U.S. patent application number 11/002921 was filed with the patent office on 2005-12-01 for cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-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., Henry, Steven S., Mabry, Thomas E., McDaniel, Stacey L., Porter, Warren J., Reel, Jon K., Shi, Qing, Stack, Douglas R., Stucky, Russell D., Thompson, Richard C., Vanmeter, Eldon E., Wilkie, Stephen.
Application Number | 20050267150 11/002921 |
Document ID | / |
Family ID | 26856569 |
Filed Date | 2005-12-01 |
United States Patent
Application |
20050267150 |
Kind Code |
A1 |
Thompson, Richard C. ; et
al. |
December 1, 2005 |
Cycloalkyl, lactam, lactone and related compounds, pharmaceutical
compositions comprising same, and methods for inhibiting
beta-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 that include 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: |
Thompson, Richard C.;
(Frankfort, IN) ; Wilkie, Stephen; (Indianapolis,
IN) ; Stack, Douglas R.; (Fishers, IN) ;
Vanmeter, Eldon E.; (Greenwood, IN) ; Shi, Qing;
(Carmel, IN) ; 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) ; Henry, Steven S.; (New
Palestine, IN) ; McDaniel, Stacey L.; (Martinsville,
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: |
26856569 |
Appl. No.: |
11/002921 |
Filed: |
December 3, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11002921 |
Dec 3, 2004 |
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10392332 |
Mar 20, 2003 |
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6906056 |
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10392332 |
Mar 20, 2003 |
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09338191 |
Jun 22, 1999 |
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6569851 |
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60160067 |
Jun 22, 1998 |
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Current U.S.
Class: |
514/309 ;
514/312; 514/317 |
Current CPC
Class: |
C07K 5/0823 20130101;
C07D 403/12 20130101; A61K 38/00 20130101; A61P 25/28 20180101;
C07K 5/0821 20130101; C07D 401/12 20130101 |
Class at
Publication: |
514/309 ;
514/317; 514/312 |
International
Class: |
A61K 031/4706; A61K
031/445 |
Claims
1-123. (canceled)
124. 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
the following formula: 375wherein R.sup.1 is selected from the
group consisting of: A) alkyl of from 1 to 20 carbon atoms; B)
alkenyl of from 2 to 10 carbon atoms and 1-2 sites of alkenyl
unsaturation; C) alkynyl of from 2 to 10 carbon atoms and from 1-2
sites of alkynyl unsaturation; D) cycloalkyl of from 3 to 12 carbon
atoms; E) cycloalkenyl of from 4 to 8 carbon atoms; F) substituted
alkyl of from 1 to 10 carbon atoms, having from 1 to 3 substituents
selected from: 1) alkoxy having the formula alkyl-O-- wherein alkyl
is as defined in A herein; 2) substituted alkoxy of the formula
substituted alkyl-O-- wherein substituted alkyl is as defined in F
herein; 3) cycloalkyl as defined in D herein; 4) substituted
cycloalkyl as defined in I herein; 5) cycloalkenyl as defined in E
herein; 6) substituted cycloalkenyl as defined in J herein; 7) acyl
selected from alkyl-C(O)--, substituted alkyl-C(O)--,
cycloalkyl-C(O)--, substituted cycloalkyl-C(O)--, optionally
substituted aryl-C(O)--, optionally substituted heteroaryl-C(O)--
and optionally substituted heterocyclic-C(O)-- wherein alkyl is
defined in A herein; wherein substituted alkyl is defined in F
herein; wherein cycloalkyl is defined in D herein; wherein
substituted cycloalkyl is defined in I herein; wherein optionally
substituted aryl is defined in F25 herein; wherein optionally
substituted heteroaryl is defined in F27 herein; and wherein
optionally substituted heterocyclic is defined in F29 herein; 8)
acylamino having the formula --C(O)NRR wherein each R is
independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 9) acyloxy selected from alkyl-C(O)O--, substituted
alkyl-C(O)O--, cycloalkyl-C(O)O--, optionally substituted
aryl-C(O)O--, optionally substituted heteraryl-C(O)O-- and
optionally substituted heterocyclic-C(O)O-- wherein alkyl is
defined in A herein; wherein substituted alkyl is defined in F
herein; wherein cycloalkyl is defined in D herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 10) amino; 11) substituted amino having the formula
--N(R).sub.2 wherein each R is independently selected from the
group consisting of: a) hydrogen; b) alkyl as defined in A herein;
c) substituted alkyl as defined in F herein; d) alkenyl as defined
in B herein; e) substituted alkenyl as defined in G herein; f)
alkynyl as defined in C herein; g) substituted alkynyl as defined
in H herein; h) optionally substituted aryl as defined in F25
herein; i) cycloalkyl as defined in D herein; j) substituted
cycloalkyl as defined in I herein; k) optionally substituted
heteroaryl as defined in F27 herein; l) optionally substituted
heterocyclic as defined in F29 herein and wherein one of R can also
be hydrogen or R and R together with the nitrogen atom to which
they are joined form an optionally substituted heterocyclic as
defined in F29 herein; 12) aminoacyl having the formula --NRC(O)R
wherein each R is independently hydrogen, alkyl, substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heterocyclic wherein alkyl is defined in A
herein; wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 13) aminoacyloxy having the formula --NRC(O)OR wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 14) oxyacylamino having the formula --OC(O)NRR wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 15) cyano; 16) halo selected from fluoro, chloro, bromo and
iodo; 17) hydroxy; 18) carboxyl; 19) optionally substituted
carboxyalkyl having the formula --C(O)O alkyl and --C(O)O
substituted alkyl wherein alkyl is as defined in A and substituted
alkyl is as defined in F; 20) keto; 21) thioketo; 22) thiol; 23)
thioalkoxy having the formula --S-alkyl, wherein alkyl is defined
in A herein; 24) substituted thioalkoxy having the formula
--S-substituted alkyl, wherein substituted alkyl is defined in F
herein; 25) optionally substituted aryl having 6 to 14 carbon atoms
and optionally substituted with 1 to 5 substituents selected from:
a) acyloxy as defined in F9 herein; b) hydroxy; c) acyl as defined
in F7 herein; d) alkyl as defined in A herein; e) alkoxy as defined
in F1 herein; f) alkenyl as defined in B herein; g) alkynyl as
defined in C herein; h) substituted alkyl as defined in F herein;
i) substituted alkoxy as defined in F2 herein; j) substituted
alkenyl as defined in G herein; k) substituted alkynyl as defined
in H herein; l) amino; m) substituted amino as defined in F11
herein; n) aminoacyl as defined in F12 herein; o) acylamino as
defined in F8 herein; p) optionally substituted alkaryl in which
the alkyl moiety has 1 to 8 carbon atoms and the aryl has 6 to 10
carbon atoms and is optionally substituted as defined in F25
herein; q) optionally substituted aryl as defined in F25 herein; r)
optionally substituted aryloxy as defined in F26 herein; s) azido;
t) carboxyl; u) optionally substituted carboxylalkyl as defined in
F19 herein; v) cyano; w) halo as defined in F16 herein; x) nitro;
y) optionally substituted heteroaryl as defined in F27 herein; z)
optionally substituted heterocyclic as defined in F29 herein; aa)
aminoacyloxy as defined in F13 herein; bb) oxyacylamino as defined
in F14 herein; cc) thioalkoxy as defined in F23 herein; dd)
substituted thioalkoxy as defined in F24 herein; ee) optionally
substituted thioaryloxy having the formula aryl-S-- wherein aryl is
optionally substituted as defined in F25 herein; ff) optionally
substituted thioheteroaryloxy having the formula heteroaryl-S--
wherein heteroaryl is optionally substituted as defined in F27
herein; gg) --SO-alkyl wherein alkyl is as defined in A herein; hh)
--SO-substituted alkyl wherein substituted alkyl is as defined in F
herein; ii) --SO-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; jj) --SO-- optionally
substituted heteroaryl wherein optionally substituted heteroaryl is
as defined in F27 herein; kk) --SO.sub.2-- alkyl wherein alkyl is
as defined in A herein; ll) --SO.sub.2-- substituted alkyl wherein
substituted alkyl is as defined in F herein; mm)
--SO.sub.2-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; nn)
--SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; and oo)
trihalomethyl wherein halo is as defined in F16 herein; 26)
optionally substituted aryloxy having the formula aryl-O-- wherein
aryl is optionally substituted aryl as defined in F25 herein; 27)
optionally substituted heteroaryl having 1 to 15 ring carbon atoms
and 1 to 4 ring heteroatoms selected from oxygen, nitrogen and
sulfur and optionally substituted with 1 to 5 substituents selected
from the same group of substituents as defined for optionally
substituted aryl in F25 herein; 28) optionally substituted
heteroaryloxy having the formula --O-heteroaryl wherein heteroaryl
is optionally substituted heteroaryl as defined in F27 herein; 29)
optionally substituted saturated or unsaturated heterocyclic from 1
to 15 ring carbon atoms and 1 to 4 ring heteroatoms selected from
nitrogen, sulfur and oxygen and optionally substituted with 1 to 5
substituents selected from the same group of substituents as
defined for substituted alkyl in F herein; 30) optionally
substituted heterocyclooxy having the formula --O-heterocyclic
wherein heterocyclic is defined as optionally substituted
heterocyclic on F29 hereof; 31) hydroxyamino; 32) alkoxyamino
wherein alkoxy is as defined in F1; 33) nitro; 34) --SO-alkyl
wherein alkyl is as defined in A herein; 35) --SO-substituted alkyl
wherein substituted alkyl is as defined in F herein; 36)
--SO-optionally substituted aryl wherein aryl is optionally
substituted as defined in F25 herein; 37) --SO-optionally
substituted heteroaryl wherein optionally substituted heteroaryl is
as defined in F27 herein; 38) --SO.sub.2-alkyl wherein alkyl is as
defined in A herein; 39) --SO.sub.2-substituted alkyl wherein
substituted alkyl is as defined in F herein; 40)
--SO.sub.2-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; 41)
--SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; G) substituted
alkenyl having 2 to 10 carbon atoms and having of from 1 to 3
substituents selected from the group consisting of: 1) alkoxy
having the formula alkyl-O-- wherein alkyl is as defined in A
herein; 2) substituted alkoxy of the formula substituted alkyl-O--
wherein substituted alkyl is as defined in F herein; 3) cycloalkyl
as defined in D herein; 4) substituted cycloalkyl as defined in I
herein; 5) cycloalkoxy; 6) substituted cycloalkoxy; 7) acyl as
defined in F7 herein; 8) acylamino as defined in F8 herein; 9)
acyloxy as defined in F9 herein; 10) amino; 11) substituted amino
as defined in F11 herein; 12) aminoacyl as defined in F12 herein;
13) aminoacycloxy as defined in F13 herein; 14) cyano; 15) halo
selected from fluoro, cholo, bromo and iodo; 16) hydroxy; 17)
carboxyl; 18) optionally substituted carboxyalkyl having the
formula --C(O)O-alkyl and --C(O)O-substituted alkyl wherein alkyl
is a defined in A and substituted alkyl is as defined in F; 19)
keto; 20) thioketo; 21) thiol; 22) thioalkoxy as defined in F23
herein; 23) substituted thioalkoxy as defined in F24 herein; 24)
optionally substituted aryl as defined in F25 herein; 25)
optionally substituted heteroaryl as defined in F27 herein; 26)
optionally substituted saturated or unsaturated heterocyclic as
defined in F29 herein; 27) optionally substituted heterocyclooxy as
defined in F30 herein; 28) nitro; 29) --SO-alkyl wherein alkyl is
as defined in A herein; 30) --SO-substituted alkyl wherein
substituted alkyl is as defined in F herein; 31) --SO-aryl wherein
optionally substituted aryl is optionally substituted as defined in
F25 herein; 32) --SO-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F27 herein; 33)
--SO.sub.2-alkyl wherein alkyl is as defined in A herein;
--SO.sub.2-substituted alkyl wherein substituted alkyl is as
defined in F herein; 34) --SO.sub.2-optionally substituted aryl
wherein optionally substituted aryl is as defined in F25 herein;
and 35) --SO.sub.2-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F27 herein; H)
substituted alkynyl having 2 to 10 carbon atoms having 1-2 sites of
alkynyl unsaturation and having 1 to 3 substituents selected from
the same group of substituents as defined for substituted alkenyl
in G herein; I) substituted cycloalkyl having 3 to 12 carbon atoms
and having from 1 to 5 substituents selected from the same group of
substituents as defined for substituted alkyl in F herein; J)
substituted cycloalkenyl as defined in E herein having from 1 to 5
substituents selected from the same group of substituents as
defined for substituted alkyl in F herein; K) optionally
substituted aryl as defined in F25 herein; L) optionally
substituted heteroaryl as defined in F27 herein; and M) optionally
substituted heterocyclic as defined in F29 herein; R.sub.2 is
independently selected from the group consisting of: N) hydrogen;
O) alkyl as defined in A herein; P) substituted alkyl as defined in
F herein; Q) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of
alkenyl unsaturation; R) substituted alkenyl as defined in G
herein; S) alkynyl of from 2 to 10 carbon atoms and from 1-2 sites
of alkynyl unsaturation; T) substituted alkynyl as defined in H
herein; U) cycloalkyl of from 3 to 12 carbon atoms; V) optionally
substituted aryl as defined in F25 herein; W) optionally
substituted heteroaryl as defined in F27 herein; and X) optionally
substituted heterocyclic as defined in F29 herein; Q is S or O;
R.sup.15 is independently selected from the group consisting of: Y)
hydrogen, Z) alkyl as defined in A herein; AA) substituted alkyl as
defined in F herein; AB) optionally substituted aryl as defined in
F25 herein; AC) optionally substituted heterocyclic as defined in
F29 herein; AD) optionally substituted heteroaryl as defined in F27
herein; R.sup.15' is independently selected from the group
consisting of: AE) hydrogen; AF)hydroxyl; AG) alkyl as defined in A
herein; AH) substituted alkyl as defined in F herein; AI)
optionally substituted aryl as defined in F25 herein; AJ)
optionally substituted heterocyclic as defined in F29 herein; AK)
optionally substituted heteroaryl as defined in F27 herein; and the
moiety: 376is selected from the group having the formulas:
377wherein R.sup.a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted 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; 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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, caroxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; t is an integer from 0 to 4; w is an integer from 0 to 3;
or pharmaceutically-acceptable salts thereof.
125. A method for treating a human patient with Alzheimer's Disease
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 the following formula: 378wherein R.sup.1 is selected
from the group consisting of: A) alkyl of from 1 to 20 carbon
atoms; B) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of
alkenyl unsaturation; C) alkynyl of from 2 to 10 carbon atoms and
from 1-2 sites of alkynyl unsaturation; D) cycloalkyl of from 3 to
12 carbon atoms; E) cycloalkenyl of from 4 to 8 carbon atoms; F)
substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 3
substituents selected from: 1) alkoxy having the formula alkyl-O--
wherein alkyl is as defined in A herein; 2) substituted alkoxy of
the formula substituted alkyl-O-- wherein substituted alkyl is as
defined in F herein; 3) cycloalkyl as defined in D herein; 4)
substituted cycloalkyl as defined in I herein; 5) cycloalkenyl as
defined in E herein; 6) substituted cycloalkenyl as defined in J
herein; 7) acyl selected from alkyl-C(O)--, substituted
alkyl-C(O)--, cycloalkyl-C(O)--, substituted cycloalkyl-C(O)--,
optionally substituted aryl-C(O)--, optionally substituted
heteroaryl-C(O)-- and optionally substituted heterocyclic-C(O)--
wherein alkyl is defined in A herein; wherein substituted alkyl is
defined in F herein; wherein cycloalkyl is defined in D herein;
wherein substituted cycloalkyl is defined in I herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 8) acylamino having the formula --C(O)NRR wherein each R is
independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 9) acyloxy selected from alkyl-C(O)O--, substituted
alkyl-C(O)O--, cycloalkyl-C(O)O--, optionally substituted
aryl-C(O)O--, optionally substituted heteraryl-C(O)O-- and
optionally substituted heterocyclic-C(O)O-- wherein alkyl is
defined in A herein; wherein substituted alkyl is defined in F
herein; wherein cycloalkyl is defined in D herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 10) amino; 11) substituted amino having the formula
--N(R).sub.2 wherein each R is independently selected from the
group consisting of: a) hydrogen; b) alkyl as defined in A herein;
c) substituted alkyl as defined in F herein; d) alkenyl as defined
in B herein; e) substituted alkenyl as defined in G herein; f)
alkynyl as defined in C herein; g) substituted alkynyl as defined
in H herein; h) optionally substituted aryl as defined in F25
herein; i) cycloalkyl as defined in D herein; j) substituted
cycloalkyl as defined in I herein; k) optionally substituted
heteroaryl as defined in F27 herein; l) optionally substituted
heterocyclic as defined in F29 herein and wherein one of R can also
be hydrogen or R and R together with the nitrogen atom to which
they are joined form an optionally substituted heterocyclic as
defined in F29 herein; 12) aminoacyl having the formula --NRC(O)R
wherein each R is independently hydrogen, alkyl, substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heterocyclic wherein alkyl is defined in A
herein; wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 13) aminoacyloxy having the formula --NRC(O)OR wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 14) oxyacylamino having the formula --OC(O)NRR wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 15) cyano; 16) halo selected from fluoro, chloro, bromo and
iodo; 17) hydroxy; 18) carboxyl; 19) optionally substituted
carboxyalkyl having the formula --C(O)O alkyl and --C(O)O
substituted alkyl wherein alkyl is as defined in A and substituted
alkyl is as defined in F; 20) keto; 21) thioketo; 22) thiol; 23)
thioalkoxy having the formula --S-alkyl, wherein alkyl is defined
in A herein; 24) substituted thioalkoxy having the formula
--S-substituted alkyl, wherein substituted alkyl is defined in F
herein; 25) optionally substituted aryl having 6 to 14 carbon atoms
and optionally substituted with 1 to 5 substituents selected from:
a) acyloxy as defined in F9 herein; b) hydroxy; c) acyl as defined
in F7 herein; d) alkyl as defined in A herein; e) alkoxy as defined
in F1 herein; f) alkenyl as defined in B herein; g) alkynyl as
defined in C herein; h) substituted alkyl as defined in F herein;
i) substituted alkoxy as defined in F2 herein; j) substituted
alkenyl as defined in G herein; k) substituted alkynyl as defined
in H herein; l) amino; m) substituted amino as defined in F11
herein; n) aminoacyl as defined in F12 herein; o) acylamino as
defined in F8 herein; p) optionally substituted alkaryl in which
the alkyl moiety has 1 to 8 carbon atoms and the aryl has 6 to 10
carbon atoms and is optionally substituted as defined in F25
herein; q) optionally substituted aryl as defined in F25 herein; r)
optionally substituted aryloxy as defined in F26 herein; s) azido;
t) carboxyl; u) optionally substituted carboxylalkyl as defined in
F19 herein; v) cyano; w) halo as defined in F16 herein; x) nitro;
y) optionally substituted heteroaryl as defined in F27 herein; z)
optionally substituted heterocyclic as defined in F29 herein; aa)
aminoacyloxy as defined in F13 herein; bb) oxyacylamino as defined
in F14 herein; cc) thioalkoxy as defined in F23 herein; dd)
substituted thioalkoxy as defined in F24 herein; ee) optionally
substituted thioaryloxy having the formula aryl-S-- wherein aryl is
optionally substituted as defined in F25 herein; ff) optionally
substituted thioheteroaryloxy having the formula heteroaryl-S--
wherein heteroaryl is optionally substituted as defined in F27
herein; gg) --SO-alkyl wherein alkyl is as defined in A herein; hh)
--SO-substituted alkyl wherein substituted alkyl is as defined in F
herein; ii) --SO-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; jj) --SO-- optionally
substituted heteroaryl wherein optionally substituted heteroaryl is
as defined in F27 herein; kk) --SO.sub.2-- alkyl wherein alkyl is
as defined in A herein; ll) --SO.sub.2-- substituted alkyl wherein
substituted alkyl is as defined in F herein; mm)
--SO.sub.2-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; nn)
--SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; and oo)
trihalomethyl wherein halo is as defined in F16 herein; 26)
optionally substituted aryloxy having the formula aryl-O-- wherein
aryl is optionally substituted aryl as defined in F25 herein; 27)
optionally substituted heteroaryl having 1 to 15 ring carbon atoms
and 1 to 4 ring heteroatoms selected from oxygen, nitrogen and
sulfur and optionally substituted with 1 to 5 substituents selected
from the same group of substituents as defined for optionally
substituted aryl in F25 herein; 28) optionally substituted
heteroaryloxy having the formula --O-heteroaryl wherein heteroaryl
is optionally substituted heteroaryl as defined in F27 herein; 29)
optionally substituted saturated or unsaturated heterocyclic from 1
to 15 ring carbon atoms and 1 to 4 ring heteroatoms selected from
nitrogen, sulfur and oxygen and optionally substituted with 1 to 5
substituents selected from the same group of substituents as
defined for substituted alkyl in F herein; 30) optionally
substituted heterocyclooxy having the formula --O-heterocyclic
wherein heterocyclic is defined as optionally substituted
heterocyclic on F29 hereof; 31) hydroxyamino; 32) alkoxyamino
wherein alkoxy is as defined in F1; 33) nitro; 34) --SO-alkyl
wherein alkyl is as defined in A herein; 35) --SO-substituted alkyl
wherein substituted alkyl is as defined in F herein; 36)
--SO-optionally substituted aryl wherein aryl is optionally
substituted as defined in F25 herein; 37) --SO-optionally
substituted heteroaryl wherein optionally substituted heteroaryl is
as defined in F27 herein; 38) --SO.sub.2-alkyl wherein alkyl is as
defined in A herein; 39) --SO.sub.2-substituted alkyl wherein
substituted alkyl is as defined in F herein; 40)
--SO.sub.2-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; 41)
--SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; G) substituted
alkenyl having 2 to 10 carbon atoms and having of from 1 to 3
substituents selected from the group consisting of: 1) alkoxy
having the formula alkyl-O-- wherein alkyl is as defined in A
herein; 2) substituted alkoxy of the formula substituted alkyl-O--
wherein substituted alkyl is as defined in F herein; 3) cycloalkyl
as defined in D herein; 4) substituted cycloalkyl as defined in I
herein; 5) cycloalkoxy; 6) substituted cycloalkoxy; 7) acyl as
defined in F7 herein; 8) acylamino as defined in F8 herein; 9)
acyloxy as defined in F9 herein; 10) amino; 11) substituted amino
as defined in F11 herein; 12) aminoacyl as defined in F12 herein;
13) aminoacycloxy as defined in F13 herein; 14) cyano; 15) halo
selected from fluoro, cholo, bromo and iodo; 16) hydroxy; 17)
carboxyl; 18) optionally substituted carboxyalkyl having the
formula --C(O)O-alkyl and --C(O)O-substituted alkyl wherein alkyl
is a defined in A and substituted alkyl is as defined in F; 19)
keto; 20) thioketo; 21) thiol; 22) thioalkoxy as defined in F23
herein; 23) substituted thioalkoxy as defined in F24 herein; 24)
optionally substituted aryl as defined in F25 herein; 25)
optionally substituted heteroaryl as defined in F27 herein; 26)
optionally substituted saturated or unsaturated heterocyclic as
defined in F29 herein; 27) optionally substituted heterocyclooxy as
defined in F30 herein; 28) nitro; 29) --SO-alkyl wherein alkyl is
as defined in A herein; 30) --SO-substituted alkyl wherein
substituted alkyl is as defined in F herein; 31) --SO-aryl wherein
optionally substituted aryl is optionally substituted as defined in
F25 herein; 32) --SO-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F27 herein; 33)
--SO.sub.2-alkyl wherein alkyl is as defined in A herein;
--SO.sub.2-substituted alkyl wherein substituted alkyl is as
defined in F herein; 34) --SO.sub.2-optionally substituted aryl
wherein optionally substituted aryl is as defined in F25 herein;
and 35) --SO.sub.2-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F27 herein; H)
substituted alkynyl having 2 to 10 carbon atoms having 1-2 sites of
alkynyl unsaturation and having 1 to 3 substituents selected from
the same group of substituents as defined for substituted alkenyl
in G herein; I) substituted cycloalkyl having 3 to 12 carbon atoms
and having from 1 to 5 substituents selected from the same group of
substituents as defined for substituted alkyl in F herein; J)
substituted cycloalkenyl as defined in E herein having from 1 to 5
substituents selected from the same group of substituents as
defined for substituted alkyl in F herein; K) optionally
substituted aryl as defined in F25 herein; L) optionally
substituted heteroaryl as defined in F27 herein; and M) optionally
substituted heterocyclic as defined in F29 herein; R.sub.2 is
independently selected from the group consisting of: N) hydrogen;
O) alkyl as defined in A herein; P) substituted alkyl as defined in
F herein; Q) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of
alkenyl unsaturation; R) substituted alkenyl as defined in G
herein; S) alkynyl of from 2 to 10 carbon atoms and from 1-2 sites
of alkynyl unsaturation; T) substituted alkynyl as defined in H
herein; U) cycloalkyl of from 3 to 12 carbon atoms; V) optionally
substituted aryl as defined in F25 herein; W) optionally
substituted heteroaryl as defined in F27 herein; and X) optionally
substituted heterocyclic as defined in F29 herein; Q is S or O;
R.sup.15 is independently selected from the group consisting of: Y)
hydrogen, Z) alkyl as defined in A herein; AA) substituted alkyl as
defined in F herein; AB) optionally substituted aryl as defined in
F25 herein; AC) optionally substituted heterocyclic as defined in
F29 herein; AD) optionally substituted heteroaryl as defined in F27
herein; R.sup.15' is independently selected from the group
consisting of: AE) hydrogen; AF) hydroxyl; AG) alkyl as defined in
A herein; AH) substituted alkyl as defined in F herein; AI)
optionally substituted aryl as defined in F25 herein; AJ)
optionally substituted heterocyclic as defined in F29 herein; AK)
optionally substituted heteroaryl as defined in F27 herein; and the
moiety: 379is selected from the group having the formulas:
380wherein R.sup.a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted 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; 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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, caroxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; t is an integer from 0 to 4; w is an integer from 0 to 3;
or pharmaceutically-acceptable salts thereof.
