 tyrosinyl]-amino-2,4-dioxo-1,5-
- dioxo-1,5-bis-(cyclopropyl- Acid bis-(cyclopropylmethyl)-2,3,4,5-
- methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-542 3-[N-(Cyclopentylacetyl)-L-
3-(L-Alaninyl)-amino-2,4- Cyclopentylacetic Acid C-O 485.3
alaninyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methyl-
(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-543
3-[N-(Cyclopentylacetyl)-L- 3-(L-Alaninyl)-amino-2,4-
Cyclopentylacetic Acid C-O 401.2 alaninyl]-amino-2,4-dioxo-1,5-bis-
dioxo-1,5-bis-(methyl)- (methyl)-2,3,4,5-tetrahydro-1H-
2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine 1,5-benzodiazepine 8C-544
3-[N-(Cyclopentylacetyl)-L- 3-(L-Alaninyl)-amino-2,4-
Cyclopentylacetic Acid C-O 481.3 alaninyl]-amino-2,4-dioxo-1,5-bi-
s- dioxo-1,5-bis-(cyclopropyl- (cyclopropylmethyl)-2,3,4,5-
methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-545 3-[N-(Cyclopentylacetyl)-L-
3-(L-Valinyl)-amino-2,4- Cyclopentylacetic Acid C-O 513.3
valinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methyl-
(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-546
3-[N-(Cyclopentylacetyl)-L- 3-(L-Valinyl)-amino-2,4-
Cyclopentylacetic Acid C-O 429.2 valinyl]-amino-2,4-dioxo-1,5-bis-
dioxo-1,5-bis-(methyl)- (methyl)-2,3,4,5-tetrahydro-1H-
2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine 1,5-benzodiazepine 8C-547
3-[N-(Cyclopentylacetyl)-L- 3-(L-Valinyl)-amino-2,4-
Cyclopentylacetic Acid C-O 509.3 valinyl]-amino-2,4-dioxo-1,5-bis-
- dioxo-1,5-bis-(cyclopropyl- (cyclopropylmethyl)-2,3,4,5-
methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-548 3-[N-(Cyclopentylacetyl)-L-
3-(L-Norvalinyl)-amino-2,4- Cyclopentylacetic Acid C-O 513.3
norvalinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl-
bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-549
3-[N-(Cyclopentylacetyl)-L- 3-(L-Norvalinyl)-amino-2,4-
Cyclopentylacetic Acid C-O 429.2 norvalinyl]-amino-2,4-dioxo-1,5-
dioxo-1,5-bis-(methyl)- bis-(methyl)-2,3,4,5-tetrahydro-1H-
2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine 1,5-benzodiazepine 8C-550
3-[N-(Cyclopentylacetyl)-L- 3-(L-Norvalinyl)-amino-2,4-
Cyclopentylacetic Acid C-O 509.3 norvalinyl]-amino-2,4-dioxo-1,5-
dioxo-1,5-bis-(cyclopropyl- bis-(cyclopropylmethyl)-2,3,4,5-
methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-551 3-[N-(Cyclopentylacetyl)-L-
3-(L-Methioninyl)-amino-2,4- Cyclopentylacetic Acid C-O 545.3
methioninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl-
bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-552
3-[N-(Cyclopentylacetyl)-L- 3-(L-Methioninyl)-amino-2,4-
Cyclopentylacetic Acid C-O 461.2 methioninyl]-amino-2,4-dioxo-1,5-
- dioxo-1,5-bis-(methyl)- bis-(methyl)-2,3,4,5-tetrahydro-1H-
2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine 1,5-benzodiazepine 8C-553
3-[N-(Cyclopentylacetyl)-L- 3-(L-Methioninyl)-amino-2,4-
Cyclopentylacetic Acid C-O 541.3 methioninyl]-amino-2,4-dioxo-1,5-
- dioxo-1,5-bis-(cyclopropyl- bis-(cyclopropylmethyl)-2,3,4,5-
methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-554 3-[N-(Cyclopentylacetyl)-L-
3-(L-Phenylalaninyl)-amino- Cyclopentylacetic Acid C-O 561.3
phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl-
1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-555
3-[N-(Cyclopentylacetyl)-L- 3-(L-Phenylalaninyl)-amino-
Cyclopentylacetic Acid C-O 477.2 phenylalaninyl]-amino-2,4-dioxo-
2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine
1,5-benzodiazepine 8C-556 3-[N-(Cyclopentylacetyl)-L-
3-(L-Phenylalaninyl)-amino- Cyclopentylacetic Acid C-O 557.3
phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo-
1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-557 3-[N-(Cyclopentylacetyl)-L-
3-(L-Phenylglycinyl)-amino- Cyclopentylacetic Acid C-O 547.3
phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-
1,5-bis-(2-methylpropyl)-2,3,4,5- methylpropyl)-2,3,4,5-
tetrahydro-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine
8C-558 3-[N-(Cyclopentylacetyl)-L- 3-(L-Phenylglycinyl)-amino-
Cyclopentylacetic Acid C-O 463.2 phenylglycinyl]-amino-2,4-dioxo-
2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-
2,3,4,5-Tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine
1,5-benzodiazepine 8C-559 3-[N-(Cyclopentylacetyl)-L-
3-(L-Phenylglycinyl)-amino- Cyclopentylacetic Acid C-O 543.3
phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo-
1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-560 3-[N-(Cyclopentylacetyl)-(2-
3-[(2-Thienyl)glycine]-amino- Cyclopentylacetic Acid C-O 551.3
thienyl)glycine]-amino-2,4-dioxo- - 2,4-dioxo-1,5-bis-(2-methyl-
1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-561
3-[N-(Cyclopentylacetyl)-(2- 3-[(2-Thienyl)glycine]-amino-
Cyclopentylacetic Acid C-O 469.2 thienyl)glycine]-amino-2,4-dioxo-
2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine
1,5-benzodiazepine 8C-562 3-[N-(Cyclopentylacetyl)-(2-
3-[(2-Thienyl)glycine]-amino- Cyclopentylacetic Acid C-O 549.2
thienyl)glycine]-amino-2,4-dioxo- - 2,4-dioxo-1,5-bis-(cyclo-
1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-563 3-[N-(Cyclopentylacetyl)-(3-
3-[(3-Thienyl)glycine]-amino- Cyclopentylacetic Acid C-O 553.3
thienyl)glycine]-amino-2,4-dioxo- - 2,4-dioxo-1,5-bis-(2-methyl-
1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-564
3-[N-(Cyclopentylacetyl)-(3- 3-[(3-Thienyl)glycine]-amino-
Cyclopentylacetic Acid C-O 469.2 thienyl)glycine]-amino-2,4-dioxo-
2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine
1,5-benzodiazepine 8C-565 3-[N-(Cyclopentylacetyl)-(3-
3-[(3-Thienyl)glycine]-amino- Cyclopentylacetic Acid C-O 549.2
thienyl)glycine]-amino-2,4-dioxo- - 2,4-dioxo-1,5-bis-(cyclo-
1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-566 3-[N-(Cyclopentylacetyl)-L-
3-(L-Serinyl)-amino-2,4- Cyclopentylacetic Acid C-O 417.2
serinyl]-amino-2,4-dioxo-1,5-bis dioxo-1,5-bis-(2-methyl-
(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-567
3-[N-(Cyclopentylacetyl)-L-
3-(L-Threoninyl)-amino-2,4- Cyclopentylacetic Acid C-O 515.3
threoninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl-
bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-568
3-[N-(Cyclopentylacetyl)-L- 3-(L-Threoninyl)-amino-2,4-dioxo-
Cyclopentylacetic Acid C-O 431.2 threoninyl]-amino-2,4-dioxo-1,5-
1,5-bis-(methyl)-2,3,4,5-tetra- bis-(methyl)-2,3,4,5-tetrahydro-
hydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-569
3-(N-(Cyclopentylacetyl)-L- 3-(L-Threoninyl)-amino-2,4-dioxo-
Cyclopentylacetic Acid C-O 511.3 threoninyl]-amino-2,4-dioxo-1,5-
1,5-bis-(cyclopropylmethyl)- bis-(cyclopropylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5-benzo- tetrahydro-1H-1,5-benzodiazepine
diazepine 8C-570 3-[N-(Cyclopentylacetyl)-L-
3-(L-Tyrosinyl)-amino-2,4- Cyclopentylacetic Acid C-O 577.3
tyrosinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methyl-
(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-571
3-[N-(Cyclopentylacetyl)-L- 3-(L-Tyrosinyl)-amino-2,4-
Cyclopentylacetic Acid C-O 493.2 tyrosinyl]-amino-2,4-dioxo-1,5-
dioxo-1,5-bis-(methyl)- bis-(methyl)-2,3,4,5-tetrahydro-
2,3,4,5-tetrahydro-1H-1,5- 1H-1,5-benzodiazepine benzodiazepine
8C-572 3-[N-(Cyclopentylacetyl)-L- 3-(L-Tyrosinyl)-amino-2,4-
Cyclopentylacetic Acid C-O 573.3 tyrosinyl]-amino-2,4-dioxo-1,5-
dioxo-1,5-bis-(cyclopropyl- bis-(cyclopropylmethyl)-2,3,4,5-
methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-573 3-[N-(4,4,4-Trifluorobutryl)-L-
3-(L-Alaninyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-O 499.2
alaninyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methyl-
(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-574
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Alaninyl)-amino-2,4-
4,4,4-Trifluorobutyric Acid C-O 415.1 alaninyl]-amino-2,4-dioxo-1-
,5- dioxo-1,5-bis-(methyl)- bis-(methyl)-2,3,4,5-tetrahydro-
2,3,4,5-tetrahydro-1H-1,5- 1H-1,5-benzodiazepine benzodiazepine
8C-575 3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Alaninyl)-amino-2,4-
4,4,4-Trifluorobutyric Acid C-O 495.2 alaninyl]-amino-2,4-dioxo-1-
,5-bis- dioxo-1,5-bis-(cyclopropyl- (cyclopropylmethyl)-2,3,4,5-
methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-576 3-[N-(4,4,4-Trifluorobutryl)-L-
3-(L-Valinyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-O 527.3
valinyl]-amino-2,4-dioxo-1,5-his- dioxo-1,5-bis-(2-methyl-
(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-577
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Valinyl)-amino-2,4-
4,4,4-Trifluorobutyric Acid C-O 443.2 valinyl]-amino-2,4-dioxo-1,-
5-bis- dioxo-1,5-bis-(methyl)- (methyl)-2,3,4,5-tetrahydro-1H-
2,3,4,5-tetrahydro-1H-1,5- 1,5-benzodiazepine benzodiazepine 8C-578
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Valinyl)-amino-2,4-
4,4,4-Trifluorobutyric Acid C-O 523.2 valinyl]-amino-2,4-dioxo-1,-
5-bis- dioxo-1,5-bis-(cyclopropyl- (cyclopropylmethyl)-2,3,4,5-
methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-579 3-[N-(4,4,4-Trifluorobutryl)-L-
3-(L-Norvalinyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-O 527.3
norvalinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl-
bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-580
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Norvalinyl)-amino-2,4-
4,4,4-Trifluorobutyric Acid C-O 443.2 norvalinyl]-amino-2,4-dioxo-
-1,5- dioxo-1,5-bis-(methyl)- bis-(methyl)-2,3,4,5-tetrahydro-
2,3,4,5-tetrahydro-1H- 1H-1,5-benzodiazepine 1,5-benzodiazepine
8C-581 3-(N-(4,4,4-Trifluorobutryl)-L- 3-(L-Norvalinyl)-amino-2,4-
4,4,4-Trifluorobutyric Acid C-O 523.2 norvalinyl]-amino-2,4-dioxo-
-1,5- dioxo-1,5-bis-(cyclopropyl- bis-(cyclopropylmethyl)-2,3,4,5-
methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-582 3-[N-(4,4,4-Trifluorobutryl)-L-
3-(L-Methioninyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-O 559.2
methioninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methylpropyl)-
bis-(2-methylpropyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-
tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-583
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Methioninyl)-amino-2,4-
4,4,4-Trifluorobutyric Acid C-O 475.1 methioninyl]-amino-2,4-diox-
o-1,5- dioxo-1,5-bis-(methyl)- bis-(methyl)-2,3,4,5-tetrahydro-
2,3,4,5-tetrahydro-1H-1,5- 1H-1,5-benzodiazepine benzodiazepine
8C-584 3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Methioninyl)-amino-2,4-
4,4,4-Trifluorobutyric Acid C-O 555.2 methioninyl]-amino-2,4-diox-
o-1,5- dioxo-1,5-bis-(cyclopropyl- bis-(cyclopropylmethyl)-2,3,4,5-
- methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-585 3-(N-(4,4,4-Trifluorobutryl)-L-
3-(L-Phenylalaninyl)-amino- 4,4,4-Trifluorobutyric Acid C-O 475.3
phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl-
1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-586
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Phenylalaninyl)-amino-
4,4,4-Trifluorobutyric Acid C-O 491.2 phenylalaninyl]-amino-2,4-d-
ioxo- 2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine
benzodiazepine 8C-587 3-[N-(4,4,4-Trifluorobutryl)-L-
3-(L-Phenylalaninyl)-amino- 4,4,4-Trifluorobutyric Acid C-O 571.2
phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo-
1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-588 3-[N-(4,4,4-Trifluorobutryl)-
3-(Phenylglycinyl)-amino- 4,4,4-Trifluorobutyric Acid C-O 561.2
phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-
1,5-bis-(2-methylpropyl)-2,3,4,5- methylpropyl)-2,3,4,5-
tetrahydro-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine
8C-589 3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Phenylglycinyl)-amino-
4,4,4-Trifluorobutyric Acid C-O 477.1
phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(methyl)-
1,5-bis-(methyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-
tetrahydro-1H-1,5-benzodiazepine benzodiazepine 8C-590
3-[N-(4,4,4-Trifluorobutryl)-L- 3-[L-(2-Thienyl)glycine]-
4,4,4-Trifluorobutyric Acid C-O 567.2 (2-thienyl)glycine]-amino-2-
,4- amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methylpropyl)-
(2-methylpropyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-
tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-591
3-[N-(4,4,4-Trifluorobutryl)-L- 3-[L-(2-Thienyl)glycine]-
4,4,4-Trifluorobutyric Acid C-O 483.1 (2-thienyl)glycine]-amino-2-
,4- amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(methyl)-2,3,4,5-
(methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-592 3-[N-(4,4,4-Trifluorobutryl)-L-
3-[L-(2-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-O 563.2
(2-thienyl)glycine]-amino-2,4- amino-2,4-dioxo-1,5-bis-
dioxo-1,5-bis-(cyclopropylmethyl)- (cyclopropylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-593 3-[N-(4,4,4-Trifluorobutryl)-L-
3-[L-(3-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-O 567.2
(3-thienyl)glycinel-amino-2,4- amino-2,4-dioxo-1,5-bis-(2-
dioxo-1,5-bis-(2-methylpropyl)- methylpropyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-594 3-[N-(4,4,4-Trifluorobutryl)-L-
3-[L-(3-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-O 483.1
(3-thienyl)glycine]-amino-2,4- amino-2,4-dioxo-1,5-bis-
dioxo-1,5-bis-(methyl)-2,3,4,5- (methyl)-2,3,4,5-tetrahydro-
tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-595
3-[N-(4,4,4-Trifluorobutryl)-L- 3-[L-(3-Thienyl)glycine]-
4,4,4-Trifluorobutyric Acid C-O 563.2 (3-thienyl)glycine]-amino-2-
,4- amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(cyclopropylmethyl)-
(cyclopropylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-
tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-596
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)-
4,4,4-Trifluorobutyric Acid C-O 567.3 cyclohexylglycinyl]-amino-2-
,4- amino-2,4-dioxo-1,5-bis-(2- dioxo-1,5-bis-(2-methylpropyl)-
methylpropyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-
tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-597
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)-
4,4,4-Trifluorobutyric Acid C-O 483.2 cyclohexylglycinyl]-amino-2-
,4- amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(methyl)-2,3,4,5-
(methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine
1H-1,5-benzodiazepine 8C-598 3-[N-(4,4,4-Trifluorobutryl)-L-
3-(L-Cyclohexylglycinyl)- 4,4,4-Trifluorobutyric Acid C-O 563.3
cyclohexylglycinyl]-amino-2,4- amino-2,4-dioxo-1,5-bis-
dioxo-1,5-bis-(cyclopropylmethyl)- (cyclopropylmethyl)-2,3,4,5-
2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine
benzodiazepine 8C-599 3-[N-(4,4,4-Trifluorobutryl)-L-
3-(L-Cyclohexylglycinyl)- 4,4,4-Trifluorobutyric Acid C-O 527.3
threoninyl]-amino-2,4-dioxo-1,5- amino-2,4-dioxo-1,5-bis-
bis-(2-methylpropyl)-2,3,4,5- (2-methylpropyl)-2,3,4,5-
tetrahydro-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine
8C-600 3-[N-(4,4,4-Trifluorobutryl)- 3-(L-Cyclohexylglycinyl)-
4,4,4-Trifluorobutyric Acid C-O 445.2
threoninyl]-amino-2,4-dioxo-1,5- amino-2,4-dioxo-1,5-bis-
bis-(methyl)-2,3,4,5-tetrahydro- (methyl)-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-601
3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)-
4,4,4-Trifluorobutyric Acid C-O 525.2 threoninyl]-amino-2,4-dioxo-
-1,5- amino-2,4-dioxo-1,5-bis- bis-(cyclopropylmethyl)-2,3,4,5-
(cyclopropylmethyl)-2,3,4,5- tetrahydro-1H-1,5-benzodiazepine
tetrahydro-1H-1,5- benzodiazepine
General Procedure C-P
[2921] A solution of the carboxylic acid (0.75 mL, 0.05 M in DCM)
was reacted with
L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-
-6-one (0.75 mL, 0.06 M in DCM) (from Example 7-I), PP-HOBT (0.3
mL, 0.15 M in DMF, this reagent was used only with alpha
substituted carboxylic acids), and EDC (0.3 mL, 0.15 M). The
reaction was mixed for 18 hours, then purified on a Varian SCX
column (500 mg column prewashed with MeOH (3.times.2.5 mL) and 20%
MeOH:DCM (3.times.2.5 mL)) eluting with 2.5 mL of 20% MeOH:DCM.
General Procedure C-Q
[2922] Step A: FMOC-Gly Wang resin (20 g, 10.8 mmole, Novabiochem
A16415) was reacted with a 30% solution of piperidine in
N-methylpyrrolidinone (NMP) for 30 minutes. The solution was
drained and the resin washed with NMP (5.times.200 mL).
Benzophenone imine (19.5 g, 108 mmole) in NMP (150 mL) was added to
the resin followed by glacial acetic acid (5.6 g, 94 mmole) and the
reaction was mixed overnight at room temperature. Reagents were
drained and the resin washed with NMP (5.times.150 mL) followed by
DCM (5.times.150 mL). The resin was dried under vacuum to afford
(benzophenone imine)-Gly Wang resin with a theoretical loading of
0.56 mmole per gram.
[2923] Step B: A suspension of the resin from Step A in NMP (9 mL)
was reacted with an alkyl bromide (5.6 mL of 1 M solution in NMP)
selected from 1-bromo-2-ethylbutane, 1-bromo-3-methylbutane,
cyclopropylmethyl bromide, 1-bromo-2-cyclohexylethane,
1-bromo4-fluorobutane, and 1-bromo-2-methylbutane; and BEMP (5.6 mL
of 1 M solution in NMP) and Bu.sub.4NI (5.6 mL of 1 M solution in
NMP) for 20 hours at room temperature. Reagents were drained and
the resin washed with NMP (3.times.15 mL). To a mixture of the
resin in THF (7 mL) was added hydroxylamine hydrochloride (2 mL of
a 1.6 M solution in water) and the reaction was mixed for 20 hours
at room temperature. Reagents were drained and the resin washed
sequentially with THF (2.times.5 mL), 0.5 M solution of
diisopropylethylamine in THF (5 mL), THF (5 mL), and NMP (3.times.5
mL).
[2924] Step C: The resin from Step B was divided into 12 equal
reactions using an isopicnic solution in NMP:CH.sub.2Cl.sub.2. To
each reaction was added sequentially a carboxylic acid (0.75 mL of
a 0.45 M solution in NMP), HOBT (0.75 mL of a 0.45 M solution in
NMP) and DIC (0.75 mL of a 0.45 M solution in NMP). The reaction
was mixed for 18 hours at room temperature. Reagents were drained
and the resin washed with NMP (5.times.0.5 mL), and DCM
(5.times.0.5 mL). The resin was mixed with TFA:H.sub.2O (95:5, 0.5
mL) for 4 hours. The filtrate was collected, resin washed with
TFA:H.sub.2O (95:5, 0.5 mL) and the filtrates combined. Solvents
were evaporated to yield the N-acyl amino acid.
General Procedure C-R
[2925] Various acylated amino acids (approximately 0.02 mmole)
(from General Procedure C-Q) in separate vials were reacted with
5-amino-7-methyl-5,7-dihydro-6H-dibenz[bd]azepin-6-one (0.1 mL, 0.3
M in DCM) (Example 7-A), PP-HOBT (0.2 mL, 0.15 M in DMF), and
EDC-HCl (0.4 mL, 0.08 M in DCM). Reactions were mixed for 18 hours
at room temperature. Reactions were diluted with 0.5 mL MeOH,
loaded onto a Varian SCX column (500 mg, Varian Sample
Preparations, pre-washed with MeOH (2.5 mL) and 10% MeOH:CHCl.sub.3
(2.5 mL)), and eluted with 10% MeOH:CHCl.sub.3 (2.5 mL). Solvents
were evaporated from the products and the crude products purified
by semi-prep reverse phase chromatography (gradient 0 to 100%, 0.1%
TFA in H.sub.2O to 0.08% TFA in CH.sub.3CN). The correct molecular
ion was detected for each product by ionspray mass spec and
analytical reverse phase chromatography (gradient 0 to 100%, 0.01%
TFA in H.sub.2O to 0.08% TFA in CH3CN) showed the products to be
greater than 90% pure.
[2926] Using the procedures indicated, the compounds shown in Table
C-4 were prepared. In this table, starting material 2 was prepared
as described in Example 7-I.
39TABLE C-4 Example General No. Compound Starting Material 1
Starting Material 2 Procedure MS 7C-1 5-{N'-(Cyclopentyl acetyl)-L-
Cyclopentyl acetic acid 5-(L-alaninyl)-amino-7- C-P 420.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-2
5-{N'-(3-cyclopentylprop- ionyl)-L- 3-cyclopentylpropionic
5-(L-alaninyl)-amino-7- C-P 434.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-3
5-{N'-(cyclohexylacetyl)-L- cyclohexylacetic acid
5-(L-alaninyl)-amino-7- C-P 434.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-4 5-{N'-(t-butylacetyl)-L--
alaninyl}- t-butylacetic acid 5-(L-alaninyl)-amino-7- C-P 408.2
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-5
5-{N'-(phenylacetyl)-L-alaninyl}- phenylacetic acid
5-(L-alaninyl)-amino-7- C-P 428.2 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-6 5-{N'-(3-bromophenylacetyl)-L-
3-bromophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 506.0,
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
508.0 dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one
7C-7 5-{N'-(3-fluorophenylacetyl)-L- 3-fluorophenylacetic acid
5-(L-alaninyl)-amino-7- C-P 446.0 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-8 5-{N'-(3-chlorophenylace- tyl)-L-
3-chlorophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 462.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-9
5-{N'-(3- 3- 5-(L-alaninyl)-amino-7- C-P 496.0
(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenyl-
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acetic acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-
(Marshallton) one 7C-10 5-{N'-(4-fluorophenylacetyl)-L-
4-fluorophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 446.0
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-11
5-{N'-(hexanoyl)-L-alaninyl}- hexanoic acid 5-(L-alaninyl)-amino-7-
C-P 408.2 amino-7-methyl-5,7-dihydro-6H- (Aldrich)
methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-12 5-{N'-(heptanoyl)-L-alaninyl}-
heptanoic acid 5-(L-alaniny)-amino-7- C-P 422.2
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-13
5-{3,4-difluorophenylacetyl)-L- 3,4-difluorophenylacetic
5-(L-alaninyl)-amino-7- C-P 464.2 alaninyl)-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-14
5-{N'-(cyclopropylacetyl)-L- cyclopropylacetic acid
5-(L-alaninyl)-amino-7- C-P 392.2 alaninyl}-amino-7-methyl-5,7-
(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
- dibenz[b,d]azepin-6-one one 7C-15
5-{N'-(2-cyclopentene-1-acetyl)-L- 2-cyclopentene-1-acetic
5-(L-alaninyl)-amino-7- C-P 418.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-16
5-{N'-(3-cyclohexylpropionyl)-L- 3-cyclohexylpropionic acid
5-(L-alaninyl)-amino-7- C-P 448.0 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-17 5-{N'-(isovaleryl)-L-al- aninyl}-
isovaleric acid 5-(L-alaninyl)-amino-7- C-P 394.0
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-18
5-{N'-(citronellyl)-L-alaninyl}- citronellic acid
5-(L-alaninyl)-amino-7- C-P 462.2 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-19 5-{N'-(3-benzoylpropionyl)-L-
3-benzoylpropionic acid 5-(L-alaninyl)-amino-7- C-P 470.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-20
5-{N'-(2-chlorophenylacetyl)-L- 2-chlorophenylacetic acid
5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-21 5-{N'-(4-pentenoyl)-L-a-
laninyl}- 4-pentenoic acid 5-(L-alaninyl)-amino-7- C-P 392.0
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-22
5-{N'-(valeryl)-L-alaninyl}-amino- valeric acid
5-(L-alaninyl)-amino-7- C-P 394.0 7-methyl-5,7-dihydro-6H-
(Eastman) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-23 5-{N'-(2-thiophenecetyl)-L-
2-thiophenecetic acid 5-(L-alaninyl)-amino-7- C-P 434.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-24
5-{N'-(4-(2-thienyl)butyryl)-L- 4-(2-thienyl)butyric acid
5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-25 5-{N'-(4-(4-nitrophenyl-
)butyryl)-L- 4-(4-nitrophenyl)butyric 5-(L-alaninyl)-amino-7- C-P
501.0 alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one
one 7C-26 5-{N'-(2,4-difluorophenylacetyl)-L-
2,4-difluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 464.2
alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one
one 7C-27 5-{N'-(2,6-difluorophenylacetyl)-L-
2,6-difluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 464.2
alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one
one 7C-28 5-{N'-(4-isopropylphenylacetyl)-L-
4-isopropylphenylacetic 5-(L-alaninyl)-amino-7- C-P 470.2
alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one
one 7C-29 5-{N'-(1-adamantaneacetyl)-L- 1-adamantaneacetic acid
5-(L-alaninyl)-amino-7- C-P 486.4 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-30 5-{N'-(cyclohexanepenta- noyl)-L-
cyclohexanepentanoic acid 5-(L-alaninyl)-amino-7- C-P 476.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-31
5-{N'-((methylthio)acetyl)-L- (methylthio)acetic acid
5-(L-alaninyl)-amino-7- C-P 398.0 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-32 5-{N'-(2-thiophenepenta- noyl)-L-
2-thiophenepentanoic acid 5-(L-alaninyl)-amino-7- C-P 476.0
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-33
5-{N'-(2-norbornaneacetyl)-L- 2-norbornaneacetic acid
5-(L-alaninyl)-amino-7- C-P 446.0 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-34 5-{N'-(3,5-difluorophen-
ylacetyl)-4- (3,5-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R
534.2 ethylnorleucinyl}-amino-7-methyl- 4-ethylnorleucine
dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure
C-Q) dibenz[bd]azepin-6-one 6-one 7C-35
5-{N'-(3,5-difluorophenylacetyl)-4- (3,5-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 520.2 methylnorleucinyl}-amino-7-
4-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-36
5-{N'-(3,5-difluorophenylacetyl)-3- (3,5-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 504.0 cyclopropylalaninyl}-amino-7-
3-cyclopropylalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-37
5-{N'-(3,5-difluorophenylacetyl)-4- (3,5-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 560.2 cyclohexylhomoalaninyl}-amino-7-
4-cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-38
5-{N'-(3,5-difluorophenylacetyl)-6- (3,5-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 524.0 fluoronorleucinyl}-amino-7-methyl
6-fluoronorleucine dihydro-6H- 5,7-dihydro-6H-dibenz(b,d]azepin-
(General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-39
5-{N'-(3,5-difluorophenylacetyl)-4- (3,5-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 520.0 methylnorleucinyl}-amino-7-
4-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-40
5-{N'-(cyclohexylacetyl)-4- (cyclohexylacetyl)-4-
5-amino-7-methyl-5,7- C-R 504.3 ethylnorleucinyl}-amino-7-methyl-
ethylnorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin-
(General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-41
5-{N'-(cyclopropylacetyl)-4- (cyclopropylacetyl)-4-
5-amino-7-methyl-5,7- C-R 462.3 ethylnorleucinyl}-amino-7-methyl-
ethylnorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin-
(General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-42
5-{N'-(isovaleryl)-4- (isovaleryl)-4- 5-amino-7-methyl-5,7- C-R
464.3 ethylnorleucinyl}-amino-7-methyl- ethylnorleucine dihydro-6H-
5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)
dibenz[bd]azepin-6-one 6-one 7C-43 5-{N'-(3- (3-
5-amino-7-methyl-5,7- C-R 566.3 (trifluoromethyl)phenylacetyl)-4-
(trifluoromethyl)phenyl- dihydro-6H- ethylnorleucinyl)-amino-7-me-
thyl- acetyl)-4-ethylnorleucine dibenz[bd]azepin-6-one
5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q) 6-one
7C-44 5-{N'-(3,4-difluorophenylacetyl)-4-
(3,4-difluorophenylacetyl- )- 5-amino-7-methyl-5,7- C-R 534.3
ethylnorleucinyl}-amino-7-methy- l- 4-ethylnorleucine dihydro-6H-
5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)
dibenz[bd]azepin-6-one 6-one 7C-45
5-{N'-(2,4-difluorophenylacetyl)-4- (2,4-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 534.3 ethylnorleucinyl}-amino-7-methyl-
4-ethylnorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin-
(General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-46
5-{N'-(3-fluorophenylacetyl)-4- (3-fluorophenylacetyl)-4-
5-amino-7-methyl-5,7- C-R 502.3 methylnorleucinyl}-amino-7-
methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-47
5-{N'-(cyclopentylacetyl)-4- (cyclopentylacetyl)-4-
5-amino-7-methyl-5,7- C-R 476.3 methylnorleucinyl}-amino-7-
methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-48
5-{N'-(cyclohexylacetyl)-4- (cyclohexylacetyl)-4-
5-amino-7-methyl-5,7- C-R 490.3 methylnorleucinyl}-amino-7-
methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-49
5-{N'-(cyclopropylacetyl)-4- (cyclopropylacetyl)-4-
5-amino-7-methyl-5,7- C-R 448.2 methylnorleucinyl}-amino-7-
methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-50
5-{N'-(2-thiopheneacetyl)-4- (2-thiopheneacetyl)-4-
5-amino-7-methyl-5,7- C-R 490.2 methylnorleucinyl}-amino-7-
methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-51
5-{N'-(isovaleryl)-4- (isovaleryl)-4- 5-amino-7-methyl-5,7- C-R
450.3 methylnorleucinyl}-amino-7- methylnorleucine dihydro-6H-
methyl-5,7-dihydro-6H- (General Procedure C-Q)
dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-52 5-{N'-(3- (3-
5-amino-7-methyl-5,7- C-R 552.3 (trifluoromethyl)phenylacetyl)-4-
(trifluoromethyl)phenyl- dihydro-6H- methylnorleucinyl}-amino-7-
acetyl)-4-methylnorleucine dibenz[bd]azepin-6-one
methyl-5,7-dihydro-6H- (General Procedure C-Q)
dibenz[b,d]azepin-6-one 7C-53 5-{N'-(4-fluorophenylacetyl)-4-
(4-fluorophenylacetyl)-4- 5-amino-7-methyl-5,7- C-R 502.3
methylnorleucinyl}-amino-7- methylnorleucine dihydro-6H-
methyl-5,7-dihydro-6H- (General Procedure C-Q)
dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-54
5-{N'-(3,4-difluorophenylacetyl)-4- (3,4-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 520.2 methylnorleucinyl}-amino-7-
4-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-55
5-{N'-(2,4-difluorophenylacetyl)-4- (2,4-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 520.3 methylnorleucinyl}-amino-7-
4-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-56
5-{N'-(3-fluorophenylacetyl)-4- (3-fluorophenylacetyl)-4-
5-amino-7-methyl-5,7- C-R 542.3 cyclohexylhomoalaninyl}-amino-7-
cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bdl]azepin-6-one dibenz[b,d]azepin-6-one
7C-57 5-{N'-(cyclopentylacetyl)-4- (cyclopentylacetyl)-4-
5-amino-7-methyl-5,7- C-R 516.3 cyclohexylhomoalaninyl}-amino-7-
cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-58
5-{N'-(cyclohexylacetyl)-4- (cyclohexylacetyl)-4-
5-amino-7-methyl-5,7- C-R 530.4 cyclohexylhomoalaninyl}-amino-7-
cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-59
5-{N'-(cyclopropylacetyl)-4- (cyclopropylacetyl)-4-
5-amino-7-methyl-5,7- C-R 488.3 cyclohexylhomoalaninyl}-amino-7-
cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-60
5-{N'-(isovaleryl)-4- (isovaleryl)-4- 5-amino-7-methyl-5,7- C-R
490.3 cyclohexylhomoalaninyl}-amino-7- cyclohexylhomoalanine
dihydro-6H- methyl-5,7-dihydro-6H- (General Procedure C-Q)
dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-61
5-{N'-(4-fluorophenylacetyl)-4- (4-fluorophenylacetyl)-4-
5-amino-7-methyl-5,7- C-R 542.3 cyclohexylhomoalaninyl}-amino-7-
cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-62
5-{N'-(3,4-difluorophenylacetyl)-4- (3,4-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 560.3 cyclohexylhomoalaninyl}-amino-7-
4-cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-63
5-{N'-(2,4-difluorophenylacetyl)-4- (2,4-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 560.3 cyclohexylhomoalaninyl}-amino-7-
4-cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (General
Procedure C-Q) dibenz(bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-64
5-{N'-(3-fluorophenylacetyl- )-6- (3-fluorophenylacetyl)-6-
5-amino-7-methyl-5,7- C-R 506.2 fluoronorleucinyl}-amino-7-methyl-
fluoronorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin-
(General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-65
5-{N'-(cyclopentylacetyl)-6- (cyclopentylacetyl)-6-
5-amino-7-methyl-5,7- C-R 480.3 fluoronorleucinyl}-amino-7-methyl-
fluoronorleucine
dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure
C-Q) dibenz[bd]azepin-6-one 6-one 7C-66 5-{N'-(cyclohexylacetyl)-6-
(cyclohexylacetyl)-6- 5-amino-7-methyl-5,7- C-R 494.3
fluoronorleucinyl)-amino-7-methyl- fluoronorleucine dihydro-6H-
5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)
dibenz[bd]azepin-6-one 6-one 7C-67 5-{N'-(cyclopropylacetyl)-6-
(cyclopropylacetyl)-6- 5-amino-7-methyl-5,7- C-R 452.2
fluoronorleucinyl)-amino-7-methyl- fluoronorleucine dihydro-6H-
5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)
dibenz[bd]azepin-6-one 6-one 7C-68 5-{N'-(isovaleryl)-6-
(isovaleryl)-6- 5-amino-7-methyl-5,7- C-R 454.2
fluoronorleucinyl)-amino-7-methyl- fluoronorleucine dihydro-6H-
5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)
dibenz[bd]azepin-6-one 6-one 7C-69 5-{N'-(3- (3-
5-amino-7-ethyl-5,7- C-R 556.2 (trifluoromethyl)phenylacetyl)-6-
(trifluoromethyl)phenyl- dihydro-6H- fluoronorleucinyl}-amino-7-m-
ethyl- acetyl)-6-fluoronorleucine dibenz[bd]azepin-6-one
5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q) 6-one
7C-70 5-{N'-(4-fluorophenylacetyl)-6- (4-fluorophenylacetyl)-6-
5-amino-7-methyl-5,7- C-R 506.2 fluoronorleucinyl}-amino-7-methyl-
- fluoronorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin-
(General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-71
5-{N'-(3,4-difluorophenylacetyl)-6- (3,4-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 524.2 fluoronorleucinyl}-amino-7-methy-
6-fluoronorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin-
(General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-72
5-{N'-(2,4-difluorophenylacetyl)-6- (2,4-difluorophenylacetyl)-
5-amino-7-methyl-5,7- C-R 524.2 fluoronorleucinyl}-amino-7-methyl-
- 6-fluoronorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin-
(General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-73
5-{N'-(4-methoxyphenylacetyl)-L- 4-methoxyphenylacetic
5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-74 5-{N'-(3-(4- 3-(4-
5-(L-alaninyl)-amino-7- C-P 472.2 methoxyphenyl)propionyl)-- L-
methoxyphenyl)propionic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-75
5-{N'-(1-naphthylacetyl)-L- 1-naphthylacetic acid
5-(L-alaninyl)-amino-7- C-P 478.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-76 5-{N'-(3,4- 3,4-
5-(L-alaninyl)-amino-7- C-P 472.2 methylenedioxyphenylacetyl)-L-
methylenedioxyphenyl- methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acetic acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-77
5-{N'-(hydrocinnamyl)-L- hydrocinnamic acid 5-(L-alaninyl)-amino-7-
C-P 442.2 alaninyl}-amino-7-methyl-5,7- (Aldrich)
methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-78 5-{N'-(octanoyl)-L-alan- inyl}-
octanoic acid 5-(L-alaninyl)-amino-7- C-P 436.2
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-79 5-{N'-(3-(3-
3-(3- 5-(L-alaninyl)-amino-7- C-P 458.2 hydroxyphenyl)propionyl)-L-
hydroxyphenyl)propionic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) one 7C-80 5-{N'-(3-(4-
3-(4- 5-(L-alaninyl)-amino-7- C-P 456.2 methylphenyl)propionyl)-L-
methylphenyl)propionic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) one 7C-81 5-{N'-(3-(4-
3-(4- 5-(L-alaninyl)-amino-7- C-P 476.1 chlorophenyl)propionyl)-L-
chlorophenyl)propionic methyl-5,7-dihydro-6H- 478.1
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Trans World) one 7C-82
5-{N'-(3-phenylbutyryl)-L- 3-phenylbutyric acid
5-(L-alaninyl)-amino-7- C-P 456.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-83 5-{N'-(3-(4- 3-(4-
5-(L-alaninyl)-amino-7- C-P 458.2 hydroxyphenyl)propionyl)-L-
hydroxyphenyl)propionic methyl-5,7-dihydro-6H-
alaninyl)-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-84
5-{N'-(3,4,5-trifluorophenylacetyl)- 3,4,5-trifluorophenylacetic
5-(L-alaninyl)-amino-7- C-P 482.1 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Fluorochem) dibenz[b,d]azepin-6-one one 7C-85 5-{N'-(4-(4- 4-(4-
5-(L-alaninyl)-amino-7- C-P 486.2 methoxyphenyl)butyryl)-L-
methoxyphenyl)butyric methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-86 5-{N'-(3-
mono-methyl succinate = 5-(L-alaninyl)-amino-7- C-P 424.1
(Methoxycarbonyl)propionyl)-L- 3- methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- (Methoxycarbonyl)propionic
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- acid one
(Aldrich) 7C-87 5-{N'-(4-pheny[butyryl)-L- 4-phenylbutyric acid
5-(L-alaninyl)-amino-7- C-P 456.2 alaninyl}-amino-7-methyl-5- ,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-- 6-
dibenz[b,d]azepin-6-one one 7C-88
5-{N'-(3-(benzylthio)-propionyl)-L- 3-(benzylthio)-propionic
5-(L-alaninyl)-amino-7- C-P 488.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Sigma-Aldrich Rare) dibenz[b,d]azepin-6-one one 7C-89
5-{N'-(3-methylpentanoyl)-L- 3-methylpentanoic acid
5-(L-alaninyl)-amino-7- C-P 408.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-90 5-{N'-(7-carbomethoxyhe-
ptanoyl)- suberic acid monomethyl 5-(L-alaninyl)-amino-7- C-P 480.2
L-alaninyl}-amino-7-methyl-5,7- ester = 7- methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- carbomethoxyheptanoic
dibenz[b,d]azepin-6-one one acid (Aldrich) 7C-91
5-{N'-(2-indanylacetyl)-L- 2-indanylacetic acid
5-(L-alaninyl)-amino-7- C-P 468.2 alaninyl}-amino-7-methyl-5,7-
(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-92 5-{N'-(5-Carbomethoxype-
ntanoyl)- monomethyl adipate = 5- 5-(L-alaninyl)-amino-7- C-P 452.2
L-alaninyl}-amino-7-methyl-5,7- Carbomethoxypentanoic
methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- acid
dibenz[b,d]azepin-6-one one (Aldrich) 7C-93 5-{N'-(2-methyl-3-
2-methyl-3- 5-(L-alaninyl)-amino-7- C-P 482.2
Benzofuranacetyl)-L-alaninyl}- Benzofuranacetic acid
methyl-5,7-dihydro-6H- amino-7-methyl-5,7-dihydro-6H- (Maybridge)
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-94
5-{N'-(propionyl)-L-alaninyl}- propionic acid
5-(L-alaninyl)-amino-7- C-P 366.1 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-95 5-{N'-(3-methoxypropionyl)-L-
3-methoxypropionic acid 5-(L-alaninyl)-amino-7- C-P 396.1
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-96
5-{N'-(3-(4- 3-(4- 5-(L-alaninyl)-amino-7- C-P 460.2
fluorophenyl)propionyl)-L- fluorophenyl)propionic
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Trans
World) one 7C-97 5-{N'-(3-(4- 3-(4- 5-(L-alaninyl)-amino-7- C-P
476.1 fluorophenoxy)propionyl)-L- fluorophenoxy)propionic
methyl-5,7-dihydro-6H- alaninyl)-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Maybridge)
one 7C-98 5-{N'-(4-toluenesulfonylacetyl)-L-
4-toluenesulfonylacetic 5-(L-alaninyl)-amino-7- C-P 506.1
alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one
one 7C-99 5-{N'-(3-pentenoyl)-L-alaninyl}- 3-pentenoic acid
5-(L-alaninyl)-amino-7- C-P 392.2 amino-7-methyl-5,7-dihydro-6H-
(Fluka) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-100 5-{N'-(4-(2,4- 4-(2,4-
5-(L-alaninyl)-amino-7- C-P 540.1, dichlorophenoxy)butyryl)-L-
dichlorophenoxy)butyric methyl-5,7-dihydro-6H- 542.1
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-101
5-{N'-(2,3-dichlorophenoxyacetyl)- 2,3-dichlorophenoxyacetic
5-(L-alaninyl)-amino-7- C-P 512.1, L-alaninyl}-amino-7-methyl-5,-
7- acid methyl-5,7-dihydro-6H- 514.1 dihydro-6H-dibenz[b,d]azepin-
-6- (Aldrich) dibenz[b,d]azepin-6-one one 7C-102 5-{N'-(3-(4- 3-(4-
5-(L-alaninyl)-amino-7- C-P 504.1, chlorobenzoyl)propionyl)-L-
chlorobenzoyl)propionic methyl-5,7-dihydro-6H- 506.1
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-103
5-{N'-(4'-fluorosuccinanilyl)-L- 4'-fluorosuccinanilic acid
5-(L-alaninyl)-amino-7- C-P 503.2 alaninyl}-amino-7-methyl-5,7-
(Sigma-Aldrich Rare) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-104
5-{N'-(n- n- 5-(L-alaninyl)-amino-7- C-P 589.3
(diphenylmethyl)glutaramyl)-L- (diphenylmethyl)glutaramic
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-
(Sigma-Aldrich Rare) one 7C-105 5-{N'-(2-fluorophenylacety- l)-L-
2-fluorophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 446.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-106
5-{N'-(cyanoacetyl)-L-alaninyl}- cyanoacetic acid
5-(L-alaninyl)-amino-7- C-P 377.1 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-107 5-{N'-(succinanilyl)-L-alaninyl}-
succinanilic acid 5-(L-alaninyl)-amino-7- C-P 485.2
amino-7-methyl-5,7-dihydro-6H- (Sigma-Aldrich Rare)
methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-108 5-{N'-(2,4-dichlorophenoxyacetyl)-
2,4-dichlorophenoxyacetic 5-(L-alaninyl)-amino-7- C-P 512.1
L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H- 514.1
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one
one 7C-109 5-{N'-(2-nitrophenylacetyl)-L- 2-nitrophenylacetic acid
5-(L-alaninyl)-amino-7- C-P 473.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-110 5-{N'-(beta-propylhydro-
cinnamyl)- beta-propylhydrocinnamic 5-(L-alaninyl)-amino-7- C-P
484.3 L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Sigma-Aldrich Rare)
dibenz[b,d]azepin-6-one one 7C-111 5-{N'-(3-(2,4- 3-(2,4-
5-(L-alaninyl)-amino-7- C-P 498.2 dimethylbenzoyl)propionyl)-L-
dimethylbenzoyl)propionic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Sigma-Aldrich Rare) one 7C-112
5-{N'-(2-fluoro-3- 2-fluoro-3- 5-(L-alaninyl)-amino-7- C-P 514.3
(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenylacetic
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-
(Fluorochem) one 7C-113 5-{N'-(2,4,6-trifluorophenylacetyl- )-
2,4,6-trifluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 482.2
L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem)
dibenz[b,d]azepin-6-one one 7C-114 5-{N'-(4-fluoro-2- 4-fluoro-2-
5-(L-alaninyl)-amino-7- C-P 514.2 (trifluoromethyl)phenylacetyl)--
L- (trifluoromethyl)phenyl- methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acetic acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem) one 7C-115
5-{N'-(2-fluoro-4- 2-fluoro-4- 5-(L-alaninyl)-amino-7- C-P 514.2
(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenyl-
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acetic acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-
(Fluorochem) one 7C-116 5-{N'-(4-hydroxyphenylacetyl)-L-
4-hydroxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 444.2
alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one
one 7C-117 5-{N'-(4-methoxyphenoxyacetyl)- 4-methoxyphenoxyacetic
5-(L-alaninyl)-amino-7- C-P 474.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Lancaster) dibenz[b,d]azepin-6-one one 7C-118
5-{N'-(2-methoxyphenylacetyl)-L- 2-methoxyphenylacetic
5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-119
5-{N'-(2-bromophenylacetyl)-L- 2-bromophenylacetic acid
5-(L-alaninyl)-amino-7- C-P 508.1 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-120 5-{N'-(4-benzyloxypheno-
xyacetyl)- 4-benzyloxyphenoxyacetic 5-(L-alaninyl)-amino-7- C-P
550.2 L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one
one 7C-121 5-{N'-(4-hydroxyphenoxyacetyl)-L- 4-hydroxyphenoxyacetic
5-(L-alaninyl)-amino-7- C-P 460.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Acros)
dibenz[b,d]azepin-6-one one 7C-122 5-{N'-(levulinyl)-L-alaninyl}-
levulinic acid 5-(L-alaninyl)-amino-7- C-P 408.2
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-123
5-{N'-(2-hydroxyphenylacetyl)-L- 2-hydroxyphenylacetic
5-(L-alaninyl)-amino-7- C-P 444.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-124 5-{N'-(3,4-
3,4-dimethoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 488.2
dimethoxyphenylacetyl)-L- acid methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- (Aldrich) dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- one 7C-125 5-{N'-(3-(4- 3-(4-
5-(L-alaninyl)-amino-7- C-P 500.2 methoxybenzoyl)propionyl)-L-
methoxybenzoyl)propionic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-126 5-{N'-(3-(4-
fenbufen = 3-(4- 5-(L-alaninyl)-amino-7- C-P 546.2
Phenylbenzoyl)propionyl)-L- Phenylbenzoyl)propionic
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-
(Sigma-Aldrich Rare) one 7C-127 5-{N'-(3-hydroxyphenylacetyl)-L-
3-hydroxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 444.2
alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one
one 7C-128 5-{N'-(N-acetyl-N-phenylglycinyl)-
N-acetyl-N-phenylglycine 5-(L-alaninyl)-amino-7- C-P 485.2
L-alaninyl}-amino-7-methyl-5,7- (Kodak) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-129 5-{N'-(thiophene-3-acet- yl)-L-
thiophene-3-acetic acid 5-(L-alaninyl)-amino-7- C-P 434.1
alaninyl}-amino-7-methyl-5,7- (Acros) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-130
5-{N'-(6-phenylhexanoyl)-L- 6-phenylhexanoic acid
5-(L-alaninyl)-amino-7- C-P 484.3 alaninyl}-amino-7-methyl-5,7-
(Avocado) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-131 5-{N'-(cyclohexanebutyr- yl)-L-
cyclohexanebutyric acid 5-(L-alaninyl)-amino-7- C-P 462.3
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-132
5-{N'-(2,3,5-trifluorophenylacetyl)- 2,3,5-trifluorophenylacetic
5-(L-alaninyl)-amino-7- C-P 482.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Fluorochem) dibenz[b,d]azepin-6-one one 7C-133
5-{N'-(2,4,5-trifluorophenylacetyl)- 2,4,5-trifluorophenylacetic
5-(L-alaninyl)-amino-7- C-P 482.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Fluorochem) dibenz[b,d]azepin-6-one one 7C-134
5-{N'-(vinylacetyl)-L-alaninyl}- vinylacetic acid
5-(L-alaninyl)-amino-7- C-P 378.2 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-135 5-{N'-(3-methylthiopropionyl)-L-
3-methylthiopropionic acid 5-(L-alaninyl)-amino-7- C-P 412.1
alaninyl}-amino-7-methyl-5,7- (Lancaster) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-136
5-{N'-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid
5-(L-alaninyl)-amino-7- C-P 473.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-137 5-{N'-(n-tert-butylsucc-
inamyl)-L- n-tert-butylsuccinamic acid 5-(L-alaninyl)-amino-7- C-P
465.2 alaninyl}-amino-7-methyl-5,7- (Sigma-Aldrich Rare)
methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-138 5-{N'-(4-bromophenylace- tyl)-L-
4-bromophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 506.1,
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
508.1 dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one
7C-139 5-{N'-(3-(4- 3-(4- 5-(L-alaninyl)-amino-7- C-P 488.2
fluorobenzoyl)propionyl)-L- fluorobenzoyl)propionic
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)
one 7C-140 5-{N'-(o-chlorophenoxyacetyl)-L- o-chlorophenoxyacetic
5-(L-alaninyl)-amino-7- C-P 478.1, alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- 480.1 dihydro-6H-dibenz[b,d]azepin-6-
(Lancaster) dibenz[b,d]azepin-6-one one 7C-141
5-{N'-(p-tolylacetyl)-L-alaninyl}- p-tolylacetic acid
5-(L-alaninyl)-amino-7- C-P 442.2 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-142 5-{N'-(m-tolylacetyl)-L-alaninyl}-
m-tolylacetic acid 5-(L-alaninyl)-amino-7- C-P 442.2
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-143
5-{N'-(3,4-dichlorophenylacetyl)- 3,4-dichlorophenylacetic
5-(L-alaninyl)-amino-7- C-P 496.1, L-alaninyl}-amino-7-methyl-5,-
7- acid methyl-5,7-dihydro-6H- 498.1 dihydro-6H-dibenz[b,d]azepin-
-6- (Fairfield) dibenz[b,d]azepin-6-one one 7C-144
5-{N'-(4-chlorophenoxyacetyl)-L- 4-chlorophenoxyacetic
5-(L-alaninyl)-amino-7- C-P 478.1, alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- 480.2 dihydro-6H-dibenz[b,d]azepin-6
(Grand Island Biological) dibenz[b,d]azepin-6-one one 7C-145
5-{N'-(3-methylphenoxyacetyl)-L- 3-methylphenoxyacetic
5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Lancaster) dibenz[b,d]azepin-6-one one 7C-146
5-{N'-(4-isopropylphenoxyacetyl)- 4-isopropylphenoxyacetic
5-(L-alaninyl)-amino-7- C-P 486.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Lancaster) dibenz[b,d]azepin-6-one one 7C-147
5-{N'-(4-phenoxyphenylacetyl)-L- 4-phenoxyphenylacetic
5-(L-alaninyl)-amino-7- C-P 520.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Trans
World) dibenz[b,d]azepin-6-one one 7C-148
5-{N'-(phenylmercaptoacetyl)-L- phenylmercaptoacetic acid
5-(L-alaninyl)-amino-7- C-P 460.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-149 5-{N'-(4-ethoxyphenylac-
etyl)-L- 4-ethoxyphenylacetic acid 5-(L-alaninyl)-amino-7- C-P
472.2 alaninyl}-amino-7-methyl-5,7- (Aldrich)
methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-150 5-{N'-(2,5-
2,5-dimethoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 488.2
dimethoxyphenylacetyl)-L- acid methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- (Aldrich) dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- one 7C-151
5-{N'-(o-tolylacetyl)-L-alaninyl}- o-tolylacetic acid
5-(L-alaninyl)-amino-7- C-P 442.2 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-152 5-{N'-(3,3-diphenylpropionyl)-L-
3,3-diphenylpropionic acid 5-(L-alaninyl)-amino-7- C-P 518.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-153
5-{N'-(3-phenoxypropionyl)-L- 3-phenoxypropionic acid
5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-154 5-{N'-(4- 4-
S-(L-alaninyl)-amino-7- C-P 496.2 (trifluoromethyl)phenylacetyl)--
L- (trifluoromethyl)phenyl- methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acetic acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Maybridge) one 7C-155
5-{N'-((4-methylphenoxy)acetyl)- (4-methylphenoxy)acetic
5-(L-alaninyl)-amino-7- C-P 458.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-156
5-{N'-(2-phenoxyphenylacetyl)-L- 2-phenoxyphenylacetic
5-(L-alaninyl)-amino-7- C-P 520.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Trans
World) dibenz[b,d]azepin-6-one one 7C-157
5-{N'-(3-phenoxyphenylacetyl)-L- 3-phenoxyphenylacetic
5-(L-alaninyl)-amino-7- C-P 520.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-158
5-{N'-(3,4-dichlorophenoxyacetyl)- 3,4-dichlorophenoxyacetic
5-(L-alaninyl)-amino-7- C-P 512.1, L-alaninyl}-amino-7-methyl-5,-
7- acid methyl-5,7-dihydro-6H- 514.1 dihydro-6H-dibenz[b,d]azepin-
-6- (Aldrich) dibenz[b,d]azepin-6-one one 7C-159
5-{N'-(4-fluorophenoxyacetyl)-L- 4-fluorophenoxyacetic acid
5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-160 5-{N'-(3,4,5- 3,4,5-
5-(L-alaninyl)-amino-7- C-P 518.2 trimethoxyphenylacetyl)-L-
trimethoxyphenylacetic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-161
5-{N'-(2,4-dichlorophenylacetyl)- 2,4-dichlorophenylacetic
5-(L-alaninyl)-amino-7- C-P 496.1, L-alaninyl}-amino-7-methyl-5,-
7- acid methyl-5,7-dihydro-6H- 498.1 dihydro-6H-dibenz[b,d]azepin-
-6- (Fairfield) dibenz[b,d]azepin-6-one one 7C-162
5-{N'-(4-thianaphthenacetyl)-L- 4-thianaphthenacetic acid
5-(L-alaninyl)-amino-7- C-P 484.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-163 5-{N'-(methoxyacetyl)-L-
-alaninyl}- methoxyacetic acid 5-(L-alaninyl)-amino-7- C-P 382.2
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-164
5-(N'-(ethoxyacetyl)-L-alaninyl}- ethoxyacetic acid
5-(L-alaninyl)-amino-7- C-P 396.2 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-165 5-{N'-(phenoxyacetyl)-L-alaninyl}-
phenoxyacetic acid 5-(L-alaninyl)-amino-7- C-P 444.2
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-166
5-{N'-(3-methoxyphenoxyacetyl)- 3-methoxyphenoxyacetic
5-(L-alaninyl)-amino-7- C-P 474.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-167
5-{N'-(4-butoxyphenylacetyl)-L- 4-butoxyphenylacetic acid
5-(L-alaninyl)-amino-7- C-P 500.3 alaninyl}-amino-7-methyl-5,7-
(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
- dibenz[b,d]azepin-6-one one 7C-168 5-{N'-(3-(2- 3-(2-
5-(L-alaninyl)-amino-7- C-P 472.2 methoxyphenyl)propionyl)-L-
methoxyphenyl)propionic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-169
5-{N'-(N,N-dimethylsuccinamyl)- N,N-dimethylsuccinamic
5-(L-alaninyl)-amino-7- C-P 437.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Lancaster) dibenz[b,d]azepin-6-one one 7C-170 5-{N'-(3-(3,4-
3-(3,4- 5-(L-alaninyl)-amino-7- C-P 486.2
methylenedioxyphenyl)propionyl)- methylenedioxyphenyl)pro-
methyl-5,7-dihydro-6H- L-alaninyl}-amino-7-methyl-5,7- pionic acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Lilly) one
7C-171 5-{N'-(2-Chloro-6- 2-Chloro-6- 5-(L-alaninyl)-amino-7- C-P
480.1, fluorophenylacetyl)-L-alaniny- l}- fluorophenylacetic acid
methyl-5,7-dihydro-6H- 482.1 amino-7-methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-172
5-{N'-(2,5-difluorophenylacetyl)-L- 2,5-difluorophenylacetic
5-(L-alaninyl)-amino-7- C-P 464.2 alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-173
5-{N'-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic
5-(L-alaninyl)-amino-7- C-P 534.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,dl]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-174 5-{N'-(3,5- 3,5-
5-(L-alaninyl)-amino-7- C-P 564.2
bis(trifluoromethyl)phenylacetyl)- bis(trifluoromethyl)phenyl
methyl-5,7-dihydro-6H- L-alaninyl}-amino-7-methyl-5,7- acetic acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)
one 7C-175 5-{N'-(3,5- 3,5-dimethylphenoxyacetic
5-(L-alaninyl)-amino-7- C-P 472.2 dimethylphenoxyacetyl)-L- acid
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- (Sigma-Aldrich
Rare) dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin6 one
7C-176 5-{N'-(4-chlorophenylacetyl)-L- 4-chlorophenylacetic acid
5-(L-alaninyl)-amino-7- C-P 462.1, alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- 464.1 dihydro-6H-dibenz[b,d]aze-
pin-6- dibenz[b,d]azepin-6-one one 7C-177
5-{N'-(3-chlorophenoxyacetyl)-L- 3-chlorophenoxyacetic
5-(L-alaninyl)-amino-7- C-P 478.1, alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- 480.2 dihydro-6H-dibenz[b,d]azepin-6- -
(Lancaster) dibenz[b,d]azepin-6-one one 7C-178
5-{N'-(benzo[b]thiophene-3- benzo[b]thiophene-3-
5-(L-alaninyl)-amino-7- C-P 484.2 acetyl)-L-alaninyl}-amino-7-
acetic acid methyl-5,7-dihydro-6H- methyl-5,7-dihydro-6H-
(Lancaster) dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-179
5-{N'-(3,5- 3,5-dimethoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P
488.2 dimethoxyphenylacetyl)-L- acid methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- (Aldrich) dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- one 7C-180
5-{N'-(2,5-dimethylphenylacetyl)- 2,5-dimethylphenylacetic
5-(L-alaninyl)-amino-7- C-P 456.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Lancaster) dibenz[b,d]azepin-6-one one 7C-181
5-{N'-(mesitylacetyl)-L-alaninyl}- mesitylacetic acid
5-(L-alaninyl)-amino-7- C-P 470.2 amino-7-methyl-5,7-dihydro-6H-
(Lancaster) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-182 5-{N'-(4-biphenylacetyl)-L-
4-biphenylacetic acid 5-(L-alaninyl)-amino-7- C-P 504.2
alaninyl}-amino-7-methyl-5,7- (Lancaster) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-183
5-{N'-(N-(tert-butoxycarbonyl)-3- boc-beta-ala-oh = N-(tert-
5-(L-alaninyl)-amino-7- C-P 381.2 aminopropionyl)-L-alaninyl}-
butoxycarbonyl)-3- methyl-5,7-dihydro-6H- 481.2
amino-7-methyl-5,7-dihydro-6H- aminopropionic acid
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one (Sigma) 7C-184
5-{N'-(trans-styrylacetyl)-L- trans-styrylacetic acid
5-(L-alaninyl)-amino-7- C-P 454.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-185 5-{N'-(4-acetamidobutyr- yl)-L-
4-acetamidobutyric acid 5-(L-alaninyl)-amino-7- C-P 437.2
alaninyl)-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin6 dibenz[b,d]azepin-6-one one 7C-186
5-{N'-(3-(2- 3-(2- 5-(L-alaninyl)-amino-7- C-P 476.2,
chlorophenyl)propionyl)-L- chlorophenyl)propionic
methyl-5,7-dihydro-6H- 478.2 alaninyl}-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Trans
World) one 7C-187 5-{N'-(butyryl)-L-alaninyl}-amino- butyric acid
5-(L-alaninyl)-amino-7- C-P 380.2 7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-188 5-{N-(trans-3-hexenoyl)-L-
trans-3-hexenoic acid 5-(L-alaninyl)-amino-7- C-P 406.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-189
5-{N'-(5-phenylvaleryl)-L- 5-phenylvaleric acid
5-(L-alaninyl)-amino-7- C-P 470.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-190 5-{N'-(3-(3- 3-(3-
5-(L-alaninyl)-amino-7- C-P 472.2 methoxyphenyl)propionyl)-L-
methoxyphenyl)propionic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) one 7C-191
5-{N'-(4-chloro-beta- 4-chloro-beta- 5-(L-alaninyl)-amino-7- C-P
490.2, methylhydrocinnamyl)-L-alaninyl}- methylhydrocinnamic acid
methyl-5,7-dihydro-6H- 492.2 amino-7-methyl-5,7-dihydro-6H-
(Sigma-Aldrich Rare) dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-192 5-{N'-(3-(trifluoromethyl)butyryl)-
3-(trifluoromethyl)butyric 5-(L-alaninyl)-amino-7- C-P 448.2
L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem)
dibenz[b,d]azepin-6-one one 7C-193 5-{N'-(methanesulfonylacetyl)-L-
methanesulfonylacetic acid 5-(L-alaninyl)-amino-7- C-P 430.1
alaninyl}-amino-7-methyl-5,7- (Lancaster) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one
7C-194 5-{N'-(alpha-naphthoxyacetyl)-L- alpha-naphthoxyacetic acid
5-(L-alaninyl)-amino-7- C-P 494.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-195 5-{N'-(3-(4- 3-(4-
5-(L-alaninyl)-amino-7- C-P 562.2 phenoxybenzoyl)propionyl)-L-
phenoxybenzoyl)propionic methyl-5,7-dihydro-6H-
alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Sigma-Aldrich Rare) one 7C-196
5-{N'-(3-(2- 3-(2- 5-(L-alaninyl)-amino-7- C-P 538.2
trifluoromethylbenzoyl)propionyl)- trifluoromethy[benzoyl)pro-
methyl-5,7-dihydro-6H- L-alaninyl}-amino-7-methyl-5,7- pionic acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-
(Sigma-Aldrich Rare) one 7C-197 5-{N'-(3-benzoylamino-3-ph- enyl-
3-benzoylamino-3-phenyl- 5-(L-alaninyl)-amino-7- C-P 561.2
propionyl)-L-alaninyl}-amino-7- propionic acid
methyl-5,7-dihydro-6H- methyl-5,7-dihydro-6H- (Sigma-Aldrich Rare)
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-198 5-{N'-(4-
levulinic acid oxime = 4- 5-(L-alaninyl)-amino-7- C-P 423.2
(hydroxyimino)pentanoyl)-L- (hydroxyimino)pentanoic
methyl-5,7-dihydro-6H- alaninyl)-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-
(Sigma-Aldrich Rare) one 7C-199 5-{N'-(4'-methylglutaranil- yl)-L-
4'-methylglutaranilic acid 5-(L-alaninyl)-amino-7- C-P 499.2
alaninyl)-amino-7-methyl-5,7- (Sigma-Aldrich Rare)
methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-200 5-{N'-((4-(4-ethyl-phen- oxy)-
(4-(4-ethyl-phenoxy)- 5-(L-alaninyl)-amino-7- C-P 564.2
phenoxy)-acetyl)-L-alaninyl}- phenoxy)-acetic acid
methyl-5,7-dihydro-6H- amino-7-methyl-5,7-dihydro-6H-
(Sigma-Aldrich Rare) dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-201 5-{N'-(3-Benzoyl-3- 3-Benzoyl-3-
5-(L-alaninyl)-amino-7- C-P 528.2, phenylpropionyl)-L-alaninyl}-
phenylpropionic acid methyl-5,7-dihydro-6H- 546.2
amino-7-methyl-5,7-dihydro-6H- (Sigma-Aldrich Rare)
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-202 5-{N'-(4- 4-
5-(L-alaninyl)-amino-7- C-P 456.2, (hydroxymethyl)phenoxyacetyl)-
-L- (hydroxymethyl)phenoxy- methyl-5,7-dihydro-6H- 474.2
alaninyl}-amino-7-methyl-5,7- acetic acid dibenz[b,d]azepin-6-one
dihydro-6H-dibenz[b,d]azepin-6- (Sigma) one 7C-203
5-{N'-(4,4,4-trifluorobutyryl)-L- 4,4,4-trifluorobutyric acid
5-(L-alaninyl)-amino-7- C-P 434.1 alaninyl}-amino-7-methyl-5,7-
(Fluorochem) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin--
6- dibenz[b,d]azepin-6-one one 7C-204
5-{N'-(3-isobutyrylamino-3-phenyl- 3-isobutyrylamino-3-
5-(L-alaninyl)-amino-7- C-P 527.3 propionyl)-L-alaninyl}-amino-7-
phenyl-propionic acid methyl-5,7-dihydro-6H- methyl-5,7-dihydro-6H-
(Sigma-Aldrich Rare) dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-205 5-{N'-((2-methylphenoxy)acetyl)-
(2-methylphenoxy)acetic 5-(L-alaninyl)-amino-7- C-P 458.2
L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one
one 7C-206 5-{N'-(3- 3- 5-(L-alaninyl)-amino-7- C-P 506.2
(phenylsulfonyl)propionyl)-L- (phenylsulfonyl)propionic
methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acid
dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)
one 7C-207 5-{N'-(4-nitrophenylacetyl)-L- 4-nitrophenylacetic acid
5-(L-alaninyl)-amino-7- C-P 473.2 alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-208 5-{N'-(3-ethoxypropionyl)-L-
3-ethoxypropionic acid 5-(L-alaninyl)-amino-7- C-P 410.2
alaninyl}-amino-7-methyl-5,7- (TCI) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-209
5-{N'-(2,3-difluoromand- elyl)-L- 2,3-difluoromandelic acid
5-(L-alaninyl)-amino-7- C-P 480.2 alaninyl}-amino-7-methyl-5,7-
(Fluorochem) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-210 5-{N'-(2,6-difluoromandelyl)-L-
2,6-difluoromandelic acid 5-(L-alaninyl)-amino-7- C-P 480.2
alaninyl}-amino-7-methyl-5,7- (Fluorochem) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-- 6- dibenz[b,d]azepin-6-one one
7C-211 5-{N'-(4-fluoromandelyl)-L- 4-fluoromandelic acid
5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl}-amino-7-methyl-5,7-
(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-212 5-{N'-(2,5-difluoromand-
elyl)-L- 2,5-difluoromandelic acid 5-(L-alaninyl)-amino-7- C-P
480.2 alaninyl}-amino-7-methyl-5,7- (Fluorochem)
methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-213 5-{N'-(dl-beta-phenyllactyl)-L-
di-beta-phenyllactic acid 5-(L-alaninyl)-amino-7- C-P 458.2
alaninyl}-amino-7-methyl-5,7- (Sigma) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-214
5-{N'-(dl-mandelyl}-ami- no-7- dl-mandelic acid or dl-
5-(L-alaninyl)-amino-7- C-P 444.2 methyl-5,7-dihydro-6H-
alpha-hydroxyphenylacetic methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one acid dibenz[b,d]azepin-6-one (Aldrich)
7C-215 5-{N'-(p-chloromandelyl)-L- p-chloromandelic acid
5-(L-alaninyl)-amino-7- C-P 444.2 alaninyl}-amino-7-methyl-5,7-
(Acros) methyl-5,7-dihydro-6H- 478.1 dihydro-6H-dibenz[b,d]azepi-
n-6- dibenz[b,d]azepin-6-one one 7C-216
5-{N'-(l-alpha-hydroxyisocaproyl)- l-alpha-hydroxyisocaproic
5-(L-alaninyl)-amino-7- C-P 424.2 L-alaninyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-217
5-{N'-(4-bromomandelyl)-L- 4-bromomandelic acid
5-(L-alaninyl)-amino-7- C-P 522.1, alaninyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- 524.1
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-218
5-{N'-(l-(+)-lactyl)-L-- alaninyl}- l-(+)-lactic acid
5-(L-alaninyl)-amino-7- C-P 382.2, amino-7-methyl-5,7-dihydro-6H-
(Sigma) methyl-5,7-dihydro-6H- 454.2 dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-219 5-{N'-(d-3-phenylacetyl)-L-
d-3-phenylacetic acid 5-(L-alaninyl)-amino-7- C-P 458.2
alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-220
5-{N'-(5-methylhexanoyl- )-L- 5-methylhexanoic acid
5-(L-alaninyl)-amino-7- C-P 422.2 alaninyl}-amino-7-methyl-5,7-
(P&B) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one
General Procedure C-S
[2927] Step A: Each amino acid (150 umol) was weight into an 8- mL
capacity vial and dissolved in 1.5 mL of 10% DMF in dichloromethane
(DCM). To each vial was added 0.8 mL (175 umol) of a solution of
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (418 mg, 1.75 mmol)(from Example 7-A) and 670 mg
(1.75 mmol) of PP-HOBT (from Example C-AF) dissolved in 7.5 mL DMF.