126. A method for inhibiting .beta.-amyloid peptide release and/or
its synthesis in a mammalian subject thereby inhibiting onset of
diseases mediated by .beta.-amyloid peptide which method comprises
administering to said mammalian subject a pharmaceutical
composition comprising a pharmaceutically inert carrier and an
effective amount of a compound or a mixture of compounds effective
for inhibiting release and/or synthesis of .beta.-amyloid peptide,
wherein said compounds are represented by the following formula IA:
381wherein R.sup.1 is selected from the group consisting of: A)
alkyl of from 1 to 20 carbon atoms; B) alkenyl of from 2 to 10
carbon atoms and 1-2 sites of alkenyl unsaturation; C) alkynyl of
from 2 to 10 carbon atoms and from 1-2 sites of alkynyl
unsaturation; D) cycloalkyl of from 3 to 12 carbon atoms; E)
cycloalkenyl of from 4 to 8 carbon atoms; F) substituted alkyl of
from 1 to 10 carbon atoms, having from 1 to 3 substituents selected
from: 1) alkoxy having the formula alkyl-O-- wherein alkyl is as
defined in A herein; 2) substituted alkoxy of the formula
substituted alkyl-O-- wherein substituted alkyl is as defined in F
herein; 3) cycloalkyl as defined in D herein; 4) substituted
cycloalkyl as defined in I herein; 5) cycloalkenyl as defined in E
herein; 6) substituted cycloalkenyl as defined in J herein; 7) acyl
selected from alkyl-C(O)--, substituted alkyl-C(O)--,
cycloalkyl-C(O)--, substituted cycloalkyl-C(O)--, optionally
substituted aryl-C(O)--, optionally substituted heteroaryl-C(O)--
and optionally substituted heterocyclic-C(O)-- wherein alkyl is
defined in A herein; wherein substituted alkyl is defined in F
herein; wherein cycloalkyl is defined in D herein; wherein
substituted cycloalkyl is defined in I herein; wherein optionally
substituted aryl is defined in F25 herein; wherein optionally
substituted heteroaryl is defined in F27 herein; and wherein
optionally substituted heterocyclic is defined in F29 herein; 8)
acylamino having the formula --C(O)NRR wherein each R is
independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 9) acyloxy selected from alkyl-C(O)O--, substituted
alkyl-C(O)O--, cycloalkyl-C(O)O--, optionally substituted
aryl-C(O)O--, optionally substituted heteraryl-C(O)O-- and
optionally substituted heterocyclic-C(O)O-- wherein alkyl is
defined in A herein; wherein substituted alkyl is defined in F
herein; wherein cycloalkyl is defined in D herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 10) amino; 11) substituted amino having the formula
--N(R).sub.2 wherein each R is independently selected from the
group consisting of: a) hydrogen; b) alkyl as defined in A herein;
c) substituted alkyl as defined in F herein; d) alkenyl as defined
in B herein; e) substituted alkenyl as defined in G herein; f)
alkynyl as defined in C herein; g) substituted alkynyl as defined
in H herein; h) optionally substituted aryl as defined in F25
herein; i) cycloalkyl as defined in D herein; j) substituted
cycloalkyl as defined in I herein; k) optionally substituted
heteroaryl as defined in F27 herein; l) optionally substituted
heterocyclic as defined in F29 herein and wherein one of R can also
be hydrogen or R and R together with the nitrogen atom to which
they are joined form an optionally substituted heterocyclic as
defined in F29 herein; 12) aminoacyl having the formula --NRC(O)R
wherein each R is independently hydrogen, alkyl, substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heterocyclic wherein alkyl is defined in A
herein; wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 13) aminoacyloxy having the formula --NRC(O)OR wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 14) oxyacylamino having the formula --OC(O)NRR wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 15) cyano; 16) halo selected from fluoro, chloro, bromo and
iodo; 17) hydroxy; 18) carboxyl; 19) optionally substituted
carboxyalkyl having the formula --C(O)O alkyl and --C(O)O
substituted alkyl wherein alkyl is as defined in A and substituted
alkyl is as defined in F; 20) keto; 21) thioketo; 22) thiol; 23)
thioalkoxy having the formula --S-alkyl, wherein alkyl is defined
in A herein; 24) substituted thioalkoxy having the formula
--S-substituted alkyl, wherein substituted alkyl is defined in F
herein; 25) optionally substituted aryl having 6 to 14 carbon atoms
and optionally substituted with 1 to 5 substituents selected from:
a) acyloxy as defined in F9 herein; b) hydroxy; c) acyl as defined
in F7 herein; d) alkyl as defined in A herein; e) alkoxy as defined
in F1 herein; f) alkenyl as defined in B herein; g) alkynyl as
defined in C herein; h) substituted alkyl as defined in F herein;
i) substituted alkoxy as defined in F2 herein; j) substituted
alkenyl as defined in G herein; k) substituted alkynyl as defined
in H herein; l) amino; m) substituted amino as defined in F11
herein; n) aminoacyl as defined in F12 herein; o) acylamino as
defined in F8 herein; p) optionally substituted alkaryl in which
the alkyl moiety has 1 to 8 carbon atoms and the aryl has 6 to 10
carbon atoms and is optionally substituted as defined in F25
herein; q) optionally substituted aryl as defined in F25 herein; r)
optionally substituted aryloxy as defined in F26 herein; s) azido;
t) carboxyl; u) optionally substituted carboxylalkyl as defined in
F19 herein; v) cyano; w) halo as defined in F16 herein; x) nitro;
y) optionally substituted heteroaryl as defined in F27 herein; z)
optionally substituted heterocyclic as defined in F29 herein; aa)
aminoacyloxy as defined in F13 herein; bb) oxyacylamino as defined
in F14 herein; cc) thioalkoxy as defined in F23 herein; dd)
substituted thioalkoxy as defined in F24 herein; ee) optionally
substituted thioaryloxy having the formula aryl-S-wherein aryl is
optionally substituted as defined in F25 herein; ff) optionally
substituted thioheteroaryloxy having the formula heteroaryl-S--
wherein heteroaryl is optionally substituted as defined in F27
herein; gg) --SO-alkyl wherein alkyl is as defined in A herein; hh)
--SO-substituted alkyl wherein substituted alkyl is as defined in F
herein; ii) --SO-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; jj) --SO-- optionally
substituted heteroaryl wherein optionally substituted heteroaryl is
as defined in F27 herein; kk) --SO.sub.2-- alkyl wherein alkyl is
as defined in A herein; ll) --SO.sub.2-- substituted alkyl wherein
substituted alkyl is as defined in F herein; mm)
--SO.sub.2-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; nn)
--SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; and oo)
trihalomethyl wherein halo is as defined in F16 herein; 26)
optionally substituted aryloxy having the formula aryl-O-- wherein
aryl is optionally substituted aryl as defined in F25 herein; 27)
optionally substituted heteroaryl having 1 to 15 ring carbon atoms
and 1 to 4 ring heteroatoms selected from oxygen, nitrogen and
sulfur and optionally substituted with 1 to 5 substituents selected
from the same group of substituents as defined for optionally
substituted aryl in F25 herein; 28) optionally substituted
heteroaryloxy having the formula --O-heteroaryl wherein heteroaryl
is optionally substituted heteroaryl as defined in F27 herein; 29)
optionally substituted saturated or unsaturated heterocyclic from 1
to 15 ring carbon atoms and 1 to 4 ring heteroatoms selected from
nitrogen, sulfur and oxygen and optionally substituted with 1 to 5
substituents selected from the same group of substituents as
defined for substituted alkyl in F herein; 30) optionally
substituted heterocyclooxy having the formula --O-heterocyclic
wherein heterocyclic is defined as optionally substituted
heterocyclic on F29 hereof; 31) hydroxyamino; 32) alkoxyamino
wherein alkoxy is as defined in F1; 33) nitro; 34) --SO-alkyl
wherein alkyl is as defined in A herein; 35) --SO-substituted alkyl
wherein substituted alkyl is as defined in F herein; 36)
--SO-optionally substituted aryl wherein aryl is optionally
substituted as defined in F25 herein; 37) --SO-optionally
substituted heteroaryl wherein optionally substituted heteroaryl is
as defined in F27 herein; 38) --SO.sub.2-alkyl wherein alkyl is as
defined in A herein; 39) --SO.sub.2-substituted alkyl wherein
substituted alkyl is as defined in F herein; 40)
--SO.sub.2-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; 41)
--SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; G) substituted
alkenyl having 2 to 10 carbon atoms and having of from 1 to 3
substituents selected from the group consisting of: 1) alkoxy
having the formula alkyl-O-- wherein alkyl is as defined in A
herein; 2) substituted alkoxy of the formula substituted alkyl-O--
wherein substituted alkyl is as defined in F herein; 3) cycloalkyl
as defined in D herein; 4) substituted cycloalkyl as defined in I
herein; 5) cycloalkoxy; 6) substituted cycloalkoxy; 7) acyl as
defined in F7 herein; 8) acylamino as defined in F8 herein; 9)
acyloxy as defined in F9 herein; 10) amino; 11) substituted amino
as defined in F11 herein; 12) aminoacyl as defined in F12 herein;
13) aminoacycloxy as defined in F13 herein; 14) cyano; 15) halo
selected from fluoro, cholo, bromo and iodo; 16) hydroxy; 17)
carboxyl; 18) optionally substituted carboxyalkyl having the
formula --C(O)O-alkyl and --C(O)O-substituted alkyl wherein alkyl
is a defined in A and substituted alkyl is as defined in F; 19)
keto; 20) thioketo; 21) thiol; 22) thioalkoxy as defined in F23
herein; 23) substituted thioalkoxy as defined in F24 herein; 24)
optionally substituted aryl as defined in F25 herein; 25)
optionally substituted heteroaryl as defined in F27 herein; 26)
optionally substituted saturated or unsaturated heterocyclic as
defined in F29 herein; 27) optionally substituted heterocyclooxy as
defined in F30 herein; 28) nitro; 29) --SO-alkyl wherein alkyl is
as defined in A herein; 30) --SO-substituted alkyl wherein
substituted alkyl is as defined in F herein; 31) --SO-aryl wherein
optionally substituted aryl is optionally substituted as defined in
F25 herein; 32) --SO-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F27 herein; 33)
--SO.sub.2-alkyl wherein alkyl is as defined in A herein;
--SO.sub.2-substituted alkyl wherein substituted alkyl is as
defined in F herein; 34) --SO.sub.2-optionally substituted aryl
wherein optionally substituted aryl is as defined in F25 herein;
and 36) --SO.sub.2-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F27 herein; H)
substituted alkynyl having 2 to 10 carbon atoms having 1-2 sites of
alkynyl unsaturation and having 1 to 3 substituents selected from
the same group of substituents as defined for substituted alkenyl
in G herein; I) substituted cycloalkyl having 3 to 12 carbon atoms
and having from 1 to 5 substituents selected from the same group of
substituents as defined for substituted alkyl in F herein; J)
substituted cycloalkenyl as defined in E herein having from 1 to 5
substituents selected from the same group of substituents as
defined for substituted alkyl in F herein; K) optionally
substituted aryl as defined in F25 herein; L) optionally
substituted heteroaryl as defined in F27 herein; and M) optionally
substituted heterocyclic as defined in F29 herein; R.sub.2 is
independently selected from the group consisting of: N) hydrogen;
O) alkyl as defined in A herein; P) substituted alkyl as defined in
F herein; Q) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of
alkenyl unsaturation; R) substituted alkenyl as defined in G
herein; S) alkynyl of from 2 to 10 carbon atoms and from 1-2 sites
of alkynyl unsaturation; T) substituted alkynyl as defined in H
herein; U) cycloalkyl of from 3 to 12 carbon atoms; V) optionally
substituted aryl as defined in F25 herein; W) optionally
substituted heteroaryl as defined in F27 herein; and X) optionally
substituted heterocyclic as defined in F29 herein; Q is S or O;
R.sup.15 is independently selected from the group consisting of: Y)
hydrogen, Z) alkyl as defined in A herein; AA) substituted alkyl as
defined in F herein; AB) optionally substituted aryl as defined in
F25 herein; AC) optionally substituted heterocyclic as defined in
F29 herein; AD) optionally substituted heteroaryl as defined in F27
herein; R.sup.15' is independently selected from the group
consisting of: AE) hydrogen; AF) hydroxyl; AG) alkyl as defined in
A herein; AH) substituted alkyl as defined in F herein; AI)
optionally substituted aryl as defined in F25 herein; AJ)
optionally substituted heterocyclic as defined in F29 herein; AK)
optionally substituted heteroaryl as defined in F27 herein; and the
moiety: 382is selected from the group having the formulas:
383wherein R.sup.a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted 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; 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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, caroxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; t is an integer from 0 to 4; w is an integer from 0 to 3;
or pharmaceutically-acceptable salts thereof.
127. The method according to claim 124, 125, or 126, wherein
R.sup.1 is aryl or optionally substituted heteroaryl.
128. The method according to claim 127, wherein R.sup.1 is selected
from the group consisting of: (a) alkyl; (b) phenyl; (c) a
substituted phenyl group of the formula: 384wherein R.sup.c is
selected from the group consisting of alkyl, substituted alkyl,
alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic,
thioalkoxy, substituted amino, cycloalkyl, and substituted
cycloalkyl; 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; and 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,
(d) 2-naphthyl, (e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or
8 positions with 1 to 5 substituents selected from the group
consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl,
thioalkoxy, aryl, and heteroaryl, (f) heteroaryl, and (g)
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.
129. The method according to claim 127, wherein R.sup.1 is selected
from the group consisting of mono-, di-, and tri-substituted phenyl
groups.
130. The method according to claim 129, 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-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and
3,4-methylenedioxyphenyl.
131. The method according to claim 129, 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.
132. The method according to claim 129, wherein R.sup.1 is a
trisubstituted phenyl selected from the group consisting of
3,4,5-trifluorophenyl, and 3,4,5-tricholorophenyl.
133. The method according to claim 127, wherein R.sup.1 is selected
from the group consisting of 2-naphthyl, quinolin-3-yl,
2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and
phenyl.
134. The method according to claim 124, 125, or 126, 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-trifluoromethyl phenyl, 4-hydroxymethyl phenyl, 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-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl,
(CH.sub.3).sub.2CH.dbd.CHCH.sub.2CH.sub.2CH(CH.sub.3- )--,
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, (phenyl).sub.2CHNHC(O)CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2NC(O)CH.sub.2--- ,
(phenyl).sub.2CHNHC(O)CH.sub.2CH.sub.2--, ethylcarbonylmethyl,
(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(phenyl)-, 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,
phenyl-C(O)NHCH(phenyl)CH.sub.2--, mesityl,
CH.sub.3CH(.dbd.NHOH)CH.sub.2- --,
4-CH.sub.3-phenyl-NHC(O)CH.sub.2CH.sub.2--,
C(O)CH(phenyl)CH.sub.2--, (CH.sub.3).sub.2CHC(O)NHCH(phenyl)-,
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, SO.sub.2CH.sub.2--,
3-cyclohexyl-n-propyl, CF.sub.3CH.sub.2CH.sub.2CH.sub.2-- and
N-pyrrolidinyl.
135. The method according to claim 124, 125, or 126, wherein
R.sub.2 is independently selected from the group consisting of
alkyl, substituted alkyl, alkenyl, cycloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, and optionally
substituted heterocyclic.
136. The method according to claim 135, wherein R.sub.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(C.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.4N
H-Boc, --(CH.sub.2).sub.4N H.sub.2, --CH.sub.2-pyridyl, pyridyl,
--CH.sub.2-naphthyl, --CH.sub.2--(N-morpholi- no),
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, and
thien-3-yl.
137. The method according to claim 124, 125, or 126, wherein the
--C(H).sub.pWC(O) moiety is: 385wherein R.sup.a, R.sup.b, V, and t
are defined as in claim 124, 125, or 126.
138. The method according to claim 124, 125 or 126, wherein the
--C(H).sub.pWC(O) moiety is: 386wherein R.sup.a, R.sup.b, V and t
are defined as in claim 124, 125, or 126.
139. The method according to claim 124, 125, or 126, wherein the
--C(H).sub.pWC(O) moiety is: 387wherein R.sup.a, R.sup.b, and w are
defined as in claims 124, 125, or 126.
140. A pharmaceutical composition comprising a
pharmaceutically-inert carrier and a pharmaceutically-effective
amount of a compound of formula IA: 388wherein R.sup.1 is selected
from the group consisting of: A) alkyl of from 1 to 20 carbon
atoms; B) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of
alkenyl unsaturation; C) alkynyl of from 2 to 10 carbon atoms and
from 1-2 sites of alkynyl unsaturation; D) cycloalkyl of from 3 to
12 carbon atoms; E) cycloalkenyl of from 4 to 12 carbon atoms; F)
substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 3
substituents selected from: 1) alkoxy having the formula alkyl-O--
wherein alkyl is as defined in A herein; 2) substituted alkoxy of
the formula substituted alkyl-O-- wherein substituted alkyl is as
defined in F herein; 3) cycloalkyl as defined in D herein; 4)
substituted cycloalkyl as defined in I herein; 5) cycloalkenyl as
defined in E herein; 6) substituted cycloalkenyl as defined in J
herein; 7) acyl having a formula selected from the group consisting
of alkyl-C(O)--, substituted alkyl-C(O)--, cycloalkyl-C(O)--,
substituted cycloalkyl-C(O)--, optionally substituted aryl-C(O)--,
optionally substituted heteroaryl-C(O)-- and optionally substituted
heterocyclic-C(O)-- wherein alkyl is defined in A herein; wherein
substituted alkyl is defined in F herein; wherein cycloalkyl is
defined in D herein; wherein substituted cycloalkyl is defined in I
herein; wherein optionally substituted aryl is defined in F25
herein; wherein optionally substituted heteroaryl is defined in F27
herein; and wherein optionally substituted heterocyclic is defined
in F29 herein; 8) acylamino having the formula --C(O)NRR wherein
each R is independently hydrogen, alkyl, substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heterocyclic wherein alkyl is defined in A
herein; wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 9) acyloxy having a formula selected from the group
consisting of alkyl-C(O)O--, substituted alkyl-C(O)O--,
cycloalkyl-C(O)O--, optionally substituted aryl-C(O)O--, optionally
substituted heteraryl-C(O)O-- and optionally substituted
heterocyclic-C(O)O-- wherein alkyl is defined in A herein; wherein
substituted alkyl is defined in F herein; wherein cycloalkyl is
defined in D herein; wherein optionally substituted aryl is defined
in F25 herein; wherein optionally substituted heteroaryl is defined
in F27 herein; and wherein optionally substituted heterocyclic is
defined in F29 herein; 10) amino; 11) substituted amino having the
formula --N(R).sub.2 wherein each R is independently selected from
the group consisting of: a) hydrogen; b) alkyl as defined in A
herein; c) substituted alkyl as defined in F herein; d) alkenyl as
defined in B herein; e) substituted alkenyl as defined in G herein;
f) alkynyl as defined in C herein; g) substituted alkynyl as
defined in H herein; h) optionally substituted aryl as defined in
F25 herein; i) cycloalkyl as defined in D herein; j) substituted
cycloalkyl as defined in I herein; k) optionally substituted
heteroaryl as defined in F27 herein; and l) optionally substituted
heterocyclic as defined in F29 wherein; wherein both R groups may
be joined together to form a heterocyclic group as defined in F29
herein; and 12) aminoacyl having the formula --NRC(O)R wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted erocyclic wherein alkyl is defined in A herein; wherein
substituted alkyl is fined in F herein; wherein optionally
substituted aryl is defined in F25 rein; wherein optionally
substituted heteroaryl is defined in F27 herein; and wherein
optionally substituted heterocyclic is defined in F29 herein; 13)
aminoacyloxy having the formula --NRC(O)OR wherein each R is
independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted erocyclic wherein alkyl is defined in A herein; wherein
substituted alkyl is fined in F herein; wherein optionally
substituted aryl is defined in F25 rein; wherein optionally
substituted heteroaryl is defined in F27 herein; and wherein
optionally substituted heterocyclic is defined in F29 herein; 14)
oxyacylamino having the formula --OC(O)NRR wherein each R is
independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; 15) cyano; 16) halo selected from fluoro, chloro, bromo and
iodo; 17) hydroxyl; 18) keto; 19) thioketo; 20) carboxyl; 21)
optionally substituted carboxyalkyl having the formula
--C(O)O-alkyl and --C(O)O-substituted alkyl wherein alkyl is as
defined in A and substituted alkyl is as defined in F; 22) thiol;
23) thioalkoxy having the formula --S-alkyl, wherein alkyl is
defined in A herein; 24) substituted thioalkoxy having the formula
--S-substituted alkyl, wherein substituted alkyl is defined in F
herein; 25) optionally substituted aryl having 6 to 14 carbon atoms
and optionally substituted with 1 to 5 substituents selected from:
a) acyloxy; b) hydroxy; c) acyl as defined in F7 herein; d) alkyl
as defined in A herein; e) alkoxy as defined in F1 herein; f)
alkenyl as defined in B herein; g) alkynyl as defined in C herein;
h) substituted alkyl as defined in F herein; i) substituted alkoxy
as defined in F2 herein; j) substituted alkenyl as defined in G
herein; k) substituted alkynyl as defined in H herein; l) amino; m)
substituted amino as defined in F11 herein; n) aminoacyl as defined
in F12 herein; o) acylamino as defined in F8 herein; p) optionally
substituted alkaryl of the formula -alkylene-aryl where alkylene
has from 1 to 10 carbon atoms and is optionally substituted with
from 1 to 3 substituents selected from the group consisting of: 1)
alkoxy as defined in F1 herein; 2) substituted alkoxy as defined in
F2 herein; 3) acyl as defined in F7 herein; 4) acylamino as defined
in F8 herein; 5) acyloxy as defined in F9 herein; 6) amino; 7)
substituted amino as defined in F11 herein; 8) aminoacyl as defined
in F12 herein; 9) aminoacyloxy as defined in F13 herein; 10)
oxyacylamino as defined in F14 herein; 11) cyano; 12) halogen
selected from fluoro, chloro, bromo and iodo; 13) hydroxyl; 14)
keto; 15) thioketo; 16) carboxyl; 17) optionally substituted
carboxyalkyl as defined in F21; 18) thiol; 19) thioalkoxy as
defined in F23 herein; 20) substituted thioalkoxy as defined in F24
herein; 21) optionally substituted aryl as defined in F25 herein;
22) optionally substituted heteroaryl as defined in F27 herein; 23)
optionally substituted saturated or unsaturated heterocyclic as
defined in F29 herein; 24) heterocyclooxy as defined in G24 herein;
25) nitro; 26) mono- and di-alkylamino as defined in F41 herein;
27) mono- and di-(substituted alkyl) amino as defined in F42
herein; 28) mono- and di-arylamino as defined in F43 herein; 29)
mono- and di-heteroarylamino as defined in F44 herein; 30) mono-
and di-heterocyclic amino as defined in F45 herein; and 31)
unsymmetric di-substituted amines as defined in F46 herein; q)
optionally substituted aryl as defined in F25 herein; r) optionally
substituted aryloxy as defined in F26 herein; s) azido; t)
carboxyl; u) optionally substituted carboxylalkyl as defined in F21
herein; v) cyano; w) halo as defined in F16 herein; x) nitro; y)
optionally substituted heteroaryl as defined in F27 herein; z)
optionally substituted heteroaryloxy as defined in F28 herein aa)
optionally substituted heterocyclic as defined in F29 herein; bb)
optionally substituted heterocyclooxy as defined in G24 herein; cc)
aminoacyloxy as defined in F13 herein; dd) oxyacylamino as defined
in F14 herein; ee) thioalkoxy as defined in F23 herein; ff)
substituted thioalkoxy as defined in F24 herein; gg) optionally
substituted thioaryloxy having the formula aryl-S-- wherein aryl is
optionally substituted as defined in F25 herein; hh) optionally
substituted thioheteroaryloxy having the formula heteroaryl-S--
wherein heteroaryl is optionally substituted as defined in F27
herein; ii) --SO-alkyl wherein alkyl is as defined in A herein; jj)
--SO-substituted alkyl wherein substituted alkyl is as defined in F
herein; kk) --SO-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; ll) --SO-optionally
substituted heteroaryl wherein optionally substituted heteroaryl is
as defined in F27 herein; mm) --SO.sub.2-alkyl wherein alkyl is as
defined in A herein; nn) --SO.sub.2-substituted alkyl wherein
substituted alkyl is as defined in F herein; oo)
--SO.sub.2-optionally substituted aryl wherein optionally
substituted aryl is as defined in F25 herein; pp)
--SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; and qq)
trihalomethyl wherein halo is as defined in F16 herein; 26)
optionally substituted aryloxy having the formula aryl-O-- wherein
aryl is optionally substituted aryl as defined in F25 herein; 27)
optionally substituted heteroaryl having 1 to 15 ring carbon atoms
and 1 to 4 ring heteroatoms selected from oxygen, nitrogen and
sulfur and optionally substituted with 1 to 5 substituents selected
from the group of substituents as defined in F25 herein 28)
optionally substituted heteroaryloxy having the formula
--O-heteroaryl wherein heteroaryl is optionally substituted
heteroaryl as defined in F27 herein; 29) optionally substituted
saturated or unsaturated heterocyclic having from 1 to 15 ring
carbon atoms and from 1 to 4 ring heteroatoms selected from
nitrogen, sulfur and oxygen and optionally substituted with 1 to 5
substituents selected from the group of substituents consisting of
alkyl as defined in A herein; substituted alkyl as defined in F
herein; alkoxy as defined in F1 herein; substituted alkoxy as
defined in F2 herein; aryl as defined in F25 herein; aryloxy; halo
as defined in F16 herein; nitro; heteroaryl as defined in F27
herein; thio; thioalkoxy as defined in F23 herein; substituted
thioalkoxy as defined in F24 herein; thioaryloxy wherein aryloxy is
as defined in F26 herein; and trihalomethyl wherein halo is as
defined in F16 herein; 30) hydroxyamino; 31) alkoxyamino wherein
alkoxy is as defined in F1; 32) nitro; 33) --SO-alkyl wherein alkyl
is as defined in A herein; 34) --SO-substituted alkyl wherein
substituted alkyl is as defined in F herein; 35) --SO-optionally
substituted aryl wherein aryl is optionally substituted as defined
in F25 herein; 36) --SO-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F27 herein; 37)
--SO.sub.2-alkyl wherein alkyl is as defined in A herein; 38)
--SO.sub.2-substituted alkyl wherein substituted alkyl is as
defined in F herein; 39) --SO.sub.2-optionally substituted aryl
wherein optionally substituted aryl is as defined in F25 herein;
40) --SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; 41) mono- and
di-alkylamino wherein alkyl is as defined in A herein; 42) mono-
and di-(substituted alkyl) amino wherein substituted alkyl is as
defined in F herein; 43) mono- and di-arylamino wherein aryl is as
defined in F25 herein; 44) mono- and di-heteroarylamino wherein
heteroaryl is as defined in F27 herein; 45) mono- and
di-heterocyclic amino wherein heterocyclic is as defined in F29
herein; and 46) unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl and optionally
substituted heterocyclic, wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F25 herein; wherein
optionally substituted heteroaryl is defined in F27 herein; and
wherein optionally substituted heterocyclic is defined in F29
herein; G) substituted alkenyl having 2 to 10 carbon atoms and
having of from 1 to 3 substituents selected from the group
consisting of: 1) alkoxy having the formula alkyl-O-- wherein alkyl
is as defined in A herein; 2) substituted alkoxy of the formula
substituted alkyl-O-- wherein substituted alkyl is as defined in F
herein; 3) acyl as defined in F7 herein; 4) acylamino as defined in
F8 herein; 5) acyloxy as defined in F9 herein; 6) amino; 7)
substituted amino as defined in F11 herein; 8) aminoacyl as defined
in F12 herein; 9) aminoacycloxy as defined in F13 herein; 10)
oxyacylamino as defined in F14 herein; 11) cyano; 12) halo selected
from fluoro, cholo, bromo and iodo; 13) hydroxyl; 14) keto; 15)
thioketo; 16) carboxyl; 17) optionally substituted carboxyalkyl
having the formula --C(O)O-alkyl and --C(O)O-substituted alkyl
wherein alkyl is as defined in A and substituted alkyl is as
defined in F; 18) thiol; 19) thioalkoxy as defined in F23 herein;
20) substituted thioalkoxy as defined in F24 herein; 21) optionally
substituted aryl as defined in F25 herein; 22) optionally
substituted heteroaryl as defined in F27 herein; 23) optionally
substituted saturated or unsaturated heterocyclic as defined in F29
herein; 24) optionally substituted heterocyclooxy having the
formula --O-heterocyclic wherein heterocyclic is as defined in F29
herein; 25) nitro; 26) --SO-alkyl wherein alkyl is as defined in A
herein; 27) --SO-substituted alkyl wherein substituted alkyl is as
defined in F herein; 28) --SO-aryl wherein optionally substituted
aryl is optionally substituted as defined in F25 herein; 29)
--SO-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F27 herein; 30)
--SO.sub.2-alkyl wherein alkyl is as defined in A herein; 31)
--SO.sub.2-substituted alkyl wherein substituted alkyl is as
defined in F herein; 32) --SO.sub.2-optionally substituted aryl
wherein optionally substituted aryl is as defined in F25 herein;
and 33) --SO.sub.2-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F27 herein; 34)
mono- and di-alkylamino as defined in F41 herein; 35) mono- and
di-(substituted alkyl) amino as defined in F42 herein; 36) mono-
and di-arylamino as defined in F43 herein; 37) mono- and
di-heteroarylamino as defined in F44 herein; 38) mono- and
di-heterocyclic amino as defined in F45 herein; and 39) unsymmetric
di-substituted amines having different substituents selected from
alkyl, substituted alkyl, optionally substituted aryl, optionally
substituted heteroaryl and optionally substituted heterocyclic; H)
substituted alkynyl having 2 to 10 carbon atoms having 1-2 sites of
alkynyl unsaturation and having 1 to 3 substituents selected from
the group consisting of: 1) alkoxy as defined in F1 herein; 2)
substituted alkoxy as defined in F2 herein; 3) acyl as defined in
F7 herein; 4) acylamino as defined in F8 herein; 5) acyloxy as
defined in F9 herein; 6) amino; 7) substituted amino as defined in
F11 herein; 8) aminoacyl as defined in F12 herein; 9) aminoacyloxy
as defined in F13 herein; 10) oxyacylamino as defined in F14
herein, 11) cyano; 12) halogen as defined in F16 herein; 13)
hydroxyl; 14) keto; 15) thioketo; 16) carboxyl; 17) carboxylalkyl
as defined in F21 herein; 18) thiol; 19) thioalkoxy as defined in
F23 herein; 20) substituted thioalkoxy as defined in F24 herein;
21) aryl as defined in F25 herein; 22) heteroaryl as defined in F27
herein; 23) heterocyclic as defined in F29 herein; 24)
heterocyclooxy as defined in G24 herein; 25) nitro; 26) --SO-alkyl
as defined in F33 herein; 27) --SO-substituted alkyl as defined in
F34 herein; 28) --SO-aryl as defined in F35 herein; 29)
--SO-heteroaryl as defined in F36 herein; 30) --SO.sub.2-alkyl as
defined in F37 herein; 31) --SO.sub.2-substituted alkyl as defined
in F38 herein; 32) --SO.sub.2-aryl as defined in F39 herein; 33)
--SO.sub.2-heteroaryl as defined in F40 herein; 34) mono- and
di-alkylamino as defined in F41 herein; 35) mono- and
di-(substituted alkyl) amino as defined in F42 herein; 36) mono-
and di-arylamino as defined in F43 herein; 37) mono- and
di-heteroarylamino as defined in F44 herein; 38) mono- and
di-heterocyclic amino as defined in F45 herein; and 39) unsymmetric
di-substituted amines as defined in F46 herein; I) substituted
cycloalkyl having 3 to 12 carbon atoms and having from 1 to 5
substituents selected from the group of substituents consisting of:
1) hydroxy; 2) acyl as defined in F7 herein; 3) acyloxy as defined
in F9 herein; 4) alkyl as defined in A herein; 5) substituted alkyl
as defined in F herein; 6) alkoxy as defined in F1 herein; 7)
substituted alkoxy as defined in F2 herein; 8) alkenyl as defined
in B herein; 9) substituted alkenyl as defined in G herein; 10)
alkynyl as defined in C herein; 11) substituted alkynyl as defined
in H herein, 12) amino; 13) substituted amino as defined in F11
herein; 14) aminoacyl as defined in F12 herein; 15) alkaryl as
defined in F25(p) herein; 16) aryl as defined in F25 herein; 17)
aryloxy as defined in F26 herein; 18) carboxyl; 19) carboxylalkyl
as defined in F21 herein; 20) cyano; 21) halo as defined in F16
herein; 22)
nitro; 23) heteroaryl as defined in F27 herein; 24) thioalkoxy as
defined in F23 herein; 25) substituted thioalkoxy as defined in F24
herein; and 26) trihalomethyl; J) substituted cycloalkenyl as
defined in E herein having from 1 to 5 substituents selected from
the group of consisting of: 1) hydroxy; 2) acyl as defined in F7
herein; 3) acyloxy as defined in F9 herein; 4) alkyl as defined in
A herein; 5) substituted alkyl as defined in F herein; 6) alkoxy as
defined in F1 herein; 7) substituted alkoxy as defined in F2
herein; 8) alkenyl as defined in B herein; 9) substituted alkenyl
as defined in G herein; 10) alkynyl as defined in C herein; 11)
substituted alkynyl as defined in H herein; 12) amino; 13)
substituted amino as defined in F11 herein; 14) aminoacyl as
defined in F12 herein; 15) alkaryl as defined in F25(p) herein; 16)
aryl as defined in F25 herein; 17) aryloxy as defined in F26
herein; 18) carboxyl; 19) carboxylalkyl as defined in F21 herein;
20) cyano; 21) halo as defined in F16 herein; 22) nitro; 23)
heteroaryl as defined in F27 herein; 24) thioalkoxy as defined in
F23 herein; 25) substituted thioalkoxy as defined in F24 herein;
and 26) trihalomethyl; K) optionally substituted aryl as defined in
F25 herein; L) optionally substituted heteroaryl as defined in F27
herein; and M) optionally substituted heterocyclic as defined in
F29 herein; R.sub.2 is independently selected from the group
consisting of: N) hydrogen; O) alkyl as defined in A herein; P)
substituted alkyl as defined in F herein; Q) alkenyl of from 2 to
10 carbon atoms and 1-2 sites of alkenyl unsaturation; R)
substituted alkenyl as defined in G herein; S) alkynyl of from 2 to
10 carbon atoms and from 1-2 sites of alkynyl unsaturation; T)
substituted alkynyl as defined in H herein; U) cycloalkyl of from 3
to 12 carbon atoms; V) optionally substituted aryl as defined in
F25 herein; W) optionally substituted heteroaryl as defined in F27
herein; and X) optionally substituted heterocyclic as defined in
F29 herein; Q is S or O; R.sup.15 is independently selected from
the group consisting of: Y) hydrogen, Z) alkyl as defined in A
herein; AA) substituted alkyl as defined in F herein; AB)
optionally substituted aryl as defined in F25 herein; AC)
optionally substituted heterocyclic as defined in F29 herein; AD)
optionally substituted heteroaryl as defined in F27 herein;
R.sup.15' is independently selected from the group consisting of:
AE) hydrogen; AF) hydroxyl; AG) alkyl as defined in A herein; AH)
substituted alkyl as defined in F herein; AI) optionally
substituted aryl as defined in F25 herein; AJ) optionally
substituted heterocyclic as defined in F29 herein; AK) optionally
substituted heteroaryl as defined in F27 herein; and the moiety:
389is selected from the group having the formulas: 390wherein
R.sup.a is independently selected from the group consisting of
alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,
substituted 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; 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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, caroxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; t is an integer from 0 to 4; w is an integer from 0 to 3;
or pharmaceutically-acceptable salts thereof.
141. The pharmaceutical composition according to claim 140, wherein
the moiety 391wherein R.sup.a and R.sup.b, V, and t are defined as
in claim 140.
142. The pharmaceutical composition according to claim 140, wherein
the moiety 392wherein R.sup.a, R.sup.b, V and t are defined as in
claim 140.
143. The pharmaceutical composition according to claim 140, wherein
the moiety 393wherein R.sup.a, R.sup.b, and w are defined as in
claim 140.
144. The pharmaceutical composition according to claim 140, wherein
R.sup.1 is aryl or optionally substituted aryl.
145. The pharmaceutical composition according to claim 144, wherein
R.sup.1 is selected from the group consisting of: (a) alkyl; (b)
phenyl; (c) a substituted phenyl group of the formula: 394wherein
R.sup.c is selected from the group consisting of alkyl, substituted
alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,
heterocyclic, thioalkoxy, substituted amino, cycloalkyl, and
substituted cycloalkyl; 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; and 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, (d) 2-naphthyl, (e) 2-naphthyl substituted at the 4, 5,
6, 7 and/or 8 positions with 1 to 5 substituents selected from the
group consisting of alkyl, alkoxy, halo, cyano, nitro,
trihalomethyl, thioalkoxy, aryl, and heteroaryl, (f) heteroaryl,
and (g) 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.
146. The pharmaceutical composition according to claim 144, wherein
R.sup.1 is selected from the group consisting of mono-, di-, and
tri-substituted phenyl groups.
147. The pharmaceutical composition according to claim 146, 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-chloropheny- l,
3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and
3,4-methylenedioxyphenyl.
148. The pharmaceutical composition according to claim 146, 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.
149. The pharmaceutical composition according to claim 146, wherein
R.sup.1 is a trisubstituted phenyl selected from the group
consisting of 3,4,5-trifluorophenyl, and
3,4,5-tricholorophenyl.
150. The pharmaceutical composition according to claim 144, wherein
R.sup.1 is selected from the group consisting of 2-naphthyl,
quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl,
and phenyl.
151. The pharmaceutical composition according to claim 140, 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-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl,
(CH.sub.3).sub.2CH.dbd.CHCH.sub.2CH.sub.2CH(CH.sub.3- )--,
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, (phenyl).sub.2CHNHC(O)CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2NC(O)CH.sub.2--- ,
(phenyl).sub.2CHNHC(O)CH.sub.2CH.sub.2--, ethylcarbonylmethyl,
(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(phenyl)-, 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,
phenyl-C(O)NHCH(phenyl)CH.sub.2--, mesityl,
CH.sub.3CH(.dbd.NHOH)CH.sub.2- --,
4-CH.sub.3-phenyl-NHC(O)CH.sub.2CH.sub.2--,
C(O)CH(phenyl)CH.sub.2--, (CH.sub.3).sub.2CHC(O)NHCH(phenyl)-,
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, SO.sub.2CH.sub.2--,
3-cyclohexyl-n-propyl, CF.sub.3CH.sub.2CH.sub.2CH.sub.2-- and
N-pyrrolidinyl.
152. The pharmaceutical composition according to claim 140, wherein
R.sub.2 is independently selected from the group consisting of
alkyl, substituted alkyl, alkenyl, cycloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, and optionally
substituted heterocyclic.
153. The pharmaceutical composition according to claim 152, wherein
R.sub.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(C.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-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.4N
H-Boc, --(CH.sub.2).sub.4NH.sub.2, --CH.sub.2-pyridyl, pyridyl,
--CH.sub.2-naphthyl, --CH.sub.2--(N-morpholi- no),
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, and
thien-3-yl.
154. A compound of formula 1A: 395wherein R.sup.1 is selected from
the group consisting of: A) alkyl of from 1 to 20 carbon atoms; B)
alkenyl of from 2 to 10 carbon atoms and 1-2 sites of alkenyl
unsaturation; C) alkynyl of from 2 to 10 carbon atoms and from 1-2
sites of alkynyl unsaturation; D) cycloalkyl of from 3 to 12 carbon
atoms; E) cycloalkenyl of from 4 to 12 carbon atoms; F) substituted
alkyl of from 1 to 10 carbon atoms, having from 1 to 3 substituents
selected from: 1) alkoxy having the formula alkyl-O-- wherein alkyl
is as defined in A herein; 2) substituted alkoxy of the formula
substituted alkyl-O-- wherein substituted alkyl is as defined in F
herein; 3) cycloalkyl as defined in D herein; 4) substituted
cycloalkyl as defined in I herein; 5) cycloalkenyl as defined in E
herein; 6) substituted cycloalkenyl as defined in J herein; 7) acyl
having a formula selected from the group consisting of
alkyl-C(O)--, substituted alkyl-C(O)--, cycloalkyl-C(O)--,
substituted cycloalkyl-C(O)--, optionally substituted aryl-C(O)--,
optionally substituted heteroaryl-C(O)-- and optionally substituted
heterocyclic-C(O)-- wherein alkyl is defined in A herein; wherein
substituted alkyl is defined in F herein; wherein cycloalkyl is
defined in D herein; wherein substituted cycloalkyl is defined in I
herein; wherein optionally substituted aryl is defined in F26
herein; wherein optionally substituted heteroaryl is defined in F28
herein; and wherein optionally substituted heterocyclic is defined
in F30 herein; 8) acylamino having the formula --C(O)NRR wherein
each R is independently hydrogen, alkyl, substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted heterocyclic wherein alkyl is defined in A
herein; wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F26 herein; wherein
optionally substituted heteroaryl is defined in F28 herein; and
wherein optionally substituted heterocyclic is defined in F30
herein; 9) acyloxy having a formula selected from the group
consisting of alkyl-C(O)O--, substituted alkyl-C(O)O--,
cycloalkyl-C(O)O--, optionally substituted aryl-C(O)O--, optionally
substituted heteraryl-C(O)O-- and optionally substituted
heterocyclic-C(O)O-- wherein alkyl is defined in A herein; wherein
substituted alkyl is defined in F herein; wherein cycloalkyl is
defined in D herein; wherein optionally substituted aryl is defined
in F26 herein; wherein optionally substituted heteroaryl is defined
in F28 herein; and wherein optionally substituted heterocyclic is
defined in F30 herein; 10) amino; 11) substituted amino having the
formula --N(R).sub.2 wherein each R is independently selected from
the group consisting of: a) hydrogen; b) alkyl as defined in A
herein; c) substituted alkyl as defined in F herein; d) alkenyl as
defined in B herein; e) substituted alkenyl as defined in G herein;
f) alkynyl as defined in C herein; g) substituted alkynyl as
defined in H herein; h) optionally substituted aryl as defined in
F26 herein; i) cycloalkyl as defined in D herein; j) substituted
cycloalkyl as defined in I herein; k) optionally substituted
heteroaryl as defined in F28 herein; and l) optionally substituted
heterocyclic as defined in F30 herein; wherein both R groups may be
joined together to form a heterocyclic group as defined in F30
herein; and 12) aminoacyl having the formula --NRC(O)R wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F26 herein; wherein
optionally substituted heteroaryl is defined in F28 herein; and
wherein optionally substituted heterocyclic is defined in F30
herein; 13) aminoacyloxy having the formula --NRC(O)OR wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocyclic wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F26 herein; wherein
optionally substituted heteroaryl is defined in F28 herein; and
wherein optionally substituted heterocyclic is defined in F30
herein; 14) oxyacylamino having the formula --OC(O)NRR wherein each
R is independently hydrogen, alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl, 15) or
optionally substituted heterocyclic wherein alkyl is defined in A
herein; wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F26 herein; wherein
optionally substituted heteroaryl is defined in F28 herein; and
wherein optionally substituted heterocyclic is defined in F30
herein; 16) cyano; 17) halo selected from fluoro, chloro, bromo and
iodo; 18) hydroxyl; 19) keto; 20) thioketo; 21) carboxyl; 22)
optionally substituted carboxyalkyl having the formula
--C(O)O-alkyl and --C(O)O-substituted alkyl wherein alkyl is as
defined in A and substituted alkyl is as defined in F; 23) thiol;
24) thioalkoxy having the formula --S-alkyl, wherein alkyl is
defined in A herein; 25) substituted thioalkoxy having the formula
--S-substituted alkyl, wherein substituted alkyl is defined in F
herein; 26) optionally substituted aryl having 6 to 14 carbon atoms
and optionally substituted with 1 to 5 substituents selected from:
a) acyloxy; b) hydroxy; c) acyl as defined in F7 herein; d) alkyl
as defined in A herein; e) alkoxy as defined in F1 herein; f)
alkenyl as defined in B herein; g) alkynyl as defined in C herein;
h) substituted alkyl as defined in F herein; i) substituted alkoxy
as defined in F2 herein; j) substituted alkenyl as defined in G
herein; k) substituted alkynyl as defined in H herein; l) amino; m)
substituted amino as defined in F11 herein; n) aminoacyl as defined
in F12 herein; o) acylamino as defined in F8 herein; p) optionally
substituted alkaryl of the formula -alkylene-aryl where alkylene
has from 1 to 10 carbon atoms and is optionally substituted with
from 1 to 3 substituents selected from the group consisting of: 1)
alkoxy as defined in F1 herein; 2) substituted alkoxy as defined in
F2 herein; 3) acyl as defined in F7 herein; 4) acylamino as defined
in F8 herein; 5) acyloxy as defined in F9 herein; 6) amino; 7)
substituted amino as defined in F11 herein; 8) aminoacyl as defined
in F12 herein; 9) aminoacyloxy as defined in F13 herein; 10)
oxyacylamino as defined in F14 herein; 11) cyano; 12) halo selected
from fluoro, chloro, bromo and iodo; 13) hydroxyl; 14) keto; 15)
thioketo; 16) carboxyl; 17) optionally substituted carboxyalkyl as
defined in F22; 18) thiol; 19) thioalkoxy as defined in F24 herein;
20) substituted thioalkoxy as defined in F25 herein; 21) optionally
substituted aryl as defined in F26 herein; 22) optionally
substituted heteroaryl as defined in F28 herein; 23) optionally
substituted saturated or unsaturated heterocyclic as defined in F30
herein; 24) heterocyclooxy as defined in G24 herein; 25) nitro; 26)
mono- and di-alkylamino as defined in F42 herein; 27) mono- and
di-(substituted alkyl) amino as defined in F43 herein; 28) mono-
and di-arylamino as defined in F44 herein; 29) mono- and
di-heteroarylamino as defined in F45 herein; 30) mono- and
di-heterocyclic amino as defined in F46 herein; and 31) unsymmetric
di-substituted amines as defined in F47 herein; q) optionally
substituted aryl as defined in F26 herein; r) optionally
substituted aryloxy as defined in F27 herein; s) azido; t)
carboxyl; u) optionally substituted carboxylalkyl as defined in F22
herein; v) cyano; w) halo as defined in F17 herein; x) nitro; y)
optionally substituted heteroaryl as defined in F28 herein; z)
optionally substituted heteroaryloxy as defined in F29 herein aa)
optionally substituted heterocyclic as defined in F30 herein; bb)
optionally substituted heterocyclooxy as defined in G24 herein; cc)
aminoacyloxy as defined in F13 herein; dd) oxyacylamino as defined
in F14 herein; ee) thioalkoxy as defined in F24 herein; ff)
substituted thioalkoxy as defined in F25 herein; gg) optionally
substituted thioaryloxy having the formula aryl-S-- wherein aryl is
optionally substituted as defined in F26 herein; hh) optionally
substituted thioheteroaryloxy having the formula heteroaryl-S--
wherein heteroaryl is optionally substituted as defined in F28
herein; ii) --SO-alkyl wherein alkyl is as defined in A herein; jj)
--SO-substituted alkyl wherein substituted alkyl is as defined in F
herein; kk) --SO-optionally substituted aryl wherein optionally
substituted aryl is as defined in F26 herein; ll) --SO-optionally
substituted heteroaryl wherein optionally substituted heteroaryl is
as defined in F28 herein; mm) --SO.sub.2-alkyl wherein alkyl is as
defined in A herein; nn) --SO.sub.2-substituted alkyl wherein
substituted alkyl is as defined in F herein; oo)
--SO.sub.2-optionally substituted aryl wherein optionally
substituted aryl is as defined in F26 herein; pp)
--SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F28 herein; and qq)
trihalomethyl wherein halo is as defined in F17 herein; 27)
optionally substituted aryloxy having the formula aryl-O-- wherein
aryl is optionally substituted aryl as defined in F26 herein; 28)
optionally substituted heteroaryl having 1 to 15 ring carbon atoms
and 1 to 4 ring heteroatoms selected from oxygen, nitrogen and
sulfur and optionally substituted with 1 to 5 substituents selected
from the group of substituents as defined in F26 herein 29)
optionally substituted heteroaryloxy having the formula
--O-heteroaryl wherein heteroaryl is optionally substituted
heteroaryl as defined in F28 herein; 30) optionally substituted
saturated or unsaturated heterocyclic having from 1 to 15 ring
carbon atoms and from 1 to 4 ring heteroatoms selected from
nitrogen, sulfur and oxygen and optionally substituted with 1 to 5
substituents selected from the group of substituents consisting of
alkyl as defined in A herein; substituted alkyl as defined in F
herein; alkoxy as defined in F1 herein; substituted alkoxy as
defined in F2 herein; aryl as defined in F26 herein; aryloxy, halo
as defined in F16 herein; nitro, heteroaryl as defined in F28
herein; thiol, thioalkoxy as defined in F24 herein; substituted
thioalkoxy as defined in F25 herein; thioaryloxy wherein aryloxy is
as defined in F27 herein; and trihalomethyl wherein halo is as
defined in F17 herein; 31) hydroxyamino; 32) alkoxyamino wherein
alkoxy is as defined in F1; 33) nitro; 34) --SO-alkyl wherein alkyl
is as defined in A herein; 35) --SO-substituted alkyl wherein
substituted alkyl is as defined in F herein; 36) --SO-optionally
substituted aryl wherein aryl is optionally substituted as defined
in F26 herein; 37) --SO-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F28 herein; 38)
--SO.sub.2-alkyl wherein alkyl is as defined in A herein; 39)
--SO.sub.2-substituted alkyl wherein substituted alkyl is as
defined in F herein; 40) --SO.sub.2-optionally substituted aryl
wherein optionally substituted aryl is as defined in F26 herein;
41) --SO.sub.2-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F28 herein; 42) mono- and
di-alkylamino wherein alkyl is as defined in A herein; 43) mono-
and di-(substituted alkyl) amino wherein substituted alkyl is as
defined in F herein; 44) mono- and di-arylamino wherein aryl is as
defined in F26 herein; 45) mono- and di-heteroarylamino wherein
heteroaryl is as defined in F28 herein; 46) mono- and
di-heterocyclic amino wherein heterocyclic is as defined in F30
herein; and 47) unsymmetric di-substituted amines having different
substituents selected from alkyl, substituted alkyl, optionally
substituted aryl, optionally substituted heteroaryl and optionally
substituted heterocyclic, wherein alkyl is defined in A herein;
wherein substituted alkyl is defined in F herein; wherein
optionally substituted aryl is defined in F26 herein; wherein
optionally substituted heteroaryl is defined in F28 herein; and
wherein optionally substituted heterocyclic is defined in F30
herein; G) substituted alkenyl having 2 to 10 carbon atoms and
having of from 1 to 3 substituents selected from the group
consisting of: 1) alkoxy having the formula alkyl-O-- wherein alkyl
is as defined in A herein; 2) substituted alkoxy of the formula
substituted alkyl-O-- wherein substituted alkyl is as defined in F
herein; 3) acyl as defined in F7 herein; 4) acylamino as defined in
F8 herein; 5) acyloxy as defined in F9 herein; 6) amino; 7)
substituted amino as defined in F11 herein; 8) aminoacyl as defined
in F12 herein; 9) aminoacycloxy as defined in F13 herein; 10)
oxyacylamino as defined in F14 herein; 11) cyano; 12) halo selected
from fluoro, cholo, bromo and iodo; 13) hydroxyl; 14) keto; 15)
thioketo; 16) carboxyl; 17) optionally substituted carboxyalkyl
having the formula --C(O)O-alkyl and --C(O)O-substituted alkyl
wherein alkyl is as defined in A and substituted alkyl is as
defined in F; 18) thiol; 19) thioalkoxy as defined in F24 herein;
20) substituted thioalkoxy as defined in F25 herein; 21) optionally
substituted aryl as defined in F26 herein; 22) optionally
substituted heteroaryl as defined in F28 herein; 23) optionally
substituted saturated or unsaturated heterocyclic as defined in F30
herein; 24) optionally substituted heterocyclooxy having the
formula --O-heterocyclic wherein heterocyclic is as defined in F30
herein; 25) nitro; 26) --SO-alkyl wherein alkyl is as defined in A
herein; 27) --SO-substituted alkyl wherein substituted alkyl is as
defined in F herein; 28) --SO-aryl wherein optionally substituted
aryl is optionally substituted as defined in F26 herein; 29)
--SO-optionally substituted heteroaryl wherein optionally
substituted heteroaryl is as defined in F28 herein; 30)
--SO.sub.2-alkyl wherein alkyl is as defined in A herein; 31)
--SO.sub.2-substituted alkyl wherein substituted alkyl is as
defined in F herein; 32) --SO.sub.2-optionally substituted aryl
wherein optionally substituted aryl is as defined in F26 herein;
and 33) --SO.sub.2-optionally substituted heteroaryl wherein
optionally substituted heteroaryl is as defined in F28 herein; 34)
mono- and di-alkylamino as defined in F42 herein; 35) mono- and
di-(substituted alkyl) amino as defined in F43 herein; 36) mono-
and di-arylamino as defined in F44 herein; 37) mono- and
di-heteroarylamino as defined in F45 herein; 38) mono- and
di-heterocyclic amino as defined in F30 herein; and 39) unsymmetric
di-substituted amines having different substituents selected from
alkyl, substituted alkyl, optionally substituted aryl, optionally
substituted heteroaryl and optionally substituted heterocyclic; H)
substituted alkynyl having 2 to 10 carbon atoms having 1-2 sites of
alkynyl unsaturation and having 1 to 3 substituents selected from
the group consisting of: 1) alkoxy as defined in F1 herein; 2)
substituted alkoxy as defined in F2 herein; 3) acyl as defined in
F7 herein; 4) acylamino as defined in F8 herein; 5) acyloxy as
defined in F9 herein; 6) amino; 7) substituted amino as defined in
F11 herein; 8) aminoacyl as defined in F12 herein; 9) aminoacyloxy
as defined in F13 herein; 10) oxyacylamino as defined in F14
herein, 11) cyano; 12) halo as defined in F17 herein; 13) hydroxyl;
14) keto; 15) thioketo; 16) carboxyl; 15) carboxylalkyl as defined
in F22 herein; 16) thiol; 17) thioalkoxy as defined in F24 herein;
18) substituted thioalkoxy as defined in F25 herein; 21) aryl as
defined in F26 herein; 22) heteroaryl as defined in F28 herein; 23)
heterocyclic as defined in F30 herein; 24) heterocyclooxy as
defined in G24 herein; 25) nitro; 26) --SO-alkyl as defined in F34
herein; 27) --SO-substituted alkyl as defined in F35 herein; 28)
--SO-aryl as defined in F36 herein; 29) --SO-heteroaryl as defined
in F37 herein; 30) --SO.sub.2-alkyl as defined in F38 herein; 31)
--SO.sub.2-substituted alkyl as defined in F39 herein; 32)
--SO.sub.2-aryl as defined in F40 herein; 33) --SO.sub.2-heteroaryl
as defined in F41 herein; 34) mono- and di-alkylamino as defined in
F42 herein; 35) mono- and di-(substituted alkyl) amino as defined
in F43 herein; 36) mono- and di-arylamino as defined in F44 herein;
37) mono- and di-heteroarylamino as defined in F45 herein; 38)
mono- and di-heterocyclic amino as defined in F46 herein; and 39)
unsymmetric di-substituted amines as defined in F47 herein; I)
substituted cycloalkyl having 3 to 12 carbon atoms and having from
1 to 5 substituents selected from the group of substituents
consisting of: 1) hydroxy; 2) acyl as defined in F7 herein; 3)
acyloxy as defined in F9 herein; 4) alkyl as defined in A herein;
5) substituted alkyl as defined in F herein; 6) alkoxy as defined
in F1 herein; 7) substituted alkoxy as defined in F2 herein; 8)
alkenyl as defined in B herein; 9) substituted alkenyl as defined
in G herein; 10) alkynyl as defined in C herein; 11) substituted
alkynyl as defined in H herein, 12) amino; 13) substituted amino as
defined in F11 herein; 14) aminoacyl as defined in F12 herein; 15)
alkaryl as defined in F26(p) herein; 16) aryl as defined in F26
herein; 17) aryloxy as defined in F27 herein; 18) carboxyl; 19)
carboxylalkyl as defined in F22 herein; 20) cyano; 21) halo as
defined in F17 herein; 22) nitro; 23) heteroaryl as defined in F28
herein; 24) thioalkoxy as defined
in F24 herein; 25) substituted thioalkoxy as defined in F25 herein;
and 26) trihalomethyl; J) substituted cycloalkenyl as defined in E
herein having from 1 to 5 substituents selected from the group of
consisting of: 1) hydroxy; 2) acyl as defined in F7 herein; 3)
acyloxy as defined in F9 herein; 4) alkyl as defined in A herein;
5) substituted alkyl as defined in F herein; 6) alkoxy as defined
in F1 herein; 7) substituted alkoxy as defined in F2 herein; 8)
alkenyl as defined in B herein; 9) substituted alkenyl as defined
in G herein; 10) alkynyl as defined in C herein; 11) substituted
alkynyl as defined in H herein; 12) amino; 13) substituted amino as
defined in F11 herein; 14) aminoacyl as defined in F12 herein; 15)
alkaryl as defined in F26(p) herein; 16) aryl as defined in F26
herein; 17) aryloxy as defined in F27 herein; 18) carboxyl; 19)
carboxylalkyl as defined in F22 herein; 20) cyano; 21) halo as
defined in F17 herein; 22) nitro; 23) heteroaryl as defined in F28
herein; 24) thioalkoxy as defined in F24 herein; 25) substituted
thioalkoxy as defined in F25 herein; and 26) trihalomethyl; K)
optionally substituted aryl as defined in F26 herein; L) optionally
substituted heteroaryl as defined in F28 herein; and M) optionally
substituted heterocyclic as defined in F30 herein; R.sub.2 is
independently selected from the group consisting of: N) hydrogen;
O) alkyl as defined in A herein; P) substituted alkyl as defined in
F herein; Q) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of
alkenyl unsaturation; R) substituted alkenyl as defined in G
herein; S) alkynyl of from 2 to 10 carbon atoms and from 1-2 sites
of alkynyl unsaturation; T) substituted alkynyl as defined in H
herein; U) cycloalkyl of from 3 to 12 carbon atoms; V) optionally
substituted aryl as defined in F26 herein; W) optionally
substituted heteroaryl as defined in F28 herein; and X) optionally
substituted heterocyclic as defined in F30 herein; Q is S or o;
R.sup.15 is independently selected from the group consisting of: Y)
hydrogen, Z) alkyl as defined in A herein; AA) substituted alkyl as
defined in F herein; AB) optionally substituted aryl as defined in
F26 herein; AC) optionally substituted heterocyclic as defined in
F30 herein; AD) optionally substituted heteroaryl as defined in F28
herein; R.sup.15' is independently selected from the group
consisting of: AE) hydrogen; AF) hydroxyl; AG) alkyl as defined in
A herein; AH) substituted alkyl as defined in F herein; AI)
optionally substituted aryl as defined in F26 herein; AJ)
optionally substituted heterocyclic as defined in F30 herein; AK)
optionally substituted heteroaryl as defined in F28 herein; and the
moiety: 396is selected from the group having the formulas:
397wherein R.sup.a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted 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; 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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, caroxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; t is an integer from 0 to 4; w is an integer from 0 to 3;
or pharmaceutically-acceptable salts thereof.
155. The compound according to claim 154, wherein the moiety
398wherein R.sup.a, R.sup.b, V, and t are defined as in claim
154.
156. The compound according to claim 154, wherein the moiety
399wherein R.sup.a, R.sup.b, V and t are defined as in claim
154.
157. The compound according to claim 154, wherein the moiety
400wherein R.sup.a, R.sup.b, and w are defined as in claim 154.
158. The compound according to claim 154, wherein R.sup.1 is aryl
or optionally substituted aryl.
159. The compound according to claim 158, wherein R.sup.1 is
selected from the group consisting of: (a) alkyl; (b) phenyl; (c) a
substituted phenyl group of the formula: 401wherein R.sup.c is
selected from the group consisting of alkyl, substituted alkyl,
alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic,
thioalkoxy, substituted amino, cycloalkyl, and substituted
cycloalkyl; 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; and 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,
(d) 2-naphthyl, (e) 2-naphthyl substituted at the 4, 5, 6, 7 and/or
8 positions with 1 to 5 substituents selected from the group
consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl,
thioalkoxy, aryl, and heteroaryl, (f) heteroaryl, and (g)
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.
160. The compound according to claim 158, wherein R.sup.1 is
selected from the group consisting of mono-, di-, and
tri-substituted phenyl groups.
161. The compound according to claim 160, 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-chloropheny- l,
3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and
3,4-methylenedioxyphenyl.
162. The compound according to claim 160, 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.
163. The compound to claim 160, wherein R.sup.1 is a trisubstituted
phenyl selected from the group consisting of 3,4,5-trifluorophenyl,
and 3,4,5-tricholorophenyl.
164. The compound according to claim 158, wherein R.sup.1 is
selected from the group consisting of 2-naphthyl, quinolin-3-yl,
2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and
phenyl.