This was followed by the addition to each vial of 2 mL
(approximately 200 umol) of a solution of EDC hydrochloride in DCM
(383 mg, 2.0 mmol in 20 mL DCM). After rocking the vials at room
temperature for 14 hours, approximately 100-125mg of
polystyrene-piperidine resin (approximately 3.6 mmol/g, 350 umol,
233 eq.) was added to each vial and rocking continued for 15
minutes. Methanol (2.5 mL) was added to each vial and the material
put on a 1 g SCX column (Varian) pre-equilibrated with 5 mL of MeOH
and 5 mL of 10% MeOH/chloroform. After pushing the liquid through
the column with nitrogen, the column was washed with 5 mL of 10%
MeOH/chloroform. The combined eluents (collected in 25 mL
roundbottom flasks) were evaporated at reduced pressure with a warm
water bath at 30-35.degree. C. and then further evaporated in a
vacuum oven at 40-45.degree. C. When the net weight of the residues
was below 100 mg, 5 mL of dioxane and, if necessary, 1 mL of MeOH
was added ton redissolve the residue and solvent was again removed
on the rotary evaporator and in the vacuum oven. After drying in
the vacuum oven overnight, an HPLC was taken of each product. HPLC
show primarily the desired product and with about 15% deblocked
product (i.e., product with the BOC group removed).
[2928] Step B: To each round bottom flask was added 5 mL of 4 N HCl
in dioxane. After sitting at room temperature for 2-3 hours, an
HPLC was taken and was solvent removed on the rotary evaporator
(bath temp 30-35.degree. C.) and in the vacuum oven overnight (at
approximately 40.degree. C.). The HPLC of the t-butyl threonine
adduct showed incomplete removal of the t-butyl group. An
additional 5 mL of 4 N HCl in dioxane was added and the reaction
(at room temperature) monitored by HPLC at 4 hours and
approximately 20 hours. Complete removal of the t-butyl group was
observed after 20 hours. All products were pure by HPLC with only a
single peak or resolved diastereomeric peaks observed except for
some trace impurities in the methione case. Yields varied from 80
to 100%. Each round bottom contained approximately 150 umoles of
the amino acid linked to
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
[2929] Step C: A stock solution of 567 mg (1.48 mmol) PP-HOBT in
8.5 mL DMF (approximately 0.175 M PP-HOBT in DMF) was prepared and
0.81 g (0.86 mL, 150 umol) of this PP-HOBT solution was added to
each of the nine round-bottom vessels containing the products from
Step B. Clear solutions were obtained for all, except where the
linked amino acid was alpha amino isobutyric acid. In this case, an
additional 0.86 mL of DMF was added but still the mixture remained
heterogeneous. The contents of each of the nine round bottoms "n"
(where n=1 to 9) were divided into four equal portions
(approximately 37 umols each) and placed in vials. Stock solutions
(0.1 M) of the carboxylic acids were then made up in 10% DMF/DCM.
The appropriate stock solution (0.3 mL, 30 umol) was then added to
each of the vials. A 0.1 M stock solution (20 mL) of EDC
hydrochloride in DMF was prepared. This stock solution (0.4 mL, 40
umol) was then added to each of the vials which were then capped
and put on a rotator for 12 hours. Normal SCX workup and
evaporation of solvent afforded products as white solids or clear
to light caramel resins. Each of these products was taken up in
methanol/chloroform and divided into three tared vials, plus a vial
for MS and HPLC characterization. After evaporation of solvent, the
final weights in each vial were determined. Product identity was
verified by ionspray mass spec and purity assessed by reverse phase
HPLC.
Example C-AF
Preparation of PP-HOBT
[2930] To a stirred solution of 7.68 g (30 mmol) sulfonyl chloride
in 120 mL of dichloromethane was added dropwise, over a 10 min
period, 5.04 g (30 mmol) of 4-piperidino-piperidine (Aldrich, 90%)
and 3.6 g (36 mmol) of triethylamine in 30 mL of dichloromethane. A
mildly exothermic reaction ensued. After stirring 2 hours at room
temperature, the orange solution was diluted with 100 mL of
dichloromethane and washed with 10% sodium bicarbonate solution
(2.times.100 mL) and brine (1.times.100 mL). After drying over
sodium sulfate, the solvent was removed at reduced pressure to
afford 10.7 g of crude product as a light tan solid (R.sub.f=0.5,
Silica, 10% MeOH/chloroform).
[2931] To this crude material was added 200 mL of 95% EtOH/5% MeOH
followed by 60 mL of hydrazine hydrate. The mixture was refluxed
for 3 hours. During the first 0.5 hour, the initially orange
solution turned deep red-orange before turning orange again. After
refluxing for 3 hours, most of the solvent, water and hydrazine was
removed at reduced pressure. To the residue was added 50 mL of EtOH
and solvent removed at reduced pressure. This was repeated 2 or
more times to give a tan solid which was further dried in the
vacuum oven to a constant weight of 13.5 g. To the flask containing
this solid was added 250 mL of water. Almost all of the solid went
into solution, then a fine light yellow precipitate formed. After
stirring cooled in an ice bath for two hours, the solid was
collected by vacuum filtration through a sintered glass filter, and
rinsed with about 20 mL of cold water. Drying in the vacuum oven at
40.degree. C overnight afforded 7.3 g (63% yield) of the title
compound (PP-HOBT) as an off-white crunchy powder, mp
195-200.degree. C. (dec).
[2932] Using the procedures indicated, the compounds shown in Table
C-5 were prepared. Starting material 2 used in these procedures was
prepared as described in General Procedure C-S.
40TABLE C-5 Example General No. Compound Starting Material 1
Starting Material 2 Procedure MS 7C-221
5-{N'-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic
5-(L-methioninyl)-amino-7- C-S 524.3 L-methioninyl}-amino-7-methy-
l- acid methyl-5,7-dihydro-6H- 5,7-dihydro-6H- (Aldrich)
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-222
5-{N'-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic
5-(L-2-phenylglycinyl)- C-S 526.5 L-2-phenylglycinyl}-amino-7- acid
amino-7-methyl-5,7- methyl-5,7-dihydro-6H- (Aldrich) dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-223
5-{N'-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic
5-(L-leucinyl)-amino-7- C-S 506.3 L-leucinyl}-amino-7-methyl-5,7-
acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
(Aldrich) dibenz[b,d]azepin-6-one one 7C-224
5-{N'-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic
5-(L-2-cyclohexylglycinyl)- C-S 532.3 L-2-cyclohexylglycinyl}-ami-
no-7- acid amino-7-methyl-5,7- methyl-5,7-dihydro-6H- (Aldrich)
dihydro-6H- dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-225
5-{N'-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic
5-(L-threoninyl)-amino-7- C-S 494.5 L-threoninyl}-amino-7-methyl-
acid methyl-5,7-dihydro-6H- 5,7-dihydro-6H- (Aldrich)
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-226
5-{N'-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic
5-(L-alpha-(2- C-S 532.2 L-alpha-(2-thienyl)glycinyl}- acid
thienyl)glycinyl)-amino-7- amino-7-methyl-5,7-dihydro-6H- (Aldrich)
methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-227 5-{N'-(2-thiopheneacetyl)-L-
2-thiopheneacetic acid 5-(L-methioninyl)-amino-7- C-S 494.3
methioninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-228
5-{N'-(2-thiopheneacetyl)-L-2- 2-thiopheneacetic acid
5-(L-2-phenylglycinyl)- C-S 496.2 phenylglycinyl}-amino-7-methyl-
(Aldrich) amino-7-methyl-5,7- 5,7-dihydro-6H- dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-229
5-{N'-(2-thiopheneacetyl)-L- 2-thiopheneacetic acid
5-(L-leucinyl)-amino-7- C-S 476.2 leucinyl}-amino-7-methyl-5,7-
(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-
dibenz[b,d]azepin-6-one one 7C-230 5-{N'-(2-thiopheneacety- l)-L-2-
2-thiopheneacetic acid 5-(L-2-cyclohexylglycinyl)- C-S 502.2
cyclohexylglycinyl}-amino-7- (Aldrich) amino-7-methyl-5,7-
methyl-5,7-dihydro-6H- dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-231 5-{N'-(2-thiopheneacetyl)-L-
2-thiopheneacetic acid 5-(L-threoninyl)-amino-7- C-S 464.3
threoninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-232
5-{N'-(2-thiopheneacetyl)-L- 2-thiopheneacetic acid 5-(L-alpha-(2-
C-S 502.1 alpha-(2-thienyl)glycinyl}-amino- (Aldrich)
thienyl)glycinyl)-amino-7- 7-methyl-5,7-dihydro-6H-
methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-233 5-{N'-(isovaleryl)-L- isovaleric
acid 5-(L-methioninyl)-amino-7- C-S 454.2 methioninyl}-amino-7-me-
thyl-5,7- (Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]a-
zepin-6- dibenz[b,d]azepin-6-one one 7C-234 5-{N'-(isovaleryl)-L-2-
isovaleric acid 5-(L-2-phenylglycinyl)- C-S 456.4
phenylglycinyl}-amino-7-methyl- (Aldrich) amino-7-methyl-5,7-
5,7-dihydro-6H- dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-235 5-{N'-(isovaleryl)-L-leucinyl}-
isovaleric acid 5-(L-leucinyl)-amino-7- C-S 436.4
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-236
5-{N'-(isovaleryl)-L-2- isovaleric acid 5-(L-2-cyclohexylglycinyl)-
C-S 462.6 cyclohexylglycinyl}-amino-7- (Aldrich)
amino-7-methyl-5,7- methyl-5,7-dihydro-6H- dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-237
5-{N'-(isovaleryl)-L-threoninyl}- isovaleric acid
5-(L-threoninyl)-amino-- 7- C-S 424.3
amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-238
5-{N'-(isovaleryl)-L-alpha-(2- isovaleric acid 5-(L-alpha-(2- C-S
462.3 thienyl)glycinyl}-amino-- 7-methyl- (Aldrich)
thienyl)glycinyl)-amino-7- 5,7-dihydro-6H- methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-239
5-{N'-(phenylacetyl)-L- phenylacetic acid
5-(L-methioninyl)-amino-7- C-S 488.5
methioninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-240
5-{N'-(phenylacetyl)-L-2- phenylacetic acid 5-(L-2-phenylglycinyl)-
C-S 490.6 phenylglycinyl}-amino-7-methyl- (Aldrich)
amino-7-methyl-5,7- 5,7-dihydro-6H- dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-241
5-{N'-(phenylacetyl)-L-leucinyl}- phenylacetic acid
5-(L-leucinyl)-amino-7- C-S 470.4 amino-7-methyl-5,7-dihydro-6H-
(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-242 5-{N'-(phenylacetyl)-L-2-
phenylacetic acid 5-(L-2-cyclohexylglycinyl)- C-S 496.3
cyclohexylglycinyl}-amino-7- (Aldrich) amino-7-methyl-5,7-
methyl-5,7-dihydro-6H- dihydro-6H- dibenz[b,d]azepin-6-one
dibenz[b,d]azepin-6-one 7C-243 5-{N'-(phenylacetyl)-L- phenylacetic
acid 5-(L-threoninyl)-amino-7- C-S 458.5
threoninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-
dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-244
5-{N'-(phenylacetyl)-L-alpha-(2- phenylacetic acid 5-(L-alpha-(2-
C-S 496.2 thienyl)glycinyl}-amino-7-methyl- (Aldrich)
thienyl)glycinyl)-amino-7- 5,7-dihydro-6H- methyl-5,7-dihydro-6H-
dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one
[2933] Additionally, the following procedures provide various
carboxylic acid esters which can be hydrolyzed using General
Procedures AC or BD below to afford the corresponding carboxylic
acids. Coupling of the resulting carboxylic acids to the amines
employed above using the General Procedures set forth above
provides for additional compounds within the scope of this
invention.
General Procedure AA
Reductive Amination
[2934] To a solution of the arylamine in ethanol in a hydrogenation
flask was added 1 equivalent of the 2-oxocarboxylic acid ester
(e.g., pyruvate ester), followed by 10% palladium on carbon (25
weight percent based on the arylamine). The reaction was
hydrogenated at 20 psi H.sub.2 on a Parr shaker until complete
reaction was indicated by tlc (30 minutes to 16 hours). The
reaction mixture was then filtered through a pad of Celite 545
(available from Aldrich Chemical Company, Inc.) and stripped free
of solvent on a rotary evaporator. The crude product residue was
then further purified via chromatography.
General Procedure AB
First Transesterification Technique
[2935] A solution of 1-5 equivalents of the desired alcohol was
added to 1 equivalent of sodium hydride in toluene. After
off-gassing had ceased, the compound to be transesterified,
dissolved in toluene, was added. After 0.5 hours, the reaction was
either heated to 40.degree. C. and placed under house vacuum
(.about.20 mmHg), or nitrogen was bubbled through the solution
while it was heated at 90.degree. C. The reaction was followed by
tlc, and when the reaction was complete the solution was cooled and
quenched with water or 1M HCl, and in smaller scale reactions
diluted with ethyl acetate. The organic phase was extracted with
saturated aqueous NaHCO.sub.3, then washed with saturated aqueous
NaCl and dried over MgSO.sub.4. The solution was stripped free of
solvent on a rotary evaporator, and the crude product residue was
then further purified by chromatography. Alternatively, the
reaction mixture was worked-up by evaporation of the solvents and
direct chromatography of the crude mixture.
[2936] This procedure is particularly useful in the case of costly
and/or high boiling alcohols.
General Procedure AC
Second Transesterification Technique
[2937] The compound to be transesterified was placed in a large
excess of the desired alcohol. A catalytic amount of dry NaH was
added, and the reaction was followed by tlc until the presence of
starting material was no longer detected. The reaction was quenched
with a few milliliters of 1N HCl, and after a few minutes of
stirring saturated aqueous NaHCO.sub.3 was added. The organic phase
was washed with saturated aqueous NaCl and dried over MgSO.sub.4.
The solution was stripped free of solvent on a rotary evaporator,
and the crude product residue was then further purified by
chromatography.
General Procedure AD
Third Transesterification Technique
[2938] The compound to be transesterified was placed in a large
excess of the desired alcohol. A catalytic amount of dry NaH was
added, and the reaction was followed by tlc until the presence of
starting material was no longer detected. The reaction was quenched
with a few milliliters of 1N HCl, and after a few minutes of
stirring saturated aqueous NaHCO.sub.3 was added. The volume of the
reaction mixture was reduced on a rotary evaporator until the
excess alcohol was removed and then the remaining residue was taken
up in ethyl acetate and additional water was added. The organic
phase was washed with saturated aqueous NaCl and dried over
MgSO.sub.4. The solution was stripped free of solvent on a rotary
evaporator, and the crude product residue was then further purified
by chromatography.
[2939] This procedure is particularly employed in the case of low
boiling, inexpensive alcohols, miscible with water.
General Procedure AE
O-Alkylation Technique
[2940] To a carboxylic acid compound (prepared, for example, by
reductive amination via General Procedure AA to provide for the
N-aryl amino acid ester, followed by hydrolysis via Procedure AF)
in DMF was added 1.5 equivalents K.sub.2CO.sub.3, followed by 1
equivalent of alkylating agent (e.g., tert-butyl bromoacetate). The
reaction was stirred at room temperature for 2 hours, then was
quenched with water and extracted into ethyl acetate. The organic
phase was washed with saturated aqueous NaHCO.sub.3, water, and
saturated aqueous NaCl, and was then dried over MgSO.sub.4. The
solution was stripped free of solvent on a rotary evaporator to
yield the crude product.
General Procedure AF
Ester Hydrolysis to Free Acid
[2941] To a carboxylic ester compound (prepared, for example, by
reductive amination via General Procedure AA to provide for the
N-aryl amino acid ester) in a 1:1 mixture of CH.sub.3OH/H.sub.2O
was added 2-5 equivalents of K.sub.2CO.sub.3. The mixture was
heated to 50.degree. C. for 0.5 to 1.5 hours until tlc showed
complete reaction. The reaction was cooled to room temperature and
the methanol was removed on a rotary evaporator. The pH of the
remaining aqueous solution was adjusted to .about.2, and ethyl
acetate was added to extract the product. The organic phase was
then washed with saturated aqueous NaCl and dried over MgSO.sub.4.
The solution was stripped free of solvent on a rotary evaporator to
yield the crude product.
General Procedure AG
N-Heteroarylation of Alanine
[2942] A solution of 1.1 equivalents of L-alanine and 2 equivalents
NaOH in DMSO was stirred at room temperature for 1 hour, then 1
equivalent of 2-chlorobenzothiazole was added. The mixture was
heated to 100.degree. C. for 4 hours, then cooled to room
temperature and poured onto ice. The pH of the resulting aqueous
solution was adjusted to .about.2, and the precipitated solid was
removed by filtration. This solid was then dissolved in 1N NaOH and
the resulting solution was filtered through a pad of Celite 545.
The pH of the filtrate was adjusted to .about.2, and the white
precipitate was removed by filtration and washed with water to
yield the crude product.
General Procedure AH
EDC Coupling
[2943] To a 1:1 mixture of the desired acid and alcohol in
CH.sub.2Cl.sub.2 at 0.degree. C. was added 1.5 equivalents
triethylamine, followed by 2.0 equivalents hydroxybenzotriazole
monohydrate, then 1.25 equivalents of
ethyl-3-(3-dimethylamino)-propyl carbodiimide-HCl (EDC). The
reaction was stirred overnight at room temperature, then
transferred to a separatory funnel and washed with water, saturated
aqueous NaHCO.sub.3, 1N HCl, and saturated aqueous NaCl, and was
then dried over MgSO.sub.4. The solution was stripped free of
solvent on a rotary evaporator to yield the crude product.
General Procedure AI
Oxime or Amine Coupling Technique
[2944] The trichlorophenyl ester (1 eq) of a carboxylic acid was
stirred in DMF or THF. The oxime or amine (1.2 eq) was added and
the mixture was stirred at ambient temperature for 1-4 hours. In
cases where the hydrochloride salt form of an amine was used, a
suitable base such as N,N-diisopropylethylamine (1.2 eq) was also
added. The resulting mixture was concentrated under reduced
pressure to yield a crude product which was used without
purification or was purified by silica gel chromatography and/or
crystallization.
General Procedure AJ
Alkylation Technique
[2945] The amine (1 eq), the .alpha.-bromo ester (1.1 eq) and a
suitable base (such as triethylamine) (2 eq) were stirred in
chloroform. The resulting solution was heated at reflux for 4-12
hours. After cooling, the mixture was diluted with chloroform and
washed with water. The organic portion was dried (sodium sulfate)
and concentrated under reduced pressure. The crude product was
purified by silica gel chromatography.
General Procedure AK
Oxime or Alcohol Coupling Technique
[2946] The carboxylic acid (1 eq) was stirred in a suitable solvent
(such as THF, dioxane or DMF). An alcohol or oxime (1-5 eq) was
added. EDC hydrochloride (1.2 eq) and hydroxybenzotriazole hydrate
(1 eq) were added. A suitable base (such as 4-methylmorpholine or
triethylamine) (0-1 eq) was added. A catalytic amount (0.1 eq) of
4-dimethylaminopyridine was added. The mixture was stirred at
ambient temperature and under a dry atmosphere of nitrogen. After
20 hours, the mixture was concentrated under reduced pressure. The
resulting concentrate was partitioned between ethyl acetate and
water. The organic portion was separated and washed with aqueous
sodium bicarbonate and brine. The organic portion was dried (sodium
sulfate) and concentrated under reduced pressure. The crude product
was used without purification or was purified by silica gel
chromatography and/or crystallization.
General Procedure AL
EDC Coupling
[2947] The carboxylic acid was dissolved in methylene chloride. The
amino acid (1 eq.), N-methylmorpholine (5 eq.) and
hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence.
A cooling bath was applied to the round bottomed flask until the
solution reached 0.degree. C. At that time, 1.2 eq. of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
was added. The solution was allowed to stir overnight and come to
room temperature under nitrogen pressure. The reaction mixture was
worked up by washing the organic phase with saturated aqueous
sodium carbonate, 0.M citric acid, and brine before drying with
sodium sulfate. The solvents were then removed to yield crude
product. Pure products were obtained by flash chromatography in an
appropriate solvent.
General Procedure AM
Triflate Displacement
[2948] To a 0.degree. C. solution of iso-butyl R-(+)-lactate in
CH.sub.2Cl.sub.2 was added 1.1 equivalents of
trifluoromethanesulfonic anhydride. After stirring at room
temperature for 20 min, 1.1 equivalents of 2,6-lutidine was added
and stirring was continued for 10 min. This solution was then
transferred to a flask containing 1 equivalent the arylamine and 1
equivalent N,N-diisopropylethylamine in CH.sub.2Cl.sub.2 or
CH.sub.3NO.sub.2 at 0.degree. C. The reaction was held overnight at
room temperature and then stripped free of solvent on a rotary
evaporator. The residue was dissolved in ethyl acetate, washed with
5% citric acid, followed by saturated aqueous NaCl, dried over
magnesium sulfate or sodium sulfate and then the solution was
stripped free of solvent on a rotary evaporator to yield the crude
product, which was then purified by chromatography.
General Procedure AN
BOC Removal
[2949] The BOC-protected compound was added to a 1:1 mixture of
CH.sub.2Cl.sub.2 and trifluoroacetic acid, and was stirred until
tlc indicated complete conversion, typically 2h. The solution was
then stripped to dryness and the residue was taken up in ethyl
acetate and extracted with dilute HCl. The acid reaction was
neutralized and extracted with ethyl acetate. The organic phase was
washed with saturated aqueous NaCl and dried over MgSO.sub.4. The
solution was stripped free of solvent on a rotary evaporator to
yield the product.
General Procedure AO
Synthesis of Pyruvate Esters
[2950] To a mixture of pyruvic acid (8.8 g, 0.1 mol) (Aldrich) in
100 mL of benzene was added iso-butanol (14.82 g, 0.2 mol) and a
catalytic amount of p-toluenesulfonic acid. The mixture was then
refluxed using a Dean Stark apparatus. After 4 hours, the reaction
appeared to be complete with the isolation of 1.8 g (0.1 mol) of
water. The benzene and iso-butanol were removed on a rotary
evaporator. The residue (14 g, 0.1 mol), which was primarily the
pyruvate iso-butyl ester by nmr [.sup.1H-Nmr (CDCl.sub.3):
.delta.=4.0 (d, 2H), 2.5 (s, 3H), 2.0 (m, 1H), 1.0 (d, 6H)], was
used without further purification. By substituting other alcohols
in place of iso-butanol (e.g., ethanol, isopropanol, n-butanol,
benzyl alcohol and the like), other esters of pyruvic acid can be
prepared in a similar manner.
General Procedure AP
Aromatic Nucleophilic Substitution of Fluorobenzenes
[2951] A mixture of 1.82 g (10 mmol) of D,L-alanine iso-butyl ester
hydrochloride, the fluorobenzene (10 mmol) and 3 g of anhydrous
potassium carbonate in 10 mL of DMSO was stirred at 120.degree. C.
for 2-5 hours. The reaction mixture was then cooled to room
temperature and diluted with 100 mL of ethyl acetate. The ethyl
acetate extract was washed with water (3.times.), dried over
MgSO.sub.4 and evaporated to dryness to afford the crude product,
which was further purified by column chromatography.
General Procedure AQ
Fourth Transesterification Technique
[2952] The ester to be transesterified was dissolved in a large
excess of the alcohol and 0.3 equivalents of titanium(IV)
isopropoxide (Aldrich) was added. The reaction was followed by tlc
until complete and then the volatiles were removed at reduced
pressure. The resulting crude material was then chromatographed to
obtain the desired product.
General Procedure AR
Synthesis on N-BOC Anilines
[2953] To a solution of the aniline in THF was added dropwise 1
equivalent of di-tert-butyl dicarbonate (Aldrich) in THF and then
1.5 equivalents of 10N aqueous sodium hydroxide at 0.degree. C.
After stirring at room temperature for 16 hours, or heating at
80.degree. C. for 3 hours, if needed, the reaction mixture was
diluted with ether and washed with NaHCO.sub.3, brine, dried over
sodium sulfate and potassium carbonate, concentrated at reduced
pressure and chromatographed to afford the N-BOC aniline.
General Procedure AS
Oxime Ester Formation
[2954] The trichlorophenyl ester (1 eq.) was stirred in DMF or THF.
The oxime (1.2 eq.) was added and the mixture was stirred at
ambient temperature for 1 to 4 hours. The resulting mixture was
concentrated under reduced pressure and the residue was purified by
silica gel chromatography and/or crystallization.
Example AA
Synthesis of D,L-alanine iso-butyl ester hydrochloride
[2955] A mixture of 35.64 g (0.4 mol) of D,L-alanine (Aldrich), 44
mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL of
iso-butanol was refluxed for 1.5 hours. The volatiles were removed
at reduced pressure at 90.degree. C. under reduced pressure to give
the title compound as an oil, which was used without further
purification.
[2956] NMR data was as follows:
[2957] .sup.1H-nmr (CDCl.sub.3): .delta.=8.72 (br s, 3H), 4.27 (q,
J=7.4 Hz, 1H), 3.95 (m, 2H), 1.96 (s, 1H), 1.73 (d, J=7.2 Hz, 3H),
0.92 (d, J=6.7 Hz, 6H).
[2958] .sup.13C-nmr (CDCl.sub.3): .delta.=170.0, 72.2, 49.2, 27.5,
18.9, 16.1.
Example AB
Synthesis of N-(3,4-dichlorophenyl)alanine
[2959] Using the procedure set forth in U.S. Pat. No. 3,598,859,
the disclosure of which is incorporated herein by reference in its
entirety, N-(3,4-dichlorophenyl)alanine was prepared. Specifically,
to a solution of 3,4-dichloroaniline (1 equivalent) (Aldrich) in
isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added
water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic
acid (2 equivalents) (Aldrich). This mixture is warmed to
40.degree. C. and sodium bicarbonate (0.25 equivalents) is added in
successive portions before heating under reflux for 4-5 days. After
cooling, the reaction mixture is poured into water and the
unreacted 3,4-dichloroaniline is removed by filtration. The
filtrate is acidified to pH 3-4 with concentrated hydrochloric acid
and the resultant precipitate is filtered, washed and dried to
yield the title compound, m.p.=148-149.degree. C.
[2960] Alternatively, following General Procedure AF above and
using N-(3,4-dichlorophenyl)alanine ethyl ester (from Example Al
below), the title compound was prepared.
Example AC
Synthesis of N-(3,5-difluorophenyl)alanine
[2961] Using the procedure set forth in U.S. Pat. No. 3,598,859,
N-(3,5-difluorophenyl)alanine was prepared using
3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid
(Aldrich).
Example AD
Synthesis of Iso-butyl 2-bromopropionate
[2962] To a mixture of iso-butanol and 1.0 equivalent of pyridine
in dry diethyl ether was added dropwise 1.3 equivalents of
2-bromopropionyl bromide at 0.degree.C. After stirring at room
temperature for 16 hours, the reaction was diluted with diethyl
ether, washed with 1N HCl, water, aqueous NaHCO.sub.3, brine and
dried over magnesium sulfate or sodium sulfate. Removal of the
solvents at reduced pressure gave the title compound as a clear
oil.
Example AE
Synthesis of N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester
[2963] N-(2-Naphthyl)alanine methyl ester (5.0 g, 20.6 mmol) (from
Example A44 below) was dissolved in dioxane (100 mL). NaOH (30 mL,
1N) was added and the resulting solution was stirred for 1 hour.
The reaction mixture was concentrated under reduced pressure. The
resulting solid was dissolved in water and the aqueous mixture was
washed with ether. The aqueous portion was adjusted to pH 3 with 1N
HCl and extracted with ethyl acetate. The organic extracts were
dried over magnesium sulfate or sodium sulfate and concentrated
under reduced pressure to yield a white solid (4.35 g, 98%).
[2964] The resulting solid (4.35 g, 20 mmol) was dissolved in
dichloromethane (300 mL). 2,4,5-Trichlorophenol (4.9 g, 25 mmol)
(Aldrich) was added followed by dicyclohexylcarbodiimide (25 mL, 1M
in dichloromethane) (Aldrich). After stirring for 18 hours, the
mixture was filtered and concentrated to provide an oil which was
purified by chromatography on silica gel using chloroform as the
eluant (R.sub.f=0.6). The title compound was obtained as a thick
oil which slowly crystallized.