165. The compound according to claim 154, 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-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl,
(CH.sub.3).sub.2CH.dbd.CHCH.sub.2CH.sub.2CH(CH.sub.3- )--,
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, (phenyl).sub.2CHNHC(O)CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2NC(O)CH.sub.2--- ,
(phenyl).sub.2CHNHC(O)CH.sub.2CH.sub.2--, ethylcarbonylmethyl,
(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(phenyl)-, 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,
phenyl-C(O)NHCH(phenyl)CH.sub.2--, mesityl,
CH.sub.3CH(.dbd.NHOH)CH.sub.2- --,
4-CH.sub.3-phenyl-NHC(O)CH.sub.2CH.sub.2--,
C(O)CH(phenyl)CH.sub.2--, (CH.sub.3).sub.2CHC(O)NHCH(phenyl)-,
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, SO.sub.2CH.sub.2--,
3-cyclohexyl-n-propyl, CF.sub.3CH.sub.2CH.sub.2CH.sub.2-- and
N-pyrrolidinyl.
166. The compound according to claim 154, wherein R.sub.2 is
independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, cycloalkyl, optionally substituted
aryl, optionally substituted heteroaryl, and optionally substituted
heterocyclic.
167. The compound according to claim 166, wherein R.sub.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(C.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, 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, and
thien-3-yl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. ______, which was converted pursuant to 37 C.F.R.
.sctn. 1.53(b) from U.S. Ser. No. 09/102,507, filed Jun. 22, 1998;
the disclosure of which is incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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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[0102] 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.
[0103] 2. State of the Art
[0104] 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.
[0105] 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.
[0106] 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 3943 amino acids designated
the .beta.-amyloid peptide (AP) or sometimes A, A P or /A4.
B-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.
[0107] 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.
[0108] 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.
[0109] 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 that are
capable of inhibiting .beta.-amyloid peptide release and/or its
synthesis in vivo.
SUMMARY OF THE INVENTION
[0110] 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 Formulas I-VI below: 1
[0111] wherein R.sup.1 is selected from the group consisting of
aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
substituted alkyl, substituted alkenyl, substituted alkynyl,
substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl
and heterocyclic;
[0112] R' is selected from the group consisting of aryl,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heterocyclic, heteroaryl, heterocyclooxy, --CH.sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CHR.sup.1, --CH.dbd.CR.sup.1R.sup.1,
--CR.sup.1.dbd.CH.sub.2, --CR.sup.1.dbd.CHR.sup.1,
--CR.sup.1.dbd.CR.sup.1R.sup.1, --C.dbd.CH and --C.dbd.CR.sup.1;
with the proviso that when R' is heteroaryl or heterocyclic, there
is no N in R' at a position beta to the C.dbd.Q group;
[0113] Q is S or O;
[0114] R.sup.15 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
[0115] R.sup.15' is selected from the group consisting of hydrogen,
hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and
heteroaryl;
[0116] 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, keto, thioketo, halo, alkoxy, substituted
alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl,
carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, amino, substituted amino,
--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,
aryl and heteroaryl;
[0117] X is selected from the group consisting of oxo (.dbd.O),
thiooxo (.dbd.S), hydroxyl (--H, --OH), thiol (H, --SH) and hydro
(H,H);
[0118] Y is represented by the formula: 2
[0119] 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;
[0120] Z is represented by the formula -T-C(X')(X")C(O)-- where T
is selected from the group consisting of a bond covalently linking
R.sup.1 to --C(X')(X")--, oxygen, sulfur, and --NR.sup.5 where
R.sup.5 is hydrogen, acyl, alkyl, substituted alkyl, aryl,
heterocyclic or heteroaryl group;
[0121] R.sup.5' is hydrogen, alkyl, substituted alkyl, aryl,
heterocyclic or heteroaryl group;
[0122] X' and X" are independently selected from the group
consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl,
heteroaryl, heterocyclic, --OR.sup.5', --SR.sup.5,
--N(R.sup.5).sub.2, --N(CO)OR.sup.15 and --N.sub.3, with the
proviso that at least one of X' or X" is other than hydrogen,
hydroxy or fluoro, and with the further proviso that both X' and X"
cannot both be --OR.sup.5', --SR.sup.5, --N(R.sup.5).sub.2,
--N(CO)OR.sup.15 and --N.sub.3; further, neither X' and X" can be
--OR.sup.5', --SR.sup.5, --N(R.sup.5).sub.2, --N(CO)OR.sup.15 or
--N.sub.3 when T is other than a bond covalently linking R.sup.1 to
--C(X')(X")--;
[0123] n is an integer equal to 1 or 2;
[0124] 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.
[0125] with the following provisos:
[0126] when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0127] when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0128] when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0129] when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C.dbd.X, does not form a
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0130] when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with >CH and >C.dbd.X, does
not form a
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0131] when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0132] when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with >CH and >C.dbd.X, does
not form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0133] when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with >CH and >C.dbd.X, does
not form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0134] when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0135] when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C.dbd.X, does not form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzo-
diazepin-2-one
[0136] when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0137] when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0138] when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0139] when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C.dbd.X, does not form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzo-
diazepin-2-one
[0140] when R1-N(R.sup.15) is (2,5-dimethoxyphenyl)ureylenyl and R2
is methyl, then W, together with >CH and >C.dbd.X, does not
form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0141] when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C.dbd.X, does not
form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
[0142] 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 as
described herein effective in inhibiting the cellular release
and/or synthesis of .beta.-amyloid peptide.
[0143] Because the in vivo generation of .beta.-amyloid peptide is
associated with the pathogenesis of AD.sup.8,9, the compounds
described herein 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 by administering to the patient a pharmaceutical
composition comprising a pharmaceutically inert carrier and an
effective amount of one or more of the compounds described
herein.
[0144] 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 as described herein.
[0145] Preferred R' groups include, by way of example, all of the
aryl (including substituted aryl), cycloalkyl, and substituted
cycloalkyl groups defined for R' above as well as the following
additional groups:
[0146] thiophene-2-yl, 2-furanyl, cyclopropyl, cyclobutyl,
1-phenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,
2-benzofuranyl, 5-chloro-benzofuran-2-yl,
5,5-dimethyl-butyrolactone-4-yl- , 4-methylsulfonyl-phenyl,
cis-2-phenyl-cyclopropyl, 5-methylsulfonylthiophen-2-yl, 1,8
dimethyl-6-hydroxy-bicyclo[2.2.2]oct-2- -yl, 1,4-benzodioxan-2-yl,
tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, cyclohex-3-enyl,
3,5-difluorophenyl, 4-methylphenyl, 2-naphthyl, 1-naphthyl,
4-chlorothiophene-yl, 4-cyanophenyl, tetrahydrofuran-2-yl,
cyclohex-3-ene-yl, 1,2,3,4-tetrahydronaphth-2-yl,
1,2,3,4-tetrahydronapht- h-3-yl, 4-trifluoromethyl-cyclohexyl,
bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.1]hept-5-ene-2-yl, 2,2
dichloropropyl, 2,4-dichlorophenyl, cis-2-methyl-cyclopropyl,
1-(4-chlorophenyl)cyclobutyl, 2-phenylphenyl,
1,2-dihydro-1-oxo-2-phenyl-bicyclo[3.3.1]non-6-ene-3-yl and
--CH.dbd.CH(.phi.)).
[0147] 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, 3-(trifluoromethyl)-4-chlorophenyl,
3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl,
3,4-methylenedioxyphenyl, 4-azidophenyl, 4-cyanophenyl,
4-ethylphenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl,
4-(1-othoxy)ethylphenyl, 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- .
[0148] 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, 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-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl,
(CH.sub.3).sub.2CH.dbd.CHCH.sub.2CH.sub.2CH(CH.sub.3)--,
phenyl-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, (phenyl).sub.2CHNHC(O)CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2NC(O)CH.sub.2--- ,
(phenyl).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(phenyl)-, 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, C(O)NHCH(phenyl)CH.sub.2--,
mesityl, CH.sub.3CH(.dbd.NHOH)CH.sub.2--,
4-CH.sub.3-phenyl-NHC(O)CH.sub.2CH.sub.2--,
C(O)CH(phenyl)CH.sub.2--, (CH.sub.3).sub.2CHC(O)NHCH(phenyl)-,
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, phenyl-SO.sub.2CH.sub.2--,
3-cyclohexyl-n-propyl, CF.sub.3CH.sub.2CH.sub.2CH.sub.2-- and
N-pyrrolidinyl.
[0149] Still other preferred R.sup.1 groups include those set forth
in the Tables below.
[0150] 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.
[0151] 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, and
thien-3-yl.
[0152] Compounds of this invention include, by way of example,
[0153]
3-[(N'-(4-methylbenzoyl)-D-phenylglycinyl)]amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0154]
3-[(N'-(4-methylbenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one
[0155]
3-[(N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
[0156]
3-[(N'-2-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
[0157]
3-[(N'-1-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one
[0158]
3-[(N'-(5-Chloro-2-thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0159]
3-[(N'-(4-Cyanobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
[0160]
3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0161]
3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0162]
3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0163]
3-[(N'-(Acetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H--
1,4-benzodiazepin-2-one
[0164]
3-[(N'-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0165]
3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0166]
(S)-3-[(N'-(2-phenoxybutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0167]
(S)-3-[(N'-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0168]
(S)-3-[(N'-(2,3-Diphenylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0169]
(S)-3-[(N'-((R,S)-(-)-.alpha.-Methoxyphenylacetyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0170]
(S)-3-[(N'-(2-Furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one
[0171]
(S)-3-[(N'-(2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0172]
(S)-3-[(N'-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0173]
(S)-3-[(N'-(2-(4-Chlorophenoxy)-2-methylpropionyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0174]
(S)-3-[(N'-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0175]
(S)-3-[(N'-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino-2,3--
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0176]
(S)-3-[(N'-(2-Benzofurancarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0177]
(S)-3-[(N'-(2-Isopropyl-2-phenylacetyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0178]
(S)-3-[(N'-(5-Chlorobenzofuran-2-carboxyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0179]
(S)-3-[(N'-(2-Ethylhexanoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0180]
(S)-3-[(N'-(2-Methylbutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0181]
(S)-3-[(N'-((R,S)-2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0182]
(S)-3-[(N'-(5,5-dimethyl-butyrolactone-4-yl)-L-alaninyl)]amino-2,3--
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0183]
(S)-3-[(N'-(2-Methyl-4,4,4-trifluorobutyryl)-L-alaninyl)]amino-2,3--
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0184]
5-{N'-(2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[0185]
5-{N'-(tetrahydro-3-furoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[0186]
3-[N'-(3,5-difluorophenyl-.alpha.-methoxyacetyl)-L-alaninyl]-amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one
[0187]
3-[N'-(3,5-difluorophenyl-.alpha.-methoxyacetyl)-L-alaninyl]-amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one
[0188] (S)-3-[(N'-(4-(Trifluoromethyl)cyclohexane
carboxyl)-L-alaninyl)]am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0189]
(S)-3-[(N'-(Bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0190]
(S)-3-[(N'-(Bicyclo(2.2.1)hept-5-ene-2-carboxyl)-L-alaninyl)]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0191] (S)-3-[(N'-(2,2-Dichlorocyclopropane
carboxyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0192]
(S)-3-[(N'-(Cycloheptanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0193]
(S)-3-[(N'-(2-Methylvaleryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[0194]
3-[(N'-(2-(4-hydroxyphenoxy)propionyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0195]
(S)-3-[(N'-(.alpha.-(Hydroxymethyl)phenylacetyl)-L-alaninyl)]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0196] (S)-3-[(N'-(1-(2,4
Dichlorophenyl)cyclopropanecarboxyl)-L-alaninyl)-
]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0197]
(S)-3-[(N'-(2-Ethylbutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0198]
(S)-3-[(N'-(2-Methylcyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0199]
(S)-3-[(N'-(1-(4-Chlorophenyl)-1-cyclobutanecarboxyl)-L-alaninyl)]a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0200]
(S)-3-[(N'-(2-Biphenylcarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0201]
(S)-3-[(N'-(Pivalyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one
[0202]
(S)-3-[(N'-(trans-Cinnamyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0203]
(S)-3-[(N'-(1,2-Dihydro-1-oxo-2-phenyl-4-isoquinolinecarboxyl)-L-al-
aninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0204]
(S)-3-[(N'-(Bicyclo(3.3.1)non-6-ene-3-carboxyl)-L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0205]
(S)-3-[(N'-(Cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0206]
(S)-3-[(N'-(3-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phen-
yl-1H-1,4-benzodiazepin-2-one
[0207] (S)-3-[(N'-(2-(4-Cyanophenoxy)-2-methyl
propionyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0208]
(S)-3-[(N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl--
5-phenyl-1H-1,4-benzodiazepin-2-one
[0209]
(S)-3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0210]
(S)-3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0211]
(S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0212]
(S)-3-[(N'-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2,3-d-
ihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0213]
(S)-3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0214]
(S)-3-[(N'-(2-(4-trifluorophenyoxy)propionyl)-L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0215]
(S)-3-[(N'-(2-(4-Biphenylyloxy)propionyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0216]
(S)-3-[(N'-(Diphenylacetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0217]
(S)-3-[(N'-(4-(methylsulfonyl)benzoyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0218]
(S)-3-[(N'-(4-chloro-.alpha.-methylphenylacetyl)-L-alaninyl)]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0219]
(S)-3-[(N'-(trans-2-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0220]
(S)-3-[(N'-(4-chloro-.alpha.,.alpha.-dimethylphenylacetyl)-L-alanin-
yl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0221]
(S)-3-[(N'-(5-methylsulfonyl)thiophene-2-carboxyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0222]
(S)-3-[(N'-(1,8-dimethyl-6-Hydroxy-bicyclo(2.2.2)octane-2-carboxyl)-
-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-on-
e
[0223]
(S)-3-[(N'-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl)]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0224]
(S)-3-[(N'-(1,4-Benzodioxan-2-carboxyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0225]
(S)-3-[(N'-(Tetrahydro-3-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0226]
(S)-3-[(N'-(Acetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5--
phenyl-1H-1,4-benzodiazepin-2-one
[0227]
(S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-phenylglycinyl)]amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0228]
(S)-3-[(N'-(Cyclopropanecarboxyl)-L-phenylglycinyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0229]
(S)-3-[(N'-(3,5-Difluorobenzoyl)-L-phenylglycinyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0230]
3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-me-
thyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0231]
3-[(N'-(trans-cinnamyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(-
2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0232]
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dih-
ydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0233]
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dih-
ydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0234]
(S)-3-[(N'-.alpha.-hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0235]
3-[(N'-(3,5-difluorobenzoyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3--
dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0236]
3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-(3-
,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0237]
(S)-3-[(N'-.alpha.-hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-di-
hydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0238]
3-[(N'-(1-phenyl]-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-di-
hydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0239]
3-[(N'-(.alpha.-methoxyphenylacetyl)-L-alaninyl)]amino]-2,3-dihydro-
-1-(2-N,N-diethylaminoethyl)--5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0240]
3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetyl]-ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0241]
3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetyl]-ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0242]
(S)-3-[(N'-((trans-2-Phenylcyclopropyl)ureylenyl)-L-alaninyl)]amino-
-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0243]
(S)-3-[(N'-((3,4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0244]
(S)-3-[(N'-((2-propenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0245]
(S)-3-[(N'-((R)-(-)-1-(1-Naphthyl)ethyl)ureylenyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0246]
(S)-3-[(N'-((2,6-Diisopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0247]
(S)-3-[(N'-((3-[(Trifluoromethyl)phenyl)ureylenyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0248]
(S)-3-[(N'-((Phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0249]
(S)-3-[(N'-((4-ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0250]
(S)-3-[(N'-((2-Bromophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0251]
(S)-3-[(N'-((o-Tolyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0252]
(S)-3-[(N'-((2-Ethyl-6-methylphenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0253]
(S)-3-[(N'-((2-Fluorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0254]
(S)-3-[(N'-((2,4-difluorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0255]
(S)-3-[(N'-((2-Ethoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0256]
(S)-3-[(N'-((3-Acetylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0257]
(S)-3-[(N'-((3-[(cyano)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0258]
(S)-3-[(N'-((Phenethyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0259]
(S)-3-[(N'-((4-n-Butylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0260]
(S)-3-[(N'-((Octyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0261]
(S)-3-[(N'-((4-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0262]
(S)-3-[(N'-((4-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0263]
(S)-3-[(N'-((Hexyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[0264]
(S)-3-[(N'-((2-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0265]
(S)-3-[(N'-((2,6-Difluorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0266]
(S)-3-[(N'-((Octadecyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0267]
(S)-3-[(N'-((4-(Trifluoromethoxy)phenyl)ureylenyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0268]
(S)-3-[(N'-((2,4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0269]
(S)-3-[(N'-((3-Ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0270]
(S)-3-[(N'-((4-Chlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0271]
(S)-3-[(N'-((4-butoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0272]
(S)-3-[(N'-((4-Phenoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0273]
(S)-3-[(N'-((1-Naphthyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0274]
(S)-3-[(N'-((2-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0275]
(S)-3-[(N'-((2-(Methylthio)phenyl)ureylenyl)-L-alaninyl)]amino-2,3--
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0276]
(S)-3-[(N'-((2-Ethylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0277]
(S)-3-[(N'-((3-Methoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0278]
(S)-3-[(N'-((3,4,5-Trimethoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0279]
(S)-3-[(N'-((2,4,6-Trimethylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0280]
(S)-3-[(N'-((2-methyl-6-t-butylphenyl)ureylenyl)-L-alaninyl)]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0281]
(S)-3-[(N'-((2-(2-thiophene-yl)ethyl)ureylenyl)-L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0282]
3-[(N'-3,5-difluorophenyl-acetamido)-L-alaninyl]-3-amino-2,3-dihydr-
o 1-methyl-5-phenyl-1H-1,4-benzodiazepine
[0283]
3-[N'-3,5-difluorophenyl-.alpha.-azidoacetyl)-L-alaninyl]-3-amino-2-
,3-dihydrol-methyl-5-phenyl-1H-1,4-benzodiazepine
[0284] 5-{N'-(cyclopropane
carboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[0285]
5-{N'-(2-methylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H--
dibenz[b,d]azepin-6-one
[0286]
5-{N'-(bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl}-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0287]
5-{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[0288]
5-{N'-((aminoacetoxy)-3,5-difluorophenylacetyl)-L-alaninyl}-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0289]
3-[N'-(3,5-difluorophenyl-.alpha.-(2-aminoacetoxy)acetyl)-L-alaniny-
l]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one
[0290]
5-{N'-(diphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
[0291]
5-{N'-(acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d-
]azepin-6-one
[0292]
5-{N'-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[0293]
5-{N'-(trans-cinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
[0294]
5-{N'-(tetrahydro-2-furoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[0295]
5-{N'-(cyclopentanecarboxyl)L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[0296]
5-{N'-(2-thiophenecarboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[0297]
5-{N'-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0298]
5-{N'-((R)-(-)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0299]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylacetyl)-L-a-
laninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepi-
n-2-one
[0300]
5-{N'-(benzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-d-
ibenz[b,d]azepin-6-one
[0301]
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylacetyl)-L-a-
laninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepi-
n-2-one
[0302]
5-{N'-(3-fluorobenzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[0303]
5-(S)-(N'-((Butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[0304]
5-(S)-(N'-((Benzylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[0305]
5-{N'-(benzylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
[0306]
5-(S)-(N'-((Ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[0307]
5-(S)-(N'-((Phenethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[0308]
5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-valinyl]-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0309]
-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-tert-leucinyl-a-
mino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0310]
5-{N'-(butylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[0311]
5-{N'-(octylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dib-
enz[b,d]azepin-6-one
[0312]
5-(S)-(N'-((2-(thiophen-2-yl)ethylureylenyl)-L-alaninyl)-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0313]
5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-alaninyl-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0314]
5-(S)-(N'-(L-valinyl)-L-alaninyl-)]amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one
[0315]
5-(R/S)-(N'-(2-hydroxy-2-phenethylureylenyl)-L-alaninyl)-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0316]
5-(S)-(N'-((hexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro--
6H-dibenz[b,d]azepin-6-one
[0317]
5-(S)-(N'-((cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[0318]
5-(S)-(N'-((isopropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[0319]
5-(S)-(N'-((tert-butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[0320]
5-(S)-(N'-((1-adamantylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[0321]
5-(S)-(N'-((2-methylpropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[0322]
5-(S)-(N'-(R/S)-3-hydroxy-3-phenylethylureylenyl)-L-alaninyl)-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0323]
5-(S)-(N'-((3-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[0324]
5-(S)-((N'-(S)-1-hydroxymethyl-3-methylbutylureylenyl)-L-alaninyl)--
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0325]
5-(S)-((N'-(1S)-(2S)-1-hydroxymethyl-2-methylbutylureylenyl)-L-alan-
inyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0326]
5-(S)-(N'-(3-chloropropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[0327]
5-(S)-(N'-octylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[0328]
5-(S)-(N'-1,1,3,3-tetramethylbutylureylenyl)-L-alaninyl)-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0329]
5-(S)-(N'-(R/S)-1-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0330]
5-(S)-((N'-(R/S)-1-hydroxymethylbutylureylenyl)-L-alaninyl)-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0331]
5-(S)-((N'-(R/S)-1,3-dimethylbutylureylenyl)-L-alaninyl)-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0332]
5-(S)-((N'-(R)-1-hydroxymethyl-3-methylbutylureylenyl)-L-alaninyl)--
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0333]
5-(S)-((N'-(R/S)-2-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0334]
5-(S)-(N'-morpholinoureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[0335]
5-(S)-(N'-(2-(2-hydroxyethoxy)-ethylureylenyl)-L-alaninyl)-amino-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0336]
5-(S)-(N'-piperidinylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b,d]azepin-6-one
[0337]
5-(S)-(N'-(N"-methyl-N"-butylureylenyl)-L-alaninyl)-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0338]
5-(S)-(N'-(1-(R/S)-hydroxymethylcyclopentylureylenyl)-L-alaninyl)-a-
mino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0339]
5-(S)-(N'-(4-hydroxybutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[0340]
5-(S)-(N'-(1-(R/S)-hydroxymethyl-2-methylpropylureylenyl)-L-alaniny-
l)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0341]
5-(S)-(N'-(2-(R/S)-hydroxycyclohexylureylenyl)-L-alaninyl)-amino-7--
methyl-5,7-dihydro-6H-dibenz[b, d]azepin-6-one
[0342]
5-(S)-(N'-(isopropyl-hydroxyureylenyl)-L-alaninyl)-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0343]
5-(S)-(N'-(benzyl-hydroxyureylenyl)-L-alaninyl)-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[0344]
5-(S)-(N'-(valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz-
[b,d]azepin-6-one
[0345]
5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[0346]
5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-alaninyl-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0347] 5-(S)-(N'-(3,5-difluoro
phenylglycinyl)-L-alaninyl-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0348]
5-(S)-(N'-(threonine)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[0349]
5-(S)-(N'-(D-valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one
[0350]
5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-
-dibenz[b,d]azepin-6-one
[0351]
5-(S)-(N"-(S)-phenylglycinyl)-N'-L-alaninyl]amino-1-methyl-5-phenyl-
-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
[0352]
5-(S)-[(N"-L-valinyl)-N'-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-
-tetrahydro-2H-1,5-benzodiazepin-2-one
[0353]
5-(S)-(N'-(thiomorpholinylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[0354]
5-(S)-(N'-(2(R/S)-hydroxybutylureylenyl)-L-alaninyl)-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0355]
5-(S)-(N'-2,2,2-trifluoroethylureylenyl)-L-alaninyl)-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0356]
5-(S)-(N'-(4R/S)-cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[0357]
5-(S)-(N'-(1R)-hydroxymethyl-3-methylthiopropylureylenyl)-L-alaniny-
l)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0358]
5-{N'-(2-hydroxy-2-methylpropionyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[0359]
5-{N'-(2-hydroxy-2-methylbutanoyl)-L-alaninyl}-amino-7-methyl-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[0360]
3-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0361]
5-(S)-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0362]
5-(S)-[N'-(L-Trifluoromethylphenylglycinyl)-L-alaninyl]-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0363]
5-(S)-[N'-(L-N-methyl-valinyl)-L-alaninyl]-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[0364]
5-(S)-(N'-(3,5-difluorophenylglycinyl)-N'-L-alaninyl]amino-2,4-diox-
o-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5 benzodiazepine
hydrochloride
[0365]
5-(S)-(N"-(3,5-difluorophenylglycinyl)-N'-L-alaninyl]amino-2,4-diox-
o-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepine
hydrochloride
[0366]
5-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[0367]
3-[N'-(2-mercapto-3-methyl-butanoyl)-L-alaninyl]-amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0368]
5-(S)-[N'-(2-mercapto-3-methylbutanoyl)-L-alaninyl]-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0369] Additional examples of suitable compounds include:
[0370]
5-(S)-[N'-(2-Amino-3,3,3-trifluoromethylbutyryl)-L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0371]
5-(S)-[N'-(2-amino-5,5,5-trifluoropentanyl)-L-alaninyl]-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0372]
5-(S)-[N'-(2-amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[0373]
1-(S)-[N'-(2-Amino-3,3,3-trifluorobutyryl)-L-alaninyl]-amino-3-meth-
yl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[0374]
1-(S)-[N'-(2-Amino-5,5,5-trifluoropentanoyl)-L-alaninyl]-amino-3-me-
thyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[0375]
1-(S)-[N'-(2-Amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-3-meth-
yl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[0376]
1-(S)-[N'-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetra-
hydro-2H-3-benzazepin-2-one
[0377]
1-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-te-
trahydro-2H-3-benzazepin-2-one
[0378]
1-(S)-[N'-(L-2-Aminobutyryl)-L-alaninyl]-amino-3-(2-methylpropyl)-4-
,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[0379] 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.p C(.dbd.X)--, forms a cycloalkyl group of the formula:
3
[0380] wherein T is selected from the group consisting of alkylene
and substituted alkylene.
[0381] A preferred cycloalkyl group is represented by the formula:
4
[0382] 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, substituted amino, aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; each R.sup.a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted 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.
[0383] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[0384] In another preferred embodiment, the cyclic group defined by
W, together with --C(H)C(.dbd.X)-- is a ring of the formula: 5
[0385] 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.sup.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.
[0386] Particularly preferred alcohol or thiol substituted groups
include 6
[0387] 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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; each R.sup.a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted 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.
[0388] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[0389] 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: 7
[0390] 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.sup.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.
[0391] Particularly preferred cyclic ketone and thioketone groups
include: 8
[0392] 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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; each R.sup.a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted 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.
[0393] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[0394] In another preferred embodiment, the cyclic group defined by
W, together with --C(H).sub.pC(.dbd.X)--, forms a ring of the
formula: 9
[0395] 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.sup.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.
[0396] Particularly preferred lactone and thiolactone groups
include: 10
[0397] 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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like; each R.sup.a is independently selected from the group
consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,
amino, substituted 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.
[0398] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[0399] In another preferred embodiment, the cyclic group defined by
W and --C(H).sub.pC(.dbd.X)--, forms a lactam ring of the formula:
11
[0400] or a thiolactam ring of the formula: 12
[0401] 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.sup.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.
[0402] Particularly preferred lactam and thiolactam groups include:
131415
[0403] 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,
substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl,
carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy,
substituted thioalkoxy, trihalomethyl and the like; each R.sup.a is
independently selected from the group consisting of alkyl,
substituted alkyl, alkoxy, substituted alkoxy, amino, substituted
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, thioalkoxy, substituted amino, 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.
[0404] Preferably t is an integer from 0 to 2 and, more preferably,
is an integer equal to 0 or 1.
[0405] In one preferred embodiment of this invention, W is a cyclic
group of the formula: 16
[0406] wherein
[0407] each R.sup.6 is independently selected from the group
consisting of acyl, acylamino, acyloxy, alkenyl, substituted
alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl,
alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl,
aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl,
substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro,
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,
and --SO.sub.2-heteroaryl;
[0408] each R.sup.7 is independently selected from the group
consisting of acyl, acylamino, acyloxy, alkenyl, substituted
alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl,
alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl,
aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl,
substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro,
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,
and --SO.sub.2-heteroaryl;
[0409] R.sup.8 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, acyl, aryl, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and
heterocyclic;
[0410] p is an integer from 0 to 4; q is an integer from 0 to
4.
[0411] Preferably, R.sup.6 and R.sup.7 are independently selected
from the group consisting of alkoxy, substituted alkoxy, alkyl,
substituted alkyl, amino, substituted amino, carboxyl,
carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted
thioalkoxy. More preferably, when present, R.sup.6 and R.sup.7 are
fluoro.
[0412] R.sup.8 is preferably selected from the group consisting of
hydrogen, alkyl, substituted alkyl, acyl, aryl, cycloalkyl and
substituted cycloalkyl. More preferably, R.sup.8 is selected from
the group consisting of hydrogen, alkyl, substituted alkyl and
cycloalkyl.
[0413] Particularly preferred R.sup.8 substituents include, by way
of example, hydrogen, methyl, 2-methypropyl, hexyl,
methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl,
cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the
like.
[0414] In another preferred embodiment of this invention, W is a
cyclic group of the formula: 17
[0415] wherein R.sup.6, R.sup.7, and p are as defined herein and r
is an integer from 0 to 3.
[0416] In still another preferred embodiment of this invention, W
is a cyclic group of the formula: 18
[0417] wherein R.sup.6 and p are as defined herein.
[0418] In yet another preferred embodiment of this invention, W is
a cyclic ring of the formula: 19
[0419] wherein R.sup.6 and p are as defined herein.