Example Al
Synthesis of N-(3,4-dichlorophenyl)alanine ethyl ester
[2965] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the
title compound was prepared as an oil. The reaction was monitored
by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification
was by preparative plate chromatography (silica gel using 25%
EtOAc/hexanes as the eluant).
[2966] NMR data was as follows:
[2967] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2 (d, 1H); 6.7 (d, 1H,);
6.4 (dd, 1H); 4.30 (bs, 1H); 4.2 (q, 2H); 4.1 (q, 1H); 1.5 (d, 3H);
1.3 (t, 3H).
[2968] .sup.13C-nmr (CDCl.sub.3): .delta.=175; 146.7; 133; 131;
121; 114.9; 112.6; 72.0; 52.4; 28.3; 19.5.
[2969] C.sub.11H.sub.13Cl.sub.2NO.sub.2 (MW=262.14).
Example A2
Synthesis of N-(3-trifluoromethyl4-chlorophenyl)alanine ethyl
ester
[2970] Following General Procedure AA above and using
4-chloro-3-(trifluoromethyl)aniline (Aldrich) and ethyl pyruvate
(Aldrich), the title compound was prepared.
[2971] Analysis: Calc.: C, 48.74; H, 4.43; N, 4.74. Found: C,
48.48; H, 4.54; N, 4.94.
[2972] C.sub.12H.sub.13F.sub.3ClNO.sub.2 (MW=295.69); mass
spectroscopy (MH.sup.+) 295.
Example A3
Synthesis of N-(3,5-dichlorophenyl)alanine ethyl ester
[2973] Following General Procedure AA above and using
3,5-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the
title compound was prepared.
[2974] Analysis: Calc.: C, 50.40; H, 5.00; N, 5.34. Found: C,
50.50; H, 5.06; N, 5.25.
[2975] C.sub.11H.sub.13Cl.sub.2NO.sub.2 (MW=262.14); mass
spectroscopy (MH.sup.+) NA.
Example A4
Synthesis of N-(3,4-difluorophenyl)alanine ethyl ester
[2976] Following General Procedure AA above and using
3,4-difluoroaniline (Aldrich) and ethyl pyruvate (Aldrich), the
title compound was prepared. The reaction was monitored by tlc on
silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by
preparative plate chromatography (silica gel using 25%
EtOAc/hexanes as the eluant).
[2977] NMR data was as follows:
[2978] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4 (m, 1H), 6.8 (d, 1H),
6.5 (m, 1H), 4.30 (bs, 1H), 4.2 (q, 2H), 4.1 (q, 1H), 1.5 (d, 3H),
1.3 (t, 3H).
[2979] .sup.13C-nmr (CDCl.sub.3): .delta.=175, 146.7, 135, 132,
125, 116, 113, 72, 52, 28, 19.
[2980] C.sub.11H.sub.13F.sub.2NO.sub.2 (MW=229.23); mass
spectroscopy (MH.sup.+) 230.
Example A5
Synthesis of N-(3,4-dichlorophenyl)alanine benzyl ester
[2981] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and benzyl pyruvate (prepared by
following General Procedure AO above using benzyl alcohol in place
of iso-butanol), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel (Rf=0.4 in 25%
EtOAc/hexanes) and purification was by preparative plate
chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[2982] NMR data was as follows:
[2983] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (d, 1H); 7.0 (m, 5H);
6.6 (d, 1H,); 6.4 (dd, 1H); 5.1 (s, 2H); 4.30 (bs, 1H); 4.08 (q,
1H); 1.94 (m, 1H); 1.47 (d, 3H); 0.91 (d,6H).
[2984] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5; 146.7; 133.5;
131.3; 121.3; 120.1; 114.9; 113.6; 72.0; 60.1; 52.4; 28.3; 19.5;
19.3.
[2985] C.sub.16H.sub.15Cl.sub.2NO.sub.2 (MW=324.31); mass
spectroscopy (MH.sup.+) 325.
Example A6
Synthesis of N-(3,4-dichlorophenyl)alanine iso-butyl ester
[2986] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared by
following General Procedure AO above), the title compound was
prepared as an oil. The reaction was monitored by tlc on silica gel
(Rf=0.55 in 25% EtOAc/hexanes) and purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[2987] NMR data was as follows:
[2988] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (d, 1H, J=8.7 Hz),
6.66 (d, 1H, J=2.7 Hz), 6.43 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.30
(bs, 1H), 4.08 (q, 1H, J=6.9 Hz), 1.94 (sept, 1H, J=6.7 Hz), 1.47
(d, 3H J=6.9 Hz), 0.91 (d, 6H, J=6.6 Hz).
[2989] .sup.13C-nmr (CDCl.sub.3) .delta.=174.5, 146.7, 133.5,
131.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.
[2990] C.sub.13H.sub.17C.sub.2NO.sub.2 (MW=290.19); mass
spectroscopy (MH.sup.+) 290.
Example A7
Synthesis of N-(3,4-dichlorophenyl)alanine iso-propyl ester
[2991] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and isopropyl pyruvate (prepared by
following General Procedure AO above using isopropanol in place of
iso-butanol), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel (Rf=0.4 in 25%
EtOAc/hexanes) and purification was by preparative plate
chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[2992] NMR data was. as follows:
[2993] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (d, 1H); 6.66 (d,
1H,); 6.43 (dd, 1H); 4.30 (bs, 1H); 4.08 (m, 1H); 1.94 (m, 1H);
1.47 (d, 3H); 0.91 (d, 6H).
[2994] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5; 146.7; 133.5;
131.3; 121.3; 114.9; 113.6; 72.0; 52.4; 19.5.
[2995] C.sub.12H.sub.15C.sub.2NO.sub.2 (MW=276.16); mass
spectroscopy (MH.sup.+) 277.
Example A8
Synthesis of N-(3,4-dichlorophenyl)alanine n-butyl ester
[2996] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and n-butyl pyruvate (prepared by
following General Procedure AO above using n-butanol in place of
iso-butanol), the title compound was prepared. The reaction was
monitored by tlc on silica gel (Rf=0.7 in 25% EtOAc/hexanes) and
purification was by preparative plate chromatography (silica gel
using 25% EtOAc/hexanes as the eluant).
[2997] NMR data was as follows:
[2998] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (d, 1H); 6.66 (d,
1H,); 6.43 (dd, 1H); 4.30 (bs, 1H); 4.2 (m, 2H); 4.08 (q, 1H); 1.94
(m, 1H); 1.47 (m, 4H); 0.91 (t, 3H).
[2999] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5; 146.7; 133.5;
131.3; 121.3; 114.9; 113.6; 72.0; 52.4; 28.3; 20.2; 19.5.
[3000] C.sub.13H.sub.17C.sub.2NO.sub.2 (MW=290.19); mass
spectroscopy (MH.sup.+) 291.
Example A9
Synthesis of N-(3,4-dichlorophenyl)alanine methyl ester (R,S
isomers)
[3001] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and methyl pyruvate (Aldrich), the
title compound was prepared as an oil. The reaction was monitored
by tlc on silica gel (Rf=0.55 in 25% EtOAc/hexanes) and
purification was by flash chromatography (silica gel using 25%
EtOAc/hexanes as the eluant).
[3002] NMR data was as follows:
[3003] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (d, J=8.73 Hz, 1H),
6.66 (d, J=2.75 Hz, 1H), 6.43 (dd, J=8.73 Hz, 2.80 Hz, 1H), 4.25
(bd, J=8.25 Hz, 1H), 4.08 (m, 1H), 3.76 (s, 3H), 1.47 (d, J=6.90
Hz).
[3004] .sup.13C-nmr (CDCl.sub.3) .delta.=174.35, 145.96, 132.87,
130.70, 120.76, 114.38, 112.90, 52.43, 51.70, 18.67.
[3005] C.sub.10H.sub.11Cl.sub.2NO.sub.2 (MW=248.11); mass
spectroscopy (MH.sup.+) 247.
Example A10
Synthesis of N-(3,4-dichlorophenyl)alanine cyclopentyl ester
[3006] Following transesterification General Procedure AB above and
using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9
above) and cyclopentanol (Aldrich), the title compound was prepared
as an oil. The reaction was monitored by silica gel tlc (Rf=0.66 in
25% EtOAc/hexanes). Purification was by preparative plate
chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3007] NMR data was as follows:
[3008] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (d, 1H, J=8.7 Hz),
6.66 (d, 1H, J=2.7 Hz), 6.43 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 5.22 (m,
1H), 4.27 (d, 1H, J=8.1 Hz), 4.02 (quint, 1H, J=7.5 Hz), 1.74 (m,
8H), 1.43 (d, 3H, J=6.9 Hz).
[3009] .sup.13C-nmr (CDCl.sub.3): .delta.=174.3, 146.7, 133.4,
131.2, 121.2. 114.9, 113.7, 78.9, 52.5, 33.2, 24.2, 24.1, 19.1.
[3010] C.sub.14H.sub.17C.sub.2NO.sub.2 (MW=302.20); mass
spectroscopy (MH.sup.+) 301.
Example A11
Synthesis of N-(3,4-dichlorophenyl)alanine n-propyl ester
[3011] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and n-propyl pyruvate (prepared by
following General Procedure AO above using n-propanol in place of
iso-butanol), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel (Rf=0.5 in 25%
EtOAc/hexanes) and purification was by preparative plate
chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3012] NMR data was as follows:
[3013] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2 (d, 1H); 6.6 (d, 1H);
6.4 (dd, 1H); 4.30 (bs, 1H); 4.2 (q, 2H); 4.08 (q, 1H); 1.94 (m,
2H); 1.5 (d, 3H); 0.95 (t, 3H).
[3014] .sup.13C-nmr (CDCl.sub.3): .delta.=178; 144.7; 130.2;
120.62; 115.11; 71.82; 52.90.
[3015] C.sub.12H.sub.15C.sub.2NO.sub.2 (MW=276.16); mass
spectroscopy (MH.sup.+) 277.
Example A12
Synthesis of N-(3,4-dichlorophenyl)alanine allyl ester
[3016] Following transesterification General Procedure AB above and
using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9
above) and allyl alcohol (Aldrich), the title compound was prepared
as an oil. The reaction was monitored by silica gel tlc (Rf=0.62 in
25% EtOAc/hexanes). Purification was by preparative plate
chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3017] NMR data was as follows:
[3018] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (d, 1H, J=8.7 Hz),
6.67 (d, 1H, J=2.8 Hz), 6.44 (dd, 1H, J=8.7 Hz, J=2.8 Hz), 5.90 (m,
1H), 5.30 (m, 2H), 4.64 (m, 2H) 4.26 (m, 1H, 4.10 (m, 1H), 1.48 (d,
3H, J=6.9 Hz).
[3019] .sup.13C-nmr (CDCl.sub.3): .delta.=174.1, 146.6, 133.5,
132.1, 131.3, 121.4 119.6, 115.0, 113.6, 66.5, 52.4, 19.3.
[3020] C.sub.12H.sub.13Cl.sub.2NO.sub.2 (MW=274.15); mass
spectroscopy (MH.sup.+) 273.
Example A13
Synthesis of N-(3,4-dichlorophenyl)alanine 4-methylpentyl ester
[3021] Following transesterification General Procedure AB above and
using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9
above) and 4-methylpentanol (Aldrich), the title compound was
prepared as an oil. The reaction was monitored by silica gel tlc
(Rf=0.70 in 25% EtOAc/hexanes). Purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3022] NMR data was as follows:
[3023] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (d, 1H, J=8.7 Hz),
6.66 (d, 1H, J=2.7 Hz), 6.43 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.28 (m,
1H), 4.10 (m, 3H), 1.55 (m, 6H), 1.19 (m, 2H), 0.87 (d, 3H, J=6.6
Hz).
[3024] .sup.13C-nmr (CDCl.sub.3): .delta.=174.6, 146.7, 133.4,
131.3, 121.3, 115.0, 113.6, 66.4, 52.4, 35.4, 28.2, 27.0, 23.0,
19.3.
[3025] C.sub.15H.sub.21Cl.sub.2NO.sub.2 (MW=318.25); mass
spectroscopy (MH.sup.+) 317.
Example A14
Synthesis of N-(3,4-dichlorophenyl)alanine
2,2-dimethyl-1,3-dioxolane-4-me- thyl ester
[3026] Following transesterification General Procedure AB above and
using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9
above) and 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal)
(Aldrich), the title compound was prepared as a mixture of
diastereomers. The reaction was monitored by silica gel tlc
(Rf=0.32 in 25% EtOAc/hexanes). Purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3027] NMR data was as follows:
[3028] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (d, 1H, J=8.7 Hz),
6.66 (d, 1H, 2.7 Hz), 6.43 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.22 (m,
6H), 3.70 (m, 1H), 1.43 (m, 9H).
[3029] .sup.13C-nmr (CDCl.sub.3): .delta.=174.34, 174.32, 146.5,
133.5, 131.3, 121.5, 115.0, 113.6, 110.52, 110.51, 73.97, 73.89,
66.6, 66.01, 65.95, 52.42, 52.37, 27.3, 25.8, 19.3.
[3030] C.sub.15H.sub.19Cl.sub.2NO.sub.4 (MW=348.23); mass
spectroscopy (MH.sup.+) 347.
Example A 15
Synthesis of N-(3,4-dichlorophenyl)alanine cyclohexylmethyl
ester
[3031] Following transesterification General Procedure AB above and
using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9
above) and cyclohexylmethanol (Aldrich), the title compound was
prepared.
[3032] NMR data was as follows:
[3033] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (d, 1H), 6.68 (d,
1H), 6.45 (dd, 1H), 4.26 (bd, 1H), 4.10 (m, 1H), 3.95 (d, 2H),
1.70-1.55 (m, 6H), 1.50 (d, 3H), 1.35-0.85 (m, 5H).
[3034] .sup.13C-nmr (CDCl.sub.3): .delta.=174.58, 146.72, 133.48,
131.27, 121.34, 114.98, 113.72, 71.06, 52.52, 37.68, 30.10, 26.83,
26.17, 19.32.
[3035] C.sub.15H.sub.21Cl.sub.2NO.sub.2 (MW=318.25); mass
spectroscopy (MH.sup.+) 317.
Example A16
Synthesis of N-(3,4-dichlorophenyl)alanine
tert-butyloxycarbonylmethyl ester
[3036] Following General Procedure AE above and using
N-(3,4-dichlorophenyl)alanine (from Example AB above) and
tert-butyl bromoacetate (Aldrich), the title compound was prepared
as a solid. The reaction was monitored by silica gel tlc (Rf=0.57
in 25% EtOAc/hexanes). Purification was by recrystallization from
ethanol.
[3037] NMR data was as follows:
[3038] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (d, 1H), 6.68 (d,
1H), 6.45 (dd, 1H), 4.55 (m, 2H), 4.20 (m, 2H), 1.55 (d, 3H), 1.45
(s, 9H).
[3039] .sup.13C-nmr (CDCl.sub.3): .delta.=173.9, 166.9, 146.5,
133.5, 131.3, 115.1, 113.6, 83.4, 62.2, 52.2, 28.6, 19.3.
[3040] C.sub.15H.sub.19Cl.sub.2NO.sub.4 (MW=348.23); mass
spectroscopy (MH.sup.+) 347.
Example A17
Synthesis of N-(3,4-dichlorophenyl)leucine iso-butyl ester
[3041] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and iso-butyl
4-methyl-2-oxopentanoate (prepared by following General Procedure
AO above using 4-methyl-2-oxovaleric acid (Fluka) and iso-butanol),
the title compound was prepared as an oil. The reaction was
monitored by tlc on silica gel (Rf=0.6 in 25% EtOAc/hexanes) and
purification was by preparative plate chromatography (silica gel
using 25% EtOAc/hexanes as the eluant).
[3042] NMR data was as follows:
[3043] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2 (d, 1H); 6.5 (d, 1H);
6.4 (dd, 1H); 4.30 (bs, 1H); 4.08 (q, 1H); 3.8(m, 2H); 1.8 (m, 3H);
0.91 (m, 12H).
[3044] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5; 146.7; 133.5;
131.3; 121.3; 114.9; 113.6; 72.0; 52; 28.3; 20.1; 19.5.
[3045] C.sub.16H.sub.23Cl.sub.2NO.sub.2 (MW=332.27); mass
spectroscopy (MH.sup.+) 333.
Example A18
Synthesis of 2-[N-(3,4-dichlorophenyl)amino]pentanoic acid
iso-butyl ester
[3046] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxopentanoate
(prepared by following General Procedure AO above using
2-oxovaleric acid (Fluka) and iso-butanol), the title compound was
prepared as an oil. The reaction was monitored by tlc on silica gel
(Rf=0.5 in 25% EtOAc/hexanes) and purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3047] NMR data was as follows:
[3048] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2 (d, 1H); 6.6 (d, 1H);
6.4 (dd, 1H); 4.3 (d, 1H); 3.8 (m, 3H); 1.9 (m, 6H); 1.0 (t, 3H),
0.9 (m, 6H).
[3049] .sup.13C-nmr (CDCl.sub.3): .delta.=178; 144.7; 130.2;
120.62; 115.11; 71.82; 52.90; 28.30; 19.53.
[3050] C.sub.15H.sub.21Cl.sub.2NO.sub.2 (MW=318.3); mass
spectroscopy (MH.sup.+) 319.
Example A19
Synthesis of N-(4-cyanophenyl)alanine iso-butyl ester
[3051] Following General Procedure AP above and using
4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester
hydrochloride (from Example AA above), the title compound was
prepared as an oil. The product was recovered by column
chromatography on silica gel using 1:5 EtOAc/hexanes as the
eluant.
[3052] NMR data was as follows:
[3053] .sup.1H-nmr (CDCl.sub.3): .delta.=7.44 (d, J=8.8 Hz, 2H),
6.57 (d, J 8.8 Hz, 2H), 4.74 (d, J=8.1 Hz, 1H), 4.18 (t, J=7.4 Hz,
1H), 3.95 (m, 2H), 1.94 (m, 1H), 1.51 (d, J=6.9 Hz, 3H), 0.91 (d,
J=6.7 Hz, 6H).
[3054] .sup.13C-nmr (CDCl.sub.3): .delta.=173.4, 149.7, 133.8,
120.1, 112.7, 99.8, 71.6, 51.2, 27.7, 18.9, 18.6.
[3055] C.sub.14H.sub.18N.sub.2O.sub.2 MW=246.31; mass spectroscopy
(MH.sup.+) 247.
Example A20
Synthesis of N-(3-chloro-4-cyanophenyl)alanine iso-butyl ester
[3056] Following General Procedure AP above and using
2-chloro-4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl
ester hydrochloride (from Example AA above), the title compound was
prepared. The product was recovered by column chromatography on
silica gel using 1:5 EtOAc/hexanes as the eluant.
[3057] NMR data was as follows:
[3058] .sup.1H-nmr (CDCl.sub.3): .delta.=7.40 (d, J=8.5 Hz, 1H),
6.62 (d, J=2.3 Hz, 1H), 6.48 (dd, J=2.4, 8.6 Hz, 1H), 4.90 (d,
J=7.6 Hz, 1H), 4.16 (quintet, J=7.1 Hz, 1H), 3.96 (dd, J=2.2, 6.7
Hz, 2H), 1.97 (m, 1H), 1.51 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.7 Hz,
6H).
[3059] .sup.13C-nmr (CDCl.sub.3): .delta.=173.0, 150.4, 138.3,
134.9, 117.3, 112.82 111.3, 100.6, 71.7, 51.1, 27.7, 18.9,
18.4.
[3060] C.sub.14H.sub.17N.sub.2O.sub.2Cl MW=280.76; mass
spectroscopy (MH.sup.+) 281.
Example A21
Synthesis of N-(3,4-dichloro)alanine iso-butyl ester (S isomer)
[3061] Following General Procedure AM above and using
3,4-dichloroaniline (Aldrich) and iso-butyl R-(+)-lactate
(Aldrich), the title compound was prepared as an oil. The reaction
was monitored by silica gel tlc (Rf=0.55 in 25% EtOAc/hexanes).
Purification was column chromatography.
[3062] NMR data was as follows:
[3063] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (d, J=8.73, 1H), 6.67
(d, J=2.75, 1H), 6.45 (dd, J=8.73, J=2.75, 1H), 4.28 (bd, J=8.36,
1H), 4.09 (quint, 1H), 3.94 (d, J=6.66, 2H), 1.95 (hept, J=6.71,
1H), 1.49 (d, J=6.90, 3H), 0.92 (d, J=6.04, 6H).
[3064] .sup.13C-nmr (CDCl.sub.3): .delta.=174.57, 146.67, 133.47,
131.28, 121.29, 114.93, 113.63, 71.01, 52.43, 28.30, 19.55,
19.33.
[3065] C.sub.13H.sub.17Cl.sub.2NO.sub.2 (MW=290.19); mass
spectroscopy (MH.sup.+) 290.
Example A22
Synthesis of N-(3,4-dichloro)alanine tetrahydrofuran-3-yl-methyl
ester
[3066] Following transesterification General Procedure AB above and
using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9
above) and tetrahydro-3-furanmethanol (Aldrich), the title compound
was prepared as an oil. The reaction was monitored by silica gel
tlc (Rf=0.33 in 25% EtOAc/hexanes). Purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3067] NMR data was as follows:
[3068] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (d, 1H, J=8.7 Hz),
6.65 (d, 1H, J=2.7 Hz), 6.42 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.30 (m,
1H), 4.09 (m, 3H), 3.78 (m, 3H), 3.53 (m, 1H), 2.56 (m, 1H), 1.94
(m, 1H), 1.58 (m, 1H), 1.46 (d, 3H, J =6.9 Hz).
[3069] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5, 146.6, 133.5,
131.3, 121.4, 114.9, 113.6, 70.86, 70.83, 68.2, 67.31, 67.29, 52.4,
38.7, 29.36, 29.33, 19.2.
[3070] C.sub.14H.sub.17Cl.sub.2NO.sub.3 (MW=318.20); mass
spectroscopy (MH.sup.+) 318.
Example A23
Synthesis of N-(3,5-dichlorophenyl)alanine n-propyl ester
[3071] Following General Procedure AA above and using
3,5-dichloroaniline (Aldrich) and n-propyl pyruvate (which can be
prepared by following General Procedure AO above using n-propanol
in place of iso-butanol), the title compound could be prepared.
Example A24
Synthesis of 2-[N-(3,4-dichlorophenyl)amino]butanoic acid iso-butyl
ester
[3072] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxobutanoate
(prepared by following General Procedure AO above using
2-oxobutyric acid (Aldrich) and iso-butanol), the title compound
was prepared as an oil. The reaction was monitored by tlc on silica
gel (Rf=0.3 in 25% EtOAc/hexanes) and purification was by
preparative plate chromatography (silica gel using 25%
EtOAc/hexanes as the eluant).
[3073] NMR data was as follows:
[3074] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2 (d, 1H); 6.6 (d, 1H);
6.4 (dd, 1H); 4.3 (d, 1H); 3.8 (m, 3H); 1.9 (m, 3H); 1.0 (t, 3H);
0.9(m, 6H).
[3075] .sup.13C-nmr (CDCl.sub.3): .delta.=178; 144.7; 130.2;
120.62; 115.11; 71.82; 52.90; 28.30; 20.5; 19.53.
[3076] C.sub.14H.sub.19Cl.sub.2NO.sub.2 (MW=304.22); mass
spectroscopy (MH.sup.+) 305.
Example A25
Synthesis of N-(4-chlorophenyl)alanine iso-butyl ester
[3077] Following General Procedure AA above and using
4-chloroaniline (Aldrich) and iso-butyl pyruvate (prepared by
following General Procedure AO above), the title compound was
prepared as an oil. The reaction was monitored by tlc on silica gel
(Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3078] NMR data was as follows:
[3079] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (d, 2H), 6.66 (d,
2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (sept, 1H), 1.47 (d, 3H),
0.91 (d, 6H).
[3080] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5, 146.7, 133.5,
131.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.
[3081] C.sub.13H.sub.18ClNO.sub.2 (MW=255.75); mass spectroscopy
(MH.sup.+) 256.
Example A26
Synthesis of N-(3,5-dichlorophenyl)alanine iso-butyl ester
[3082] Following General Procedure AA above and using
3,5-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared by
following General Procedure AO above), the title compound was
prepared as an oil. The reaction was monitored by tlc on silica gel
(Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3083] NMR data was as follows:
[3084] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (d, 2H), 6.66 (m,
1H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (m, 1H), 1.47 (d, 3H), 0.91
(d, 6H).
[3085] .sup.13C-nmr (CDCl.sub.3): .delta.=175; 146.7; 133; 131;
121; 114.9; 112.6; 72.0; 52.4; 28.3; 19.5.
[3086] C.sub.13H.sub.17Cl.sub.2NO.sub.2 (MW=290.2); mass
spectroscopy (MH.sup.+) 291.
Example A27
Synthesis of N-(4-ethylphenyl)alanine methyl ester
[3087] A solution of 0.68 g (5 mmol) of 4'-aminoacetophenone
(Aldrich), 0.60 mL of 90% methyl pyruvate (Aldrich) and 0.05 g
(0.25 mmol) of p-toluenesulfonic acid in ethanol was hydrogenated
in the presence of a catalytic amount of 10% Pd/C at from 30 to 15
psi of hydrogen for 16 hours. The catalyst was removed by filtering
the reaction mixture through Celite and the solvent was evaporated
to provide the crude product. The product was purified by column
chromatography (silica gel using 1:9 EtOAc/hexanes as the eluant)
to provide the title compound.
[3088] NMR data was as follows:
[3089] .sup.1H-nmr (CDCl.sub.3): .delta.=1.19 (t, J=7.6 Hz, 3H),
1.47 (d, J=6.8 Hz, 3H), 2.54 (q, J=7.6 Hz, 2H), 3.74 (s, 3H), 4.04
(bs, 1H), 4.13 (m, 1H), 6.57 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.4 Hz,
2H).
[3090] .sup.13C-nmr (CDCl.sub.3): .delta.=15.8, 18.0, 27.9, 52.17,
52.19, 113.5; 128.6, 134.1, 144.4, 175.3.
[3091] C.sub.12H.sub.17NO.sub.2 MW=207.27; mass spectroscopy
(MH.sup.+) 208.
Example A28
Synthesis of N-(4-(1-ethoxy)ethylphenyl)alanine methyl ester
[3092] Following the procedure for Example A27 above, the title
compound was isolated as another reaction product by column
chromatography (silica gel using 1:9 EtOAc/hexanes as the
eluant).
[3093] NMR data was as follows:
[3094] .sup.1H-nmr (CDCl.sub.3): .delta.=1.15 (t, J=7.0 Hz, 3H),
1.40 (d, J=6.5 Hz, 3H), 1.47 (d, J=6.1 Hz, 3H), 3.31 (q, J=5.1 Hz,
2H), 3.74 (s, 3H), 4.14 (m, 2H 4.29 (q, J=6.4 Hz, 1H), 6.57 (d,
J=8.5 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H).
[3095] .sup.13C-nmr (CDCl.sub.3): .delta.=15.4, 19.0, 23.9, 51.9,
52.2, 63.4, 77.3, 113.1, 127.3, 133.6, 145.8, 175.1.
[3096] C.sub.14H.sub.12NO.sub.3 MW=251.33; mass spectroscopy
(MH.sup.+) 251.
Example A29
Synthesis of N-(3,4-dichloro)alanine 2,2-dimethylpropyl ester (R,S
isomers)
[3097] Following transesterification General Procedure AQ above and
using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9
above) and neopentyl alcohol (Aldrich), the title compound was
prepared. The reaction was monitored by silica gel tlc (Rf=0.72 in
25% EtOAc/hexanes). Purification was by flash chromatography
(silica gel using 25% EtOAc/hexanes as the eluant).
[3098] NMR data was as follows:
[3099] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (d, 1H, J=8.7 Hz),
6.68 (d, 1H, J=2.7 Hz), 6.45 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.29 (m,
1H), 4.11 (m, 1H), 3.85 (m, 2H), 1.49 (d, 3H, J=6.9 Hz), 0.93 (s,
9H).
[3100] .sup.13C-nmr (CDCl.sub.3): .delta.=174.6, 146.7, 133.5,
131.3, 121.3, 114.9, 113.7, 75.2, 52.4, 32.0, 26.9, 19.4.
[3101] C.sub.14H.sub.19Cl.sub.2NO.sub.2 (MW=304.22); mass
spectroscopy (MH.sup.+) 303.
Example A30
Synthesis of N-(3,4-dichlorophenyl)glycine iso-butyl ester
[3102] 3,4-Dichloroaniline (Aldrich) was treated with di-tert-butyl
dicarbonate (Aldrich) using conventional procedures to produce the
N-BOC aniline. The N-BOC aniline was treated with sodium hydride in
THF and then with iso-butyl 2-bromoacetate (from Example AD above)
to produce the N-BOC N-(3,4-dichlorophenyl)glycine iso-butyl ester.
The BOC group was then removed using General Procedure AN above to
afford the title compound. The reaction was monitored by tlc on
silica gel (Rf=0.78 in 50% EtOAc/hexanes) and purification was by
preparative plate chromatography (silica gel using 50%
EtOAc/hexanes as the eluant).
[3103] NMR data was as follows:
[3104] .sup.1H-nmr (CDCl.sub.3): .delta.=7.19 (dd, J=4.1, 4.7, 3.4,
1H); 6.65 (d, J=2.7, 1H); 6.44 (dd, J=2.7, 4.5, 4.2, 1H): 4.4 (m,
1H): 3.97 (dd, J=3.6, 3.0, 2.3, 2H); 3.87 (s, 2H); 1.9 (m, 1H);
0.93 (d, J=6.7, 6H).
[3105] .sup.13C-nmr (CDCl.sub.3): .delta.=171.2, 147.0, 133.5,
131.3, 121.2, 114.5, 113.3, 72.2, 46.0, 28.2, 19.6.
[3106] C.sub.12H.sub.15Cl.sub.2NO.sub.2 (MW=276); mass spectroscopy
(MH.sup.+) 277.
Example A31
Synthesis of N-(3,4-dichlorophenyl)alanine 2-ethylbutyl ester
[3107] Following General Procedure AA above and using
3,4-dichloroaniline (Aldrich) and 2-ethylbutyl pyruvate (prepared
by following General Procedure AO above using 2-ethylbutanol
(Aldrich) in place of iso-butanol), the title compound was prepared
as an oil. The reaction was monitored by tlc on silica gel (Rf=0.6
in 25% EtOAc/hexanes) and purification was by preparative plate
chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3108] NMR data was as follows:
[3109] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2 (d, 1H); 6.6 (d, 1H);
6.4 (dd, 1H); 4.2 (t, 2H); 4.1 (q, 1H); 1.5 (d, 3H); 1.4 (m, 4H);
1.0 (m, 6H).
[3110] .sup.13C-nmr (CDCl.sub.3): .delta.=178; 144.7; 130.2;
120.62; 115.11; 70.7; 51.90; 26.3; 19.53, 18.5.
[3111] C.sub.15H.sub.21Cl.sub.2NO.sub.2 (MW=318.25); mass
spectroscopy (MH.sup.+) 319.
Example A32
Synthesis of N-(3-chloro-4-iodophenyl)alanine iso-butyl ester
[3112] Following General Procedure AR above and using
3-chloro-4-iodoaniline (Aldrich), N-BOC-3-chloro-4-iodoaniline was
prepared. To a stirred slurry of 5.0 equivalents of sodium hydride
in DMF was added 1.0 equivalent of N-BOC-3-chloro-4-iodoaniline and
then 1.1 equivalents of iso-butyl 2-bromopropionate (from Example
AD above) were slowly added. The reaction was heated to 100.degree.
C. for 10 hours, cooled, diluted with dichloromethane and washed
with cold 1N HCl, water and brine. The solvents were removed at
reduced pressure and the residue was chromatographed to provide
N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester as a clear
oil. Following General Procedure AN above, the BOC group was
removed from N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester
to provide the title compound. The BOC-removal reaction was
monitored by tlc on silica gel (Rf=0.58 in 30% EtOAc/hexanes) and
purification was by preparative plate chromatography (silica gel
using 30% EtOAc/hexanes as the eluant). The compound was further
purified by chromatography on an HPLC chiral column (Chiralcel
OD).
[3113] NMR data was as follows:
[3114] .sup.1H-nmr (CDCl.sub.3): .delta.=7.52 (d, J=8.7, 1H); 6.72
( d, J=2.7, 1H); 6.25 (dd, J=2.7, 5.9, 2.7, 1H); 4.35 (d, J=6.6,
1H): 4.08 (quintex, J=7.2, 6.7, 1H); 3.93 (d, J=6.7, 2H): 1.94 (m,
1H); 1.47 (d, J=6.9, 3H); 0.92 (d, J=6.9, 6H).