[0420] In still another preferred embodiment of this invention, W
is a cyclic ring of the formula: 20
[0421] wherein R.sup.6, R.sup.8 and p are as defined herein;
and
[0422] each R.sup.9 is independently selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl and heterocyclic; and g is an integer from 0 to 2.
[0423] When present, R.sup.9 is preferably alkyl or substituted
alkyl.
[0424] In another preferred embodiment of this invention, W is a
cyclic ring of the formula: 21
[0425] wherein R.sup.6, R.sup.8, R.sup.9, g and p are as defined
herein.
[0426] In yet another preferred embodiment of this invention, W is
a cyclic ring of the formula: 22
[0427] wherein R.sup.6, R.sup.8, R.sup.9, g and p are as defined
herein.
[0428] In still another preferred embodiment of this invention, W
is a cyclic ring of the formula: 23
[0429] wherein R.sup.6, each R.sup.8 and p are as defined
herein.
[0430] In another preferred embodiment of this invention, W is a
cyclic ring of the formula: 24
[0431] wherein R.sup.6, each R.sup.8, R.sup.9, g and p are as
defined herein.
[0432] In another preferred embodiment of this invention, W is a
cyclic ring of the formula: 25
[0433] wherein R.sup.6, R.sup.8 and p are as defined herein;
and
[0434] R.sup.10 is selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, substituted amino, aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl, heterocyclic, thioalkoxy and substituted
thioalkoxy.
[0435] In another preferred embodiment of this invention, W is a
cyclic ring of the formula: 26
[0436] wherein R.sup.6, R.sup.10 and p are as defined herein;
and
[0437] D-E is selected from the group consisting of alkylene,
alkenylene, substituted alkylene, substituted alkenylene and
--N.dbd.CH--.
[0438] In another preferred embodiment of this invention, W is a
cyclic ring of the formula: 27
[0439] wherein R.sup.6, R.sup.8, R.sup.9, g and p are as defined
herein; and
[0440] Q is oxygen, sulfur, --S(O)-- or --S(O).sub.2--.
[0441] In another preferred embodiment of this invention, W is a
cyclic ring of the formula: 28
[0442] wherein R.sup.6, R.sup.8 and p are as defined herein.
[0443] In another preferred embodiment of this invention, W is a
cyclic ring of the formula: 29
[0444] wherein R.sup.8 is as defined herein.
[0445] In the above formulae, preferably each R.sup.6 is
independently selected from the group consisting of alkyl,
substituted alkyl, alkoxy and halo; each R.sup.7 is independently
selected from the group consisting of alkyl, substituted alkyl,
alkoxy and halo; each R.sup.8 is independently selected from the
group consisting of alkyl, substituted alkyl, cycloalkyl and aryl;
each R.sup.9 is independently selected from the group consisting of
alkyl, substituted alkyl, cycloalkyl and aryl; and g, p, q and r
are 0 or 1. More preferably, g, p, q and r are 0.
[0446] In another preferred embodiment, the cyclic group defined by
W, together with --C(H)C(.dbd.X)--, forms a ring of the formula:
30
[0447] 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.sup.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.
[0448] 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: 31
[0449] 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.sup.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.
[0450] In another preferred embodiment, R.sup.15 is H, R.sup.1 is
alkyl or aryl, Rb is alkyl, substituted alkyl, cycloalkyl or aryl,
R.sup.2 is methyl, and the compound is a compound of Formulas I, II
or VI.
[0451] This invention also provides for novel pharmaceutical
compositions comprising a pharmaceutically inert carrier and one or
more of the compounds described in Formulas I-VI above.
[0452] Still further, this invention provides for novel compounds
of Formulas I-VI: 32
[0453] 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;
[0454] R' is selected from the group consisting of aryl,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heteroaryl, heterocyclic, --CH.sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CHR.sup.1, --CH.dbd.CR.sup.1R.sup.1,
--CR.sup.1.dbd.CH.sub.2, --CR.sup.1.dbd.CHR.sup.1,
--CR.sup.1.dbd.CR.sup.1R.sup.1, --C.dbd.CH and --C.dbd.CR.sup.1;
with the proviso that when R' is heteroaryl or heterocyclic, there
is no N in R' at a position beta to the C.dbd.Q group;
[0455] Q is S or O;
[0456] R.sup.15 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
[0457] R.sup.15' is selected from the group consisting of hydrogen,
hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and
heteroaryl;
[0458] W, together with --C(H)C(.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,
keto, thioketo, halo, alkoxy, substituted alkoxy, thioalkoxy,
substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, amino, substituted amino, --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, aryl and heteroaryl;
[0459] X is selected from the group consisting of oxo (.dbd.O),
thiooxo (.dbd.S), hydroxyl (--H, --OH), thiol (H, --SH) and hydro
(H,H);
[0460] Y is represented by the formula: 33
[0461] 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;
[0462] Z is represented by the formula -T-C(X')(X")C(O)-- where T
is selected from the group consisting of a bond covalently linking
R.sup.1 to --C(X')(X")--, oxygen, sulfur, and --NR.sup.5 where
R.sup.5 is hydrogen, acyl, alkyl, substituted alkyl, aryl,
heterocyclic or heteroaryl group;
[0463] R.sup.5' is hydrogen, alkyl, substituted alkyl, aryl,
heterocyclic or heteroaryl group;
[0464] X' and X" are independently selected from the group
consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl,
heteroaryl, heterocyclic, --OR.sup.5', --SR.sup.5,
--N(R.sup.5).sub.2, --N(CO)OR.sup.15 and --N.sub.3, with the
proviso that at least one of X' or X" is other than hydrogen,
hydroxy or fluoro, and with the further proviso that both X' and X"
cannot both be --OR.sup.5', --SR.sup.5, --N(R.sup.5).sub.2,
--N(CO)OR.sup.15 and --N.sub.3; further, neither X' and X" can be
--OR.sup.5', --SR.sup.5, --N(R.sup.5).sub.2, --N(CO)OR.sup.15 or
--N.sub.3 when T is other than a bond covalently linking R.sup.1 to
--C(X')(X")--;
[0465] n is an integer equal to 1 or 2;
[0466] 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,
[0467] with the following provisos:
[0468] when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0469] when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0470] when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0471] when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C.dbd.X, does not form a
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0472] when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with >CH and >C.dbd.X, does
not form a
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0473] when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[0474] when R1 is .alpha.-methoxyphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with >CH and >C.dbd.X, does
not form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0475] when R1 is .alpha.-hydroxy-diphenylacetyl, R2 is methyl, and
R15 is hydrogen, then W, together with >CH and >C.dbd.X, does
not form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0476] when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0477] when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C.dbd.X, does not form a
2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzo-
diazepin-2-one
[0478] when R1 is diphenylacetyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0479] when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0480] when R1 is trans-cinnamyl, R2 is methyl, and R15 is
hydrogen, then W, together with >CH and >C.dbd.X, does not
form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[0481] when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is
methyl, and R15 is hydrogen, then W, together with >CH and
>C.dbd.X, does not form a
2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzo-
diazepin-2-one
[0482] when R1-N(R.sup.15) is (2,5-dimethoxyphenyl)ureylenyl and R2
is methyl, then W, together with >CH and >C.dbd.X, does not
form a 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[0483] when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15
is hydrogen, then W, together with >CH and >C.dbd.X, does not
form a 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
[0484] As is appreciated by the skilled person, compounds of the
present invention exist as isomers. Herein, the Cahn-Prelog-Ingold
designations of (R)- and (S)- and, for amino acid derived portions
of the compounds, the L- and D- designations of stereochemistry
relative to the isomers of glyceraldehyde are used to refer to
specific isomers where designated. The specific isomers can be
prepared by stereospecific synthesis or can be resolved and
recovered by techniques known in the art, such as, chromatography
on chiral stationary phases, and fractional recrystallization of
addition salts formed by reagents used for that purpose. Useful
methods of resolving and recovering specific stereoisomers are
known in the art and described, for example, in Stereochemistry of
Organic Compounds, E. L. Eliel and S. H. Wilen (Wiley-Interscience
1994), Enantiomers, Racemates and Resolutions, J. Jacques, A.
Collet and S. J. Wilen (Wiley-Interscience 1981), and European
Patent Application No. EP-A-838448, published Apr. 29, 1998. It is
to be understood that the invention extends to all of the isomeric
forms of the compounds of the present invention, including the
diastereomeric, enantiomeric and racemic forms of the
compounds.
[0485] Preferred compounds described herein include those set forth
in the tables below:
1TABLE 1-1 34 Ex. R R.sup.1 R.sup.2 R.sup.3 1-1 2-thiophene-yl
methyl phenyl methyl 1-2 2-furanyl methyl phenyl methyl 1-3
cyclobutyl methyl phenyl methyl 1-4 1-phenyl methyl phenyl methyl
cyclopropyl 1-5 cyclohexyl methyl phenyl methyl 1-6 2-benzofuranyl
methyl phenyl methyl 1-7 5-chloro methyl phenyl methyl
benzofuran-2-yl 1-8 5,5-dimethyl- methyl phenyl methyl
butyrolactone-4-yl 1-9 3-furoyl methyl phenyl methyl 1-10 4-methyl
methyl phenyl methyl sulfonyl phenyl 1-11 cis-2-phenyl methyl
phenyl methyl 1-12 5-methyl methyl phenyl methyl sulfonyl
thiophen-2-yl 1-13 1,8-dimethyl-6- methyl phenyl methyl hydroxy-
bicyclo[2.2.2]oct-2-yl 1-14 1,4-benzo methyl phenyl methyl
dioxan-2-yl 1-15 tetrahydro methyl phenyl methyl furan-3-yl 1-16
cyclohex-3-ene-yl methyl phenyl phenyl 1-17 cyclopropyl methyl
phenyl phenyl 1-18 3,5-difluoro methyl phenyl phenyl phenyl 1-19 2-
methyl 2-pyridyl methyl pyrrolidinone 1-21 1-phenyl methyl
2-pyridyl methyl 1-22 1-phenyl 2-oxo-3,3- 2-pyridyl methyl
cyclopropyl dimethylbutyl 1-23 3,5- 2-oxo-3,3- 2-pyridyl methyl
difluorophenyl dimethylbutyl 1-24 2- 2-oxo-3,3- 2-pyridyl methyl
pyrrolidinone- dimethylbutyl 5-yl 1-26 1-phenyl 2-diethyl 2-pyridyl
methyl cyclopropyl aminoethyl 1-27 4-methylphenyl methyl phenyl
phenyl 1-28 4-methylphenyl methyl phenyl methyl 1-29 3-pyridyl
methyl phenyl methyl 1-30 2-naphthyl methyl phenyl methyl 1-31
1-naphthyl methyl phenyl methyl 1-32 4-chloro- methyl phenyl methyl
thiophene-yl 1-33 4-cyanophenyl methyl phenyl methyl 1-34
tetrahydrofuran- methyl phenyl methyl 2-yl 1-35 3,5-difluoro methyl
phenyl methyl phenyl 1-36 cyclohex-3-ene-yl methyl phenyl methyl
1-37 1,2,3,4- methyl phenyl methyl tetrahydro naphth-2-yl 1-38
cyclopentyl methyl phenyl methyl 1-39 4-trifluoro methyl phenyl
methyl methyl cyclohexyl 140 bicyclo[2.2.1] methyl phenyl methyl
hept-2-yl 1-41 bicyclo[2.2.1] methyl phenyl methyl hept-5-ene-2-yl
1-42 2,2-dichloro methyl phenyl methyl cyclopropyl 1-43 cycloheptyl
methyl phenyl methyl 1-44 1-(2,4-dichloro methyl phenyl methyl
phenyl)- cyclopropyl 1-45 cis-2-methyl methyl phenyl methyl
cyclopropyl 1-46 1-(4-chloro methyl phenyl methyl phenyl)
cyclobutyl 1-47 2-phenylphenyl methyl phenyl methyl 1-48
1,2-dihydro-1- methyl phenyl methyl oxo-2-phenyl- 4-isoquinolinyl
1-49 bicyclo[3.3.1]non- methyl phenyl methyl 6-ene-3 -yl 1-50
cyclopropyl methyl phenyl methyl 1-51 tetrahydro methyl phenyl
methyl furan-2-yl 1-52 3,5-difluoro methyl phenyl methyl phenyl
1-53 cyclohex-3-ene-yl methyl phenyl methyl 1-54 1,2,3,4- methyl
phenyl methyl tetrahydro naphth-3-yl 1-55 cyclopentyl methyl phenyl
methyl
[0486]
2TABLE 1-2 35 Ex. R 1-56 tetrahydrofuran-3-yl 1-57 cyclopropyl 1-59
bicyclo[2.2.1]heptan-2-yl 1-60 tetrahydrofuran-2-yl 1-61
cyclopentyl 1-62 thiophene-2-yl
[0487]
3TABLE 2-1 36 Ex. R X.sup.1 X.sup.2 R.sup.1 R.sup.2 R.sup.3 2-1
benzyl phenyl H methyl phenyl methyl 2-2 phenyl ethyl H methyl
phenyl methyl 2-4 phenyl isopropyl H methyl phenyl methyl 2-5 butyl
ethyl H methyl phenyl methyl 2-6 ethyl methyl H methyl phenyl
methyl 2-7 2,2,2- methyl H methyl phenyl methyl trifluoro ethyl 2-8
phenyl phenyl H methyl phenyl phenyl 2-9 4-chloro methyl H methyl
phenyl methyl phenyl 2-10 4-chloro methyl methyl methyl phenyl
methyl phenyl 2-11 phenyl methyl hydroxyl methyl phenyl methyl 2-12
phenyl phenyl hydroxyl methyl 2-pyridyl methyl 2-15 phenyl phenyl
hydroxyl 2-oxo-3,3- 2-pyridyl methyl 2-17 phenyl phenyl hydroxyl
2-diethyl 2-pyridyl methyl amino ethyl 2-18 3,5- methyl hydroxyl
methyl phenyl methyl difluoro phenyl 2-19 3,5- methyl hydroxyl
methyl phenyl methyl difluoro phenyl
[0488]
4TABLE 2-2 37 Ex. R R.sup.1 X.sup.1 X.sup.2 2-20 phenyl methyl
phenyl H 2-21 H methyl H H 2-22 propyl methyl methyl H 2-23 phenyl
methyl hydroxymethyl H 2-24 ethyl methyl ethyl H 2-25 methyl methyl
methyl methyl 2-26 phenyl methyl phenyl H 2-27 H phenyl H H 2-28
isopropyl methyl thioacetyl H 2-29 isopropyl methyl thio H
[0489]
5TABLE 2-3 38 Ex. R X.sup.1 X.sup.2 2-30 phenyl methyl H 2-31 butyl
methyl H 2-32 phenyl phenyl H 2-33 phenyl methyl hydroxyl 2-34
phenyl hydroxyl methyl 2-35 methyl hydroxyl methyl 2-36 ethyl
hydroxyl methyl 2-37 isopropyl thioacetyql H 2-38 H H H 2-39
isopropyl thiol H
[0490]
6TABLE 3-1 39 Ex. R.sup.1 R.sup.2 3-1 phenyl methyl 3-2 2-pyridyl
methyl
[0491]
7TABLE 3-2 40 Ex. R 3-5 Methyl
[0492]
8TABLE 4-1 41 Ex. R R.sup.1 R.sup.2 R.sup.3 R.sup.4 4-1 phenyl
methyl ethyl H phenoxy 4-2 phenyl methyl phenyl H methoxy 4-3
phenyl methyl methyl methyl 4-chlorophenoxy 4-4 phenyl methyl
methyl H phenoxy 4-5 phenyl methyl 3,5- H methoxy difluoro phenyl
4-6 phenyl methyl 3,5- H methoxy difluoro phenyl 4-7 phenyl methyl
methyl H 4-hydroxyphenoxy 4-8 phenyl methyl methyl H 4-
trifluoromethoxy phenoxy 4-9 phenyl methyl methyl H 4-phenylphenoxy
4-10 2-pyridyl 2-(diethyl phenyl H methoxy amino) ethyl 4-16 phenyl
methyl methyl methyl 4-cyano phenoxy
[0493]
9TABLE 5-1 42 Ex. R R' X 5-1 trans-2-phenylcyclopropyl H O 5-2
3,4-dichlorophenyl H O 5-3 2-propenyl H O 5-4 (1-naphthyl)ethyl H O
5-5 2,6-diisopropylphenyl H O 5-6 3-[(trifluoromethyl)phenyl H O
5-7 phenyl H O 5-8 (4-ethoxycarbonyl)phenyl H O 5-9 2-bromophenyl H
O 5-10 o-tolyl H O 5-11 2-ethyl-6-methylphenyl H O 5-12
2-fluorophenyl H O 5-13 2,4-difluorophenyl H O 5-14 2-ethoxyphenyl
H O 5-15 3-acetylphenyl H O 5-16 3-[(cyano)phenyl H O 5-18
phenethyl H O 5-19 4-n-butylphenyl H O 5-20 octyl H O 5-21
4-biphenyl H O 5-22 4-isopropylphenyl H O 5-23 hexyl H O 5-24
2-isopropylphenyl H S 5-25 2,6-difluorophenyl H O 5-26 octadecyl H
O 5-27 4-(trifluoromethoxy)phenyl H O 5-28 2,4-dichlorophenyl H O
5-29 3-ethoxycarbonylphenyl H O 5-30 4-chlorophenyl H O 5-31
4-butoxyphenyl H O 5-32 4-phenoxyphenyl H O 5-33 1-naphthyl H O
5-34 2-biphenyl H O 5-35 2-(methylthio)phenyl H O 5-36
2-ethylphenyl H O 5-37 3-methoxyphenyl H O 5-38
3,4,5-trimethoxyphenyl H O 5-39 2,4,6-trimethylphenyl H O 5-40
2-methyl-6-t-butylphenyl H O 5-41 2-(2-thiophene-yl H O
[0494]
10TABLE 5-2 43 Ex. R R' 5-43 (2-thiophene-yl)ethyl H 5-44 phenethyl
H 5-45 butyl H 5-46 benzyl H 5-47 ethyl H 5-48
2-hydroxy-2-phenethyl H 5-49 hexyl H 5-50 cyclohexyl H 5-51
isopropyl H 5-52 t-butyl H 5-53 1-adamantyl H 5-54 2-methylpropyl H
5-55 3-hydroxy-3-phenylethyl H 5-56 3-methylbutyl H 5-57
(S)-1-hydroxymethyl-3- H methylbutyl 5-58 (1S)-(2S)-1- H
hydroxymethyl-2- methylbutyl 5-59 3-chloropropyl H 5-60 octyl H
5-61 1,1,3,3-tetramethylbutyl H 5-62 (R/S)-1-methylbutyl H 5-63
5-(S)-((N'-(R/S)-1- H hydroxymethylbutyl 5-64
(R/S)-1,3-dimethylbutyl H 5-65 (R)-1-hydroxymethyl-3- H methylbutyl
5-66 (R/S)-2-methylbutyl H 5-67 morpholino H 5-68
2-(2-hydroxyethoxy)-ethyl H 5-69 piperidinyl H 5-70
N"-methyl-N"-butyl H 5-71 1-(R/S)- H hydroxymethylcyclopentyl 5-72
4-hydroxybutyl H 5-73 1-(R/S)-hydroxymethyl-2- H 5-74
2-(R/S)-hydroxycyclohexyl H 5-75 isopropyl OH 5-76 1-(benzyl) OH
5-77 thiomorpholinyl H 5-78 2(R/S)-hydroxybutyl H 5-79
2,2,2-trifluoroethyl H 5-80 (4R/S)-cyclohexyl 5-81 hydroxymethyl-3-
methylthiopropyl
[0495]
11TABLE 6-1 44 Ex. R R' 6-1 phenyl H 6-2 3-fluorophenyl H 6-3
benzyl H 6-4 butyl H 6-5 octyl H
[0496]
12TABLE 7-1 45 Ex. R R' R" 7-1 3,5- NH.sub.2 isopropyl
difluorophenyl 7-2 3,5- NH.sub.2 t-butyl difluorophenyl 7-3
isopropyl NH.sub.2 methyl 7-4 phenyl NH.sub.2 methyl 7-5
3,5-difluoro NH.sub.2 methyl (Isomer A) phenyl 7-6 3,5-difluoro
NH.sub.2 methyl (Isomer B) phenyl 7-8 isopropyl NH.sub.2 methyl 7-9
phenyl NH.sub.2 methyl 7-10 3,5- NH.sub.2 methyl (Mixture of
difluorophenyl isomers) 7-11 phenyl CF.sub.3C(O)NH-- methyl 7-12
issopropyl NHCH.sub.3 methyl 7-13 1-trifluoro NH.sub.2 methyl
methyl-2,2,2- trifluoroethyl
[0497]
13TABLE 7-2 46 Ex. R R' 7-15 isopropyl --NH.sub.2
[0498]
14TABLE 7-3 47 Ex. R R' 7-17 phenyl NH.sub.2 7-18 isopropyl
NH.sub.2
[0499]
15TABLE 7-4 48 Ex. R R' 7-19 3,5-difluoro NNH.sub.2--HCl phenyl
7-20 3,5-difluoro NH.sub.2--HCl phenyl
[0500]
16TABLE 7-5 49 Ex. R. 36361 1-trifluoromeethyl ethyl 36362
3,3,3-trifluoropropyl 36363 2,2,2-trifluoroethyl
[0501]
17TABLE 7-6 50 Ex. R R.sup.1 36364 1-trifluoromethyl ethyl methyl
36365 3,3,3-trifluoropropyl methyl 36366 2,2,2-trifluoroethyl
methyl 36367 ethyl methyl 36368 1-(trifluoromethyl)-2,2,2- methyl
trifluoroethyl 36369 ethyl isobutyl
[0502]
18TABLE 8-1 51 Ex. R 8-1 3,5-difluorophenyl
[0503]
19TABLE 9-1 52 Ex. R' 9-1 methyl
[0504]
20TABLE 9-2 53 Ex. R 9-2 methyl
[0505]
21TABLE 10-1 54 Ex. R 10-1 3,5-difluorophenylmethyl
[0506]
22TABLE 10-2 55 Ex. R R' 10-2 methyl phenyl
[0507] Also included within the scope of this invention are
prodrugs of the compounds of Formulas I-VI described above
including acylated forms of alcohols and thiols, aminals of one or
more amines, and the like, as well as acid addition salts of
amines. This invention is not intended to encompass subject matter
disclosed and claimed in co-pending U.S. Ser. No. 08/996,422, the
contents of which are hereby incorporated by reference in its
entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0508] As above, this invention relates to compounds that 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.
[0509] Definitions
[0510] The term ".beta.-amyloid peptide" refers to a 39-43 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:
23 (SEQ ID NO: 1) 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
[0511] or a sequence which is substantially homologous thereto.
[0512] "Alkyl" refers to monovalent alkyl groups preferably having
from 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms and
most 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.
[0513] "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, substituted amino aminoacyl, aminoacyloxy, oxyacylamino,
cyano, halogen, hydroxyl, keto, thioketo, 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.
[0514] "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.
[0515] "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, substituted
amino aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen,
hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol,
thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic,
heterocyclooxy, heterocyclooxy, 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.
[0516] "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.
[0517] "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, substituted
amino aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen,
hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol,
thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic,
heterocyclooxy, 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.
[0518] "Alkaryl" refers to -alkylene-aryl groups where alkylene and
aryl are as defined herein. Such alkaryl groups are exemplified by
benzyl, phenethyl and the like.
[0519] "Alkoxy" refers to the group "alkyl-O-", where alkyl is as
defined above. 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.
[0520] "Substituted alkoxy" refers to the group "substituted
alkyl-O-" where substituted alkyl is as defined above.
[0521] "Alkylalkoxy" refers to the group "-alkylene-O-alkyl" where
alkylene and alkyl are as defined above. Such groups include
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.
[0522] "Alkylthioalkoxy" refers to the group "-alkylene-5-alkyl"
where alkylene and alkyl are as defined above. Such groups include
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.
[0523] "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.
[0524] "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, substituted amino aminoacyl, aminoacyloxy, oxyacylamino,
cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl,
thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl,
heterocyclic, heterocyclooxy, 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.
[0525] "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.
[0526] "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, substituted amino aminoacyl, aminoacyloxy, oxyacylamino,
cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl,
thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl,
heterocyclic, heterocyclooxy, 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.
[0527] "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.
[0528] "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.
[0529] Substituted amino" refers to the group --N(R)2, where each R
is independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,
heteroaryl, heterocyclic and where both R groups are joined to form
a heterocyclic group. When both R groups are hydrogen, --N(R)2 is
an amino group. Examples of substituted amino groups include, by
way of example, mono- and di-alkylamino, mono- and di-(substituted
alkyl)amino, mono- and di-arylamino, mono- and diheteroarylamino,
mono and di-heterocyclic amino, and unsymmetric di-substituted
amines having different substituents selected from the group
consisting of alkyl, substituted alkyl, aryl, heteroaryl,
heterocyclic and the like.
[0530] "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.
[0531] "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.
[0532] "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.
[0533] "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. Unless
otherwise constrained by the definition for the aryl substituent,
such aryl groups can optionally be substituted with from 1 to 5
substituents and preferably 1 to 3 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,
substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy,
azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
heteroaryloxy, heterocyclic, heterocyclooxy, 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. Preferred
substituents include alkyl, alkoxy, halo, cyano, nitro,
trihalomethyl, and thioalkoxy.
[0534] "Aryloxy" refers to the group aryl-O-- wherein the aryl
group is as defined above including optionally substituted aryl
groups as also defined above.
[0535] "Carboxyalkyl" refers to the group "--C(O)Oalkyl" and
"--C(O)O-substituted alkyl" where alkyl and substituted alkyl are
as defined above.
[0536] "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,
cyclohexyl, cycloheptyl, cyclooctyl, and the like, or multiple ring
structures such as adamantanyl, bicyclo[2.2.1]heptyl,
bicyclo(2.2.1)hept-5-ene-yl, bicyclo(3.3.1)non-6-ene-3-carboxyl)
and the like.
[0537] "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, substituted amino aminoacyl,
alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo,
nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,
trihalomethyl and the like.
[0538] "Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to
12 carbon atoms having at least one cyclic ring and preferably no
more than four rings, which rings are optionally fused, and which
include 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.
[0539] "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, substituted amino aminoacyl, alkaryl,
aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro,
heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and
the like.
[0540] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo
and preferably is either fluoro or chloro.
[0541] "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).
[0542] Unless otherwise constrained by the definition for the
heteroaryl substituent, such heteroaryl groups can be optionally
substituted with from 1 to 5 substituents and preferably 1 to 3
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, substituted amino, aminoacyl,
acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl,
cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, 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. Preferred substituents
include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and
thioalkoxy. 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.
[0543] "Heteroaryloxy" refers to "O-heteroaryl", where heteroaryl
is as defined herein.
[0544] "Heterocyclooxy" refers to "O-heterocyclic", where
heterocyclic is as defined herein.
[0545] "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.
[0546] 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.
[0547] 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.
[0548] "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.
[0549] "Thiol" refers to the group --SH.
[0550] "Thioalkoxy" refers to the group --S-alkyl.
[0551] "Substituted thioalkoxy" refers to the group --S-substituted
alkyl.
[0552] "Thioaryloxy" refers to the group aryl-S-- wherein the aryl
group is as defined above including optionally substituted aryl
groups also defined above.
[0553] "Thioheteroaryloxy" refers to the group heteroaryl-S--
wherein the heteroaryl group is as defined above including
optionally substituted aryl groups as also defined above.
[0554] As to any of the above groups that 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.
[0555] "Pharmaceutically acceptable salts" refers to
pharmaceutically acceptable salts of a compound of Formulas I-VI
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.
[0556] 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.
[0557] 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.
[0558] 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.
[0559] Compound Preparation
[0560] Amidation Chemistry
[0561] Compounds including amide linkages can be readily prepared
by conventional amidation of a carboxyl acid as shown in reaction
(1) below where, for the sake of illustration, n is one: 56
[0562] wherein R.sup.1, R.sup.2, W, X, and Z 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.
[0563] Various compounds as described herein can be prepared by
N-substitution reactions of compound 2. Reaction of compound 2 with
an carboxylic acid derivative can also lead to various compounds as
described herein. Both reactions are described below.
[0564] Synthesis of Carboxylic Acid Starting Materials
[0565] 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 n is one or two.
[0566] A. Synthesis of Carboxylic Acids
[0567] When 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.
[0568] 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: 57
[0569] 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.
[0570] As above, reaction (2) involves coupling of a suitable
haloacetic 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.
[0571] 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.
[0572] 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).
[0573] In still another alternative embodiment, the esterified
amino acids described above can be prepared by reductive amination
of a suitable pyruvate ester in the manner illustrated in reaction
(3) below: 58
[0574] wherein R is typically an alkyl group and R.sup.1 and
R.sup.2 are as defined above.
[0575] 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 that 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 8.
[0576] 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 the reaction is complete, 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.
[0577] Subsequent hydrolysis of the ester 8 leads to the
corresponding carboxylic acid derivative 1 which can be employed in
reaction (1) above.
[0578] For compounds where 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.
[0579] 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.
[0580] When n is one, a first synthetic method involves
conventional coupling of an carboxylic acid derivative with a
primary amine of an esterified amino acid as shown in reaction (4)
below: 59
[0581] wherein R is typically an alkyl group and R.sup.1, R.sup.2,
X' and X" are as defined above.