[3115] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5, 148.3, 140.7,
139.5, 114.4, 114.3, 82.6, 72.0, 52.2, 28.3, 19.6, 19.3.
[3116] C.sub.13H.sub.17ClNO.sub.2 (MW=381.5); mass spectroscopy
(MH.sup.+) 382.
Example A33
Synthesis of N-(4-azidophenyl)alanine iso-butyl ester
[3117] Following General Procedure AA above and using
4-azidoaniline (Aldrich) and iso-butyl pyruvate (prepared by
following General Procedure AO above), the title compound was
prepared as an oil. The reaction was monitored by tlc on silica gel
(Rf=0.3 in 25% EtOAc/hexanes) and purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3118] NMR data was as follows:
[3119] .sup.1H-nmr (CDCl.sub.3): .delta.=7.3 (d, 2H), 6.8 (d, 2H),
4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (sept, 1H), 1.47 (d, 3H), 0.91
(d, 6H).
[3120] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5, 148.7, 131.5,
130.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.
[3121] C.sub.13H.sub.18N.sub.4O.sub.2 (MW=262.31); mass
spectroscopy (MH.sup.+) 263.
Example A34
Synthesis of N-[(4-phenylcarbonyl)phenyl]alanine iso-butyl
ester
[3122] Following General Procedure AA above and using
4'-aminobenzophenone (Aldrich) and iso-butyl pyruvate (prepared by
following General Procedure AO above), the title compound was
prepared as an oil. The reaction was monitored by tlc on silica gel
(Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative
plate chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3123] NMR data was as follows:
[3124] .sup.1H-nmr (CDCl.sub.3): .delta.=7.7 (d, 2H), 7.1 (m, 5H),
6.9 (d, 2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (sept, 1H), 1.47 (d,
3H), 0.91 (d, 6H).
[3125] .sup.13C-nmr (CDCl.sub.3): .delta.=199, 178.5, 149.7, 131.5,
130.3, 126, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.
[3126] C.sub.20H.sub.23NO.sub.3 (MW=325.41); mass spectroscopy
(MH.sup.+) 326.
Example A35
Synthesis of N-(3,5-difluorophenyl)alanine iso-butyl ester
[3127] Following General Procedure AH above and using
N-(3,5-difluorophenyl)alanine (from Example AC above) and
iso-butanol, the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel (Rf=0.9 in 3%
methanol/methylene chloride) and purification was by preparative
plate chromatography (silica gel using 3% methanol/methylene
chloride as the eluant).
[3128] NMR data was as follows:
[3129] .sup.1H-nmr (CDCl.sub.3): .delta.=6.1 (m, 3H), 4.5 (bs, 1H),
4.1 (d, 1H), 3.95 (m, 2H), 2.0 (m, 1H), 1.5 (d, J=7 Hz, 3H),
0.95(d, J=6 Hz, 6H).
[3130] .sup.13C-nmr (CDCl.sub.3): .delta.=174.44, 166.40, 166.19,
163.16, 162.95, 149.43, 96.73, 96.60, 96.48, 96.35, 94.06, 93.72,
93.37, 72.03, 52.30, 28.29, 19.47, 19.23.
[3131] C.sub.13H.sub.17F.sub.2NO.sub.2 (MW=290.2); mass
spectroscopy (MH.sup.+) 291.
Example A36
Synthesis of N-(3,4-dichlorophenyl)alanine 0-acylacetamidoxime
ester
[3132] Following General Procedure AK above and using
N-(3,4-dichlorophenyl)alanine (from Example AB above) and acetamide
oxime (prepared according to the procedures described in J. Org.
Chem., 46, 3953 (1981)), the title compound was prepared as a
semisolid. The reaction was monitored by tlc on silica gel (Rf=0.4
in ethyl acetate) and purification was by preparative plate
chromatography (silica gel using ethyl acetate as the eluant).
[3133] NMR data was as follows:
[3134] .sup.1H-nmr (DMSO-d.sub.6): .delta.=7.27 (d, 1H), 6.81 (s,
1H) 6.4 (broad s, 2H), 6.62 (d, 1H), 6.45 (d, 1H), 4.22 (m, 1H),
1.74 (s, 3H), 1.40 (d, 3H).
[3135] C.sub.11H.sub.13Cl.sub.2N.sub.3O.sub.2 (MW=290.15); mass
spectroscopy (MH.sup.+) 291.
Example A37
Synthesis of N-(3,4-dichlorophenyl)alanine pyrrolyl amide
[3136] Following General Procedure AL above and using
N-(3,4-dichlorophenyl)alanine (from Example AB above) and pyrrole
(Aldrich), the title compound was prepared as an oil. The reaction
was monitored by tlc on silica gel (Rf=0.28 in 10% ethyl
acetate/hexanes) and purification was by preparative plate
chromatography (silica gel using 10% ethyl acetate/hexanes as the
eluant).
[3137] NMR data was as follows:
[3138] .sup.1H-nmr (CDCl.sub.3): .delta.=7.36 (d, J=2.2, 2H); 7.20
(d, J=8.7, 1H); 6.71 (d, J=2.7, 1H); 6.5 (m, 1H); 6.38 (t, J=2.4,
2H); 4.8 (m, 1H); 4.57 (d, J=8.7, 1H); 1.59 (d, J=6.8, 3H).
[3139] .sup.13C-nmr (CDCl.sub.3): .delta.=171.9, 146.1, 133.6,
131.5, 121.9, 119.6, 115.4, 114.7, 113.8, 51.8, 20.2.
[3140] C.sub.13H.sub.12Cl.sub.2N.sub.2O (MW=283); mass spectroscopy
(MH.sup.+) 284.
Example A38
Synthesis of N-(3,4-dichlorophenyl)alanine 0-acylbutyramideoxime
ester
[3141] Following General Procedure AI above and using
N-(3,4-dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared
from N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9)
using essentially the same procedure as described in Example AE
above) and butyramide oxime (prepared according to the procedures
described in J. Org. Chem., 46, 3953 (1981)), the title compound
was prepared as a semisolid. The reaction was monitored by tlc on
silica gel (Rf=0.25 in 50% ethyl acetate/hexanes) and purification
was by preparative plate chromatography (silica gel using 50% ethyl
acetate/hexanes as the eluant).
[3142] NMR data was as follows:
[3143] .sup.1H-nmr (d.sub.6-DMSO): .delta.=7.27 (d, 1H), 6.83 (s,
1H) 6.38 (broad s, 2H), 6.61 (d, 1H), 6.46 (d, 1H), 4.25 (m, 1H),
2.02 (t, 2H), 1.55 (m, 2H), 1.40 (d, 3H), 0.88 (t, 3H).
[3144] C.sub.13H.sub.17Cl.sub.2N.sub.3O.sub.2 (MW=318.20); mass
spectroscopy (MH.sup.+) 319.
Example A39
Synthesis of 2-[N-(naphth-2-yl)amino]butanoic acid ethyl ester
[3145] Following General Procedure AJ above and using
2-aminonaphthalene (Aldrich) and ethyl 2-bromobutyrate (Aldrich),
the title compound was prepared as a solid, m.p. 81-83.degree. C.
The reaction was monitored by silica gel tlc (Rf=0.5 in
CHCl.sub.3). Purification was by chromatography (silica gel using
chloroform as the eluant).
[3146] NMR data was as follows: .sup.1H-nmr (d.sup.6-DMSO):
.delta.=7.63 (m, 2H), 7.54 (d, 1H), 7.31(t, 1H), 7.12 (t, 1H), 7.03
(d, 1H), 6.62 (s, 1H), 6.32 (d, 1H), 4.15 (m, 3H), 1.42 (d, 3H),
1.19 (t, 3H).
[3147] C.sub.16H.sub.19NO.sub.2 (MW=257.34); mass spectroscopy
(MH.sup.+) 258.
Example A40
Synthesis of N-(2-naphthyl)alanine iso-butyl ester
[3148] Following General Procedure AA above and using
2-aminonaphthalene (Aldrich) and iso-butyl pyruvate (prepared by
following General Procedure AO above), the title compound was
prepared as an oil. Purification was by preparative plate
chromatography (silica gel using 25% EtOAc/hexanes as the
eluant).
[3149] NMR data was as follows:
[3150] .sup.1H-nmr (CDCl.sub.3): .delta.=7.65 (m, 3H), 7.38 (t, 1H,
J=6.9 Hz), 7.23 (t, 1H, J=6.9 Hz), 6.93 (m, 1H), 6.81 (d, 1H, J=2.3
Hz), 4.31 (q, 1H, J=6.9 Hz), 3.95 J=6.7 Hz, J=1.6 Hz), 1.96 (sept,
1H, J=6.7 Hz), 1.57 (d, 3H, J=6.9 Hz), 0.93 (dd, 6H, J=6.7 Hz,
J=1.6 Hz).
[3151] .sup.13C-nmr (CDCl.sub.3) .delta.=174.6, 144.2, 134.9,
129.1, 127.8, 127.6, 126.3, 126.0, 122.3, 118.1, 105.3, 71.2, 52.0,
27.7, 18.9, 18.8.
Example A41
Synthesis of N-(2-methylquinolin-6-yl)alanine iso-butyl ester
[3152] Following General Procedure AA above and using
6-amino-2-methylquinoline (Lancaster) and iso-butyl pyruvate
(prepared by following General Procedure AO above), the title
compound was prepared. The reaction was monitored by silica gel tlc
(Rf=0.44 in 50% EtOAc/hexanes). Purification was by flash
chromatography (silica gel using 50% EtOAc/hexanes as the
eluant).
[3153] NMR data was as follows:
[3154] .sup.1H-nmr (CDCl.sub.3): .delta.=7.90 (m. 2H), 7.10 (m,
2H), 6.66 (d, 1H, J=2.6), 4.50 (bd, 1H), 4.24 (m, 1H), 3.91 (d, 2H,
J=6.6 Hz), 2.64 (s, 3H), 1.91 (sept 1H, J=6.7 Hz), 1.52 (d, 3H,
J=6.9 Hz), 0.87 (d, 6H, J=6.7 Hz).
[3155] .sup.13C-nmr (CDCl.sub.3) .delta.=175.0, 155.4, 144.6,
143.4, 134.9, 130.2, 128.4, 122.8, 121.8, 104.9, 71.8, 52.7, 28.3,
25.4, 19.5, 19.4.
[3156] C.sub.17H.sub.22Cl.sub.2N.sub.2O.sub.2 (MW=286.38); mass
spectroscopy (MH.sup.+) 287.
Example A42
Synthesis of N-(3,4-methylenedioxyphenyl)alanine iso-butyl
ester
[3157] Following reductive amination General Procedure AA above and
using 3,4-methylenedioxyaniline (Aldrich) and methyl pyruvate
(Aldrich), N-(3,4-methylenedioxyphenyl)alanine methyl ester was
prepared. The methyl ester was then transesterified following
General Procedure AQ above and using iso-butanol to provide the
title compound as an oil. The reaction was monitored by silica gel
tlc (Rf=0.61 in 25% EtOAc/hexanes). Purification was by preparative
plate chromatography with silica gel using 25% EtOAc/hexanes as the
eluant.
[3158] NMR data was as follows:
[3159] .sup.1H-nmr (CDCl.sub.3): .delta.=6.63 (d, 1H, 8.3Hz), 6.25
(d, 1H, J=2.3 Hz), 6.04 (dd, 1H, J=8.3 Hz, J=2.3 Hz), 5.83 (s, 2H),
3.96 (m, 4H), 1.92 (sept, 1H, 3J =6.7 Hz), 1.44 (d, 3H, J=6.9 Hz),
0.90 (d, 6H, J=6.6 Hz).
[3160] .sup.13C-nmr (CDCl.sub.3): .delta.=175.4, 148.9, 142.9,
140.8, 109.2, 105.8, 101.2, 97.4, 71.6, 53.6, 28.3, 19.6, 19.5.
[3161] C.sub.14H.sub.19NO.sub.4 (MW=265.31); mass spectroscopy
(M.sup.+) 265.
Example A43
Synthesis of N-(3,4-ethylenedioxyphenyl)alanine iso-butyl ester
[3162] Following reductive amination General Procedure AA above and
using 1,4-benzodioxa-6amine (Aldrich) and methyl pyruvate
(Aldrich), N-(3,4-ethylenedioxyphenyl)alanine methyl ester was
prepared. The methyl ester was then transesterified following
General Procedure AQ above using iso-butanol to provide the title
compound. Purification was by preparative plate chromatography.
[3163] NMR data was as follows:
[3164] .sup.1H-nmr (CDCl.sub.3): .delta.=0.91 (d, .delta.=7 Hz,
6H), 1.42 (d, J=7 Hz, 3H), 1.8-2 (m, 1H), 3.8-3.95 (m, 3H), 4.0-4.1
(m, 1H), 4.15-4.25 (m, 4H), 6.12-6.2 (m, 2H), 6.65-6.75 (m,
1H).
[3165] .sup.13C-nmr (CDCl.sub.3): .delta.=19.55, 19.56, 19.67,
28.3, 53.4, 64.7, 65.3, 71.7, 103.1, 108.0, 118.3, 142.1, 144.6,
175.4.
[3166] C.sub.15H.sub.21NO.sub.4 (MW=279.34); mass spectroscopy
(MH.sup.+) 280.
Example A44
Synthesis of N-(2-naphthyl)alanine methyl ester
[3167] Following reductive amination General Procedure AA above and
using 2-aminonaphthalene (Aldrich) and methyl pyruvate (Aldrich),
the title compound was prepared. The reaction was monitored by
silica gel tlc (Rf=0.50 in 25% EtOAc/hexanes). Purification was by
flash chromatography with silica gel using 25% EtOAc/hexanes as the
eluant.
[3168] NMR data was as follows:
[3169] .sup.1H-nmr (CDCl.sub.3): .delta.=7.65 (m, 3H), 7.48 (m,
1H), 7.25 (m, 1H), 6.91 (m, 1H), 6.79 (m, 1H), 4.31 (m, 2H), 3.76
(s, 3H), 1.55 (d, 3H).
[3170] .sup.13C-nmr (CDCl.sub.3): .delta.=175.66, 144.78, 135.55,
129.78, 128.47, 128.22, 126.96, 126.67, 123.01, 118.66, 105.88,
52.95, 52.51, 19.45.
[3171] C.sub.14H.sub.15NO.sub.2 (MW=229.28); mass spectroscopy
(MH.sup.+) 229.
Example A45
Synthesis of N-(benzothiazol-6-yl)alanine ethyl ester
[3172] To a solution of 6-aminobenzothiazole (Lancaster) in
dichloromethane was added 1.2 equivalents of pyridine, followed by
1.5 equivalents of trifluoroacetic anhydride. The reaction was
stirred at room temperature for 3 hours and then washed with 5%
citric acid, dried over MgSO.sub.4, and stripped free of solvent on
a rotary evaporator to yield 6-trifluoroacetamidothiazole. This
material was dissolved in THF and then added to a suspension of KH
in THF at 0.degree. C. A catalytic amount of 18-crown-6 was added,
followed by ethyl 2-bromopropionate (Aldrich). The reaction was
held at room temperature for 1 hour, and then heated to reflux for
24 hours, and then cooled to room temperature. The reaction mixture
was stripped free of solvent on a rotary evaporator and the
resulting residue was dissolved in ether. This solution was washed
with water, saturated aqueous NaCl, and dried over MgSO.sub.4. The
solution was stripped free of solvent on a rotary evaporator and
the title compound was obtained by chromatography of the residue
using 5% methanol/dichloromethane (Rf=0.59) as the eluant.
[3173] NMR data was as follows:
[3174] .sup.1H-nmr (CDCl.sub.3): .delta.=8.69 (s, 1H), 7.90 (d, 1H,
J=8.8 Hz), 7.04 (d, 1H, J=2.3 Hz), 6.84 (dd, 1H, J=8.8 Hz, J=2.4
Hz), 4.41 (bd, 1H, J=7.5 Hz), 4.20 (m, 3H), 1.53 (d, 3H, J=6.9 Hz),
1.27 (t, 3H, J=7.1 Hz).
[3175] .sup.13C-nmr (CDCl.sub.3): .delta.=174.9, 150.2, 147.1,
145.6, 136.3, 124.6, 115.7, 103.5, 61.9, 52.9, 19.4, 14.8.
[3176] C.sub.12H.sub.14N.sub.2O.sub.2S (MW=250.32); mass
spectroscopy (MH.sup.+) 251.
Example A46
Synthesis of N-(indol-5-yl)alanine iso-butyl ester (S isomer)
[3177] Following General Procedure AM and using 5-aminoindole
(Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound
was prepared as an oil. The reaction was monitored by silica gel
tlc (Rf=0.46 in 33% EtOAc/hexanes). Purification was by preparative
plate chromatography with silica gel using 33% EtOAc/hexanes as the
eluant.
[3178] NMR data was as follows:
[3179] .sup.1H-nmr (CDCl.sub.3): .delta.=8.11 (bs, 1H), 7.07 (d,
J=8.8 Hz, 1H), 6.98 (d, J=2.8 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.61
(m, 1H), 6.32 (m, 1H), 4.18 (q, J=6.9 H 1H), 3.95 (bs, 1H), 3.87
(d, J=6.7 Hz, 2H), 1.89 (hept, J=6.7 Hz, 1H), 1.48 (d, J=6.96 Hz,
3H), 0.86 (dd, J=6.7 Hz, J=1.6 Hz, 6H).
[3180] .sup.13C-nmr (CDCl.sub.3): .delta.=176.15, 141.06, 131.28,
129.24, 125.34, 113.34, 112.53, 104.21, 102.17, 71.65, 54.28,
28.36, 19.87, 19.62.
[3181] C.sub.15H.sub.20N.sub.2O.sub.2 (MW=260.34); mass
spectroscopy (MH.sup.+) 261.
Example A47
Synthesis of N-(naphth-2-yl)alanine 0-acylacetamidoxime ester
[3182] Following General Procedure AI above using
N-(naphth-2-yl)alanine 2,4,6-trichlorophenyl ester (from Example AE
above) and acetamide oxime (prepared according to the procedures
described in J. Org. Chem., 46, 3953 (1981)), the title compound
was prepared as a semisolid. The reaction was monitored by tlc on
silica gel (Rf=0.4 in ethyl acetate) and purification was by
preparative plate chromatography (silica gel using ethyl acetate as
the eluant).
[3183] NMR data was as follows:
[3184] .sup.1H-nmr (d.sup.6-DMSO): .delta.=7.64 (t, 2H), 7.54 (d,
1H), 7.32 (t, 1H), 7.13 (t, 1H) 7.04 (d, 1H), 6.78 (s, 1H) 6.42
(broad s, 2H), 6.32 (d, 1H), 4.33 (m, 1H), 1.72 (s, 3H), 1.46 (d,
3H).
[3185] C.sub.15H.sub.17N.sub.3O.sub.2 (MW=271.32); mass
spectroscopy: 271.
Example A48
Synthesis of N-(2-naphthyl)alanine ethyl ester
[3186] Following reductive amination General Procedure AA above and
using 2-aminonaphthalene (Aldrich) and ethyl pyruvate (Aldrich),
the title compound was prepared as a solid having a melting point
of 52-56.degree. C. The reaction was monitored by silica gel tlc
(Rf=0.50 in 25% EtOAc/hexanes). Purification was by flash
chromatography with silica gel using 25% EtOAc/hexanes as the
eluant.
[3187] NMR data was as follows:
[3188] .sup.1H-nmr (CDCl.sub.3): .delta.=7.65 (m, 3H), 7.48 (m,
1H), 7.25 (m, 1H), 6.91 (m, 1H), 6.79 (m, 1H), 4.31 (m, 2H), 3.76
(s, 3H), 1.55 (d, 3H).
[3189] .sup.13C-nmr (CDCl.sub.3): .delta.=175.66, 144.78, 135.55,
129.78, 128.47, 128,22, 126.96, 126.67, 123.01, 118.66, 105.88,
52.95, 52.51, 19.45.
[3190] C.sub.14H.sub.15NO.sub.2 (MW=229.28); mass spectroscopy
(MH.sup.+) 229.
Example A49
Synthesis of N-(3,4-dichlorophenyl)alanine O-acylpropionamidoxime
ester
[3191] Following General Procedure AI above using
N-(3,4-dichlorophenyl)al- anine 2,4,6-trichlorophenyl ester
(prepared from N-(3,4-dichlorophenyl)ala- nine methyl ester (from
Example A9) using essentially the same procedure as described in
Example AE above) and propionamide oxime (prepared according to the
procedures described in J. Org. Chem., 46, 3953 (1981)), the title
compound was prepared as a semisolid. The reaction was monitored by
tlc on silica gel (Rf=0.2 in 50% ethyl acetatelhexane) and
purification was by preparative plate chromatography (silica gel
using 50% ethyl acetate/hexane as the eluant).
[3192] NMR data was as follows:
[3193] .sup.1H-nmr (d.sup.6-DMSO): .delta.=7.27 (d, 1H), 6.83 (s,
1H), 6.64 (d, 1H), 6.47 (d, 1H), 6.38 (broad s, 2H), 4.24 (m, 1H),
2.07 (q, 2H), 1.41 (d, 3H).
[3194] C.sub.12H.sub.15Cl.sub.2N.sub.3O.sub.2 (MW=304.17); mass
spectroscopy (MH.sup.+) 305.
Example A50
Synthesis of N-(4-ethoxycarbonylphenyl)alanine iso-butyl ester (S
isomer)
[3195] Following General Procedure AM and using ethyl
4-aminobenzoate (Aldrich) and iso-butyl R-(+)-lactate (Aldrich),
the title compound was prepared as an oil. The reaction was
monitored by silica gel tlc (Rf=0.21 in 10% EtOAc/hexanes).
Purification was by preparative plate thin layer chromatography
using 25% EtOAc/hexanes as the eluant.
[3196] NMR data was as follows:
[3197] .sup.1H-nmr (CDCl.sub.3): .delta.=7.82 (d, J=8.73 Hz, 2H),
6.51 (d, J=8.79 Hz, 2H), 4.81 (d, J=7.82 Hz, 1H), 4.25 (q, J=7.14
Hz, 2H), 4.15 (quint, J=7.40 Hz, 1H), 3.87 (m, 2H), 1.87 (sept,
J=6.70 Hz, 1H), 1.43 (d, J=6.95 Hz, 3H), 1.30 (t, J=7.14 Hz, 3H),
0.84 (d, J=6.71 Hz, 6H).
[3198] .sup.13C-nmr (CDCl.sub.3): .delta.=174.5, 167.3, 151.0,
132.0, 119.9, 112.5, 71.9, 60.8, 51.9, 28.2, 19.5, 19.2, 15.0.
[3199] C.sub.16H.sub.23NO.sub.4 (MW=293.37); mass spectroscopy
(MH.sup.+) 294.
Example A51
Synthesis of N-[3,5-di(trifluoromethyl)phenyl]alanine iso-butyl
ester (S isomer)
[3200] Following General Procedure AM and using
3,5-di(trifluoromethyl)ani- line (Aldrich) and iso-butyl
R-(+)-lactate (Aldrich), the title compound was prepared as an oil.
The reaction was monitored by silica gel tlc (Rf=0.38 in 10%
EtOAc/hexanes). Purification was by preparative plate thin layer
chromatography using 10% EtOAc/hexanes as the eluant.
[3201] NMR data was as follows:
[3202] .sup.1H-nmr (CDCl.sub.3): .delta.=7.13 (s, 1H), 6.91 (s,
2H), 4.97 (d, J=8.24 Hz, 1H), 4.18 (m, 1H), 3.93 (d, J=6.59 Hz,
2H), 1.93 (sept, J=6.71 Hz, 1H), 1.49 (d, J=7.02 Hz, 3H), 0.89 (d,
J=6.59 Hz, 6H).
[3203] .sup.13C-nmr (CDCl.sub.3): .delta.=174.4, 147.9, 133.6,
133.2, 132.7, 132.3, 129.4, 125.8, 122.2, 118.6, 112.81, 112.76,
111.42, 111.37, 111.32, 111.27, 111.22, 72.2, 52.0, 32.1, 28.24,
28.17, 23.2, 19.5, 19.3, 19.2, 18.9, 14.6.
[3204] C.sub.15H.sub.17F.sub.6NO.sub.2 (MW=357.30); mass
spectroscopy (MH.sup.+) 358.
Example A52
Synthesis of N-(3,5-dimethoxyphenyl)alanine iso-butyl ester
[3205] N-(3,5-dimethoxyphenyl)alanine (crude, 454 mg) (prepared
according to the procedure described in U.S. Pat. No. 3,598,859
using 3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid
(Aldrich)) was treated in dry iso-butanol (10 mL) with 0.1 mL of
chlorotrimethylsilane and the reaction mixture refluxed overnight.
The excess alcohol was removed at reduced pressure and the residue
dissolved in ethyl acetate. The ethyl acetate solution was washed
with saturated aqueous NaHCO.sub.3, dried with Na.sub.2SO.sub.4 and
the solvent removed to provide the title compound. The reaction was
monitored by silica gel tlc (Rf=0.3 in 20% EtOAc/hexanes).
Purification was by preparative thin layer chromatography using 20%
EtOAc/hexanes as the eluant.
[3206] NMR data was as follows:
[3207] .sup.1H-nmr (CDCl.sub.3): .delta.=0.9 (d, J=7, 6H), 1.47 (d,
J=7, 3H), 1.9-2.0 (m, 1H), 3.7 (s, 6H), 3.85-4.0 (m, 2H), 4.1-4.2
(m, 1H), 4.3 (brs, 1H), 5.8 (s, 1H) 5.9 (s, 1H).
[3208] .sup.13C-nmr (CDCl.sub.3): .delta.=19.49, 19.52, 19.54,
28.3, 52.5, 55.6, 71.7, 91.1, 92.7, 149.2, 162.3, 175.2.
[3209] C.sub.15H.sub.23NO.sub.4 (MW=281.35).
Example A53
Synthesis of N-(2-napthyl)alanine O-acylpropionamidoxime ester
[3210] Following General Procedure AS and using
N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE
above) and propionamide oxime (prepared according to the procedures
described in J. Org. Chem., 46, 3953 (1981)), the title compound
was prepared. The reaction was monitored by silica gel tlc (Rf=0.5
in EtOAc). Purification was by silica gel chromatography using 1:1
EtOAc/hexanes as the eluant.
[3211] NMR data was as follows:
[3212] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.03 (t, 3H), 1.45 (d,
3H).
[3213] C.sub.16H.sub.19N.sub.3O.sub.2 (MW=285.35); mass
spectroscopy (M.sup.+) 285.
Example A54
Synthesis of N-(2-napthyl)alanine 0-acylbutyramidoxime ester
[3214] Following General Procedure AS and using
N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE
above) and butyramide oxime (prepared according to the procedures
described in J. Org. Chem., 46, 3953 (1981)), the title compound
was prepared as an oil. The reaction was monitored by silica gel
tic (Rf=0.6 in EtOAc). Purification was by silica gel
chromatography using 1:1 EtOAc/hexanes as the eluant.
[3215] NMR data was as follows:
[3216] .sup.1H-nmr (DMSO-d.sub.6): .delta.=0.86 (t, 3H), 1.46 (d,
3H).
[3217] C.sub.17H.sub.21N.sub.3O.sub.2 (MW=299.37); mass
spectroscopy (MH.sup.+) 299.
Example A55
Synthesis of N-(2-napthyl)alanine O-acylisovaleramidoxime ester
[3218] Following General Procedure AS and using
N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE
above) and isovaleramide oxime (prepared according to the
procedures described in J. Org. Chem., 46, 3953 (1981)), the title
compound was prepared as an oil. The reaction was monitored by
silica gel tlc (Rf=0.3 in 1:1 EtOAc/hexanes). Purification was by
silica gel chromatography using 1:1 EtOAc/hexanes as the
eluant.
[3219] NMR data was as follows:
[3220] .sup.1H-nmr (DMSO-d.sub.6): .delta.=0.86 (t, 3H), 1.45 (d,
3H).
[3221] C.sub.18H.sub.23N.sub.3O.sub.2 (MW=313.40); mass
spectroscopy (MH.sup.+) 313.
Example A56
Synthesis of N-(2-napthyl)alanine O-acylbenzamidoxime ester
[3222] Following General Procedure AS and using
N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE
above) and benzamide oxime (prepared according to the procedures
described in J. Org. Chem., 46, 3953 (1981)), the title compound
was prepared as an oil. The reaction was monitored by silica gel
tlc (Rf=0.3 in 1:1 EtOAc/hexanes). Purification was by silica gel
chromatography using 1:1 EtOAc/hexanes as the eluant.
[3223] NMR data was as follows:
[3224] .sup.1H-nmr (DMSO-d.sub.6): .delta.=4.42 (m, 1H), 1.53 (d,
3H).
[3225] C.sub.20H.sub.19N.sub.3O.sub.2 (MW=333.39); mass
spectroscopy (MH.sup.+) 333.
Example A57
Synthesis of N-(2-napthyl)alanine O-acylcyclopropanecarboxamidoxime
ester
[3226] Following General Procedure AS and using
N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE
above) and cyclopropanecarboxamide oxime (prepared according to the
procedures described in J. Org. Chem., 46, 3953 (1981)), the title
compound was prepared as an oil. The reaction was monitored by
silica gel tlc (Rf=0.3 in 1:1 EtOAc/hexanes). Purification was by
silica gel chromatography using 1:1 EtOAc/hexanes as the
eluant.
[3227] NMR data was as follows:
[3228] .sup.1H-nmr (DMSO-d.sub.6): .delta.=0.85 (m, 4H), 1.43 (d,
3H).
[3229] C.sub.17H.sub.19N.sub.3O.sub.2 (MW=297.36); mass
spectroscopy (MH.sup.+) 297.
Example A58
Synthesis of N-(2-napthyl)alanine O-acylcyclopropylacetamidoxime
ester
[3230] Following General Procedure AS and using
N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE
above) and cyclopropylacetamide oxime (prepared according to the
procedures described in J. Org. Chem., 46, 3953 (1981)), the title
compound was prepared as an oil. The reaction was monitored by
silica gel tlc (Rf=0.3 in 1:1 EtOAc/hexanes). Purification was by
silica gel chromatography using 1:1 EtOAc/hexanes as the
eluant.
[3231] NMR data was as follows:
[3232] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.43 (d, 3H), 1.91 (d,
2H).
[3233] C.sub.18H.sub.21N.sub.3O.sub.2 (MW=311.39); mass
spectroscopy (MH.sup.+) 311.
Example A59
Synthesis of N-(2-napthyl)alanine O-acylcyclopentanecarboxamidoxime
ester
[3234] Following General Procedure AS and using
N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE
above) and cyclopentanecarboxamide oxime (prepared according to the
procedures described in J. Org. Chem., 46, 3953 (1981)), the title
compound was prepared as an oil. The reaction was monitored by
silica gel tlc (Rf=0.3 in 1:1 EtOAc/hexanes). Purification was by
silica gel chromatography using 1:1 EtOAc/hexanes as the
eluant.
[3235] NMR data was as follows:
[3236] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.43 (d, 3H), 2.43 (m,
1H).
[3237] C.sub.17H.sub.19N.sub.3O.sub.2 (MW=297.36).
General Procedure BA
Coupling of R.sup.1C(X')(X")C(O)Cl with
H.sub.2NCH(R.sup.2)C(O)XR.sup.3
[3238] To a stirred solution of (D,L)-alanine iso-butyl ester
hydrochloride (from Example BB below) (4.6 mmol) in 5 mL of
pyridine was added 4.6 mmol of an acid chloride. Precipitation
occurred immediately. The mixture was stirred for 3.5 h, diluted
with 100 mL of diethyl ether, washed with 10% HCl three times,
brine once, 20% potassium carbonate once and brine once. The
solution was dried over magnesium sulfate, filtered, and evaporated
at reduced pressure to yield the product. Other amino acid esters
may also be employed in this procedure.
General Procedure BB
Coupling of R.sup.1C(X')(X")C(O)OH with
H.sub.2NCH(R.sup.2)C(O)XR.sup.3
[3239] A solution of the acid (3.3 mmol) and CDI in 20 mL THF was
stirred for 2 h. L-alanine iso-butyl ester hydrochloride (from
Example BB below) (3.6 mmol) was added, followed by 1.5 mL (10.8
mmol) of triethylamine. The reaction mixture was stirred overnight.
The reaction mixture was diluted with 100 mL of diethyl ether,
washed with 10% HCl three times, brine once, 20% potassium
carbonate once and brine once. The solution was dried over
magnesium sulfate, filtered, and evaporated at reduced pressure to
yield the product. Other amino acid esters may also be employed in
this procedure.
General Procedure BC
[3240] Esterification of R.sup.1C(X')(X")C(O)NHCH(R.sup.2)C(O)OH
With HOR.sup.3
[3241] To a stirred solution of phenylacetylvaline (1.6470 g, 7.0
mmol) in 20 mL THF was added CDI (1.05 g, 6.5 mmol) and the mixture
was stirred for 1.5 h. 2-Methylbutanol (0.53 g, 6 mmol) was added
the mixture, followed by addition of NaH (0.16 g, 6.5 mmol).
Bubbling occurred immediately. The reaction mixture was stirred
overnight. The reaction mixture was diluted with 100 mL of diethyl
ether, washed with 10% HCl three times, brine once, 20% potassium
carbonate once and brine once. The solution was dried over
magnesium sulfate, filtered, and evaporated at reduced pressure to
yield the product. Other N-acyl amino acids and alcohols may also
be employed in this procedure.
General Procedure BD
Ester Hydrolysis to the Free Acid
[3242] Ester hydrolysis to the free acid was conducted by
conventional methods. Below are two examples of such conventional
de-esterification methods.
[3243] To the ester in a 1:1 mixture of CH.sub.3OH/H.sub.2O was
added 2-5 equivalents of K.sub.2CO.sub.3. The mixture was heated to
about 50.degree. C. for about 0.5 to 1.5 hours until tlc showed
complete reaction. The reaction was cooled to room temperature and
the methanol was removed at reduced pressure. The pH of the
remaining aqueous solution was adjusted to about 2, and ethyl
acetate was added to extract the product. The organic phase was
then washed with saturated aqueous NaCl and dried over MgSO.sub.4.
The solution was stripped free of solvent at reduced pressure to
yield the product.
[3244] The amino acid ester was dissolved in dioxane/water (4:1) to
which was added LiOH (.about.2 eq.) that was dissolved in water
such that the total solvent after addition was about 2:1
dioxane:water. The reaction mixture was stirred until reaction
completion and the dioxane was removed under reduced pressure. The
residue was diluted with EtOAc, the layers were separated and the
aqueous layer acidified to pH 2. The aqueous layer was back
extracted with EtOAc, the combined organics were dried over
Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure
after filtration. The residue was purified by conventional methods
(e.g., recrystallization).
[3245] The following exemplifies this later example. The methyl
ester of 3-NO.sub.2 phenylacetyl alanine 9.27 g (0.0348 mols) was
dissolved in 60 mL dioxane and 15 mL of H.sub.2O and adding LiOH
(3.06 g, 0.0731 mol) that has been dissolved in 15 mL of H.sub.2.
After stirring for 4 hours, the dioxane was removed under reduced
pressure and the residue diluted with EtOAc, the layers were
separated and the aqueous layer acidified to pH 2. The aqueous
layer was back extracted with EtOAc (4.times.100 mL), the combined
organics were dried over Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure after filtration. The residue was
recrystallized from EtOAc/isooctane giving 7.5 g (85%) of
3-nitrophenylacetyl alanine. C.sub.11H.sub.12N.sub.2O.sub.5
requires C=52.38, H=4.80, and N=11.11. Analysis found C=52.54,
H=4.85, and N=11.08. [.alpha.].sub.23=-29.9 @ 589 nm.
General Procedure BE
Low Temperature BOP Coupling of Acid and Alcohol
[3246] A solution of methylene chloride containing the carboxylic
acid (100M %) and N-methyl morpholine (150 M %) was cooled to
-20.degree. C. under nitrogen. BOP (105 M %) was added in one
portion and the reaction mixture was maintained at -20.degree. C.
for 15 minutes. The corresponding alcohol (120 M %) was added and
the reaction mixture was allowed to warm to room temperature and
stirred for 12 hours. The reaction mixture was then poured into
water and extracted with ethyl acetate (3.times.). The combined
ethyl acetate portions were backwashed with saturated aqueous
citric acid (2.times.), saturated aqueous sodium bicarbonate
(2.times.), brine (1.times.), dried over anhydrous magnesium
sulfate or sodium sulfate and the solvent removed under reduced
pressure to yield the crude product.
General Procedure BF
[3247] EDC Coupling of Acid and Amine
[3248] The acid derivative was dissolved in methylene chloride. The
amine (1 eq.), N-methylmorpholine (5 eq.), and hydroxybenzotriazole
monohydrate (1.2 eq.) were added in sequence. The reaction was
cooled to about 0.degree. C. and then 1.2 eq. of
1-(3-dimethylaminopropyl)-3-ethylcarbodi- imide hydrochloride was
added. The solution was allowed to stir overnight and come to room
temperature under N. pressure. The reaction mix was worked up by
washing the solution with saturated, aqueous NACO.sub.2CO.sub.3,
0.1M citric acid, and brine before drying with NA.sub.2SO.sub.4 and
removal of solvents to yield crude product. Pure products were
obtained by flash chromatography in an appropriate solvent.
General Procedure BG
EDC Coupling of Acid and Amine
[3249] A round bottom flask was charged with carboxylic acid (1.0
eq.), hydroxy-benzotriazole hydrate (1.1 eq.) and amine (1.0 eq.)
in THF under nitrogen atmosphere. An appropriate amount (1.1 eq.
for free amines and 2.2 eq. for hydrochloride amine salts) of base,
such as Hunig's base was added to the well stirred mixture followed
by EDC (1.1 eq.). After stirring from 4 to 17 hours at room
temperature the solvent was removed at reduced pressure, the
residue taken up in EtOAc (or similar solvent)/water. The organic
layer was washed with saturated aqueous sodium bicarbonate
solution, 1N HCl, brine and dried over anhydrous sodium sulfate. In
some cases, the isolated product was analytically pure at this
stage while, in other cases, purification via chromatography and/or
recrystallization was required prior to biological evaluation.
General Procedure BH
Coupling of R.sup.1C(X')(X")C(O)Cl with
H.sub.2NCH(R.sup.2)C(O)XR.sup.3
[3250] An excess of oxalyl chloride in dichloromethane was added to
the acid derivative together with one drop of DMF. The resulting
mixture was stirred for about 2 hours or until bubbling ceases. The
solvent was then removed under reduced pressure and rediluted with
dry methylene chloride. To the resulting solution was added about
1.1 eq. of the appropriate amino acid ester and triethylamine (1.1
eq. in methylene chloride). The system was stirred at room
temperature for 2 hours and then the solvent was removed under
reduced pressure. The residue was dissolved in ethyl acetate,
washed with 1N HCl followed by 1N NaOH. The organic layer was dried
over anhydrous soldium sulfate, filtered and the solvent removed
under reduced pressure to provide for the desired product.
General Procedure BI
P-EPC coupling
[3251] P-EPC coupling employs an amino acid ester and a substituted
acetic acid compound. The acetic acid derivative is well known in
the art and is typically commercially available. The amino acid
ester is prepared by conventional methods from the known and
typically commercially available N-BOC amino acid as described in
General Procedure BJ below.
[3252] Specifically, the appropriate amino ester free base (0.0346
mmols) and substituted phenylacetic acid (0.069 mmols) were
dissolved in 2.0 mL CHCl.sub.3 (EtOH free), treated with 150 mg of
P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at
23.degree. C. The reaction was filtered through a plug of cotton,
rinsed with 2.0 mL of CHCl.sub.3 and the filtrate evaporated under
a stream of nitrogen. The purity of each sample was determined by
.sup.1H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg
of final product was obtained from each reaction and was tested
without additional purification.
General Procedure BJ
Synthesis of Amino Acid Esters From the Corresponding N-BOC Amino
Acid
[3253] A. Esterification of the Acid.
[3254] The N-BOC amino acid was dissolved in dioxane and treated
with an excess of alcohol (.about.1.5 eq.) and catalytic DMAP (100
mg) at 0.degree. C. Stirring was continued until reaction
completion whereupon the product was recovered by conventional
methods.
[3255] B. Removal of N-BOC Group.
[3256] The N-BOC protected amino acid was dissolved in methylene
chloride (0.05M) and treated with 10 eq. of TFA at room temperature
under a nitrogen atmosphere. The reaction was monitored by tlc
until starting material was consumed usually within 1-5 hours. An
additional 10 eq. of TFA was added to the reaction if the starting
material was still present after 5 hours. The reaction was
carefully neutralized with Na.sub.2CO.sub.3, separated, the organic
layer washed with brine and dried over anhydrous Na.sub.2SO.sub.4.
The crude amine was then used without purification.
[3257] Specific exemplification of these procedures are as
follows:
[3258] 1. Racemic (+/-)-N-BOC-.alpha.-amino butyric acid (Aldrich)
(9.29 g, 0.0457 mol) was dissolved in 100 mL of dioxane and treated
with iso-butyl alcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457)
and catalytic DMAP (100 mg) at 0.degree. C. After stirring for 17
hours, the organics were evaporated at reduced pressure, the
residue diluted with EtOAc washed with NaHCO.sub.3, brine and dried
over Na.sub.2SO.sub.4. Evaporation yields 8.42 g (71%) of an oil.
C.sub.13H.sub.25NO.sub.4 requires: C=60.21, H=9.72, and N=5.40.
Anal found: C=59.91, H=9.89, and N=5.67.
[3259] The above N-BOC amino acid ester (8.00 g, 0.032 mol) was
deprotected as above giving 3.12 g (61%) of the free base as a
colorless oil which solidifies upon standing.
[3260] 2. L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was
dissolved in 100 mL of CH.sub.2Cl.sub.2, iso-butyl alcohol (21.9
mL, 0.238 mol) and treated with DMAP (100 mg) and EDC (10.0 g, 0.52
mol) at 0.degree. C. The mixture was stirred for 17 hours, diluted
with H.sub.2O, washed with 1.0 N HCl, NaHCO.sub.3, then brine and
the organics were dried over Na.sub.2SO.sub.4. Filtration and
evaporation yields 11.8 g (quantitative) of L-N-BOC alanine
iso-butyl ester which is contaminated with a small amount of
solvent. A sample was vacuum dried for analytical analysis.
C.sub.12H.sub.23NO.sub.4 requires: C=58.79, H=9.38, and N=5.71.
Anal found: C=58.73, H=9.55, and N=5.96.
[3261] The above N-BOC amino acid ester (11.8 g, 0.0481 mol) was
deprotected as above. The free base was converted to the
corresponding HCl salt using saturated HCl (g)/EtOAc to give
L-N-alanine iso-butyl ester hydrochloride. Obtained 4.2 g (48%) of
a colorless solid. C.sub.7H.sub.15NO.sub.2. HCl requires: C=46.28,
H=8.88, and N=7.71. Anal found: C=46.01, H =8.85, and N=7.68.
General Procedure BK
Methyl ester formation from amino acids
[3262] The amino acid (amino acid or amino acid hydrochloride) is
suspended in methanol and chilled to 0.degree. C. HCl gas is
bubbled through this solution for 5 minutes. The reaction is
allowed to warm to room temperature then stirred for 4 hours. The
solvents are then removed at reduced pressure to afford the desired
amino acid methyl ester hydrochloride. This product is usually used
without further purification.
Example BA
Synthesis of free and polymer bound PEPC
N-ethyl-N'-3-(1-pyrrolidinyl)prop- ylurea
[3263] To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250
mL chloroform was added 50 g (0.39 mol)
3-(1-pyrrolidinyl)propylamine dropwise with cooling. Once the
addition was complete, the cooling bath was removed and the
reaction mixture stirred at room temperature for 4 hours. The
reaction mixture was then concentrated under reduced pressure to
give 74.5 g (96.4%) of the desired urea as a clear oil.
[3264] 1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)
[3265] To a solution of 31.0 g (0.156 mol)
N-ethyl-N'-3-(1-pyrrolidinyl)pr- opylurea in 500 mL dichloromethane
was added 62.6 g (0.62 mol) triethylamine and the solution was
cooled to 0.degree. C. To this solution were then added 59.17 g
(0.31 mol) 4-toluenesulfonyl chloride in 400 mL dichloromethane
dropwise at such a rate as to maintain the reaction at 0-5.degree.
C. After the addition was complete, the reaction mixture was warmed
to room temperature and then heated to reflux for 4 hours. After
cooling to room temperature, the reaction mixture was washed with
saturated aqueous potassium carbonate (3.times.150 mL). The aqueous
phases were combined and extracted with dichloromethane. All
organic phases were combined and concentrated under reduced
pressure. The resultant orange slurry was suspended in 250 mL
diethyl ether and the solution decanted off from the solid. The
slurry/decantation process was repeated 3 more times. The ether
solutions were combined and concentrated under reduced pressure to
give 18.9 g (67%) of the desired product as a crude orange oil. A
portion of the oil was distilled under vacuum to give a colorless
oil distilling at 78-82.degree. C. (0.4 mm Hg).
[3266] Preparation of a polymer supported form of
1-(3-(1-pyrrolidinyl)pro- pyl)-3-ethylcarbodiimide (P-EPC)
[3267] A suspension of 8.75 g (48.3 mmol)
1-(3-(1-pyrrolidin-yl)propyl)-3-- ethylcarbodiimide and 24.17 g
(24.17 mmol) Merrifield's resin (2% cross-linked, 200-400 mesh,
chloromethylated styrene/divinylbenzene copolymer, 1 meq. Cl/g) in
dimethylformamide was heated at 100.degree. C. for 2 days. The
reaction was cooled and filtered and the resulting resin washed
sequentially with 1L DMF, 1L THF and 1L diethyl ether. The
remaining resin was then dried under vacuum for 18 hours.
Example BB
Preparation of alanine iso-butyl ester hydrochloride
[3268] A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich)
(or L-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride
(Aldrich) and 200 mL of isobutanol was refluxed for 1.5 hours and
the volatiles were removed completely on a rotavapor of 90.degree.
C. under reduced pressure to give (D,L)-alanine iso-butyl ester
hydrochloride (or L-alanine iso-butyl ester hydrochloride), which
was pure enough to be used for further transformations.
Example BC
Preparation of 3,5-dichlorophenylacetic acid
[3269] To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol
(Aldrich) in 75 mL of dichloromethane at 0.degree. C. was added 1.8
mL of methane sulfonylchloride followed by 3.5 mL of triethylamine
added dropwise. After 2 hours the solution was diluted to 150 mL
with dichloromethane, washed with 3N HCl, saturated aqueous
NaHCO.sub.3 dried with Na.sub.2SO.sub.4 and the solvents removed to
yield the desired 3,5-dichlorobenzyl methanesulfonate as a yellow
oil that was used without purification.
[3270] The crude sulfonate was dissolved in 50 mL of DMF at
0.degree. C. and then 3 g of KCN was added. After 2 hours an
additional 50 mL of DMF was added and the solution was stirred for
16 hours. The red solution was diluted with 1 L of H.sub.2O and
acidified to pH 3 with 3N HCl. The aqueous solution was extracted
with dichloromethane. The combined organics were washed with 3N
HCl, dried with Na.sub.2SO.sub.4 and the solvents removed at
reduced pressure to yield crude 3,5-dichlorophenylacetonitrile
which was used without purification.
[3271] The nitrile was added to a mixture of 40 mL of concentrated
sulfuric acid and 50 mL H.sub.2O and heated to reflux for 48 hours,
cooled to room temperature and stirred for 48 hours. The reaction
was diluted into 1 L of crushed ice, warmed to room temperature and
extracted with 2.times.200 mL of dichloromethane and 2.times.200 mL
of ethylacetate. Both sets of organics were combined and washed
with saturated aqueous NaHCO.sub.3. The NaHCO.sub.3 fractions were
combined and acidified to pH 1 with 3N HCl. The white solid was too
fine to filter and was extracted out with 2.times.200 mL of
dichloromethane. The combined organics were dried with
Na.sub.2SO.sub.4 and the solvents removed at reduced pressure to
yield crude 3,5-dichlorophenylacetic acid as a white solid. The
solid was slurried with hexane and filtered to get 1.75g of white
solid.
[3272] NMR (CDCl.sub.3): (in ppm) 3.61 (s, 2H), 7.19 (s,1H), 7.30
(s, 1H)
Example BD
Synthesis of N-(3-chlorophenylacetyl)alanine
[3273] The title compound was prepared using L-alanine (Nova
Biochem) and 3-chlorophenyl acetic acid (Aldrich) by following
General Procedures BF or BG, followed by hydrolysis using General
Procedure BD.
Example B1
Synthesis of N-(phenylacetyl)-D,L-alanine iso-butyl ester
[3274] Following General Procedure BA above and using phenylacetyl
chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride
(from Example BB above), the title compound was prepared. The
reaction was monitored by tlc on silica gel and purification was by
extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[3275] NMR data was as follows:
[3276] .sup.1H-nmr (CDCl.sub.3): .delta.=7.23-7.36 (m, 5H), 6.18
(d, 1H), 4.58 (t, J=7.3 Hz, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.90
(m, 1H), 1.34 (d, J=7.2 Hz, 3H), 0.89 (d, J=6.8 Hz, 6H).
[3277] .sup.13C-nmr (CDCl.sub.3): .delta.=172.7, 170.3, 134.5,
129.2, 128.8, 127.2, 71.3, 48.1, 43.4, 27.5, 18.8, 18.3.
[3278] C.sub.15H.sub.21NO.sub.3 (MW=263.34; Mass Spectroscopy
(MH.sup.+=264))
Example B2
Synthesis of N-(3-phenylpropionyl)-D,L-alanine iso-butyl ester
[3279] Following General Procedure BA above and using
3-phenylpropionyl chloride (Aldrich) and D,L-alanine iso-butyl
ester hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of from
51.degree.-54.degree. C. The reaction was monitored by tlc on
silica gel and purification was by extraction with Et.sub.2O
followed by washes with aqueous K.sub.2CO.sub.3 and aqueous
HCl.
[3280] NMR data was as follows:
[3281] .sup.1H-nmr (CDCl.sub.3): .delta.=7.25 (m, 2H), 7.19 (m,
3H), 6.28 (d, J=7.2 Hz, 1H), H), 4.58 (quint., J=7.2 Hz, 1H), 3.89
(m, 2H), 2.95 (t, J=7.7 Hz, 2H), 2.50 (m, 2H), 1.92 (m, 1H), 1.33
(d, J=7.1 Hz, 3H), 0.91 (d, J=6.7 Hz, 6H).
[3282] .sup.13C-nmr (CDCl.sub.3): .delta.=173.0, 171.5, 140.6,
128.3, 128.1, 126.0, 71.2, 47.8, 37.9, 31.4, 27.5, 18.79, 18.77,
18.3.
[3283] C.sub.16H.sub.23NO.sub.3 (MW=277.37, Mass Spectroscopy
(MH.sup.+278))
Example B3
Synthesis of N-(3-methylpentanoyl)-L-alanine iso-butyl ester
[3284] Following General Procedure BB and using 3-methylpentanoic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example BB above), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel and purification was by
extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[3285] NMR data was as follows:
[3286] .sup.1H-nmr (CDCl.sub.3): .delta.=6.08 (d, J=5.9 Hz, 1H),
4.62 (quint., J=7.3 Hz, 1H), 3.92 (m, 2H), 2.22 (m, 1H), 1.84-2.00
(m, 3H), 1.40 (d, J=7.2 Hz, 3H), 1.35 (m, 1H), 1.20 (m, 1H),
0.85-0.96 (m, 12H).
[3287] .sup.13C-nmr (CDCl.sub.3): .delta.=173.3, 172.1, 71.4, 47.9,
43.9, 32.3, 29.38, 29.35, 27.6, 19.10, 19.06, 18.93, 18.91, 18.72,
18.67, 11.3.
[3288] C.sub.13H.sub.25NO.sub.3 (MW=243.35, Mass Spectroscopy
(MH.sup.+244))
Example B4
Synthesis of N-[(4-chlorophenyl)acetyl]-L-alanine iso-butyl
ester
[3289] Following General Procedure BB and using
4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester
hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of
111.degree.-113.degree. C. The reaction was monitored by tlc on
silica gel and purification was by extraction with Et.sub.2O
followed by washes with aqueous K.sub.2CO.sub.3 and aqueous
HCl.
[3290] NMR data was as follows:
[3291] .sup.1H-nmr (CDCl.sub.3): .delta.=7.30 (d, J=8.2 Hz, 2H),
7.21 (d, J=8.3 Hz, 2H), 6.18 (d, J=5.5 Hz, 1H), 4.57 (quint., J=7.2
Hz, 1H), 3.88 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.36 (d, J=7.1
Hz, 3H), 0.90 (d, J=6.8 Hz, 6H).
[3292] .sup.13C-nmr (CDCl.sub.3): .delta.=172.8, 169.8, 133.1,
133.0, 130.6, 128.9, 71.4, 48.2, 42.6. 27.6, 18.85, 18.82,
18.4.
[3293] C.sub.15H.sub.20NO.sub.3Cl (MW=297.78, Mass Spectroscopy
(MH.sup.+298))
Example B5
Synthesis of N-[(3,4-dichlorophenyl)acetyl]-L-alanine iso-butyl
ester
[3294] Following General Procedure BB and using
3,4-dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl
ester hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of 81.degree.-83.degree.
C. The reaction was monitored by tlc on silica gel and purification
was by extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[3295] NMR data was as follows:
[3296] .sup.1H-nmr (CDCl.sub.3): .delta.=0.90 (d, J=6.8 Hz, 6H),
1.38 (d, J=7.1 Hz, 3H), 1.91 (m, 1H), 3.50 (s, 2H), 3.90 (m, 2H),
4.57 (quint., J=7.1 Hz, 1H), 6.31 (d, J=4.9 Hz, 1H),7.12 (m, 1H),
7.38 (m, 2H).
[3297] .sup.13C-nmr (CDCl.sub.3): .delta.=18.4, 18.8, 18.9, 27.6,
42.2, 48.3, 71.5, 128.6, 130.6, 131.2, 131.3, 132.6, 134.7, 169.2,
172.8.
[3298] C.sub.15H.sub.19NO.sub.3Cl.sub.2 (MW=332.23, Mass
Spectroscopy (MH.sup.+332))
Example B6
Synthesis of N-[(4-methylphenyl)acetyl]-D,L-alanine iso-butyl
ester
[3299] Following General Procedure BB and using
4-methylphenylacetic acid (Aldrich) and D,L-alanine iso-butyl ester
hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of
102.degree.-104.degree. C. The reaction was monitored by tlc on
silica gel (Rf=0.6 in 33% ethyl acetate/hexanes) and purification
was by extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[3300] NMR data was as follows:
[3301] .sup.1H-nmr (CDCl.sub.3): .delta.=0.90 (d, J=6.7 Hz, 6H),
1.35 (d, J=7.2 Hz, 3H), 1.91 (m, 1H), 2.34 (s, 3H), 3.55 (s, 2H),
3.88 (m, 2H), 4.58 (m, 1H), 6.05 (bd, 1H), 7.16 (s, 4H).
[3302] .sup.13C-nmr (CDCl.sub.3): .delta.=18.5, 18.85, 18.87, 21.0,
27.6, 43.1, 48.1, 71.3, 129.2, 129.6, 131.3, 136.9, 170.6,
172.8.
[3303] C.sub.16H.sub.23NO.sub.3 (MW=277.37, Mass Spectroscopy
(MH.sup.+278))
Example B7
Synthesis of N-[(3-pyridyl)acetyl]-D,L-alanine iso-butyl ester
[3304] Following General Procedure BF and using 3-pyridylacetic
acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester
hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of 62.degree.-64.degree.
C. The reaction was monitored by tlc on silica gel (Rf=0.48 10%
methanol/dichloromethane) and purification was by silica gel
chromatography.
[3305] NMR data was as follows:
[3306] .sup.1H-nmr (CDCl.sub.3): .delta.=8.40 (d, J=2.8, 2H); 7.6
(m, 1H): 7.16 (m, 2H); 4.5 (quint., J=7.2, 7.2, 1H); 3.8 (m, 2H);
3.48 (s, 2H); 1.8 (m, 1H); 1.30 (d, J=7.2, 3H); 0.81 (d, J=6.7,
6H).
[3307] .sup.13C-nmr (CDCl.sub.3): .delta.=173.4, 170.1, 150.6,
148.8, 137.4, 131.4, 124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4,
18.6.
[3308] C.sub.14H.sub.20N.sub.2O.sub.3 (MW=264, Mass Spectroscopy
(MH.sup.+265)) Example B8
Synthesis of N-[(1-naphthyl)acetyl]-L-alanine iso-butyl ester
[3309] Following General Procedure BB and using 1-naphthylacetic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example BB above), the title compound was prepared as a solid
having a melting point of 69.degree.-73.degree. C. The reaction was
monitored by tlc on silica gel and purification was by extraction
with Et.sub.2O followed by washes with aqueous K.sub.2CO and
aqueous HCl.
[3310] NMR data was as follows:
[3311] .sup.1H-nmr (CDCl.sub.3): .delta.=0.83 (m, 6H), 1.25 (d,
J=7.1 Hz, 3H), 1.81 (m, 1H), 3.79 (m, 2H), 4.04 (2s, 2H), 4.57
(quint., J=7.3 Hz, 1H), 5.99 (d, J=7.1 Hz 1H), 7.44 (m, 2H), 7.53
(m, 2H), 7.85 (m, 2H), 7.98 (m, 1H).
[3312] .sup.13C-nmr (CDCl.sub.3): .delta.=18.2, 18.81, 18.83, 27.5,
41.5, 48.2, 71.3, 123.7, 125.6, 126.1, 126.6, 128.2, 128.5, 128.7,
130.7, 132.0, 133.9, 170.3, 172.5.
[3313] C.sub.19H.sub.23NO.sub.3 (MW=313.40, Mass Spectroscopy
(MH.sup.+314))
Example B9
Synthesis of N-[(2-naphthyl)acetyl]-L-alanine iso-butyl ester
[3314] Following General Procedure BB and using 2-naphthylacetic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example BB above), the title compound was prepared as a solid
having a melting point of 128.degree.-129.degree. C. The reaction
was monitored by tlc on silica gel and purification was by
extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[3315] NMR data was as follows:
[3316] .sup.1H-nmr (CDCl.sub.3): .delta.=0.86 (m, 6H), 1.35 (d,
J=7.1 Hz, 3H), 1.78 (m, 1H), 3.76 (s, 2H), 3.87 (m, 2H), 4.62
(quint., J=7.2 Hz, 1H), 6.13 (d, J=7.1 Hz, 1H), 7.41 (m, 1H), 7.48
(m, 2H), 7.74 (s, 1H), 7.83 (m, 3H).
[3317] .sup.13C-nmr (CDCl.sub.3): .delta.=18.4, 18.82, 18.85, 27.6,
43.7, 48.2, 71.4, 125.9, 126.3, 127.2, 127.6, 127.7, 128.2, 128.7,
132.0, 132.5, 133.5, 170.3, 172.8.
[3318] C.sub.19H.sub.23NO.sub.3 (MW=313.40, Mass Spectroscopy
(MH.sup.+314)).
Example B10
Synthesis of N-(4-phenylbutanoyl)-L-alanine iso-butyl ester
[3319] Following General Procedure BB and using 4-phenylbutanoic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example BB above), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel and purification was by
extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[3320] NMR data was as follows:
[3321] .sup.1H-nmr (CDCl.sub.3): .delta.=0.92 (d, J=6.7 Hz, 6H),
1.38 (d, J=7.1 Hz, 3H), 1.96 (m, 3H), 2.21 (t, J=7.1 Hz, 2H), 2.64
(t, J=7.3 Hz, 2H), 3.90 (m, 2H), 4.59 (quint., J=7.2 Hz, 1H), 6.31
(d, 1H), 7.16 (m, 3H), 7.24 (m, 2H).
[3322] .sup.13C-nmr (CDCl.sub.3): .delta.=18.3, 18.75, 18.78, 26.8,
27.5, 34.9, 35.3, 47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1,
173.0.
[3323] C.sub.17H.sub.25NO.sub.3 (MW=291.39, Mass Spectroscopy
(MH.sup.+292)).
Example B11
Synthesis of N-(5-phenylpentanoyl)-L-alanine iso-butyl ester
[3324] Following General Procedure BB and using 5-phenylpentanoic
acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from
Example BB above), the title compound was prepared as an oil. The
reaction was monitored by tlc on silica gel and purification was by
extraction with Et.sub.2O followed by washes with aqueous
K.sub.2CO.sub.3 and aqueous HCl.
[3325] NMR data was as follows:
[3326] .sup.1H-nmr (CDCl.sub.3): .delta.=7.23 (m, 2H), 7.17 (m,
3H), 6.30 (d, 1H), 4.59 (quint., J=7.3 Hz, 1H), 3.91 (m, 2H), 2.61
(t, J=7.2 Hz, 2H), 2.22 (t, J=7.2 Hz, 2H), 1.93 (m, 1H), 1.66 (m,
4H), 1.38 (d, J=7.2 Hz, 3H), 0.92 (d, J=6.7 Hz 6H).
[3327] .sup.13C-nmr (CDCl.sub.3): 8 173.1, 172.3, 142.0, 128.2,
128.1, 125.6, 71.2, 47.8, 36.1, 35.5, 30.8, 27.5, 25.0, 18.80,
18.77, 18.4.
[3328] C.sub.18H.sub.27NO.sub.3 (MW=305.39, Mass Spectroscopy
(MH.sup.+306)).
Example B12
Synthesis of N-[(4-pyridyl)acetyl]-D,L-alanine iso-butyl ester
[3329] Following General Procedure BF and using 4-pyridylacetic
acid hydrochloride (Aldrich) and (D,L)-alanine iso-butyl ester
hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of 64.degree.-66.degree.
C. The reaction was monitored by tlc on silica gel (Rf=0.43 10%
methanol/dichloromethane) and purification was by silica gel
chromatography.
[3330] NMR data was as follows:
[3331] .sup.1H-nmr (CDCl.sub.3): .delta.=8.51 (dd, J=1.6, 2.8, 1.6,
2H); 7.23 (dd, J=4.3, 1.6, 4.4, 2H); 6.71 (d, J=6.8, 1H); 4.56
(quint., J=7.3, 7.2, 1H); 3.88 (m, 2H); 3.53 (s, 2H); 1.89 (m, 1H);
1.36 (d, J=7.2, 3H); 0.88 (d, J=6.7, 6H).
[3332] .sup.13C-nmr (CDCl.sub.3): .delta.=173.5, 169.3, 150.5,
144.4, 125.1, 72.1, 48.9, 43.0, 28.2, 19.5, 19.5, 18.9.
[3333] C.sub.14H.sub.20N.sub.2O.sub.3 (MW=264, Mass Spectroscopy
(MH.sup.+265))
Example B13
Synthesis of N-(phenylacetyl)-L-alanine iso-butyl ester
[3334] Following General Procedure BB and using phenylacetyl
chloride (Aldrich) and L-alanine iso-butyl ester hydrochloride
(from Example BB above), the title compound was prepared as a solid
having a melting point of 45.degree.-47.degree. C. The reaction was
monitored by tlc on silica gel and purification was by extraction
with Et.sub.2O followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[3335] NMR data was as follows:
[3336] .sup.1H-nmr (CDCl.sub.3): .delta.=7.24-7.39 (m, 5H), 6.14
(d, 1H), 4.58 (t, J=7.3 Hz, 1H), 3.88 (m, 2H), 3.58 (s, 2H), 1.90
(m, 1H), 1.35 (d, J=7.2 Hz, 3H), 0.89 (d, J=6.7 Hz, 6H).
[3337] .sup.13C-nmr (CDCl.sub.3): .delta.=172.8, 170.4, 134.5,
129.3, 128.9, 127.2, 71.3, 48.1, 43.5, 27.5, 18.9, 18.8, 18.4.
[3338] C.sub.15H.sub.21NO.sub.3 (MW=263.34, Mass Spectroscopy
(MH.sup.+264)).
Example B14
Synthesis of 2-[(3,4-dichlorophenyl)acetamido]butyric acid
iso-butyl ester
[3339] Following General Procedure BI above and using
3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl
2-aminobutyrate (prepared following General Procedure BJ above) the
title compound was prepared. The reaction was monitored by tlc on
silica gel and purification was by filtration as described in the
general procedure.
[3340] NMR data was as follows:
[3341] .sup.1H-nmr (CDCl.sub.3): .delta.=7.36 (m, 3H), 6.03 (bd,
1H), 4.54 (m, 1H), 3.87 (m, 2H), 3.49 (s, 2H), 1.93 (m, 2H), 1.72
(m, 1H), 0.88 (d, 6H), 0.80 (t, 3H).
Example B15
Synthesis of 2-1(3-methoxyphenyl)acetamido]butyric acid iso-butyl
ester
[3342] Following General Procedure BI above and using
3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3343] NMR data was as follows:
[3344] .sup.1H-nmr (CDCl.sub.3): .delta.=6.75 (m, 4H), 5.93 (bd,
1H), 4.51 (m, 1H), 3.83 (m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1.82
(m, 2H), 1.60 (m, 1H), 0.84 (d, 6H), 0.74 (t, 3H).
[3345] C.sub.17H.sub.25NO.sub.4 (MW=307.39, Mass Spectroscopy
(MH.sup.+309)).