[0582] Reaction (4) merely involves coupling of a suitable
carboxylic acid derivative 9 with the primary amine of amino acid
ester 10 under conditions that provide for the N-acetyl derivative
11. Alternatively, the carboxylic acid R'COOH can be used in place
of compound 9 to provide intermediates useful for preparing
compounds of Formula VI above. 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, or
tetrahydrofuran. 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, and
N-methylmorpholine.
[0583] Reaction (4) is preferably conducted at from about 0.degree.
C. to about 60.degree. C. until the reaction is complete, 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, and
filtration or alternatively is hydrolyzed to the corresponding acid
without purification and/or isolation other than conventional
work-up (e.g., aqueous extraction, etc.).
[0584] In reaction (4), each of the reagents (carboxylic acid
derivative 9 and amino acid ester 10) are well known in the art
with a plurality of each being commercially available.
[0585] When 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 and 1-hydroxybenzotriazole,
which can be used to facilitate coupling. The reaction is
conventionally conducted in an inert aprotic polar diluent such as
dimethylformamide, dichloromethane, chloroform, acetonitrile, or
tetrahydrofuran. De-esterification of the resulting ester provides
for carboxylic acids 1 having n equal to 2.
[0586] 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.
[0587] Carboxylic acids 1 having n equal to 1 or 2 can also be
prepared by using 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 preparing such compounds.
[0588] Polymers suitable for use in making a polymer-supported
coupling reagent are either commercially available or may be
prepared by methods well known to those of skill 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 backbone must be inert to both the
carbodiimide and reaction conditions under which the ultimate
polymer-bound coupling reagents will be used.
[0589] 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.
[0590] 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. 60
[0591] Such methods are described more fully in PCT Application
PCT/US97/22986, 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.
[0592] The carboxylic acid coupling reactions employing these
reagents are performed at about ambient temperature to about
45.degree. C., for from about 3 to 120 hours. Typically, the
product is isolated by washing the reaction mixture 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.
[0593] Sulfonamidation Chemistry
[0594] Sulfonamides, such as those in Formula III, can be readily
prepared using known sulfonamidation reactions. These typically
involve the reaction of sulfonyl chlorides with primary or
secondary amines in the presence of a tertiary amine or other
suitable acid scavenger (See, for Example, page-923, Morrison and
Boyd, Organic Chemistry, fourth edition).
[0595] Synthesis of Sulfonic Acid Starting Materials
[0596] Suitable sulfonic acids can be prepared by several divergent
synthetic routes with the particular route selected relative to the
ease of compound preparation, and commercial availability of
starting materials.
[0597] A. Synthesis of Sulfonic Acids
[0598] Alkyl sulfonic acids can be prepared using means well known
to those of skill in the art, as described, for example, in U.S.
Pat. Nos. 2,493,038 and 2,697,722, the contents of which are hereby
incorporated by reference. One method for preparing alkyl sulfonic
acids is by the oxidation of disulfides, which can themselves be
prepared by the oxidation of thiols. Aromatic sulfonic acids can be
produced by the sulfonating action of sulfuric acid, SO.sub.3,
oleum or alkyl sulfonic acids on aromatic compounds using
techniques well known to those of skill in the art.
[0599] Activation of Sulfonic Acids
[0600] Suitable sulfonic acid derivatives can be prepared, for
example, by reacting a sulfonic acid with a chlorinating reagent
such as phosphorous pentachloride or sulfonyl chloride.
[0601] Preparation of Ureas
[0602] Ureas can be prepared by any known methodology, but
preferably are prepared by reacting an amine with an isocyanate, as
described on page 844 of Morrison and Boyd, Organic Chemistry,
Fourth Edition, Allyn and Bacon, ed., Boston (1983). Suitable
isocyanates can be prepared using methods known to those of skill
in the art.
[0603] Preparation of Cyclic Amino Compounds
[0604] Cyclic amino compounds 2 employed in reaction (1) above are
generally aminolactams, aminolactones, aminothiolactones and
aminocycloalkyl compounds which can be represented by the formula:
61
[0605] wherein 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.
[0606] The aminolactams, aminolactones and aminothiolactones of the
formulas 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.
[0607] Specifically, 3-amino substituted lactams 13 with 5, 6 or 7
ring atoms may be prepared by the direct cyclization of a suitable
a, omega-diamino acid ester 12 as shown in reaction (5) below:
62
[0608] 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 16 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.
[0609] 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: 63
[0610] wherein L and R.sup.6 are as defined above.
[0611] 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: 453-14536 (1996).sup.19.
[0612] 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: 64
[0613] where R.sup.6 is as defined above.
[0614] 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.
[0615] In another method, lactams 20 can be prepared from cyclic
ketones 19 using either the well known Beckmann 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: 65
[0616] wherein L is as defined above.
[0617] Application of these two reactions leads to a wide variety
of lactams especially lactams having two hydrogen atoms on the
carbon a to the lactam carbonyl which lactams form a preferred
group of lactams in the synthesis of the compounds described 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.
[0618] 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.
[0619] 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: 66
[0620] where R.sup.10 is exemplified by alkyl, substituted alkyl,
alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and
heterocyclic.
[0621] In this reaction, ketone 21 is converted to an
.alpha.-(w-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 heteroatoms at non-reactive sites in these
rings is feasible in preparing heterobicyclic lactams.
[0622] 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: 67
[0623] 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.
[0624] 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 as 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.
[0625] 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: 68
[0626] In this reaction, proline derivative 27 is cyclized via a
tributyltin-radical cyclization to provide for lactam 28.
[0627] Some of the lactams described above contain the requisite
amino group a 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.
[0628] For example, in a first general synthetic procedure, azide
or amine displacement of a leaving group a 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.
[0629] 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.
[0630] 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.
[0631] 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
[0632] In a second general synthetic procedure, reaction of an
enolate with an alkyl nitrite ester to prepare the a 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
[0633] 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.
[0634] 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:
69
[0635] where Pr is as defined above and R.sup.12 is typically
hydrogen, an alkyl or an aryl group.
[0636] 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=H or a protecting group such as Boc. For
example, when R=H, treatment of the acid with diphenylphosphoryl
azide in the presence of t-butanol provides the product wherein
Pr=Boc.
[0637] 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.
[0638] 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).
[0639] A second general method employs reductive amination on an
amino function that is then cyclized to an appropriate ester or
other carbonyl function.
[0640] 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
[0641] 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. 70
[0642] 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 described 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.
[0643] Monocyclic lactams as described by Nedenskov, et al., Acta
Chem. Scand., 12: 1405-1410 (1958).sup.52 are represented by the
formula: 71
[0644] where R.sub.1 and R.sub.2 are exemplified by alkyl, aryl or
alkenyl (e.g., allyl).
[0645] 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: 72
[0646] where R is exemplified by CH.sub.3-- or PhCH.sub.2--.
[0647] 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: 73
[0648] where R is exemplified by benzyl (includes both the cis and
trans hydroxy lactams).
[0649] 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: 74
[0650] wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or
benzyl.
[0651] 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: 75
[0652] 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: 76
[0653] 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.
[0654] 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: 77
[0655] 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.
[0656] 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: 78
[0657] 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.
[0658] Additional references for the synthesis of .alpha.
aminolactams are as follows:
[0659] 1. Shirota, et al., J. Med. Chem., 20: 1623-1627
(1977).sup.60 which describes the synthesis of 79
[0660] 2. Overberger, et al., J. Am. Chem. Soc., 85: 3431
(1963).sup.61 which describes the preparation of optically active
-methylcaprolactam of the formula: 80
[0661] 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: 81
[0662] 4. Overberger, et al., Macromolecules, 1: 1 (1968).sup.63
describes the synthesis of eight-membered lactams from
3-methylcycloheptanone as shown below: 82
[0663] 5. The synthesis of benzolactams (benzazepinones) has been
reported by Busacca, et al., Tet. Lett., 33: 165-168 (1992).sup.64:
83
[0664] by Croisier, et al., U.S. Pat. No. 4,080,449.sup.65: 84
[0665] 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: 85
[0666] Another tricyclic lactam series is disclosed by Flynn, et
al., J. Med. Chem., 36: 2420-2423 (1993).sup.67 and references
cited therein.
[0667] 6. Orito, et al., Tetrahedron, 36: 1017-1021 (1980).sup.68
discloses phenyl substituted benzazepinones represented by the
formula: 86
[0668] wherein R=H or CH.sub.3--;
[0669] Kawase, et al., J. Org. Chem., 54: 3394-3403 (1989).sup.69
discloses a N-methoxy benzazepinone represented by the formula:
87
[0670] 7. Lowe, et al., J. Med. Chem., 37: 3789-3811 (1994).sup.70
describes several synthetic pathways to substituted benzazepinones
of the formula: 88
[0671] 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.
[0672] 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: 89
[0673] where X is O and R.sub.2=H or CH.sub.3 or X=S and R.sub.2=H.
In either case, R.sub.1=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
[0674] 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: 90
[0675] where X is O or H.sub.2 and R is CO.sub.2R.
[0676] 10. Further examples of benzazepinones are found in
Warshawsky, et al., Bioorg. Med. Chem. Lett., 6: 957-962
(1996).sup.75 which discloses 91
[0677] The synthesis can be generalized to produce R=alkyl or
aryl.
[0678] 11. Ben-Ishai, et al., Tetrahedron, 43: 439-450
(1987).sup.76 describes syntheses which could lead to several
benzolactams of the formula 92
[0679] wherein n=0, 1,2 and R.ident.CH.sub.3, PhCH.sub.2-- and
H.
[0680] 12. van Niel et al., Bioorg. Med. Chem. Lett., 5: 1421-1426
(1995).sup.77 reports the synthesis of 93
[0681] 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.
[0682] 13. Kawase, et al., J. Org. Chem., 54: 3394-3403
(1989).sup.78 describes a synthetic method for the preparation of:
94
[0683] In addition to the above, saturated bicyclic
.alpha.-aminolactams are also contemplated for use in the synthesis
of compounds of formulas I-VI. 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:
95
[0684] 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: 96
[0685] 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.
[0686] 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: 97
[0687] 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: 98
[0688] and by Wyvratt, et al., Eur. Pat. Appl. 61187 (1982).sup.83
who describe a lactam of the formula: 99
[0689] 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: 100
[0690] 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: 101
[0691] wherein X=O, S and NR where R is, for example, alkyl,
substituted alkyl, aryl, heteroaryl, heterocyclic, heterocyclooxy,
and the like.
[0692] 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:
102
[0693] 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, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy,
heterocyclic, heterocyclooxy, halo, cyano, nitro, trihalomethyl,
and the like.
[0694] 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: 103
[0695] Ring expansion methodology based on P 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
[0696] 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
104
[0697] wherein 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, heterocyclooxy, alkenyl, substituted alkenyl, and the
like.
[0698] 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: 105
[0699] wherein R' is as defined in the reference and R can be
alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy,
heteroaryl, cycloalkyl, heterocyclic, heterocyclooxy, alkenyl,
substituted alkenyl, and the like.
[0700] 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: 106
[0701] 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: 107
[0702] 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.
4,460,579.sup.94 and Kametani, et al., Heterocycles, 2: 831-840
(1978)..sup.95
[0703] The Friedinger procedure can be extended to afford
disubstituted thialactams of the following structure: 108
[0704] 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.
[0705] Still further is the Kametani procedure which provides for
lactams as follows: 109
[0706] In principle, the Kametani procedure allows for a wide
selection of R1 and R2 groups limited primarily by stability to the
reaction conditions.
[0707] 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: 110
[0708] The first synthetic route is: 111
[0709] 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.
[0710] The second compound series can be prepared as follows:
112
[0711] 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.
[0712] 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 involve
the 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 used in 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.
[0713] Deoxygenation of the lactam by reagents such as diborane,
LiAlH.sub.4, and the like leads to azaheterocycles (.dbd.X is
dihydro).
[0714] 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 Formulas I-VI,
.dbd.X being H, OH can be oxidized to provide for cycloalkylones
(.dbd.X being oxo).
[0715] Additionally, the 5,7-dihydro-6H-dibenz[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-dibenz[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.
[0716] After forming the 5,7-dihydro-6H-dibenz[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.
[0717] 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.
[0718] 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
oxalyl 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-[-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-aminobenzophenone.
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)-glycinyl]amin-
obenzophenone. 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-
e 1. Subsequent removal of the Cbz group affords the
3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one.
[0719] 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.
[0720] 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.
[0721] 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 Formulas I-VI above.
[0722] In the synthesis of the compounds described herein 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.
[0723] Pharmaceutical Formulations
[0724] When employed as pharmaceuticals, the compounds described
herein 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.
[0725] The pharmaceutical compositions contain, as the active
ingredient, one or more of the compounds described above,
associated with pharmaceutically acceptable carriers. The
pharmaceutical compositions can be prepared, for example, by mixing
the active ingredient with an excipient, diluting the active
ingredient with an excipient, or enclosing the active ingredient
within a carrier such as a capsule (including microparticles,
nanoparticles, and liposomes), 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.
[0726] 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.
[0727] 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.
[0728] 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
Formulas I-VI 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).
[0729] 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, and the severity of the patient's symptoms.
[0730] 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.
[0731] 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.
[0732] The liquid forms in which the compositions 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.
[0733] 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.
[0734] The following formulation examples illustrate the
pharmaceutical compositions of the present invention.
FORMULATION EXAMPLE 1
[0735] Hard gelatin capsules containing the following ingredients
are prepared:
24 Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch
305.0 Magnesium stearate 5.0
[0736] The above ingredients are mixed and filled into hard gelatin
capsules in 340 mg quantities.
FORMULATION EXAMPLE 2
[0737] A tablet formula is prepared using the ingredients
below:
25 Quantity Ingredient (mg/tablet) Active Ingredient 25.0
Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0
Stearic acid 5.0
[0738] The components are blended and compressed to form tablets,
each weighing 240 mg.
FORMULATION EXAMPLE 3
[0739] A dry powder inhaler formulation is prepared containing the
following components:
26 Ingredient Weight % Active Ingredient 5 Lactose 95
[0740] The active ingredient is mixed with the lactose and the
mixture is added to a dry powder inhaling appliance.
FORMULATION EXAMPLE 4
[0741] Tablets, each containing 30 mg of active ingredient, are
prepared as follows:
27 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
[0742] 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 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
[0743] Capsules, each containing 40 mg of medicament are made as
follows:
28 Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg
Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg
[0744] 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
[0745] Suppositories, each containing 25 mg of active ingredient
are made as follows:
29 Ingredient Amount Active Ingredient 25 mg Saturated fatty acid
glycerides to 2,000 mg
[0746] 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
[0747] Suspensions, each containing 50 mg of medicament per 5.0 ml
dose are made as follows:
30 Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose
(89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and
Color q.v. Purified water to 5.0 ml
[0748] 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
[0749]
31 Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg
Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg
[0750] 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
[0751] A subcutaneous formulation may be prepared as follows:
32 Ingredient Quantity Active Ingredient 1.0 mg corn oil 1 ml
[0752] (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
[0753] A topical formulation may be prepared as follows:
33 Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30
g Liquid Paraffin 20 g White Soft Paraffin to 100 g
[0754] 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.
[0755] 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.
[0756] 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.
[0757] 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.
[0758] 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).
[0759] Utility
[0760] 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.
[0761] 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, the
contents of each of which is incorporated herein by reference.
[0762] 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.
[0763] 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 a "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.
[0764] 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.
[0765] 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.
[0766] 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
[0767] In the examples below, the following abbreviations have the
following meanings. If an abbreviation is not defined, it has its
generally accepted meaning.
[0768]
BEMP=2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-di-
azaphosphorine
[0769] Boc=t-butoxycarbonyl
[0770] BOP=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate
[0771] bd=broad doublet
[0772] bs=broad singlet
[0773] d=doublet
[0774] dd=doublet of doublets
[0775] DIC=diisopropylcarbodiimide
[0776] DMF=dimethylformamide
[0777] DMAP=dimethylaminopyridine
[0778] DMSO=dimethylsulfoxide
[0779] EDC=ethyl-1-(3-dimethyaminopropyl)carbodiimide
[0780] eq.=equivalents
[0781] EtOAc=ethyl acetate
[0782] g=grams
[0783] HOBT=1-hydroxybenzotriazole hydrate
[0784] Hunig's base=diisopropylethylamine
[0785] L=liter
[0786] m=multiplet
[0787] M=molar
[0788] max=maximum
[0789] meq=milliequivalent
[0790] mg=milligram
[0791] mL=milliliter
[0792] mm=millimeter
[0793] mmol=millimole
[0794] MOC=methoxyoxycarbonyl
[0795] N=normal
[0796] N/A=not available
[0797] ng=nanogram
[0798] nm=nanometers
[0799] OD=optical density
[0800] PEPC=1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide
[0801] PP-HOBT=piperidine-piperidine-1-hydroxybenzotrizole
[0802] psi=pounds per square inch
[0803] =phenyl
[0804] q=quartet
[0805] quint.=quintet
[0806] rpm=rotations per minute
[0807] s=singlet
[0808] t=triplet
[0809] TFA=trifluoroacetic acid
[0810] THF=tetrahydrofuran
[0811] tlc=thin layer chromatography
[0812] L=microliter
[0813] UV=ultra-violet
[0814] 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.
[0815] 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.
[0816] 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.
[0817] 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.
[0818] The term "Sigma" indicates that the compound or reagent is
commercially available from Sigma, P.O. Box 14508, St. Louis Mo.
63178 USA;
[0819] The term "Chemservice" indicates that the compound or
reagent is commercially available from Chemservice, Inc.,
Westchester, Pa.
[0820] The term "Bachem" indicates that the compound or reagent is
commercially available from Bachem Biosciences Inc., 3700 Horizon
Drive, Renaissance at Gulph Mills, King of Prussia, Pa. 19406
USA.
[0821] The term "Maybridge" indicates that the compound or reagent
is commercially available from Maybridge Chemical Co. Trevillett,
Tintagel, Cornwall PL34 OHW United Kingdom.
[0822] The term "TCI" indicates that the compound or reagent is
commercially available from TCI America, 9211 North Harborgate
Street, Portland Oreg. 97203.
[0823] 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.
[0824] 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.
[0825] The term "Oakwood" indicates that the compound or reagent is
commercially available from Oakwood, Columbia, S.C.
[0826] The term "Advanced Chemtech" indicates that the compound or
reagent is commercially available from Advanced Chemtech,
Louisville, Ky.
[0827] The term "Pfaltz & Bauer" indicates that the compound or
reagent is commercially available from Pfaltz & Bauer,
Waterbury, Conn., USA.
[0828] I. Coupling Procedures
General Procedure A
First EDC Coupling Procedure
[0829] 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
O 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
[0830] 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 filtration,
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
[0831] 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
[0832] 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
[0833] 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-.alpha.-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 was 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
[0834] 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
[0835] 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
[0836] 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
[0837] 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
EEDO Coupling Procedure
[0838] 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.
[0839] II. Carboxylic Acids
General Procedure II-A
Ester Hydrolysis to Free Acid
[0840] Ester hydrolysis to the free acid was conducted by
conventional methods. Below are two examples of such conventional
de-esterification methods.
[0841] 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.
[0842] 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
[0843] A carboxylic acid is dissolved in dichloromethane and this
solution is cooled to 0.degree. C. DMF (0.5 mL, catalytic) is
added, followed by the dropwise addition of oxalyl chloride (18 mL,
0.20 mol) over a 5 minute period. The reaction is stirred for 3 h
and then rotoevaporated at reduced pressure to give an oil which is
placed on a high vacuum pump for 1 h to afford the acid
chlorides.
General Procedure II-C
Schotten-Baumann Procedure
[0844] The acid chloride (from General Procedure II-B) is 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) or another
amino acid such as tert-leucine or phenyl glycine. The reaction is
stirred for 1 h at 0.degree. C. and then overnight at room
temperature. The reaction is diluted with water (100 mL), then
extracted with ethyl acetate (3.times.150 mL). The organic layer is
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 affords the desired
product in high yield.
General Procedure II-D
Reductive Amination
[0845] To a solution of an arylamine in ethanol in a hydrogenation
flask is added 1 equivalent of a 2-oxocarboxylic acid ester (e.g.,
pyruvate ester), followed by 10% palladium on carbon (25 weight
percent based on the arylamine). The reaction mixture is
hydrogenated at 20 psi H.sub.2 on a Parr shaker until complete
reaction is indicated by tlc (30 minutes to 16 hours). The reaction
mixture is 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 can then be
further purified via chromatography.
[0846] 3. Cyclic Ketone Derivatives
General Procedure 3-A
Jones Oxidation Procedure
[0847] The compound to be oxidized is stirred in acetone and the
Jones reagent is added in portions until the starting material is
consumed. The reaction mixture is quenched with isopropanol and the
mixture is filtered through Celite and concentrated under reduced
pressure. The residue is partitioned between ethyl acetate and
water and the organic portion is dried over sodium sulfate and then
concentrated under reduced pressure. The crude product is purified
by silica gel chromatography and/or recrystallization.
General Procedure 3-B
Swern Oxidation Procedure
[0848] To a stirred mixture of oxalyl chloride (0.1.5 mL, 1.2 mmol)
in 10 mL of dichloromethane cooled to -78.degree. C. is added DMSO
(0.106 mL, 1.5 mmol) and the mixture is stirred for 10 minutes. A
solution of the alcohol (0.1828 g, 0.60 mmol) in 20 mL of
chloroform is added dropwise. The reaction mixture is stirred at
-78.degree. C. for 2 hours, and then 0.5 mL (3.6 mmol) of
triethylamine is added. Stirring is continued for 1 hour and then
the mixture is allowed to warm to room temperature and stirring is
continued at ambient temperature overnight. The mixture is then
diluted with 50 mL of dichloromethane, washed with brine
(3.times.), dried over magnesium sulfate, filtered and evaporated
to dryness to give a crude product that is typically purified by
column chromatography.
[0849] 5. Lactams
General Procedure 5-A
N-Alkylation of Lactams
[0850] 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 occurred
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-alkylated lactams. Various bases, such as LiN(SiMe.sub.3), may
also be employed.
General Procedure 5-B
BOC Removal Procedure
[0851] The BOC-protected compound in a 1:1-2:1 mixture of
CH.sub.2Cl.sub.2 and trifluoroacetic acid was stirred until tlc
indicated complete conversion, typically 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 A-Aminolactams
[0852] 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 a position and reduced by hydrogenation to
provide four isomeric monochlorides (two racemic mixtures). 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.-aminolactams.
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
[0853] 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:
[0854] 3-amino-1,2,3,4-tetrahydroisoquinolin-3-one
[0855] 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
[0856] 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
[0857] cis and
trans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one
[0858] 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one
[0859] 4-amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one
[0860] 9-amino(fluoren-1-yl)glycine
d-lactam-1,2,3,4-tetrahydroisoquinolin- -3-one.
[0861] 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.
[0862] Step B--Coupling Procedure: To 0.0291 moles of
N-bismethoxycarbonylaminoacetic acid (or the appropriate
carbocyclic acid) in 200 mL of THF was added one mole equivalent of
EDCCHCl, 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%.
[0863] 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.
[0864] Step D--Removal of the Methoxyoxycarbonyl Group (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
separatory 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%.
[0865] 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
[0866] 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, 100M %) 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.
[0867] 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).
[0868] 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
[0869] 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-a-benzyl amine as a thick yellow
oil.
[0870] Step B: Following General Procedure 5-D and using
4-pyridyl-a-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
[0871] Step A: 2-Pyridyl-a-benzyl amine was prepared by
substituting 2-cyanopyridine (Aldrich) for 4-cyanopyridine in the
procedure described in Example 5-B.
[0872] Step B: Following General Procedure 5-D and using
4-pyridyl-a-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
[0873] Step A: Following the procedure described in J. Med. Chem.,
1982, 25, 1248, and using 3-benzoyl-pyridine (Aldrich),
3-pyridyl-a-benzyl amine was prepared.
[0874] Step B: Following General Procedure 5-D and using
3-pyridyl-a-benzyl amine, the title compound was prepared.
Example 5-E
Synthesis of
4-Amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one
[0875] 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 filtrate 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.
[0876] 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.
[0877] 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-A17 (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.
[0878] 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
[0879] 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.
[0880] 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
[0881] Step A: Following General Procedure 5-D and using
a-phenylbenzylamine (Aldrich),
4-amino-1-phenyl-1,2,3,4-tetrahydroisoquin- olin-3-one was
prepared.
[0882] 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/hexanes (70:30) to give the pure cis isomer.
[0883] 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
[0884] 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.
[0885] 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.
[0886] 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
[0887] 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.
[0888] Step B: Reduction of N-phenethyl benzamide using the
procedure of Example 5-E, Step C afforded N-benzyl-N-phenethylamine
as an oil.
[0889] 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
[0890] 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# 298-124, Aldrich), and methyl
carbamate (CAS# 598-55-0, Aldrich).
[0891] 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
[0892] 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
[0893] 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
[0894] 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.
[0895] Selected .sup.1H-NMR data for the title compound
(CDCl.sub.3): d=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
[0896] 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
[0897] 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.
[0898] Selected .sup.1H-NMR data for the title compound
(CDCl.sub.3): d=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
[0899] 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
[0900] 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.
[0901] Selected .sup.1H-NMR data for the title compound
(CDCl.sub.3): d=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
[0902] 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
[0903] 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.
[0904] Selected .sup.1H-NMR data for the title compound
(CDCl.sub.3): d=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
[0905] 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-d-valerolactam
Step A:--Synthesis of L-(+)-Ornithine Methyl Ester
Hydrochloride
[0906] 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-d-valerolactam
[0907] 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-d-valerolactam (44% yield).
Step C:--Synthesis of N-Boc-(S)-3-Amino-d-valerolactam
[0908] (S)-3-Amino-d-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 rotary evaporated to afford
N-Boc-(S)-3-amino-d-valerolactam.
Step D:--Synthesis of (S)-3-Amino-1-benzyl-d-valerolactam
[0909] Following General Procedure 5-A and using
N-Boc-(S)-3-amino-d-valer- olactam and benzyl bromide provided
N-Boc-(S)-3-amino-1-benzyl-d-valerolac- tam. 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-oxo-bicyclo[3.2.1]octane
Hydrochloride
Step A:--Synthesis of 2-Aza-3-oxo-bicyclo[3.2.1]octane and
3-Aza-2-oxo-bicyclo[3.2.1]octane (9:1 Mixture)
[0910] To (")-norcamphor (Aldrich) in 1 mL/mmole of acetic acid was
added 1.5 eq. of hydroxylamine-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-oxo-bicyclo[3.2.1]octane and
3-aza-2-oxo-bicyclo[3.2.1]octane.
Step B:--Synthesis of 2-Aza-2-benzyl-3-oxo-bicyclo[3.2.1]octane
[0911] Following General Procedure 5-A and using the product for
Step A and benzyl bromide,
2-aza-2-benzyl-3-oxo-bicyclo[3.2.1]octane was prepared.
Step C:--Synthesis of
2-Aza-2-benzyl-4-oximino-3-oxo-bicyclo[3.2.1]octane
[0912] To a solution of 2-aza-2-benzyl-3-oxo-bicyclo[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-oxo-bicyclo[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-oxo-bicyclo[3.2.1]octane
[0913] A solution of
2-aza-2-benzyl-4-oximino-3-oxo-bicyclo[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).
[0914] 6. Benzazepinone Derivatives and Related Compounds
General Procedure 6-A
Alkylation of 1-Amino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
[0915] 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.
[0916] 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
chromatography (30% EtOAc/hexanes) yielded
1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin--
2-one in 87% yield.
[0917] 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
[0918] 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:
[0919] 5-methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
(from 4-methyl-.alpha.-tetralone (Aldrich)); and
[0920]
5,5-dimethyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from
4,4-dimethyl-.alpha.-tetralone (Aldrich)).
[0921] 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
mixture 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-2H-1-benzazepin-2-one in 87% yield.
[0922] 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.
[0923] Step D: The BOC-protected
3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-b- enzazepin-2-one (11.0 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
[0924] 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.
[0925] 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 rotary 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.
[0926] 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.
[0927] 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
[0928] 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
[0929] 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, followed 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.
[0930] 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
[0931] 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.
[0932] 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
[0933] 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.
[0934] 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
[0935] 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.
[0936] 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
[0937] Step A: 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]azepin-6-one was prepared.
[0938] 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.
[0939] 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
[0940] 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
[0941] 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
[0942] 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.
[0943] NMR data was as follows:
[0944] .sup.1-nmr (CDCl.sub.3): d=7.62 (d, 2H), 7.26-7.47 (m, 6H),
3.51 (m, 2H), 3.32 (s, 3H).
[0945] C.sub.5H.sub.13NO (MW=223.27); mass spectroscopy (MH+)
223.
[0946] 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
[0947] 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.
[0948] C.sub.15H.sub.12N.sub.2O.sub.2 (MW=252.275); mass
spectroscopy (MH+) 252.
[0949] 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
[0950] 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.
[0951] NMR data was as follows:
[0952] .sup.1H-nmr (DMSOd6): d=9.11 (bs, 3H), 7.78-7.41(m, 8H),
4.83 (s, 1H), 3.25 (s, 3H).
[0953] C.sub.15H.sub.14N.sub.2O HCl (MW=274.753); mass spectroscopy
(MH+ free base) 238.
[0954] 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
[0955] 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)
(Aldrich) 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.
[0956] Isomer 1: Retention time 3.37 minutes.