Example B16
Synthesis of 2-[(4-nitrophenyl)acetamido]butyric acid iso-butyl
ester
[3346] Following General Procedure BI above and using
4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3347] NMR data was as follows:
[3348] .sup.1H-nmr (CDCl.sub.3): .delta.=8.16 (d, 2H), 7.44 (d,
2H), 6.04 (bd, 1H), 4.55 (m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1.86
(m, 2H), 1.67 (m, 1H), 0.85 (d, 6H), 0.85 (t 3H).
[3349] C.sub.16H.sub.22N.sub.2O.sub.5 (MW=322.36, Mass Spectroscopy
(MH.sup.+323)).
Example B17
Synthesis of 2-[(3,4-methylenedioxyphenyl)acetamido]butyric acid
iso-butyl ester
[3350] Following General Procedure BI above and using
3,4-(methylenedioxy)-phenyl acetic acid (Aldrich) and iso-butyl
2-aminobutyrate (prepared following General Procedure BJ above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[3351] NMR data was as follows:
[3352] .sup.1H-nmr (CDCl.sub.3): .delta.=6.72 (m, 3H), 5.92 (bd,
1H), 4.54 (m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.66
(m, 1H), 0.89 (d, 6H), 0.79 (t, 3H).
Example B18
Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl
ester
[3353] Following General Procedure BI above and using
3-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3354] NMR data was as follows:
[3355] .sup.1H-nmr (CDCl.sub.3): .delta.=7.37 (m, 1H), 7.16 (m,
1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93
(m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H).
Example B19
Synthesis of 2-[(4-chlorophenyl)acetamido]butyric acid iso-butyl
ester
[3356] Following General Procedure BI above and using
4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3357] NMR data was as follows:
[3358] .sup.1H-nmr (CDCl.sub.3): .delta.=7.22 (m, 2H), 7.11 (m,
2H), 5.80 (m, 1H), 4.44 (m, 1H), 3.78 (m, 2H), 3.43 (s, 2H), 1.77
(m, 2H), 1.56 (m, 1H), 0.83 (d, 6H) 0.71 (t, 3H).
Example B20
Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acid iso-butyl
ester
[3359] Following General Procedure BI above and using
3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3360] NMR data was as follows:
[3361] .sup.1H-nmr (CDCl.sub.3): .delta.=8.15 (m, 2H), 7.65 (m,
1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91
(m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H).
Example B21
Synthesis of 2-[(2-hydroxyphenyl)acetamido]butyric acid iso-butyl
ester
[3362] Following General Procedure BI above and using
2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3363] NMR data was as follows:
[3364] .sup.1H-nmr (CDCl.sub.3): .delta.=7.14 (m, 1H), 7.01 (m,
1H), 6.93 (m, 1H), 6.79 (m, 1H), 6.46 (m, 1H), 4.51 (m, 1H), 3.87
(m, 2H), 3.57 (s, 2H), 2.01 (m, 2H), 1.75 (m, 1H), 0.89 (d, 6H),
0.85 (t, 3H).
Example B22
Synthesis of 2-[(2-naphthyl)acetamido]butyric acid iso-butyl
ester
[3365] Following General Procedure BI above and using
2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3366] NMR data was as follows:
[3367] .sup.1H-nmr (CDCl.sub.3): .delta.=7.83 (m, 7H), 5.95 (m,
1H), 4.58 (m, 1H), 3.84 (m, 2H), 3.75 (s, 2H), 1.89 (m, 2H), 1.63
(m, 1H), 0.91 (d, 6H), 0.81 (t, 3H).
[3368] C.sub.20H.sub.25NO.sub.3 (MW=327.42, Mass Spectroscopy
(MH.sup.+328)).
Example B23
Synthesis of 2-[(2,4-dichlorophenyl)acetamido]butyric acid
iso-butyl ester
[3369] Following General Procedure BI above and using
2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl
2-aminobutyrate (prepared following General Procedure BJ above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[3370] NMR data was as follows:
[3371] .sup.1H-nmr (CDCl.sub.3): .delta.=7.49 (m, 1H), 7.22 (m, 2H)
5.98 (m, 1H), 4.52 (m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m,
2H), 1.62 (m, 1H) 0.87 (d, 6H), 0.80 (t, 3H).
Example B24
Synthesis of 2-[(4-bromophenyl)acetamido]butyric acid iso-butyl
ester
[3372] Following General Procedure BI above and using
4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3373] NMR data was as follows:
[3374] .sup.1H-nmr (CDCl.sub.3): .delta.=7.43 (d, 2H), 7.19 (d, 2H)
5.85 (m, 1H), 4.51 (m, 1H), 3.81 (m, 2H), 3.47 (s, 2H), 1.84 (m,
2H), 1.61 (m, 1H) 0.84 (d, 6H), 0.76 (t, 3H).
[3375] C.sub.16H.sub.22NO.sub.3Br (MW=356.26, Mass Spectroscopy
(MH.sup.+358)).
Example B25
Synthesis of 2-[(3-chlorophenyl)acetamido])butyric acid iso-butyl
ester
[3376] Following General Procedure BI above and using
3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3377] NMR data was as follows:
[3378] .sup.1H-nmr (CDCl.sub.3): .delta.=7.25 (m, 3H), 7.12 (m, 1H)
5.80 (m, 1H), 4.52 (m, 1H), 3.86 (m, 2H), 3.50 (s, 2H), 1.87 (m,
2H), 1.67 (m, 1H) 0.88 (d, 6H), 0.77 (t, 3H).
[3379] C.sub.16H.sub.22NO.sub.3Cl (MW=311.81 Mass Spectroscopy
(MH.sup.+313)).
Example B26
Synthesis of 2-[(3-fluorophenyl)acetamido]butyric acid iso-butyl
ester
[3380] Following General Procedure BI above and using
3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3381] NMR data was as follows:
[3382] .sup.1H-nmr (CDCl.sub.3): .delta.=7.31 (m, 1H), 7.01 (m, 3H)
5.95 (m, 1H), 4.54 (m, 1H), 3.84 (m, 2H), 3.54 (s, 2H), 1.88 (m,
2H), 1.65 (m, 1H) 0.87 (d, 6H), 0.81 (t, 3H).
[3383] C.sub.16H.sub.22NO.sub.3F (MW=295.35 Mass Spectroscopy
(MH.sup.+296)).
Example B27
Synthesis of 2-[(benzothiazol-4-yl)acetamido]butyric acid iso-butyl
ester
[3384] Following General Procedure BI above and using
4-benzothiazol-4-yl acetic acid (Chemservice) and iso-butyl
2-aminobutyrate (prepared following General Procedure BJ above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[3385] NMR data was as follows:
[3386] .sup.1H-nmr (CDCl.sub.3): .delta.=7.82 (m, 1H), 7.51-7.21
(m, 4H) 5.84 (m, 1H), 4.51 (m, 1H), 3.90 (s, 2H), 3.79 (m, 2H),
1.78 (m, 2H), 1.58 (m, 1H) 0.80 (d, 6H), 0.66 (t, 3H).
Example B28
Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl
ester
[3387] Following General Procedure BI above and using
2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3388] NMR data was as follows:
[3389] .sup.1H-nmr (CDCl.sub.3): .delta.=7.18 (m, 4H), 5.79 (m,
1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81
(m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H).
[3390] C.sub.17H.sub.25NO.sub.3 (MW=291.39 Mass Spectroscopy
(M+291)).
Example B29
Synthesis of 2-[(2-fluorophenyl)acetamido]butyric acid iso-butyl
ester
[3391] Following General Procedure BI above and using
2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3392] NMR data was as follows:
[3393] .sup.1H-nmr (CDCl.sub.3): .delta.=7.28 (m, 1H), 7.09 (m, 3H)
6.03 (m, 1H), 4.54 (m, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.89 (m,
2H), 1.64 (m, 1H) 0.88 (d, 6H), 0.80 (t, 3H).
Example B30
Synthesis of 2-[(4-fluorophenyl)acetamido]butyric acid iso-butyl
ester
[3394] Following General Procedure BI above and using
4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3395] NMR data was as follows:
[3396] .sup.1H-nmr (CDCl.sub.3): .delta.=7.20 (m, 2H), 6.97 (m, 2H)
5.87 (m, 1H), 4.492 (m, 1H), 3.83 (m, 2H), 3.48 (s, 2H), 1.86 (m,
2H), 1.60 (m, 1H) 0.87 (d, 6H), 0.78 (t, 3H).
[3397] C.sub.16H.sub.22NO.sub.3F (MW=295.35 Mass Spectroscopy
(MH.sup.+296)).
Example B31
Synthesis of 2-[(3-bromophenyl)acetamido]butyric acid iso-butyl
ester
[3398] Following General Procedure BI above and using
3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3399] NMR data was as follows:
[3400] .sup.1H-nmr (CDCl.sub.3): .delta.=7.45 (m, 2H), 7.23 (m, 2H)
5.95 (m, 1H), 4.55 (m, 1H) 3.84 (m, 2H) 3.55 (s, 2H), 1.89 (m, 2H),
1.68 (m, 1H) 0.91 (d, 6H), 0.81 (t, 3H).
[3401] C.sub.16H.sub.22NO.sub.3Br (MW=356.26 Mass Spectroscopy
(M.sup.+357)).
Example B32
Synthesis of 2-[(3-trifluoromethylphenyl)acetamido]butyric acid
iso-butyl ester
[3402] Following General Procedure BI above and using
3-trifluoromethyl-phenylacetic acid (Aldrich) and iso-butyl
2-aminobutyrate (prepared following General Procedure BJ above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[3403] NMR data was as follows:
[3404] .sup.1H-nmr (CDCl.sub.3): .delta.=7.52 (m, 1H), 7.47 (m, 2H)
6.01 (m, 1H), 4.56 (m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m,
2H), 1.62 (m, 1H) 0.87 (d, 6H), 0.80 (t, 3H).
[3405] C.sub.17H.sub.22NO.sub.3F.sub.3 (MW=345.36 Mass Spectroscopy
(MH.sup.+345)).
Example B33
Synthesis of 2-[(2-thienyl)acetamido]butyric acid iso-butyl
ester
[3406] Following General Procedure BI above and using
2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3407] NMR data was as follows:
[3408] .sup.1H-nmr (CDCl.sub.3): .delta.=6.89 (m, 3H), 6.07 (bd,
1H), 4.50 (m, 1H), 3.82 (m, 2H), 3.71 (s, 2H), 1.85 (m, 2H), 1.62
(m, 1H), 0.81 (d, 6H), 0.75 (t, 3H).
[3409] C.sub.14H.sub.21NO.sub.3S (MW=283.39, Mass Spectroscopy
(MH.sup.+284)).
Example B34
Synthesis of 2-(phenylacetamido)butyric acid iso-butyl ester
[3410] Following General Procedure BH above and using phenylacetic
acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following
General Procedure BJ above), the title compound was prepared. The
reaction was monitored by tlc on silica gel and purification was by
chromatography on silica gel using 9:1 toluene:EtOAc as the
eluant.
[3411] NMR data was as follows:
[3412] .sup.1H-nmr (CDCl.sub.3): .delta.=7.17-7.28 (m, 5H), 6.23
(bd, 1H), 4.51 (m, 1H), 3.86 (m, 2H), 3.54 (s, 2H), 1.87 (m, 2H),
1.62 (m, 1H), 0.87 (d, 6H), 0.78 (t, 3H).
[3413] C.sub.16H.sub.23NO.sub.3 (MW=277.36, Mass Spectroscopy
(MH.sup.+277)).
Example B35
Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester
[3414] Step A. Preparation of N-(phenylacetyl) valine
[3415] To a stirred solution of 5.15 g (44 mmol) of valine (Bachem)
in 50 mL (100 mmol) of 2N NaOH cooled to 0.degree. C. was added
dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A
colorless oil precipitated. The reaction mixture was allowed to
warm to room temperature and stirred for 18 hours, washed with 50
mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white
precipitate formed was filtered off, washed thoroughly with water,
followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the
title compound.
[3416] NMR data was as follows:
[3417] .sup.1H-nmr (DMSO-d.sub.6): .delta.=12.63 (s, 1H), 8.25 (d,
J=8.6Hz, 1H), 7.27 (m, 5H), 4.15 (m, 1H), 3.56 (d, J=13.8Hz, 1H),
3.47 (d, J=13.8Hz, 1H), 2.05 (m, 1H), 0.87 (d, J=6.8,Hz, 3H), 0.84
(d, J=6.8Hz, 3)
[3418] .sup.13C-nmr (DMSO-d.sub.6): .delta.=173.2, 170.4, 136.6,
129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0
[3419] C.sub.13H.sub.17NO.sub.3 (MW=235.29; Mass Spectroscopy
(MH.sup.+=236))
[3420] Step B. Synthesis of N-(phenylacetyl)valine 2-methylbutyl
ester
[3421] Following General Procedure BC and using the
N-(phenylacetyl) valine prepared in Step A above and
2-methylbutan-1-ol (Aldrich), the title compound was prepared as a
diastereomeric mixture. The reaction was monitored by tlc on silica
gel and purification was by filtration as described in the general
procedure.
[3422] NMR data was as follows:
[3423] .sup.1H-nmr (CDCl.sub.3): .delta.=7.25-7.40 (m, 5H), 5.95
(d, 1H), 4.56 (m, 1H), 3.84-4.00 (m, 2H), 3.61 (s, 2H), 2.10 (m,
1H), 1.68 (m, 1H), 1.38 (m, 1H), 1.15 (m 1H), 0.82-0.94 (m, 9H),
0.76 (d, 3H).
[3424] .sup.13C-nmr (CDCl.sub.3): .delta.=171.84, 171.81, 170.7,
134.6, 129.31, 129.27, 128.9, 127.3, 69.8, 57.0, 43.7, 33.9,
31.3,25.9, 25.8, 18.9, 17.4, 16.34, 16.27, 11.12, 11.07.
[3425] C.sub.18H.sub.27NO.sub.3 (MW=305.42, Mass Spectroscopy (MH
306)).
Example B36
Synthesis of N-(phenylacetyl)-L-methionine iso-butyl ester
[3426] L-Methionine (0.129 g, 0.869 mmols) (Aldrich) was taken-up
in dioxane (5.0 mL) and treated with a saturated solution of sodium
bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich)
(0.114 mL, 0.822 mmols). After stirring for 17 hours at room
temperature the mixture was diluted with ethyl acetate, the layers
separated and the aqueous layer acidified to pH 2 with 5N HCl. The
crude product was extracted into ethyl acetate, dried over sodium
sulfate, vacuum dried and used without further purification.
N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in
3.0 mL dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC
(0.094 g, 0.492 mmol), and catalytic DMAP (0.015 g). After stirring
for 17 hours at 23.degree. C., the mixture was evaporated at
reduced pressure to an oil, the residue was diluted in EtOAc and
washed with 0.1 N HCl and saturated sodium bicarbonate.
Chromatography on silica gel using 98:2 CHCl.sub.3/MeOH as eluant
provided the pure product.
[3427] NMR data was as follows:
[3428] .sup.1H-nmr (CDCl.sub.3): .delta.=7.4-7.23 (m, 5H), 6.14
(bd, 1H), 4.70 (m, 1H), 3.89 (d, 2H), 3.62 (s, 2H), 2.43 (m, 2H),
2.12 (m, 1H), 1.93 (m, 2H), 0.94 (d, 6H).
[3429] C.sub.17H.sub.25NO.sub.3S (MW=323.17, Mass Spectroscopy
(M.sup.-323)
Example B37
Synthesis of N-(phenylacetyl)-L-leucine iso-butyl ester
[3430] L-Leucine (Aldrich) (0.1 14 g, 0.869 mmols) was taken-up in
dioxane (5.0 mL) and treated with a saturated solution of sodium
bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich)
(0.114 mL, 0.822 mmols). After stirring for 17 hours at room
temperature the mixture was diluted with ethyl acetate, the layers
separated and the aqueous layer acidified to pH 2 with 5N HCl. The
crude product was extracted into ethyl acetate, dried over sodium
sulfate, vacuum dried and used without further purification.
[3431] N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was
dissolved in 2.0 mL CHCl.sub.3 (EtOH free) and iso-butyl alcohol
(0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents).
The mixture was rotated for 4 days, filtered through a plug of
cotton and the filtrate evaporated at reduced pressure to an oil
which was sufficiently pure for testing.
[3432] NMR data was as follows:
[3433] .sup.1H-nmr (CDCl.sub.3): .delta.=7.22 (m, 5H), 5.57 (d,
1H), 4.35 (m, 1H), 3.35 (m, 3H), 1.35 (m, 4H), 0.68 (m, 9H).
[3434] C.sub.18H.sub.27NO.sub.3 (MW=305.40, Mass Spectroscopy
(M.sup.+305)).
Example B38
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl
ester
[3435] Following General Procedure BC above and using
N-(3-chlorophenylacetyl alanine (from Example BD above) and
3-methylbut-2-en-1-ol (Aldrich), the title compound can be
prepared. The reaction was monitored by tlc on silica gel and
purification was by liquid chromatography using 30% EtOAc/hexane as
the eluant.
[3436] NMR data was as follows:
[3437] .sup.1H-nmr (CDCl.sub.3): .delta.=7.39-7.16 (m, 4H), 6.06
(bd, 1H), 5.38-5.29 (m, 1H), 4.63 (d, J=9Hz, 2H), 3.56 (s, 2H),
1.79 (s, 3H), 1.7 (s, 3H), 1.39 (d, J=9 Hz, 3H).
Example B39
Synthesis of N-[(3-chlorophenyl)acetyl]alanine cyclopropylmethyl
ester
[3438] Following General Procedure BC above, and using
N-(3-chlorophenylacetyl alanine (from Example BD above) and
cyclopropylmethanol (Aldrich), the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[3439] NMR data was as follows:
[3440] .sup.1H-nmr (CDCl.sub.3): .delta.=7.2-7.1 (m, 4H), 6.09 (bs,
1H), 4.6 (dq, J=9Hz, 1H), 3.96 (dd, J=9 Hz, 2H), 3.59 (s, 2H), 1.2
(d, J=9 Hz, 3H), 1.2-1.0 (m, 1H), 0.603-0.503 (m, 2H), 0.300-0.203
(m, 2H).
Example B40
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 2-thienylmethyl
ester
[3441] Following General Procedure BC above, and using
N-(3-chlorophenylacetyl alanine (from Example BD above) and
2-thiophenemethanol (Aldrich) the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[3442] NMR data was as follows:
[3443] .sup.1H-nmr (CDCl.sub.3): .delta.=7.37-6.97 (m, 7H), 5.97
(q, J=14 Hz, 2H), 4.6 (dq, J=9 Hz, 1H), 3.76 (s, 2H), 1.38 (d, J=9
Hz, 3H).
Example B41
Synthesis of N-[(3-chlorophenyl)acetyl]alanine
(1-methylcyclopropyl)methyl ester
[3444] Following General Procedure BC above, and using
N-(3-chlorophenylacetyl alanine (from Example BD above) and
(1-methylcyclopropyl)methanol (Aldrich) the title compound can be
prepared. The reaction was monitored by tlc on silica gel and
purification was by liquid chromatography using 3:7 EtOAc:hexane as
the eluant.
[3445] NMR data was as follows:
[3446] .sup.1H-nmr (CDCl.sub.3): .delta.=8.6 (bd, J=9 Hz, 1H), 3.86
(q, J=14 Hz, 2H), 3.4 (s, 2H), 2.29 (q, J=9 Hz, 1H), 1.3 (d, J=9
Hz, 3H), 1.03 (s, 3H), 0.5-0.4 (m, 2H), 0.4-0.28 (m, 2H).
Example B42
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-thienylmethyl
ester
[3447] Following General Procedure BC above, and using
N-(3-chlorophenylacetyl alanine (from Example BD above) and
3-thiophenemethanol (Aldrich) the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[3448] NMR data was as follows:
[3449] .sup.1H-nmr (CDCl.sub.3): .delta.=8.03 (bd, J=9 Hz, 1H),
7.56-7.5 (m, 1H), 7.47 (bs, 1H), 7.4-7.17 (m, 4H), 7.06 (d, J=9 Hz,
1H), 5.1 (s, 2H), 4.3 (dq, 1H), 1.3 (d, J=9 Hz, 3H).
Example B43
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 2-methylcyclopentyl
ester
[3450] Following General Procedure BC above, and using
N-(3-chlorophenylacetyl alanine (from Example BD above) and
2-methylcyclopentanol (Aldrich) the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[3451] NMR data was as follows:
[3452] .sup.1H-nmr (CDCl.sub.3): .delta.=7.39-7.16 (m, 4H), 6.3
(bd, 1H), 4.79-4.7 (m, 1H), 4.6-4.25 (m, J=9 Hz, 1H), 3.577 (s,
2H), 2.09-1.8 (m, 2H), 1.74-1.6 (m, 2H), 1.39 (dd, J=9 Hz, 3H), 1.2
(dt, J=9 Hz, 1H), 0.979 (dd, J=9 Hz, 2H)
[3453] C.sub.17H.sub.22NO.sub.3Cl (MW=323.82, Mass Spectroscopy
(MH.sup.+323).
Example B44
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 2-methylprop-2-enyl
ester
[3454] Following General Procedure BC above, and using
N-(3-chlorophenylacetyl alanine (from Example BD above) and
2-methylprop-2-en-1-ol (Aldrich) the title compound can be
prepared. The reaction was monitored by tlc on silica gel and
purification was by liquid chromatography using 3:7 EtOAc:hexane as
the eluant.
[3455] NMR data was as follows:
[3456] .sup.1H-nmr (CDCl.sub.3): .delta.=7.39-7.16 (m, 4H), 6.03
(bs, 1H), 4.77 (s, 2H), 4.7-4.29 (m, 3H), 2.59 (s, 2H), 1.73 (s,
3H), 1.43 (d, J=9 Hz, 3H)
[3457] C.sub.15H.sub.18NO.sub.3Cl (MW=295.76, Mass Spectroscopy
(MH.sup.+295)).
Example B45
Synthesis of N-[(3-chlorophenyl)acetyl]alanine cyclohex-2-enyl
ester
[3458] Following General Procedure BC above, and using
N-(3-chlorophenylacetyl alanine (from Example BD above) and
cyclohex-2-en-1-ol (Aldrich) the title compound can be prepared.
The reaction was monitored by tlc on silica gel and purification
was by liquid chromatography using 3:7 EtOAc:hexane as the
eluant.
[3459] NMR data was as follows:
[3460] .sup.1H-nmr (CDCl.sub.3): .delta.=8.6 (bd, J=9 Hz, 1H),
7.4-7.2 (m, 4H), 6.0-5.8 (m, 1H), 5,7-5.5 (m, 1H), 5.1 (bs, 1H),
4.13-4.29 (m, 1H), 3.5 (s, 2H), 2.1-1.9 (m, 2H), 1.8-1.69 (m, 1H),
1.69-1.49 (m, 4H), 1.3 (dd, J=9 Hz, 3H)
[3461] C.sub.17H.sub.20NO.sub.3Cl (MW=321.8, Mass Spectroscopy
(MH.sup.+321.2)).
Example B46
Synthesis of N-[(2-phenylbenzoxazol-5-yl)acetyl]alanine iso-butyl
ester
[3462] Following General Procedure BI above, and using
5-(2-phenylbenzoxazol)-yl-acetic acid (CAS# 62143-69-5) and alanine
iso-butyl ester (prepared following General Procedure BJ above),
the title compound was prepared.
[3463] NMR data was as follows:
[3464] .sup.1H-nmr (CDCl.sub.3): .delta.=8.24 (m, 3H), 7.68 (m,
1H), 7.51 (m, 5H), 6.04 (m, 1H), 4.58 (m, 1H), 3.85 (m, 2H), 3.68
(s, 2H), 1.9 (m, 1H), 1.35 (d, 3H), 0.87 (d, 6H).
[3465] C.sub.22H.sub.24N.sub.2O.sub.4 (MW=380, Mass Spectroscopy
(MH.sup.+381)).
Example B47
Synthesis of N-[(3-methylthiophenyl)acetyl]alanine iso-butyl
ester
[3466] Following General Procedure BI above, and using
3-methylthiophenylacetic acid (CAS# 18698-73-2) and alanine
iso-butyl ester (prepared following General Procedure BJ above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[3467] NMR data was as follows:
[3468] .sup.1H-nmr (CDCl.sub.3): .delta.=7.14 (m, 2H), 7.01 (m,
1H), 4.56 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.46 (s, 3H), 1.89
(m, 1H), 1.35 (d, 3H) 0.85 (d, 6H).
[3469] C.sub.16H.sub.23NO.sub.3S (MW=309, Mass Spectroscopy
(MH.sup.+310)).
Example B48
Synthesis of N-4-[(2-furyl)acetyl]alanine iso-butyl ester
[3470] Following General Procedure BI above, and using
2-furylacetic acid (CAS# 2745-26-8) and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3471] NMR data was as follows:
[3472] .sup.1H-nmr (CDCl.sub.3): .delta.=7.36 (m, 1H), 6.34 (m,
1H), 6.21 (m, 1H), 4.56 (m, 1H), 3.91 (m, 2H), 3.61 (s, 2H), 1.92
(m, 1H), 1.38 (d, 3H) 0.89 (d, 6H).
[3473] C.sub.13H.sub.19NO.sub.4 (MW=253, Mass Spectroscopy
(MH.sup.+254)).
Example B49
Synthesis of N-[(benzofuran-2-yl)acetyl]alanine iso-butyl ester
[3474] Following General Procedure BI above, and using
benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3475] NMR data was as follows:
[3476] .sup.1H-nmr (CDCl.sub.3): .delta.=7.51 (m, 1H), 7.44 (m,
1H),7.25 (m, 2H), 6.67 (s, 1H), 4:60 (m, 1H), 3.87 (m, 2H), 3.77
(s, 2H), 1.88 (m, 1H), 1.38 (d, 3H), 0.87 (d, 6H).
[3477] C.sub.17H.sub.21NO.sub.4 (MW=303, Mass Spectroscopy
(MH.sup.+304)).
Example B50
Synthesis of N-[(benzothiophen-3-yl)acetyl]alanine iso-butyl
ester
[3478] Following General Procedure BI above, and using
thianaphthen-3-ylacetic acid (Lancaster) and alanine iso-butyl
ester (prepared following General Procedure BJ above), the title
compound was prepared. The reaction was monitored by tlc on silica
gel and purification was by filtration as described in the general
procedure.
[3479] NMR data was as follows:
[3480] .sup.1H-nmr (CDCl.sub.3): .delta.=7.89 (m, 1H), 7.76 (m,
1H), 7.38 (m, 3H), 6.07 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.82
(s, 4H), 1.84 (m, 1H), 1.32 (d, 3H) 0.85 (d, 6H).
[3481] C.sub.17H.sub.21NO.sub.3S (MW=319, Mass Spectroscopy
(MH.sup.+320)).
Example B51
Synthesis of N-[(2-chloro-5-thienyl)acetyl]alanine iso-butyl
ester
[3482] Following General Procedure BI above, and using
5-chloro-2-thienyl)acetic acid (CAS# 13669-19-7) and alanine
iso-butyl ester (prepared following General Procedure BJ above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[3483] NMR data was as follows:
[3484] .sup.1H-nmr (CDCl.sub.3): .delta.=6.77 (m, 1H), 6.68 (d,
1H), 6.31 (bm, 1H), 4.59 (m, 1H), 3.91 (m, 2H), 3.38 (s, 2H), 1.90
(m, 1H), 1.39 (d, 3H) 0.89 (d, 6H).
[3485] C.sub.13H.sub.18NO.sub.3SCl (MW=303, Mass Spectroscopy
(MH.sup.+303)).
Example B52
Synthesis of N-[(3-methylisoxazol-5-yl)acetyl]alanine iso-butyl
ester
[3486] Following General Procedure BI above, and using
(3-methyl-isoxazol-5-yl)acetic acid (CAS# 19668-85-0) and alanine
iso-butyl ester (prepared following General Procedure BJ above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
[3487] NMR data was as follows:
[3488] .sup.1H-nmr (CDCl.sub.3): .delta.=6.07 (s, 2H), 4.56 (m,
1H), 3.92 (m, 2H), 3.68 (s, 2H), 2.29 (s, 3H), 1.94 (m, 1H), 1.89
(d, 3H) 0.91 (d, 6H).
[3489] C.sub.13H.sub.20N.sub.2O.sub.4 (MW=268, Mass Spectroscopy
(MH.sup.+269)).
Example B53
Synthesis of N-[(2-phenylthiothienyl)acetyl]alanine iso-butyl
ester
[3490] Following General Procedure BI above, and using
(2-phenyl-thiothienyl)acetic acid and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3491] NMR data was as follows:
[3492] .sup.1H-nmr (CDCl.sub.3): .delta.=7.21-7.11 (m, 6H), 6.92
(d, 1H), 4.56(m, 1H), 3.87 (m, 2H), 3.72 (s. 2H), 1.94 (m, 1H),
1.38 (d, 3H) 0.89 (d, 6H).
[3493] C.sub.19H.sub.23NO.sub.3S.sub.2 (MW=377, Mass Spectroscopy
(MH.sup.+378)).
Example B54
Synthesis of N-[(6-methoxybenzothiophen-2-yl)acetyl]alanine
iso-butyl ester
[3494] Following General Procedure BI above, and using
(6-methoxythianaphthen-2-yl)acetic acid and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3495] NMR data was as follows:
[3496] .sup.1H-nmr (CDCl,): .delta.=7.59 (d, 1H), 7.33 (d, 1H),
7.16 (s, 1H), 7.03 (dd, 1H), 4:56 (m, 1H), 3.87(s, 3H), 3.84 (m,
2H), 3.76 (s, 2H); 1.85 (m, 1H), 1.30 (d, 3H) 0.86 (d, 6H).
[3497] C.sub.18H.sub.23NO.sub.4S (MW 349, Mass Spectroscopy
(MH.sup.+350)).
Example B55
Synthesis of N-[(3-phenyl-1,2,4-thiadiazol-5-yl)acetyl]alanine
iso-butyl ester
[3498] Following General Procedure BI above, and using
(3-phenyl-1,2,4-thiadiazol-5-yl)acetic acid (CAS# 90771-06-5) and
alanine iso-butyl ester (prepared following General Procedure BJ
above), the title compound was prepared. The reaction was monitored
by tlc on silica gel and purification was by filtration as
described in the general procedure.
[3499] NMR data was as follows:
[3500] .sup.1H-nmr (CDCl.sub.3): .delta.=7.47 (m, 5H), 4.66 (m,
1H), 4.16 (s, 2H), 3.91 (m, 2H), 1.93 (m, 1H), 1.48 (d, 3H) 0.93
(d, 6H).
[3501] C.sub.17H.sub.21N.sub.3O.sub.3S (MW=347, Mass Spectroscopy
(MH.sup.+348)).
Example B56
Synthesis of N-[-phenyloxazol-4-yl)acetyl]alanine iso-butyl
ester
[3502] Following General Procedure BI above, and using
(2-phenyloxazol-4-yl)acetic acid (CAS# 22086-89-1) and alanine
iso-butyl ester (prepared following General Procedure BJ above),
the title compound was prepared. The reaction was monitored by tlc
on silica gel and purification was by filtration as described in
the general procedure.
Example B57
Synthesis of N-[(3-methylphenyl)acetyl]alanine iso-butyl ester
[3503] Following General Procedure BI above, and using
3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3504] NMR data was as follows:
[3505] .sup.1H-nmr (CDCl.sub.3): .delta.=7.21 (m, 1H), 7.07 (m,
3H), 4.54 (m, 1H), 3.83 (m, 2H), 3.52 (s, 2H), 2.35 (s, 3H), 1.87
(m, 1H), 1.32 (d, 3H), 0.88 (d, 6H).
[3506] C.sub.16H.sub.23NO.sub.3 (MW=277, Mass Spectroscopy
(MH.sup.+278)).
Example B58
Synthesis of N-[(2,5-difluorophenyl)acetyl]alanine iso-butyl
ester
[3507] Following General Procedure BI above, and using
2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3508] NMR data was as follows: .sup.1H-nmr (CDCl.sub.3):
.delta.=7.08-6.94 (m, 3H), 4.57 (m, 1H), 3.91 (m, 2H), 3.56 (s,
2H), 1.92 (m, 1H), 1.41 (d, 3H) 0.91 (d, 6H).
[3509] C.sub.15H.sub.19NO.sub.3F.sub.2 (MW=299, Mass Spectroscopy
(MH.sup.+300)).
Example B59
Synthesis of N-[(3,5-diflurophenyl)acetyl]alanine iso-butyl
ester
[3510] Following General Procedure BI above, and using
3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3511] NMR data was as follows:
[3512] .sup.1H-nmr (CDCl,): .delta.=6.81 (m, 2H), 6.74 (m, 1H),
6.06 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.51 (s, 2H), 1.94 (m,
1H), 1.36 (d, 3H) 0.87 (d, 6H).
[3513] C.sub.15H.sub.19NO.sub.3F.sub.2 (MW=299, Mass Spectroscopy
(MH.sup.+300)).