[0957] NMR data was as follows:
[0958] 1H-nmr (CDCl.sub.3): d=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).
[0959] Optical Rotation: [a].sub.20=-96 @ 589 nm (c=1, MeOH).
[0960] C.sub.23H.sub.27N.sub.3O.sub.4 (MW=409.489); mass
spectroscopy (MH+) 409.
[0961] 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.
[0962] Isomer 2: Retention time 6.08 minutes.
[0963] NMR data was as follows:
[0964] .sup.1H-nmr (CDCl.sub.3): d=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).
[0965] Optical Rotation: [a].sub.20=69 @ 589 nm (c=1, MeOH).
[0966] C.sub.23H.sub.27N.sub.3O.sub.4 (MW=409.489); mass
spectroscopy (MH+) 409.
[0967] 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
[0968] 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.
[0969] Isomer 1:
[0970] C.sub.18H.sub.19N.sub.3O.sub.2.HCl (MW=345.832); mass
spectroscopy (MH+ free base) 309.
[0971] Optical Rotation: [a].sub.20-55 @ 589 nm (c=1, MeOH).
[0972] Isomer 2:
[0973] C.sub.18H.sub.19N.sub.3O.sub.2.HCl (MW=345.832); mass
spectroscopy (MH+ free base) 309.
[0974] Optical Rotation: [a].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-5,7-d-
ihydro-6H-dibenz[b,d]azepin-6-one
[0975] 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.
[0976] Isomer 1: Retention time 3.23 minutes.
[0977] Optical Rotation: [a].sub.20=-120 @ 589 nm (c=1, MeOH).
[0978] C.sub.25H.sub.31N.sub.3O.sub.4 (MW=437.544); mass
spectroscopy (MH+438
[0979] Isomer 2: Retention time 6.64 minutes.
[0980] Optical Rotation: [a].sub.20=50 @ 589 nm (c=1, MeOH).
[0981] 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
[0982] 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.
[0983] Isomer 1:
[0984] C.sub.20H.sub.23N.sub.3O.sub.2.HCl (MW=373.88); mass
spectroscopy (MH+ free base) 338.
[0985] Optical Rotation: [a].sub.20=-38 @ 589 nm (c=1, MeOH).
[0986] Isomer 2:
[0987] C.sub.20H.sub.23N.sub.3O.sub.2.HCl (MW=373.88); mass
spectroscopy (MH+ free base) 338.
[0988] Optical Rotation: [a].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
[0989] 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.
[0990] Isomer 1: Retention time 3.28 minutes.
[0991] Optical Rotation: [a].sub.20=-128 @ 589 nm (c=1, MeOH).
[0992] C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451.571); mass
spectroscopy (MH+) 452
[0993] Isomer 2: Retention time 5.52 minutes.
[0994] Optical Rotation: [a].sub.20=26 @ 589 nm (c=1, MeOH).
[0995] 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
[0996] 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.
[0997] Isomer 1:
[0998] C.sub.21H.sub.25N.sub.3O.sub.2.HCl (MW=387.91); mass
spectroscopy (MH+ free base) 352.
[0999] Optical Rotation: [a].sub.20=-34 @ 589 nm (c=1, MeOH).
[1000] Isomer 2:
[1001] C.sub.21H.sub.25N.sub.3O.sub.2.HCl (MW=387.91); mass
spectroscopy (MH+ free base) 352.
[1002] Optical Rotation: [a].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
[1003] 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.2 and
treated with TMSI (1.36 ml, 9.54 mmol). After stirring for 15
minutes 12 (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
[1004] 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
[1005] 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
[1006] 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).
[1007] C.sub.23H.sub.28N.sub.2O.sub.3 (MW=380.41); mass
spectroscopy (MH+) 381
[1008] Anal. Calcd for C.sub.3H.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
[1009] 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
[1010] 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).
[1011] C.sub.22H.sub.24N.sub.2O.sub.5 (MW=396.44); mass
spectroscopy (MH+) 397
[1012] 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
[1013] 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.
[1014] 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
[1015] 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.
[1016] 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
[1017] 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-I
Synthesis of
L-Alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin--
6-one Hydrochloride
[1018] 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.
[1019] 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
[1020] 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.
[1021] 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
[1022] 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
[1023] 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]az-
epin-6-one
[1024] 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
[1025] 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
[1026] Step 1: 2-Bromo-5-fluorotoluene was stirred in THF at -78 C.
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 warn 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.
[1027] 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.
[1028] 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.
[1029] 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.
[1030] 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.
[1031] 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.
[1032] 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
[1033] 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
[1034] 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-dihydr- o-6H-dibenz[b,
d]azepin-6-one Hydrochloride
[1035] 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
[1036] 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
[1037] 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
[1038] 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
[1039] 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.
[1040] 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
[1041] 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
[1042] 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-0,5,7-dihydro-6H-dibenz-
[b,d]azepin-6-one Hydrochloride
[1043] 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 7-0), 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
[1044] 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
[1045] 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.
[1046] Desired enantiomer 1: retention time of 9.97 minutes.
[1047] Undesired enantiomer 2: retention time of 8.62 minutes.
[1048] NMR data was as follows:
[1049] .sup.1H-nmr (CDCl.sub.3): d=9.39 (s, 2H), 7.75-7.42 (m, 8H),
4.80 (s, 1H), 3.30 (s, 3H).
[1050] C.sub.15H.sub.15ClN.sub.2O (MW=274.75); mass spectroscopy
(MH.sup.+) 239.1.
[1051] 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.
[1052] 8. Benzodiazepine Derivatives and Related Compounds
General Procedure 8-A
N-1-Methylation of Benzodiazepines
[1053] 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
[1054] 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
[1055] 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
[1056] 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
[1057] 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
.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
[1058] 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
[1059] 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
[1060] 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
[1061] 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 diluted 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
[1062] 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
[1063] 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
[1064] 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
[1065] 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. 4979948-6) 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
[1066] 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
[1067] 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 EC, 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.
[1068] C.sub.15H.sub.19N.sub.3O (MW 257.37); mass spectroscopy
257.
[1069] 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-benzodiazepin-2-one
[1070] 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.
[1071] .sup.1H NMR data of the E/Z isomers was as follows:
[1072] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
[1073] 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-
imido]-5-(1-piperidinyl)-1,4-benzodiazepin-2-one
[1074] 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.
[1075] .sup.1H NMR data of the E/Z isomers was as follows:
[1076] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
[1077] 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
[1078] 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-pheny-
l-1H-1,4-benzodiazepin-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
[1079] 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-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1080]
(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.
[1081] C.sub.24H.sub.28N.sub.4O.sub.4 (MW 436.56); mass
spectroscopy 436.
[1082] 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.
Step C--Preparation of
3-(L-Alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one
[1083] 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.
[1084] 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
[1085] 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 20630% ethyl acetate/hexanes.
[1086] C.sub.24H.sub.2.degree. ClN.sub.3O.sub.3 (MW=433.92); mass
spectroscopy 433.
[1087] 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
[1088] 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-chlor-
o-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one
[1089] 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.
[1090] C.sub.24H.sub.28ClN.sub.4O.sub.4 (MW=471.18); mass
spectroscopy 471
[1091] 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
[1092] Following General Procedure 8-C using
3-[N-tert-butylcarbamate)-L-a-
laninyl]-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. 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
[1093] 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.
[1094] C.sub.24H.sub.19BrFN.sub.3O.sub.3 (MW=496.36); mass
spectroscopy 497.
[1095] 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
[1096] 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
[1097] 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.
[1098] C.sub.24H.sub.26BrFN.sub.4O.sub.4 (MW=533.12); mass
spectroscopy 533.2.
[1099] 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-1,3-dihydro-1-methyl-5-
-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one
[1100] 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-1-
H-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
[1101] 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.
[1102] C.sub.25H.sub.30N.sub.4O.sub.4 (MW=450.2); mass spectroscopy
(M+1) 451.2.
[1103] 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
[1104] 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-benzodi-
azepin-2-one, the title intermediate was prepared as a white
foam.
[1105] C.sub.20H.sub.22N.sub.4O.sub.2 (MW=350.46); mass
spectroscopy (M+1) 351.4.
[1106] 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-benzodiazepin-2-one
[1107] 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.
[1108] C.sub.24H.sub.19Cl.sub.2N.sub.3O.sub.3 (MW=468.36); mass
spectroscopy 468.
[1109] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
[1110] .sup.13C NMR (75 MHz, CDCl.sub.3): d=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
[1111] 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
[1112] 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.
[1113] 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
[1114] 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-cyclohexyl-2,3-dihydr-
o-1-methyl-1H-1,4-benzodiazepin-2-one
[1115] 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.
[1116] C.sub.24H.sub.27N.sub.3O.sub.3 (MW=405.54); mass
spectroscopy 405.
[1117] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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
[1118] 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.
[1119] 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
[1120] 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.
[1121] 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
[1122] 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.
[1123] 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-(a-Isopropylthio)-N-(benzyloxycarbonyl)-glycin-
yl]-amino-5-nitrobenzophenone
[1124] 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 15620% ethyl acetate/hexanes giving an off-white
foam.
[1125] C.sub.26H.sub.25N.sub.3O.sub.6S (MW=507.61); mass
spectroscopy found 507.9.
[1126] 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
[1127] 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
[1128]
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 263%
isopropyl alcohol/methylene chloride.
[1129] C.sub.23H.sub.18N.sub.4O.sub.5 (MW=430.45); mass
spectroscopy found (M+H) 431.2.
[1130] 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
[1131] 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.
[1132] C.sub.24H.sub.20N.sub.4O.sub.5 (MW=444.48); mass
spectroscopy found (M+H) 445.2.
[1133] 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
[1134] 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-di-
hydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one
[1135] 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.
[1136] C.sub.24H.sub.27N.sub.5O.sub.6 (MW=481.56); mass
spectroscopy found (M+H) 482.3.
[1137] 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
[1138] 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
[1139] 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.
[1140] 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
[1141] 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.
[1142] C.sub.24H.sub.27FN.sub.4O.sub.4 (MW 454.50); mass
spectroscopy found (M+H) 455.4.
[1143] Anal. calcd for C.sub.24H.sub.17FN.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
[1144] 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
[1145] 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.
[1146] C.sub.13H.sub.10FNO (MW=215.24); mass spectroscopy found
(M+H) 216.3.
[1147] .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-(a-Isopropylthio)-N-(benzyloxycarbonyl)-glycin-
yl-amino-3-fluorobenzophenone
[1148] A solution of a-(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 15620% ethyl acetate/hexanes giving an
off-white foam.
[1149] C.sub.26H.sub.25N.sub.2O.sub.4S (MW=480.60); mass
spectroscopy found (M+NH.sub.4.sup.+) 498.3.
[1150] .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
[1151] 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
[1152]
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 263%
isopropyl alcohol/methylene chloride.
[1153] C.sub.23H.sub.18FN.sub.3O.sub.3 (MW=403.44); mass
spectroscopy found (M+H) 404.4.
[1154] Anal. calcd for C.sub.23H.sub.18FN.sub.3O.sub.3C, 0.5;
H.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
[1155] 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.
[1156] C.sub.24H.sub.20FN.sub.3O.sub.3 (MW=417.47); mass
spectroscopy found (M+H) 418.3.
[1157] 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
[1158] 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
[1159] 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.
[1160] C.sub.24H.sub.27FN.sub.4O.sub.4 (MW=454.50); mass
spectroscopy found (M+H) 455.3.
[1161] 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
[1162] 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
[1163] 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.
[1164] C.sub.13H.sub.10FNO (MW=215.24); mass spectroscopy found
(M+H) 216.3.
[1165] 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
[1166] 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 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.
[1167] C.sub.26H.sub.25N.sub.2O.sub.4S (MW=480.60); mass
spectroscopy found (M+NH.sub.4.sup.+) 498.2.
[1168] .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
[1169] 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-(4-fluorop-
henyl]-1H-1,4-benzodiazepin-2-one
[1170]
2-[N-(.alpha.-Amino)-N'-(benzyloxycarbonyl)-glycinyl]-amino-4'-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 263%
isopropyl alcohol/methylene chloride.
[1171] C.sub.23H.sub.18FN.sub.3O.sub.3 (MW=403.44); mass
spectroscopy found (M+H) 404.4.
[1172] Anal. calcd for
C.sub.23H.sub.18FN.sub.3O.sub.3C1.25H.sub.2O: C, 64.85; H, 4.85.
Found: C, 64.80; H, 4.55.
Step E--Preparation of
3-(Benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5--
(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one
[1173] 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.
[1174] C.sub.24H.sub.20FN.sub.3O.sub.3 (MW=417.47); mass
spectroscopy found (M+H) 418.2.
[1175] 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
[1176] 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
[1177] 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.
[1178] C.sub.24H.sub.27FN.sub.4O.sub.4 (MW=454.50); mass
spectroscopy found (M+H) 455.4.
[1179] Anal. calcd for C.sub.24H.sub.27FN.sub.4O.sub.4C, 1.5;
H.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
[1180] 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
[1181] 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.
[1182] 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.
[1183] 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.
[1184] 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:
[1185]
3-(N'-L-alaninyl)amino-1,3-dihydro-1-isopropyl-5-phenyl-2H-1,4-benz-
odiazepin-2-one
[1186]
3-(N'-L-alaninyl)amino-1,3-dihydro-1-propyl-5-phenyl-2H-1,4-benzodi-
azepin-2-one
[1187]
3-(N'-L-alaninyl)amino-1,3-dihydro-1-cyclopropylmethyl-5-phenyl-2H--
1,4-benzodiazepin-2-one
[1188]
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
[1189] 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.
[1190] 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.
[1191] 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
[1192]
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
[1193]
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
[1194] 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
[1195]
2,4-Dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodi-
azepine (CAS No. 113021-844) 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
[1196] 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-benzo-
diazepine (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-equatorial 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
[1197] 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 EC 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
[1198] N-(t-Butoxycarbonyl)-R-2-thienylglycine (CAS No. 74462-03-1)
was prepared from L-a-(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
[1199] 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
[1200] 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-tetrahydro-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
[1201]
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
[1202] 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
[1203] 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:--Synthesis of
3-[N'-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-
-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1204] 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
[1205] 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
[1206]
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
[1207] 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
[1208] 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
[1209] 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,-tetrahydro-1H-1,5-benzo-
diazepine 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
[1210] 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)-S-phenylglycinyl]-amino-2,4-
-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
[1211] 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)-S-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
[1212] 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
[1213]
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
[1214] 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
[1215] 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
[1216] 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
[1217] 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
[1218] 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
[1219] 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
[1220] 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 EC 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
[1221] 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
[1222] 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-be-
nzodiazepine
[1223] 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, 2 L). 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
[1224] 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
[1225] 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
[1226] 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
[1227] 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
[1228] 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-benzodiazepin-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
[1229]
(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.
[1230] C.sub.26H.sub.32N.sub.4O.sub.4 (MW 464.62); mass
spectroscopy 464.3.
[1231] 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
[1232] 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.
[1233] 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
[1234]
(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.
[1235] 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
[1236] 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.
[1237] 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
[1238] 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
[1239] N-(t-Butoxycarbonyl)-L-3-thienylglycine was prepared from
L-a-(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
[1240] 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
[1241] Following General Procedure 8-N above using the product from
Step B, the title compound was prepared.
[1242] Using the following combinatorial procedures, the following
additional intermediates and examples were prepared.
General Procedure C-A
[1243] 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
[1244] To a 4 mL vial was added 840 .mu.L of 0.05 mM stock solution
of starting material 1 in DMF/chloroform, 100 .mu.L of a 0.21 mM
stock solution of starting material 2 in chloroform and 100 .mu.L
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
[1245] To a 4 mL vial was added 540 .mu.L of 0.05 mM stock solution
of starting material 1 in DMF/chloroform, 100 .mu.L of a 0.44 mM
stock solution of starting material 2 in chloroform and 100 .mu.L
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
[1246] To a 4 mL vial was added 540 .mu.L of 0.05 mM stock solution
of starting material 1 in DMF/chloroform, 100 .mu.L of a 0.44 mM
stock solution of starting material 2 in chloroform, 100 .mu.L of a
0.38 mM stock solution of 1-(3-dimethylaminopropyl)-3-ethyl
carbodiimide in chloroform and 100 .mu.L 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
[1247] To a 4 mL vial was added 870 .mu.L of 0.05 mM stock solution
of starting material 1 in DMF/chloroform, 1000 .mu.L of a 0.05 mM
stock solution of starting material 2 in chloroform, 1000 .mu.L of
a 0.05 mM stock solution of 1-(3-dimethylaminopropyl)-3-ethyl
carbodiimide in chloroform and 100 .mu.L 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 {fraction
(1/3)} its original volume and then passed over a plug (200 mg) of
AG 1-8x 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
[1248] Starting material 1 (9.1 .mu.L, 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.
[1249] NMR data was as follows:
[1250] .sup.1H NMR (300 MHz, CDCl.sub.3) 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),
4.65-4.80 (m, 1H), 5.45-5.55 (m, 1H), 7.20-7.80 (m, 11H).
General Procedure C-G
[1251] To a 4 mL vial containing 0.03 mmol of starting material 2
was added 100 .mu.L of 0.25 mM stock solution of starting material
1 in chloroform, 100 .mu.L of a 0.3 mM stock solution of
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and
100 .mu.L 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 {fraction (1/3)} its original volume and then
passed over a plug (200 mg) of AG 1-8x 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
[1252] The intermediates shown in Table C-1 (i.e., Starting
material 2) were synthesized in parallel in using the following
procedure:
[1253] 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 .mu.L 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.
[1254] 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.
[1255] 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 {fraction (1/3)} its original volume and then passed
over a plug (500 mg) of AG 1-8x 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.
[1256] 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.
General Procedure C-I
[1257] To a 4 mL vial containing 0.03 mmol of starting material 2
(from General Procedure C-H) was added 100 .mu.L of 0.25 mM stock
solution of starting material 1 in chloroform, 100 .mu.L of a 0.3
mM stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
in chloroform and 100 .mu.L 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 {fraction (1/3)} its
original volume and then passed over a plug (200 mg) of AG 1-8x
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.
General Procedure C-J
[1258] A vial was charged with a CHCl.sub.3 solution of Starting
material 1 (71 .mu.mol), a DMF solution of HOBt monohydrate (71
.mu.mol), a CHCl.sub.3 solution of diisopropylcarbodiimide (71
.mu.mol), and a CHCl.sub.3 solution of starting material 2 (60
.mu.mol). 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
[1259] To a 4 mL vial was added 870 .mu.L of 0.05 mM stock solution
of starting material 1 in DMF/chloroform, 1000 .mu.L of a 0.05 mM
stock solution of starting material 2 in chloroform, 1000 .mu.L of
a 0.05 mM stock solution of 1-(3-dimethylaminopropyl)-3-ethyl
carbodiimide in chloroform and 100 .mu.L 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 {fraction
(1/3)} its original volume and then passed over a plug (200 mg) of
AG 1-8x 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-L
[1260] 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-(+)-phenylglycine (Aldrich), L-(2-thienyl)glycine (Sigma),
L-(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).
[1261] The amino acid (60 .mu.moles), 305 mg (150 mmoles) of
N,O-bistrimethylsilylacetamide 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
[1262] Into each fritted screw capped vial containing a resin bound
amino acid (from General Procedure C-L) was introduced 81 mg (60
mmoles) of 1-hydroxybenzotriazole hydrate (HOBT H.sub.2O), 115 mg
(60 mmoles) 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 mmoles) 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-benzodiaz-
epin (Example 8-R, Step C) and
3-amino-2,4-dioxo-1,5-bis(cyclopropylmethyl-
)-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
[1263] 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 mL 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
[1264] To each vial containing a specific amino acid benzodiazepine
(from General Procedure C-N) is 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. The vials are capped and shaken
for 4 days. The reaction mixture is then concentrated under a
continuous flow of nitrogen. The residue is subjected to affinity
chromatography on a pretreated SCX column (pretreatment includes
flushing with 2 mL of a 10% solution of acetic acid in methanol
followed by 2 mL of methanol). Once loaded, all columns are eluted
with 5 mL of methanol. Each solution is transferred to a tared vial
followed by concentration under a stream of nitrogen with final
concentration under vacuum.
General Procedure C-P
[1265] A solution of the carboxylic acid (0.75 mL, 0.05 M in DCM)
is 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 is used only with a substituted
carboxylic acids), and EDC (0.3 mL, 0.15 M). The reaction is 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
[1266] 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.
[1267] 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-bromo-4-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).
[1268] 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
[1269] 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[b,d]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 CH.sub.3CN) showed the products to
be greater than 90% pure.
General Procedure C-S
[1270] Step A: Each amino acid (150 .mu.mol) was weighed 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 .mu.mol)
of a solution of
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (481 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 .mu.mol) 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 100-125 mg of
polystyrene-piperidine resin (approximately 3.6 mmol/g, 350
.mu.mol, 2.33 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
warn 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 to 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).
[1271] 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 .mu.moles of
the amino acid linked to
5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-- one.
[1272] 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 .mu.mol) 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 a 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 .mu.mols 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 .mu.mol) 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 .mu.mol) 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
[1273] 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).
[1274] 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).
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
[1275] To a solution of triethyl amine (519 .mu.L, 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.
[1276] NMR data was as follows:
[1277] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
[1278] IR (CDCl.sub.3): 1709.7, 1676.6, 1489, 1166.3 cm.sup.-1.
[1279] 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
[1280]
(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.
[1281] NMR data was as follows:
[1282] .sup.1H NMR (CDCl.sub.3): d=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).
[1283] IR (CDCl.sub.3): 1673.3, 1601.1, 1506.1 cm.sup.-1.
[1284] 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
[1285] 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.
[1286] NMR data was as follows:
[1287] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
[1288] IR (CHCl.sub.3): 1706.04, 1685.3, 1505.9, 1489.1, 1450.3,
1244.7 cm.sup.-1.
[1289] 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
[1290] 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.
[1291] NMR data was as follows:
[1292] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
[1293] 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
[1294] To a solution of HOBt-H.sub.2O (697 mg, 5.16 mmol),
N,N-diisopropylethylamine (900 .mu.L, 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 (EDCI; 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.
[1295] NMR data was as follows:
[1296] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
[1297] IR (CHCl.sub.3): 1705.8, 1678.8, 1488.7, 1450.2, 1230.4,
1164.4 cm.sup.-1.
[1298] 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
[1299]
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.
[1300] NMR data was as follows:
[1301] .sup.1H NMR (300 MHz, CDCl.sub.3): d=1.30-1.50 (m, 3H),
1.80-2.20 (br s, 2H), 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).
[1302] EX MS (M+1): 441.2.
Example C-AC
Synthesis of
3-(L-Alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-ph-
enyl-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
[1303] 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.
[1304] NMR data was as follows:
[1305] .sup.1H NMR (300 MHz, CDCl.sub.3): d=1.50-2.10 (m, 4H),
3.70-3.90 (m, 1H), 4.35-4.55 (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).
[1306] IR (CHCl.sub.3): 1720.4, 1683.0, 1604.8, 1505.5, 1451.1,
1323.9, 1254.5, 1148.4 cm.sup.-1.
[1307] IEX MS (M+1): 496.3.
Step B: Synthesis of
3-Amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-
-1H-1,4-benzodiazepin-2-one
[1308] 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.
[1309] NMR data was as follows:
[1310] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
[1311] 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
[1312] To a solution of HOBt-H.sub.2O (373 mg, 2.76 mmol),
N,N-diisopropylethylamine (481 .mu.L, 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 (EDCI; 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.
[1313] NMR data was as follows:
[1314] .sup.1H NMR (300 MHz, CDCl.sub.3): d=1.40-2.10 (m, 16H),
3.70-3.85 (m, 1H), 4.30-4.55 (m, 2H), 5.10 (br s, 1H), 5.45-5.55
(m, 1H), 7.25-7.80 (m, 10H).
[1315] 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.
[1316] 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
[1317]
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.
[1318] NMR data was as follows:
[1319] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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=27.73 Hz, J.sub.2=8.34 Hz, 1H).
[1320] 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
[1321] 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), a-chloroacetyl
chloride (5.9 .mu.L, 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.
[1322] NMR data was as follows:
[1323] .sup.1H NMR (300 MHz, CDCl.sub.3): d=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).
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
[1324] 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
[1325] 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- bodiimide 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, 0.1
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.
[1326] 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-pyrid-
yl)-1H-1,4-benzodiazepin-2-one
[1327] 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).
[1328] .sup.1HNMR (CDCl.sub.3): d=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
[1329] 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
[1330] 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- bodiimide 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.
[1331] MS (FD.sup.+) 522 (m/z).
[1332] .sup.1HNMR (CDCl.sub.3): d=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-diethylami-
noethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[1333] 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.
[1334] MS (IS.sup.+) 423 (m/e).
[1335] .sup.1HNMR (CDCl.sub.3): d=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-1,4-benzodiazepin-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
[1336] 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
[1337] 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- bodiimide 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.
[1338] MS (FD.sup.+) 521 (m/z).
[1339] .sup.1HNMR (CDCl.sub.3): d=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), 4.50-4.64 (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
[1340] 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-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzod-
iazepin-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.
[1341] MS (IS.sup.+) 422 (m/e).
[1342] .sup.1HNMR (CDCl.sub.3) d 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-
,4-benzodiazepin-2-one
Step A: Synthesis of
3-Amino-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-ben-
zodiazepin-2-one
[1343] 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)).
[1344] MS (IS.sup.+) 273 (m/e).
[1345] .sup.1HNMR (CDCl.sub.3): d=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).
Step B: Synthesis of
3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihyd-
ro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one
[1346] 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- bodiimide 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.
[1347] 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.
[1348] MS (IS.sup.+) 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
[1349] 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-1,4-benzodiazepin-2-one
Step A: Synthesis of
3-Amino-2,3-dihydro-1-methyl-5-(2-thiophen-2-yl)-1H-1-
,4-benzodiazepin-2-one
[1350] 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)).
[1351] MS (IS.sup.+) 272 (m/e).
[1352] .sup.1HNMR (CDCl.sub.3): d=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
[1353] The title compound was synthesized in a manner similar to
the procedure described in Example C-AH, Step B.
[1354] MS (IS.sup.+) 443 (m/e).
[1355] .sup.1HNMR (CDCl.sub.3): d=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
[1356] The title compound was synthesized in a manner similar to
the procedure described in Example C-AE, Step C.
[1357] MS (IS.sup.+) 343 (m/e).
[1358] .sup.1HNMR (CDCl.sub.3): d=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).
[1359] 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
[1360] 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
[1361] 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 (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.
[1362] This procedure is particularly useful in the case of costly
and/or high boiling alcohols.
General Procedure AC
Second Transesterification Technique
[1363] 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
[1364] 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.
[1365] This procedure is particularly employed in the case of low
boiling, inexpensive alcohols, miscible with water.
General Procedure AE
O-Alkylation Technique
[1366] 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
[1367] 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
[1368] 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
[1369] To a 1:1 mixture of the desired acid and alcohol in
CH.sub.2Cl.sub.2 at O 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
[1370] 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 14 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
[1371] 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
[1372] 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
[1373] 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, 0.1M 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
[1374] 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
[1375] 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 2 h. 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
[1376] 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): =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
[1377] 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
[1378] 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
[1379] 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
[1380] 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
[1381] 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.
[1382] NMR data was as follows:
[1383] .sup.1H-nmr (CDCl.sub.3): d=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).
[1384] .sup.13C-nmr (CDCl.sub.3): d=170.0, 72.2, 49.2, 27.5, 18.9,
16.1.
General Procedure BA
Coupling of Acid Halides with H.sub.2NCH(R)C(O)XR.sup.3
[1385] To a stirred solution of (D,L)-alanine iso-butyl ester
hydrochloride (from Example BB below) (4.6 mmol) in 5 mL of
pyridine is added 4.6 mmol of an acid chloride. Following
precipitation of the pyridinium hydrochloride, the mixture is
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
[1386] 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
Esterification of R.sup.1C(X')(X")C(O)NHCH(R.sup.2)C(O)OH with
HOR.sup.3
[1387] CDI is added to a stirred solution of an N-acyl amino acid,
and the mixture is stirred for about 1.5 h. An alcohol is added the
mixture, followed by addition of an equivalent of NaH. Bubbling
should occur immediately to evolve the generated hydrogen gas. The
reaction mixture is stirred overnight, diluted with diethyl ether,
washed with 10% HCl three times, brine once, 20% potassium
carbonate once and brine once. The solution is then dried over
magnesium sulfate, filtered, and evaporated at reduced pressure to
yield the product.
General Procedure BD
Ester Hydrolysis to the Free Acid
[1388] Ester hydrolysis to the free acid was conducted by
conventional methods. Below are two examples of such conventional
de-esterification methods.
[1389] 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.
[1390] 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).
[1391] 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.2O.
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. [ ].sub.23=-29.9 @ 589 nm.
General Procedure BE
Low Temperature BOP Coupling of Acid and Alcohol
[1392] 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
EDC Coupling of Acid and Amine
[1393] 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.sub.2 pressure. The reaction mixture was worked
up by washing the solution with saturated, aqueous
Na.sub.2CO.sub.3, O. 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
[1394] 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
[1395] 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 sodium sulfate, filtered and the solvent removed
under reduced pressure to provide for the desired product.
General Procedure BI
P-EPC coupling
[1396] 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.
[1397] 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 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
[1398] A. Esterification of the Acid.
[1399] 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.
[1400] B. Removal of N-BOC Group.