Example B60
Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester
[3514] Following General Procedure BI above, and using
3-thiopheneacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3515] NMR data was as follows:
[3516] .sup.1H-nmr (CDCl.sub.3): .delta.=7.33 (m, 1H), 7.14 (m,
1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60
(s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H).
[3517] Optical Rotation: [.alpha.9 .sub.23 -52 (c 1 MeOH) @ 589
nm.
[3518] C.sub.13H.sub.19NO.sub.3S (MW=269, Mass Spectroscopy
(MH.sup.+269)).
Example B61
Synthesis of N-[(4-methylphenyl)acetyl]-L-alanine iso-butyl
ester
[3519] Following General Procedure BI above, and using
4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel and
purification was by filtration as described in the general
procedure.
[3520] NMR data was as follows:
[3521] .sup.1H-nmr (CDCl.sub.3): .delta.=7.11 (s, 4H), 5.93 (m,
1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.33 (s, 3H), 1.89
(m, 1H), 1.32 (d, 3H), 0.89 (d, 6H).
[3522] C.sub.16H.sub.23NO.sub.3 (MW=277.35, Mass Spectroscopy
(MH.sup.+278)).
Example B62
Synthesis of N-(phenylacetyl)-L-alanine S-1-(methoxycarbonyl)
iso-butyl ester
[3523] Following General Procedure BK and using
(S)-(+)-2-hydroxy-2-methyl- butyric acid (Aldrich) in place of the
amino acid, methyl (S)-(+)-2-hydroxy-2-methylbutyrate was
prepared.
[3524] Methyl (S)-(+)-2-hydroxy-2-methylbutyrate was then coupled
with carbobenzyloxy-L-alanine (Aldrich) using General Procedure BE
to provide carbobenzyloxy-L-alanine S-1-(methoxycarbonyl) iso-butyl
ester.
[3525] Carbobenzyloxy-L-alanine S-1-(methoxycarbonyl) iso-butyl
ester (1.0 g) was then dissolved in 20 mL of methanol and 6N HCl
(0.5 mL) and 10% palladium on carbon (0.1 g) were added. This
reaction mixture was hydrogenated at 40 psi of hydrogen on a Parr
apparatus for 5 hours at room temperature and then filtered through
a pad of Celite. The filtrate was concentrated at reduced pressure
to provide L-alanine S-1-(methoxycarbonyl) iso-butyl ester
hydrochloride (98% yield).
[3526] L-Alanine S-1-(methoxycarbonyl) iso-butyl ester
hydrochloride was then coupled to phenylacetic acid using General
Procedure BG to provide the title compound.
[3527] NMR data was as follows:
[3528] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35-7.20 (m, 5H), 6.22
(bd, 1H), 4.83 (d, 1H), 4.65 (p, 1H), 3.68 (s, 3H), 3.55 (s, 2H),
2.21 (m, 1H), 1.40 (d, 3H), 0.97 (d, 3H), 0.93 (d, 3H).
[3529] .sup.13C-nmr (CDCl.sub.3): .delta.=173.25, 171.18, 170.22,
135.11, 129.94, 129.50, 127.88, 52.67, 48.49, 43.98, 30.53, 19.21,
18.75, 17.58.
Example B63
Synthesis of N-[(3-nitrophenyl)acetyl]-L-alanine iso-butyl
ester
[3530] Following General Procedure BH above and using
3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester
hydrochloride (from Example BB above), the title compound was
prepared. The reaction was monitored by tlc on silica gel and
purification was by recrystallization from butyl chloride.
[3531] NMR data was as follows:
[3532] .sup.1H-nmr (CDCl.sub.3): .delta.=8.17 (m, 2H), 7.68 (d,
1H), 7.52 (t, 1H), 6.18 (m, 1H), 4.48 (m, 1H), 3.94 (m, 2H), 3.67
(s, 2H), 1.93 (m, 1H), 1.42 (d, 3H), 0.91 (d, 3H).
[3533] Optical Rotation: [.alpha.].sub.23 -49 (c 5, MeOH).
Example B64
Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester
[3534] Following General Procedure BG and using
3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester
(Aldrich), the title compound was prepared as a solid with a
melting. point of 93.degree.-95.degree. C. The reaction was
monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification
was by chromatography on silica gel using EtOAc as the eluant
followed by recrystallization from 1-chlorobutane.
[3535] NMR data was as follows: .sup.1H-nmr (DMSO-d.sub.6):
.delta.=1.30 (d, 3H); 3.52 (s, 2H).
[3536] C.sub.13H.sub.15NO.sub.3F.sub.2 (MW=271.26, Mass
Spectroscopy (MH.sup.+271)).
Example B65
Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester
[3537] Following General Procedure BG above and using
3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester
hydrochloride (Aldrich), the title compound was prepared. The
reaction was monitored by tlc on silica gel and purification was by
recrystallization from butyl chloride.
[3538] NMR data was as follows:
[3539] .sup.1H-nmr (CDCl.sub.3): .delta.=8.18 (s, 1H), 8.15 (d, 1H)
7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t,
2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27
(t, 3H).
[3540] Optical Rotation: [.alpha.].sub.23 -30 (c 5, MeOH).
Example B66
Synthesis of N-[(3-chlorophenyl)acetyl]alanine iso-butyl ester
[3541] Following General Procedure BG above and using
3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester
(prepared following General Procedure BJ above), the title compound
was prepared. The reaction was monitored by tlc on silica gel.
[3542] NMR data was as follows:
[3543] .sup.1H-nmr (CDCl.sub.3): .delta.=7.29 (m, 3H), 7.18 (m,
1H), 6.0 (m, 1H), 4.56 (m, 1H), 3.89 (m, 2H), 3.53 (s, 2H), 1.91
(m, 1H), 1.39 (d, 3H), 0.91 (d, 3H).
[3544] Optical Rotation: [.alpha.].sub.23 -45 (c 5, MeOH).
[3545] C.sub.15H.sub.20NO.sub.3Cl (MW=297.78, Mass Spectroscopy
(MH.sup.+297)).
Example B67
Synthesis of N-[(3-chlorophenyl)acetyl]alanine
2-(NN-dimethylamino)ethyl ester
[3546] Following General Procedure BC above, and using
N-(3-chlorophenyl-acetyl)alanine (from Example BD above) and
2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can be
prepared. The reaction was monitored by tic on silica gel and
purification was by liquid chromatography using 0.1:2:0.79
NH.sub.4OH:EtOH:CHCl.sub.3 as the eluant.
[3547] NMR data was as follows:
[3548] .sup.1H-nmr (CDCl.sub.3): 7.37 (s, 1H), 7.33-7.2 (m, 3H),
4.675-4.6 (m, 1H), 4.5-4.37 (m, 1H), 4.25-4.13 (m, 1H), 3.6 (d, J=7
Hz, 2H), 2.86 (bs, 2H), 2.3 (s, 6H), 1.23 (d, J=9 Hz, 3H).
[3549] C.sub.15H.sub.12N.sub.2O.sub.3Cl (MW=313.799, Mass
Spectroscopy (M.sup.+313)).
Example B68
Synthesis of 2-[(3,5-dichlorophenyl)acetamido]hexanoic acid methyl
ester
[3550] Following General Procedure BF above, an using
3,5-dichlorophenylacetic acid (from Example BC above) and
L-norleucine methyl ester hydrochloride (Bachem), the title
compound was prepared as a solid having a melting point of
77.degree.-78.degree. C. The reaction was monitored by tlc on
silica gel (Rf=0.70 in 40% EtOAC/hexanes) and purification was by
flash chromatography on silica gel using 40% EtOAc/hexanes as the
eluant.
[3551] NMR data was as follows:
[3552] .sup.1H-nmr (CDCl.sub.3): .delta.=7.20 (s), 7.18 (s), 6.6
(m), 4.55 (m), 3.7 (s), 3.5 (s), 3.4 (s), 2.0 (s), 1.8 (m), 1.6
(m), 1.2 (m), 0.8 (t).
[3553] .sup.13C-nmr (CDCl.sub.3): .delta.=173.54, 169.67, 138.43,
135.72, 128.33, 128.07, 78.04, 77.62, 77.19, 53.04, 52.90, 43.14,
32.57, 27.87, 22.81, 14.41.
Example B69
Synthesis of N-[(3,5-diclorophenyl)acetyl]-L-alanine iso-butyl
ester
[3554] Following General Procedure BF above, and using
3,5-dichlorophenylacetic - acid (from Example BC above) and
L-alanine iso-butyl ester hydrochloride (from Example BB above),
the title compound was prepared as a solid having a melting point
of 115.degree.-116.degree. C. The reaction was monitored by tlc on
silica gel (Rf=0.40 in 3% methanol/dichloromethane) and
purification was by flash chromatography on silica gel using 3%
methanol/dichloromethane as the eluant.
[3555] NMR data was as follows:
[3556] .sup.1H-nmr (CDCl.sub.3): .delta.=7.27 (d, J=2 Hz, 1H), 7.19
(s, 2H), 6.22 (d, J=6 Hz, 1H), 4.59 (quint., J=7 Hz, 1H), 3.9 (q,
J=4 Hz, 2H), 3.5 (s, 2H), 1.9 (m, 1H), 1.4 (d, J=7 Hz, 3H), 0.91
(d, J=7 Hz, 6H).
[3557] .sup.13C-nmr (CDCl.sub.3): .delta.=173.45, 169.37, 138.31,
135.75, 128.39, 128.11, 78.04, 77.61, 77.19, 72.19, 54.03, 48.97,
43.12, 28.24, 19.52, 19.49, 19.09.
[3558] C.sub.15H.sub.19NO.sub.3Cl.sub.2 (MW=331.9, Mass
Spectroscopy (MH.sup.+332)).
Example B70
Synthesis of N-(cyclohexylacetyl)-L-alanine iso-butyl ester
[3559] Following General Procedure BB above, and using
cyclohexylacetic acid (Aldrich) and L-alanine iso-butyl ester
hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of 92.degree.
C.-93.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.39 in 1:3 EtOAc:hexane) and purification was by extraction
with Et.sub.2O followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[3560] NMR data was as follows:
[3561] 1H-nmr (CDCl.sub.3): .delta.=0.93 (d, J.=6.7 Hz, 6H),
0.85-1.01 (m, 2H), 1.05-1.35 (m, 3H), 1.40 (d, J=7.1 Hz, 3H),
1.60-1.85 (m, 6H), 1.95 (m, 1H), 2.06 (d, J=7.0 Hz, 2H), 3.92 (m,
2H), 4.61 (m, 1H), 6.08 (bd, 1H).
[3562] .sup.13C-nmr (CDCl.sub.3): .delta.=18.7, 18.9, 26.0, 26.1,
27.6, 33.0, 35.3, 44.6, 47.9, 71.4, 171.8, 173.3.
[3563] C.sub.15H.sub.27NO.sub.3 (MW=269.39, Mass Spectroscopy
(MH.sup.+270)).
Example B71
Synthesis of N-(cyclopentylacetyl)-L-alanine iso-butyl ester
[3564] Following General Procedure BB above, and using
cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester
hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of 62.degree.
C.-64.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.37 in 1:3 EtOAc:hexane) and purification was by extraction
with Et.sub.2O followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[3565] NMR data was as follows:
[3566] .sup.1H-nmr (CDCl.sub.3): .delta.=0.87 (d, J=6.8 Hz, 6H),
1.01-1.17 (m, 2H), 1.34 (d, J=7.2 Hz, 3H), 1.40-1.62 (m, 4H),
1.70-1.83 (m, 2H), 1.89 (m, 1H), 2.15 (m, 3H), 3.86 (m, 2H), 4.55
(m, 1H), 6.30 (d, J=7.1 Hz, 1H).
[3567] .sup.13C-nmr (CDCl.sub.3): .delta.=18.4, 18.78, 18.80, 24.8
(very high), 27.5, 32.27, 32.32,36.9, 42.5, 47.7, 71.2, 172.2,
173.2.
[3568] Elemental Analysis-Calc (%): C, 65.85;H, 9.87; N. 5.49;
Found (%): C, 66.01;H, 10.08; N, 5.49.
[3569] C.sub.14H.sub.25NO.sub.3 (MW=255.36, Mass Spectroscopy
(MH.sup.+256)).
Example B72
Synthesis of N-[(cyclohex-1-enyl)acetyl]-L-alanine iso-butyl
ester
[3570] Following General Procedure BB above, and using
cyclohex-1-enyl acetic acid (Alfa) and L-alanine iso-butyl ester
hydrochloride (from Example BB above), the title compound was
prepared as a solid having a melting point of 49.degree.
C.-51.degree. C. The reaction was monitored by tlc on silica gel
(Rf=0.40 in 1:3 EtOAc:hexane) and purification was by extraction
with Et.sub.2O followed by washes with aqueous K.sub.2CO.sub.3 and
aqueous HCl.
[3571] NMR data was as follows:
[3572] .sup.1H-nmr (CDCl.sub.3): .delta.=0.91 (d, J=4.5 Hz, 3H),
0.93 (d, J=6.7 Hz, 3H), 1.40 (d, J=7.2 Hz, 3H), 1.52-1.70 (m, 4H),
1.97 (m, 3H), 2.06 (bs, 2H), 2.89 (s, 2H), 3.92 (m, 2H), 4.59 (m,
1H), 5.65 (s, 1H), 6.33 (d, J=6.6 Hz, 1H).
[3573] .sup.13C-nmr (CDCl.sub.3): .delta.=18.7, 18.91, 18.93, 21.9,
22.7, 25.3, 27.6, 28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6,
173.1.
[3574] Elemental Analysis-Calc (%): C, 67.38;H, 9.42; N, 5.24;
Found (%): C, 67.34;H, 9.54; N, 5.16.
[3575] C.sub.15H.sub.25NO.sub.3 (MW=267.37, Mass Spectroscopy
(MH.sup.+268)).
Example B73
Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl
thioester
[3576] Following General Procedure BC above, and using
N-[(3-chlorophenyl)acetyl]alanine and 3-methyl-2-butene thioester
(TCI), the title compound can be prepared. The reaction was
monitored by tlc on silica gel and purification was by liquid
chromatography using 3:7 EtOAc:Hexane as the eluant.
[3577] NMR data was as follows:
[3578] .sup.1H-nmr (DMSO-d.sub.6): .delta.=5.2-5.075 (m, 1H), 4.37
(dq, J=9 Hz, 1H), 3.56 (s), 3.43 (d, J=12 Hz. 2H), 1.266 (d, J=12
Hz, 6H) 1.3 (d, J=9 Hz, 3H).
[3579] C.sub.16H.sub.20NO.sub.2ClS (MW=325.86, Mass Spectroscopy
(M.sup.+325)).
Example B74
Synthesis of N-[(2-phenyl)-2-fluoroacetyl]alanine ethyl ester
[3580] Following General Procedure BF above, and using
.alpha.-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester
(Aldrich), the title compound was prepared. The reaction was
monitored by tlc on silica gel (Rf=0.75 in 1:1 EtOAc:hexane) and
purification was by chromatography on silica gel using 1:2 ethyl
acetate/hexanes as the eluent.
[3581] NMR data was as follows:
[3582] .sup.1H-nmr (DMSO-d.sub.6): .delta.=1.14 (q, 3H), 1.34 (d,
3H), 4.07 (m, 2H), 4.33 (m, 1H), 5.84 (d, 1H), 6.01 (d, 1H),
7.40-7.55 (m, 5H), 8.87 (m, 1H).
[3583] C.sub.13H.sub.16NO.sub.3F (MW=253.27, Mass Spectroscopy
(MH.sup.+253)).
Example B75
Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine methyl
ester
[3584] Following General Procedure BF above, and using
3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl
ester hydrochloride (Bachem), the title compound was prepared.
[3585] NMR data was as follows: .sup.1H-nmr (CDCl.sub.3):
.delta.=7.4-7.3 (m, 5H), 6.9-6.7 (m, 3H), 6.55 (d 1H, 7.1 Hz), 5.56
(d 1H 7 Hz), 3.72 (s 3H), 3.57 (s 2H)
[3586] .sup.13C-nmr (CDCl.sub.3): .delta.=197.6, 177.6, 171.8,
169.3, 136.7, 129.6, 129.3, 127.8, 113.0, 112.9, 112.7, 111.4,
103.8, 103.5, 65.1, 57.2, 53.5, 45.1, 43.3, 43.3
[3587] C.sub.17H.sub.15NO.sub.3F.sub.2 (MW=319.31, Mass
Spectroscopy (MH+320)).
Example B76
Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine iso-butyl
ester
[3588] The 3,5-difluorophenylacetic acid (Aldrich) was EDC coupled
to L-phenylglycine methyl ester hydrochloride (Bachem) via General
Procedure BF above.
[3589] The resulting compound was placed in a large excess of the
desired alcohol. A catalytic amount of dry NaH was added, and the
reaction was followed by tlc until the presence of starting
material was no longer detected. The reaction was quenched with a
few milliliters of IN HCl, and after a few minutes of stirring
saturated aqueous NaHCO.sub.3 was added. The volume of the reaction
mixture was reduced on a rotary evaporator until the excess alcohol
was removed and then the remaining residue was taken up in ethyl
acetate and additional water was added. The organic phase was
washed with saturated aqueous NaCl and dried over MgSO.sub.4. The
solution was stripped free of solvent on a rotary evaporator, and
the crude product residue was then further purified by
chromatography.
[3590] NMR data was as follows:
[3591] 1H-nmr (CDCl.sub.3): .delta.=7.35-7.3 (m 5H), 6.8-6.7 (m 3H)
6.60 (d 1H, 7Hz), 5.55 (d 1H 7.1 Hz), 3.9 (m 2H), 3.60 (s 2H), 1.85
(m 1H 7 Hz), 0.8 (q 6H 7 Hz)
[3592] .sup.13C-nmr (CDCl.sub.3): .delta.=171.3, 169.3, 165.4,
138.5, 137.0, 129.5, 129.2, 127.6, 113.1, 113.0, 112.8, 112.7,
103.8, 103.5, 103.2, 75.5, 57.2, 43.4, 43.3, 28.2, 19.3
[3593] C.sub.20H.sub.21NO.sub.3F.sub.2 (MW=361.39, Mass
Spectroscopy (MH.sup.+362)).
Example B77
Synthesis of N-(cyclopentylacetyl)-L-phenylglycine methyl ester
[3594] Following General Procedure BD above, and using
cyclopentylacetic acid (Aldrich) with L-phenylglycine methyl ester
hydrochloride (Bachem) the title compound was prepared.
[3595] NMR data was as follows:
[3596] 1H-nmr (CDCl.sub.3): .delta.=7.35 (s, 5H), 6.44 (bd, 1H),
5.6 (d, 1H), 3.72 (s, 3H), 2.24 (bs, 3H), 1.9-1.4 (m, 6H), 1.2-1.05
(m, 2H)
[3597] .sup.13C-nmr (CDCl.sub.3): .delta.=172.3, 171.7, 136.7,
129.0, 128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38, 24.8
Example B78
Synthesis of N-(cyclopentylacetyl)-L-alanine methyl ester
[3598] Following General Procedure BD above, and using
cyclopentylacetic acid (Aldrich) with L-alanine methyl ester
hydrochloride (Sigma) the title compound was prepared.
[3599] NMR data was as follows:
[3600] .sup.1H-nmr (CDCl.sub.3): .delta.=6.38 (d, 1H), 4.50 (m,
1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30,
3H), 11H)
[3601] .sup.13C-nmr (CDCl.sub.3): .delta.=173.7, 172.5, 52.1, 47.6,
42.3, 36.8, 32.15, 32.14, 18.0
[3602] C.sub.11H.sub.19NO.sub.3 (MW=213.28, Mass Spectroscopy
(MH.sup.+214)).
Example B79
Synthesis of N-(cyclopropylacetyl)-L-phenylglycine methyl ester
[3603] Following General Procedure BD above, and using
cyclopropylacetic acid (Aldrich) with L-phenylglycine methyl ester
hydrochloride (Bachem), the title compound was prepared.
[3604] NMR data was as follows:
[3605] .sup.1H-nmr (CDCl.sub.3): .delta.=7.35 (m, 5H) 6.97 (bd,
J=7.2 Hz, 1H) 5.59 (d, J=7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m, 2H),
1.05-0.95 (m, 1H), 0.62 (m, 2H), 0.02 (m, 2H)
[3606] .sup.13C-nmr (CDCl.sub.3): .delta.=171.9, 174.6, 136.6,
129.0, 128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33
Example B80
Synthesis of N-(cyclopropylacetyl)-L-alanine methyl ester
[3607] Following General Procedure BD above, and using
cyclopropylacetic acid (Aldrich) with L-alanine methyl ester
hydrochloride (Sigma), the title compound was prepared.
[3608] NMR data was as follows:
[3609] .sup.1H-nmr (CDCl.sub.3): .delta.=6.60 (d, 1H), 4.55 (m,
1H), 3.69 (s, 3H), 2.10 (m, 2H), 1:34 (d, 3H), 0.95 (m, 1H), 0.58
(m, 2H) 0.15 (m, 2H)
[3610] .sup.13C-nmr (CDCl.sub.3): .delta.=173.7, 172.3, 52.3, 47.7,
41.0, 18.2, 6.7, 4.27, 4.22
Example B81
Synthesis of N-[(3-nitrophenyl)acetyl]-L-methionine iso-butyl
ester
[3611] Following General Procedure BH above, and using
nitrophenylacetic acid (Aldrich) and L-methionine (Aldrich), the
title compound was prepared as a tan oil. The reaction was
monitored by tlc on silica gel.
[3612] NMR data was as follows: .sup.1H-nmr (CDCl.sub.3):
.delta.=8.16 (m,2H) 7.67 (d,1H) 7.32 (t, 1H), 6.31 (bd, 1H), 4.69
(m, 1H), 3.90 (d, 2H), 3.68 (s, 2H), 2.47 (t, 2H), 2.15 (m, 1H),
2.02 (s, 3H), 1.90 (m, 2H), 0.91 (d, 6H).
[3613] C.sub.17H.sub.24N.sub.2O.sub.5S (MW=368.4, Mass Spectroscopy
(MH.sup.+368)).
[3614] Additionally, each of the carboxylic acids described above
(or the carboxylic acids prepared by hydrolysis of the above
carboxylic acid esters) could be coupled with an appropriate
.alpha.-aminolactam to provide for compounds of the formula:
109
[3615] where R.sup.1--[Z].sub.m--NH--CHR.sup.2--C(O)-- is the
residue of the carboxylic acid (i.e., R.sup.1, R.sup.2, Z, and m
are as defined above) and W" is selected from the following
structures: 110
Example Bio-1
Cellular Screen for the Detection of Inhibitors of .beta.-Amyloid
Production
[3616] Numerous compounds of formula I above were assayed for their
ability to inhibit .beta.-amyloid production in a cell line
possessing the Swedish mutation. This screening assay employed
cells (K293=human kidney cell line) which were stably transfected
with the gene for amyloid precursor protein 751 (APP751) containing
the double mutation Lys.sub.651Met.sub.652 to
Asn.sub.651Leu.sub.652 (APP751 numbering) in the manner described
in International Patent Application Publication No. 94/10569.sup.8
and Citron et al..sup.12. This mutation is commonly called the
Swedish mutation and the cells, designated as "293 751 SWE", were
plated in Corning 96-well plates at 2-4.times.10.sup.4 cells per
well in Dulbecco's minimal essential media (Sigma, St. Louis, Mo.)
plus 10% fetal bovine serum. Cell number is important in order to
achieve .beta.-amyloid ELISA results within the linear range of the
assay (.about.0.2 to 2.5 ng per mL).
[3617] Following overnight incubation at 37.degree. C. in an
incubator equilibrated with 10% carbon dioxide, media were removed
and replaced with 200 .mu.L of a compound of formula I (drug)
containing media per well for a two hour pretreatment period and
cells were incubated as above. Drug stocks were prepared in 100%
dimethyl sulfoxide such that at the final drug concentration used
in the treatment, the concentration of dimethyl sulfoxide did not
exceed 0.5% and, in fact, usually equaled 0.1%.
[3618] At the end of the pretreatment period, the media were again
removed and replaced with fresh drug containing media as above and
cells were incubated for an additional two hours. After treatment,
plates were centrifuged in a Beckman GPR at 1200 rpm for five
minutes at room temperature to pellet cellular debris from the
conditioned media. From each well, 100 .mu.L of conditioned media
or appropriate dilutions thereof were transferred into an ELISA
plate precoated with antibody 266 [P. Seubert, Nature (1992)
359:325-327]against amino acids 13-28 of .beta.-amyloid peptide as
described in International Patent Application Publication No.
94/10569.sup.8 and stored at 4.degree. C. overnight. An ELISA assay
employing labelled antibody 3D6 [P. Seubert, Nature (1992)
359:325-327]against amino acids 1-5 of .beta.-amyloid peptide was
run the next day to measure the amount of .beta.-amyloid peptide
produced.
[3619] Cytotoxic effects of the compounds were measured by a
modification of the method of Hansen, et al..sup.13. To the cells
remaining in the tissue culture plate was added 25 .mu.L of a
3-(4,5-dimethylthiazol-2-yl)- -2,5-diphenyltetrazolium bromide
(MTT) (Sigma, St. Louis, Mo.) stock solution (5 mg/nL) to a final
concentration of 1 mg/mL. Cells were incubated at 37.degree. C. for
one hour, and cellular activity was stopped by the addition of an
equal volume of MTT lysis buffer (20% w/v sodium dodecylsulfate in
50% dimethylformamide, pH 4.7). Complete extraction was achieved by
overnight shaking at room temperature. The difference in the
OD.sub.562nm and the OD.sub.650nm was measured in a Molecular
Device's UV.sub.max microplate reader as an indicator of the
cellular viability.
[3620] The results of the .beta.-amyloid peptide ELISA were fit to
a standard curve and expressed as ng/mL .beta.-amyloid peptide. In
order to normalize for cytotoxicity, these results were divided by
the MTT results and expressed as a percentage of the results from a
drug free control. All results are the mean and standard deviation
of at least six replicate assays.
[3621] The test compounds were assayed for .beta.-amyloid peptide
production inhibition activity in cells using this assay. The
results of this assay demonstrate that the compounds of formula I
inhibit .beta.-amyloid peptide production by at least 30% as
compared to control.
Example Bio-2
In Vivo Suppression of .beta.-Amyloid Release and/or Synthesis
[3622] This example illustrates how the compounds of this invention
could be tested for in vivo suppression of .beta.-amyloid release
and/or synthesis. For these experiments, 3 to 4 month old PDAPP
mice are used [Games et al., (1995) Nature 373:523-527]. Depending
upon which compound is being tested, the compound is usually
formulated at between 1 and 10 mg/mL. Because of the low solubility
factors of the compounds, they may be formulated with various
vehicles, such as corn oil (Safeway, South San Francisco, Calif.);
10% ethanol in corn oil; 2-hydroxypropyl-.beta.-cyclo- dextrin
(Research Biochemicals International, Natick Mass.); and
carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis Mo.).
[3623] The mice are dosed subcutaneously with a 26 gauge needle and
3 hours later the animals are euthanized via CO.sub.2 narcosis and
blood is taken by cardiac puncture using a 1 cc 25G 5/8" tuberculin
syringe/needle coated with solution of 0.5 M EDTA, pH 8.0. The
blood is placed in a Becton-Dickinson vacutainer tube containing
EDTA and spun down for 15 minutes at 1500.times.g at 5.degree. C.
The brains of the mice are then removed and the cortex and
hippocampus are dissected out and placed on ice.
[3624] 1. Brain Assay
[3625] To prepare hippocampal and cortical tissue for enzyme-linked
immunosorbent assays (ELISAs) each brain region is homogenized in
10 volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mM
Tris-HCl, pH 8.0) using a Kontes motorized pestle (Fisher,
Pittsburgh Pa.). The homogenates are gently rocked on a rotating
platform for three to four hours at room temperature and stored at
-20.degree. C. prior to quantitation of .beta.-amyloid.
[3626] The brain homogenates are diluted 1:10 with ice-cold casein
buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium
azide, 20 .mu.g/ml aprotinin, 5 mM EDTA, pH 8.0, 10 .mu.g/ml
leupeptin], thereby reducing the final concentration of guanidine
to 0.5 M, before centrifugation at 16,000.times.g for 20 minutes at
4.degree. C. Samples are further diluted, if necessary, to achieve
an optimal range for the ELISA measurements by the addition of
casein buffer with 0.5 M guanidine hydrochloride added. The
.beta.-amyloid standards (140 or 142 amino acids) were prepared
such that the final composition equaled 0.5 M guanidine in the
presence of 0.1% bovine serum albumin (BSA).
[3627] The total .beta.-amyloid sandwich ELISA, quantitating both
.beta.-amyloid (aa 1-40) and .beta.-amyloid (aa 1-42) consists of
two monoclonal antibodies (mAb) to .beta.-amyloid. The capture
antibody, 266 [P. Seubert, Nature (1992) 359:325-327], is specific
to amino acids 13-28 of .beta.-amyloid. The antibody 3D6
[Johnson-Wood et al., PNAS USA (1997) 94:1550-1555], which is
specific to amino acids 1-5 of .beta.-amyloid, is biotinylated and
served as the reporter antibody in the assay. The 3D6 biotinylation
procedure employs the manufacturer's (Pierce, Rockford Ill.)
protocol for NHS-biotin labeling of immunoglobulins except that 100
mM sodium bicarbonate, pH 8.5 buffer is used. The 3D6 antibody does
not recognize secreted amyloid precursor protein (APP) or
full-length APP but detects only .beta.-amyloid species with an
amino terminal aspartic acid. The assay has a lower limit of
sensitivity of .about.50 pg/ml (11 pM) and shows no
cross-reactivity to the endogenous murine .beta.-amyloid peptide at
concentrations up to 1 ng/ml.
[3628] The configuration of the sandwich ELISA quantitating the
level of .beta.-amyloid (aa 1-42) employs the mAb 21F12
[Johnson-Wood et al., PNAS USA (1997) 94:1550-1555](which
recognizes amino acids 33-42 of .beta.-amyloid) as the capture
antibody. Biotinylated 3D6 is also the reporter antibody in this
assay which has a lower limit of sensitivity of .about.125 pg/ml
(28 pM).
[3629] The 266 and 21F12 capture mAbs are coated at 10 .mu.g/ml
into 96 well immunoassay plates (Costar, Cambidge Mass.) overnight
at room temperature. The plates are then aspirated and blocked with
0.25% human serum albumin in PBS buffer for at least 1 hour at room
temperature, then stored desiccated at 4.degree. C. until use. The
plates are rehydrated with wash buffer (Tris-buffered saline, 0.05%
Tween 20) prior to use. The samples and standards are added to the
plates and incubated overnight at 4.degree. C. The plates are
washed .gtoreq.3 times with wash buffer between each step of the
assay. The biotinylated 3D6, diluted to 0.5 .mu.g/ml in casein
incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) is
incubated in the well for 1 hour at room temperature. Avidin-HRP
(Vector, Burlingame Calif.) diluted 1:4000 in casein incubation
buffer is added to the wells for 1 hour at room temperature. The
colorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge Mass.),
is added and allowed to react for 15 minutes, after which the
enzymatic reaction is stopped with addition of 2 N H.sub.2SO.sub.4.
Reaction product is quantified using a Molecular Devices Vmax
(Molecular Devices, Menlo Park Calif.) measuring the difference in
absorbance at 450 nm and 650 nm.
[3630] 2. Blood Assay
[3631] The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/l
sodium phosphate-H.sub.2O (monobasic), 2.16 gm/l sodium
phosphate-7H.sub.2O (dibasic), 0.5 gm/l thimerosal, 8.5 gm/l sodium
chloride, 0.5 ml Triton X-405, 6.0 g/l globulin-free bovine serum
albumin; and water). The samples and standards in specimen diluent
are assayed using the total .beta.-amyloid assay (266 capture/3D6
reporter) described above for the brain assay except the specimen
diluent was used instead of the casein diluents described.
[3632] Formulations other than those described above can also be
used for oral delivery and intravenous delivery to a mammal. For
oral delivery, the compound can be mixed with either 100% corn oil
or, alternatively, in a solution containing 80% corn oil, 19.5%
oleic acid and 0.5% labrafil. The compound can be mixed with the
above solutions in concentrations ranging from 1 mg/mL to 10 mg/mL.
The compound in solution is preferably administered orally to the
mammal at a dose volume of 5 mL/kg of body weight. For IV delivery,
the compound is preferably mixed with a solution of 3% ethanol, 3%
solutol HS-15 and 94% saline. The compound is preferably mixed with
the above solution in concentrations ranging from 0.25 mg/mL to 5
mg/mL. The compound in solution is preferably administered by IV to
the mammal at a dose volume of 2 mL/kg of body weight.
[3633] From the foregoing description, various modifications and
changes in the composition and method will occur to those skilled
in the art. All such modifications coming within the scope of the
appended claims are intended to be included therein.
* * * * *