[1401] 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.
[1402] Specific exemplification of these procedures are as
follows:
[1403] 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.
[1404] 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.
[1405] 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 O 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.
[1406] 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. Anal. Calc. for C.sub.7H.sub.15NO.sub.2. HCl:
C=46.28, H=8.88, and N=7.71. Found: C=46.01, H=8.85, and
N=7.68.
General Procedure BK
Methyl Ester Formation from Amino Acids
[1407] 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)propylurea
[1408] 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.
1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)
[1409] To a solution of 31.0 g (0.156 mol)
N-ethyl-N'-3-(1-pyrrolidinyl)pr- opyl-urea 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).
Preparation of a Polymer Supported Form of
1-(3-(1-pyrrolidinyl)propyl)-3-- ethylcarbodiimide (P-EPC)
[1410] 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 1 L DMF, 1 L THF and 1 L diethyl ether. The
remaining resin was then dried under vacuum for 18 hours.
Example BB
Preparation of Alanine iso-butyl Ester Hydrochloride
[1411] 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.
[1412] III. Preparation of Final Compounds
Example 1-1
Preparation of
(S)-3-[(N'-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1413] Following General Procedure C-B above using
2-thiophenecarboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-b-
enzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 447 (M+H).
Example 1-2
Preparation of
(S)-3-[(N'-(2-Furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[1414] Following General Procedure C-B above using 2-furoic acid
and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 431 (M+H).
Example 1-3
Preparation of
(S)-3-[(N'-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1415] Following General Procedure C-B above using
cyclobutanecarboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-b-
enzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 419 (M+H).
Example 1-4
Preparation of
(S)-3-[(N'-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1416] Following General Procedure C-B above using
1-phenyl-1-cyclopropane- carboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above,
the title compound was prepared. The molecular weight as determined
by mass spectrometry (FD) was: 481 (M+H).
Example 1-5
Preparation of
(S)-3-[(N'-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1417] Following General Procedure C-B above using
cyclohexanecarboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-b-
enzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 447 (M+H).
Example 1-6
Preparation of:
(S)-3-[(N'-(2-Benzofurancarboxyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1418] Following General Procedure C-B above using
2-benzofurancarboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-b-
enzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 481 (M+H).
Example 1-7
Preparation of
(S)-3-[(N'-(5-Chlorobenzofuran-2-carboxyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1419] Following General Procedure C-B above using
5-chlorobenzofuran-2-ca- rboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 515 (M+H).
Example 1-8
Preparation of
(S)-3-[(N'-(5,5-dimethyl-butyrolactone-4-yl)-L-alaninyl)]am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1420] Following General Procedure C-B above using terebic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 477 (M+H).
Example 1-9
Preparation of
(S)-3-[(N'-(3-Furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methy-
l-5-phenyl-1H-1,4-benzodiazepin-2-one
[1421] Following General Procedure D above using 3-furoic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 523 (M+H).
Example 1-10
Preparation of
(S)-3-[(N'-(4-(methylsulfonyl)benzoyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1422] Following one or more of the general procedures outlined
above, using 4-(methylsulfonyl)benzoic acid and
(S)-3-[(L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in
Example 8-B above, the title compound was prepared. The molecular
weight as determined by mass spectrometry (FD) was: 519 (M+H).
Example 1-11
Preparation of
(S)-3-[(N'-(trans-2-Phenyl-1-cyclopropanecarboxyl)-L-alanin-
yl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1423] Following General Procedure D above using
trans-2-phenyl-1-cyclopro- panecarboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-p-
henyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B
above, the title compound was prepared. The molecular weight as
determined by mass spectrometry (FD) was: 481 (M+H).
Example 1-12
Preparation of
(S)-3-[(N'-(5-methylsulfonyl)thiophene-2-carboxyl)-L-alanin-
yl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1424] Following one or more of the general procedures outlined
above, using (5-methylsulfonyl)thiophene-2-carboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 525 (M+H).
Example 1-13
Preparation of
(S)-3-[(N'-(1,8-dimethyl-6-Hydroxy-bicyclo(2.2.2)octane-2-c-
arboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one
[1425] Following General Procedure D above using
1,8-dimethyl-6-hydroxy-bi- cyclo(2.2.2)octane-2-carboxylic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in
Example 8-B above, the title compound was prepared. The molecular
weight as determined by mass spectrometry (FD) was: 489 (M+H).
Example 1-14
Preparation of
(S)-3-[(N'-(1,4-Benzodioxan-2-carboxyl)-L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1426] Following General Procedure D above using
1,4-benzodioxan-2-carboxy- lic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,-
4-benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 499 (M+H).
Example 1-15
Preparation of
(S)-3-[(N'-(Tetrahydro-3-furoyl)-L-alaninyl)]amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1427] Following General Procedure D above using
tetrahydro-3-furoic acid and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzod-
iazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 435 (M+H).
Example 1-16
Preparation of
(S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-phenylglycinyl)]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1428] Following General Procedure D above using
3-cyclohexenecarboxylic acid and
(S)-3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 507
(M+H).
Example 1-17
Preparation of
(S)-3-[(N'-(Cyclopropanecarboxyl)-L-phenylglycinyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1429] Following General Procedure D above using
cyclopropanecarboxylic acid and
(S)-3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 467
(M+H).
Example 1-18
Preparation of
(S)-3-[(N'-(3,5-Difluorobenzoyl)-L-phenylglycinyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1430] Following General Procedure D above using
3,5-difluorobenzoic acid and
(S)-3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4--
benzodiazepin-2-one, the title compound was prepared. The molecular
weight as determined by mass spectrometry (FD) was: 539 (M+H).
Example 1-19
Preparation of
3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihy-
dro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[1431] Following General Procedure C-J above using L-pyroglutamic
acid and
3-[(L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodia-
zepin-2-one, as described in Example C-AE, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 448 (M+H).
Example 1-21
Preparation of
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-
-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[1432] Following General Procedure C-J above using
1-phenyl-1-cyclopropane- carboxylic acid and
3-[(L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyrid-
yl)-1H-1,4-benzodiazepin-2-one, as described in Example C-AE, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 482 (M+H).
Example 1-22
Preparation of
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-
-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[1433] Following General Procedure C-J above using
1-phenyl-1-cyclopropane- carboxylic acid and
3-[(L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-o-
xobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, as described in
Example C-AG, the title compound was prepared. The molecular weight
as determined by mass spectrometry (FD) was: 566 (M+H).
Example 1-23
Preparation of
3-[(N'-(3,5-difluorobenzoyl)-L-alaninyl)]amino]-2,3-dihydro-
-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[1434] Following General Procedure C-J above using
3,5-difluorobenzoic acid and
3-[(L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-
-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, as described in Example
C-AG, the title compound was prepared. The molecular weight as
determined by mass spectrometry (FD) was: 561 (M+H).
Example 1-24
Preparation of
3-[(N'-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihy-
dro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[1435] Following General Procedure C-J above using L-pyroglutamic
acid and
3-[(L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyrid-
yl)-1H-1,4-benzodiazepin-2-one, as described in Example C-AG, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 533 (M+H).
Example 1-26
Preparation of
3-[(N'-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-
-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepi-
n-2-one
[1436] Following General Procedure C-J above using
1-phenyl-1-cyclopropane- carboxylic acid and
3-[(L-alaninyl)]amino]-2,3-dihydro-1-(2-N,N-diethylami-
noethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, as described in
Example C-AF, the title compound was prepared. The molecular weight
as determined by mass spectrometry (FD) was: 567 (M+H).
Example 1-27
Preparation of
3-[(N'-(4-methylbenzoyl)-D-phenylglycinyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1437] Following one or more of the general procedures outlined
above, using 4-methylbenzoic acid and
3-[(D-phenylglycinyl)]amino-2,3-dihydro-1--
methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 517 (M+H).
Example 1-28
Preparation of
3-[(N'-(4-methylbenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1438] Following one or more of the general procedures outlined
above, using 4-methylbenzoylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B
above, the title compound was prepared. The molecular weight as
determined by mass spectrometry (FD) was: 455 (M+H).
Example 1-30
Preparation of
3-[(N'-(2-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[1439] Following General Procedure C-A above using 2-naphthoic acid
and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 491 (M+H).
Example 1-31
Preparation of
3-[(N'-(1-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[1440] Following General Procedure C-A above using 1-naphthoic acid
and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: (M+H).
Example 1-32
Preparation of
3-[(N'-(5-Chloro-2-thiophenecarboxyl)-L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1441] Following General Procedure C-A above using
5-chloro-2-thiophenecar- boxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,-
4-benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 481 (M+H).
Example 1-33
Preparation of
3-[(N'-(4-Cyanobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1442] Following General Procedure C-A above using 4-cyanobenzoic
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 466 (M+H).
Example 1-34
Preparation of
3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1443] Following General Procedure C-A above using
tetrahydro-2-furoic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 466 (M+H).
Example 1-35
Preparation of
3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1444] Following General Procedure C-A above using
3,5-difluorobenzoic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 477 (M+H).
Example 1-36
Preparation of
3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1445] Following General Procedure C-A above using
3-cyclohexenecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 445 (M+H).
Example 1-37
Preparation of
3-[(N'-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1446] Following General Procedure C-A above using
1,2,3,4-tetrahydro-2-na- phthoic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,-
4-benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 495 (M+H).
Example 1-38
Preparation of
3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1447] Following General Procedure C-A above using
cyclopentanecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 433 (M+H).
Example 1-39
Preparation of (S)-3-[(N'-(4-(Trifluoromethyl)cyclohexane
carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodia-
zepin-2-one
[1448] Following General Procedure D above using
trifluoromethyl)cyclohexa- ne carboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-
-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 515 (M+H).
Example 1-40
Preparation of
(S)-3-[(N'-(Bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl)]a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1449] Following General Procedure D above using
(bicyclo[2.2.1]heptane-2-- carboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 459 (M+H).
Example 1-41
Preparation of
(S)-3-[(N'-(Bicyclo(2.2.1)hept-5-ene-2-carboxyl)-L-alaninyl-
)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1450] Following General Procedure D above using
bicyclo(2.2.1)hept-5-ene-- 2-carboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 457 (M+H).
Example 1-42
Preparation of (S)-3-[(N'-(2,2-Dichlorocyclopropane
carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodia-
zepin-2-one
[1451] Following General Procedure D above using
2,2-dichlorocyclopropane carboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1-
H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 473 (M+H).
Example 1-43
Preparation of
(S)-3-[(N'-(Cycloheptanecarboxyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1452] Following General Procedure D above using
cycloheptanecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 461 (M+H).
Example 1-44
Preparation of
(S)-3-[(N'-(1-(2,4-Dichlorophenyl)cyclopropanecarboxyl)-L-a-
laninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1453] Following General Procedure D above using
2,4-dichlorophenyl)cyclop- ropanecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phe-
nyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above,
the title compound was prepared. The molecular weight as determined
by mass spectrometry (FD) was: (M+H).
Example 1-45
Preparation of
(S)-3-[(N'-(2-Methylcyclopropanecarboxyl)-L-alaninyl)]amino-
-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1454] Following General Procedure D above using
2-methylcyclopropanecarbo- xylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4--
benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 419 (M+H).
Example 1-46
Preparation of
(S)-3-[(N'-(1-(4-Chlorophenyl)-1-cyclobutanecarboxyl)-L-ala-
ninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1455] Following General Procedure D above using
4-chlorophenyl)-1-cyclobu- tanecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above,
the title compound was prepared. The molecular weight as determined
by mass spectrometry (FD) was: 529 (M+H).
Example 1-47
Preparation of
(S)-3-[(N'-(2-Biphenylcarboxyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1456] Following General Procedure D above using
2-biphenylcarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 517 (M+H).
Example 1-48
Preparation of
(S)-3-[(N'-(1,2-Dihydro-1-oxo-2-phenyl-4-isoquinolinecarbox-
yl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-
-one
[1457] Following General Procedure D above using
1,2-dihydro-1-oxo-2-pheny- l-4-isoquinolinecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-me-
thyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example
8-B above, the title compound was prepared. The molecular weight as
determined by mass spectrometry (FD) was: 584 (M+H).
Example 1-49
Preparation of
(S)-3-[(N'-(Bicyclo(3.3.1)non-6-ene-3-carboxyl)-L-alaninyl)-
]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1458] Following General Procedure D above using
bicyclo(3.3.1)non-7-ene-3- -carboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1-
H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 485 (M+H).
Example 1-50
Preparation of
(S)-3-[(N'-(Cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1459] Following General Procedure D above using
cyclopropanecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 405 (M+H).
Example 1-51
Preparation of
(S)-3-[(N'-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1460] Following General Procedure D above using
tetrahydro-2-furoic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 435 (M+H).
Example 1-52
Preparation of
(S)-3-[(N'-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihy-
dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1461] Following General Procedure D above using
3,5-difluorobenzoic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 477 (M+H).
Example 1-53
Preparation of
(S)-3-[(N'-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1462] Following General Procedure D above using
3-cyclohexenecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 445 (M+H).
Example 1-54
Preparation of
(S)-3-[(N'-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]ami-
no-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1463] Following General Procedure D above using
1,2,3,4-tetrahydro-2-naph- thoic acid and
(S)-3-(-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-
,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 495 (M+H).
Example 1-55
Preparation of
(S)-3-[(N'-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1464] Following General Procedure D above using
cyclopentanecarboxylic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 433 (M+H).
Example 1-56
Preparation of
5-{N'-(tetrahydro-3-furoyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1465] Following General Procedure C-P above using
tetrahydro-3-furoic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one, as described in Example 7-B, the title compound was prepared.
The molecular weight as determined by mass spectrometry (FD) was:
408 (M+H).
Example 1-57
Preparation of 5-{N'-(cyclopropane
carboxyl)-L-alaninyl}-amino-7-methyl-5,-
7-dihydro-6H-dibenz[b,d]azepin-6-one
[1466] Following General Procedure C-P above using cyclopropane
carboxylic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one, as described in Example 7-B, the title compound was prepared.
The molecular weight as determined by mass spectrometry (FD) was:
378 (M+H).
Example 1-59
Preparation of
5-{N'-(bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl}-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1467] Following General Procedure C-P above using
bicyclo[2.2.1]heptane-2- -carboxylic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b-
,d]azepin-6-one, as described in Example 7-B, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 432 (M+H).
Example 1-60
Preparation of
5-{N'-(tetrahydro-2-furoyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1468] Following General Procedure C-P above using
tetrahydro-2-furoic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one, as described in Example 7-B, the title compound was prepared.
The molecular weight as determined by mass spectrometry (FD) was:
408 (M+H).
Example 1-61
Preparation of
5-{N'-(cyclopentanecarboxyl)-L-alaninyl}-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1469] Following General Procedure C-P above using
cyclopentanecarboxylic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one, as described in Example 7-B, the title compound was prepared.
The molecular weight as determined by mass spectrometry (FD) was:
406 (M+H).
Example 1-62
Preparation of
5-{N'-(2-thiophenecarboxyl)-L-alaninyl}-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1470] Following General Procedure C-P above using
2-thiophenecarboxylic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one, as described in Example 7-B, the title compound was prepared.
The molecular weight as determined by mass spectrometry (FD) was:
420 (M+H).
Example 2-1
Preparation of
(S)-3-[(N'-(2,3-Diphenylpropionyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1471] Following General Procedure C-B above using
2,3-diphenylpropionic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-
diazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 545 (M+H).
Example 2-2
Preparation of
(S)-3-[(N'-(2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1472] Following General Procedure C-B above using
2-phenoxypropionic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 485 (M+H).
Example 2-4
Preparation of
(S)-3-[(N'-(2-Isopropyl-2-phenylacetyl)-L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1473] Following General Procedure C-B above using
2-isopropyl-2-phenylace- tic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-be-
nzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 497 (M+H).
Example 2-5
Preparation of
(S)-3-[(N'-(2-Ethylhexanoyl)-L-alaninyl)]amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1474] Following General Procedure C-B above using 2-ethylhexanoic
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 463 (M+H).
Example 2-6
Preparation of
(S)-3-[(N'-(2-Methylbutyryl)-L-alaninyl)]amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1475] Following General Procedure C-B above using 2-methylbutyric
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 421 (M+H).
Example 2-7
Preparation of
(S)-3-[(N'-(2-Methyl-4,4,4-trifluorobutyryl)-L-alaninyl)]am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1476] Following General Procedure C-B above using
2-methyl-4,4,4-trifluor- obutyric acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl
1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 475 (M+H).
Example 2-8
Preparation of
(S)-3-[(N'-(Diphenylacetyl)-L-phenylglycinyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1477] Following General Procedure D above using diphenylacetic
acid and
3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodia-
zepin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 593 (M+H).
Example 2-9
Preparation of
(S)-3-[(N'-(4-chloro-.alpha.-methylphenylacetyl)-L-alaninyl-
)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1478] Following General Procedure D above using
4-chloro-.alpha.-methylph- enylacetic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-13 above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 503 (M+H).
Example 2-10
Preparation of
(S)-3-[(N'-(4-chloro-.alpha.,.alpha.-dimethylphenylacetyl)--
L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1479] Following General Procedure D above using
4-chloro-.alpha.,.alpha.-- dimethylphenylacetic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-
-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B
above, the title compound was prepared. The molecular weight as
determined by mass spectrometry (FD) was: 517 (M+H).
Example 2-11
Preparation of
(S)-3-[(N'-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl-
)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1480] Following General Procedure D above using
(S)-(+)-2-hydroxy-2-pheny- lpropionic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 485 (M+H).
Example 2-12
Preparation of
(S)-3-[(N'-(.alpha.-hydroxy-diphenylacetyl)-L-alaninyl)]ami-
no-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[1481] Following one or more of the general procedures outlined
above, using .alpha.-hydroxy-diphenylacetic acid and
(S)-3-(L-alaninyl)amino-2,3-
-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, as
described in Example C-AE, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 548
(M+H).
Example 2-17
Preparation of
(S)-3-[(N'-(.alpha.-hydroxy-diphenylacetyl)-L-alaninyl)]ami-
no-2,3-dihydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin--
2-one
[1482] Following one or more of the general procedures outlined
above, using .alpha.-hydroxy-diphenylacetic acid and
(S)-3-(L-alaninyl)amino-2,3-
-dihydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,
the title compound was prepared. The molecular weight as determined
by mass spectrometry (FD) was: 633 (M+H).
Example 2-18
Preparation of
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylace-
tyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benz-
odiazepin-2-one
A. Preparation of
3,5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylacetic Acid
[1483] The compound was prepared according to the general procedure
of Stiller et al., J. Med. Chem., 15: 1029 (1972). A solution of
alpha-keto-3,5-difluorophenylacetic acid (prepared according to
Middleton et al., J. Org Chem., 45: 2883 (1980)) in diethyl ether
was cooled to 0.degree. C. Methylmagnesium chloride (4.7 eq., 3.0 M
solution in THF) was added dropwise via syringe pump at a rate of
10 ml/min so that the internal temperature did not exceed
5.5.degree. C. The cooling bath was removed and stirring continued
at ambient for 1.5 hours. After approximately 30 minutes, the
clumps of solid dissolved. The mixture was poured onto ice and
acidified with 1N HCl. The aqueous layer was extracted thrice with
ethyl acetate. The combined organics were washed with 5%
NaHSO.sub.3, water and brine. The organic layer was dried over
sodium sulfate, filtered, and concentrated to a yellowish solid.
The solid was recrystallized from dichloromethane, giving a white
crystalline solid having a melting point of 102.5-103.2 C. C9H8F2O3
(MW 202.17); mass spectroscopy found (M-H) 201.2. Anal calcd for
C9H8F2O3: C, 53.47; H, 3.99. Found: C, 53.76; H, 3.82.
B. Preparation of the Title Compound
[1484] Following General Procedure D above using
3,5-difluorophenyl-.alpha- .-hydroxy-.alpha.-methylacetic acid and
3-(L-alaninyl)-amino-2,3-dihydro-1-
-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one (Example
8-b), the title compound was prepared. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.=1.43 (3H, d, J=7.1 Hz), 1.79 (3H, s), 3.47 (3H, s),
4.15 (1H, s), 4.58 (1H, p, J=7.3 Hz), 5.45 (1H, d, J=8.0 Hz), 6.70
(1H, m), 7.14-7.27 (3H, m), 7.32-7.47 (6H, m), 7.55-7.63 (3H, m),
7.78 (1H, d, J=7.8 Hz). HRMS calc for C28H27N4O4F2 521.2000
(MH.sup.+), Found: 521.2
Example 2-19
Preparation of
3-[N'-(3,5-difluorophenyl-.alpha.-hydroxy-.alpha.-methylace-
tyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benz-
odiazepin-2-one
[1485] Following General Procedure D above using
3,5-difluorophenyl-.alpha- .-hydroxy-.alpha.-methylacetic acid
(described above in Example 2-18) and
3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzo-
diazepin-2-one (Example 8-b), the title compound was prepared.
[1486] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.=1.48 (3H, d, J=7.0
Hz), 1.78 (3H, s), 3.45 (3H, s), 3.86 (1H, s), 4.62 (1H, p, J=7.1
Hz), 5.42 (1H, d, J=7.6 Hz), 6.69 (1H, m), 7.13-7.59 (12H, m), 7.67
(1H, d, J=7.6 Hz). HRMS calc for C28H27N4O4F2 521.2000 (MH.sup.+),
Found: 521.2
Example 2-20
Preparation of
3-[(N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-met-
hyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1487] Following General Procedure C-A above using diphenylacetic
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 531 (M+H).
Example 2-21
Preparation of
3-[(N'-(Acetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-ph-
enyl-1H-1,4-benzodiazepin-2-one
[1488] Following General Procedure C-A above using acetic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 379 (M+H).
Example 2-22
Preparation of
(S)-3-[(N'-(2-Methylvaleryl)-L-alaninyl)]amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1489] Following General Procedure D above using 2-methylvaleric
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 435 (M+H).
Example 2-23
Preparation of
(S)-3-[(N'-(.alpha.-(Hydroxymethyl)phenylacetyl)-L-alaninyl-
)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1490] Following General Procedure D above using
.alpha.-(hydroxymethyl)ph- enylacetic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 485 (M+H).
Example 2-24
Preparation of
(S)-3-[(N'-(2-Ethylbutyryl)-L-alaninyl)]amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1491] Following General Procedure D above using 2-ethylbutyric
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 435 (M+H).
Example 2-25
Preparation of
(S)-3-[(N'-(Pivalyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-
-5-phenyl-1H-1,4-benzodiazepin-2-one
[1492] Following General Procedure D above using pivalic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 421 (M+H).
Example 2-26
Preparation of
(S)-3-[(N'-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1493] Following General Procedure D above using diphenylacetic
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 531 (M+H).
Example 2-27
Preparation of
(S)-3-[(N'-(Acetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-m-
ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1494] Following General Procedure D above using acetic acid and
3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodia-
zepin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 441 (M+H).
Example 2-28
Preparation of
3-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1495] Following General Procedure D above using
2-thioacetyl-3-methyl butanoic acid (Coric et al., J. Med. Chem.
39, 1210 (1996)) and
3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-
-one, as described in Example 8-B, the title compound was
prepared.
[1496] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.01 (6H, d, J=6.8
Hz), 1.04 (3H, d, J=7.2 Hz), 1.07 (3H, d, J=6.8 Hz), 1.45 (3H, d,
J=6.8 Hz), 1.49 (3H, d, J=7.2 Hz), 2.35 (2H, m), 2.38 (3H, s), 2.40
(3H, s), 3.45 (3H, s), 3.46 (3H, s), 3.84 (1H, d, J=7.9 Hz), 3.85
(1H, d, J=7.9 Hz), 4.63 (2H, m), 5.47 (1H, d, J=7.9 Hz), 5.48 (1H,
d, J=7.9 Hz), 6.73 (1H, d, J=8.4 Hz), 6.80 (1H, d, J=7.5 Hz),
7.20-7.62 (20H, m). MS calcd for C.sub.26H.sub.31N.sub.4O.sub.4S
495.21 (MH.sup.+), found 495.2.
Example 2-29
Preparation of
3-[N'-(2-mercapto-3-methyl-butanoyl)-L-alaninyl]-amino-2,3--
dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1497] A solution of
3-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one as
prepared in Example 2-28 in degassed methanol was treated with
degassed 1N NaOH (3 equiv.). After stirring at ambient temperature
for 3 hours, the reaction was acidified to pH 1 by adding 1N HCl.
The solution was concentrated in vacuo; the residue was partitioned
between ethyl acetate and brine. The organic phase was dried over
sodium sulfate, filtered, and concentrated to afford the title
compound.
[1498] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 0.99 (3H, d, J=6.0
Hz), 1.01 (3H, d, J=6.8 Hz), 1.05 (3H, d, J=6.4 Hz), 1.06 (3H, d,
J=6.8 Hz), 1.51 (6H, d, J=6.8 Hz), 1.90 (1H, d, J=8.8 Hz), 1.91
(1H, d, J=8.8 Hz), 2.31 (2H, o, J=6.8 Hz), 3.17 (1H, dd, J=9.2 Hz),
3.22 (1H, dd, H=6.4, 8.8 Hz), 3.48 (6H, s), 4.67 (2H, p, J=6.8 Hz),
5.48 (1H, d, J=7.6 Hz), 5.49 (1H, d, J=7.6 Hz), 7.04 (1H, d, J=7.2
Hz), 7.09 (1H, d, J=7.2 Hz), 7.23-7.27 (2H, m), 7.34-7.40 (8H, m),
7.45-7.49 (2H, m), 7.58-7.64 (8H, m). MS calcd for
C.sub.24H.sub.29N.sub.4O.sub.3S 453.20 (MH.sup.+), found 453.1.
Example 2-30
Preparation of
5-{N'-(2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1499] Following General Procedure C-P above using
2-phenylpropionic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
as described in Example 7-B, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 442
(M+H).
Example 2-31
Preparation of
5-{N'-(2-methylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dih-
ydro-6H-dibenz[b,d]azepin-6-one
[1500] Following General Procedure C-P above using 2-methylhexanoic
acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
as described in Example 7-B, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 422
(M+H).
Example 2-32
Preparation of
5-{N'-(diphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1501] Following General Procedure C-P above using diphenylacetic
acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
as described in Example 7-B, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 504
(M+H).
Example 2-33
Preparation of
5-{N'-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1502] Following one or more of the general procedures outlined
above, using (S)-(+)-2-hydroxy-2-phenylpropionic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
as described in Example 7-B, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 458
(M+H).
Example 2-34
Preparation of
5-{N'-((R)-(-)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1503] Following one or more of the general procedures outlined
above, using (R)-(-)-2-hydroxy-2-phenylpropionic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
as described in Example 7-B, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 458
(M+H).
Example 2-35
Preparation of
5-{N'-(2-hydroxy-2-methylpropionyl)-L-alaninyl}-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1504] Following General procedure D above using 2-methyllactic
acid (Aldrich) and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]aze-
pin-6-one, as described in Example 7-B, the title compound was
prepared. The product was purified by flash chromatography
CHCl.sub.3/MeOH (98:2) to yield the title compound.
[1505] C22H25N3O4 (MW=395.457); mass spectroscopy (MH.sup.+)
396.
[1506] Anal. Calcd for C22H25N3O4; C, 66.06; H, 6.25; N, 10.50.
Found: C, 65.91; H, 6.30; N, 10.52.
Example 2-36
Preparation of
5-{N'-(2-hydroxy-2-methylbutanoyl)-L-alaninyl}-amino-7-meth-
yl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1507] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in
Example 7-B, and 2-hydroxy-2-methylbutyric acid (Aldrich) the title
compound was prepared. The product was purified by flash
chromatography (CHCl.sub.3/MeOH (98:2) yielding the title
compound.
[1508] C23H27N3O4 (MW=409-483); mass spectroscopy (MH.sup.+)
410.
[1509] Anal. Calcd for C23H27N3O4; C, 67.46; H, 6.65; N, 10.26.
Found: C, 67.63; H, 6.64; N, 10.31.
Example 2-37
Preparation of
5-(S)-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amin-
o-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1510] Following General Procedure D, using
2-thioacetyl-3-methylbutanoic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one, as described in Example 7-B, the title compound was
prepared.
[1511] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 0.86-0.96 (12H,
m), 1.25 (3H, d, J=7.2 Hz), 2.05 (2H, m), 2.33 (3H, s), 2.35 (3H,
s), 3.25 (6H, s), 4.02 (2H, m), 4.56 (2H, m), 5.09 (1H, d, J=7.9
Hz), 5.12 (1H, d, H=7.9 Hz), 7.39-7.70 (16H, m), 8.48 (1H, d, J=7.2
Hz), 8.53 (1H, d, J=7.5 Hz), 8.56 (2H, d, J=8.3 Hz). MS calcd for
C.sub.25H.sub.30N.sub.3O.sub.4S 468.20 (MH.sup.+), found 468.2.
Example 2-38
Preparation of
5-{N'-(acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-di-
benz[b,d]azepin-6-one
[1512] Following General Procedure C-P using acetic acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
as described in Example 7-B, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 352
(M+H).
Example 2-39
Preparation of
5-(S)-[N'-(2-mercapto-3-methylbutanoyl)-L-alaninyl]-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1513] A solution of
5-(S)-[N'-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl-
]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example
2-37) in degassed methanol was treated with degassed 1N NaOH (3
equiv.). After stirring at ambient temperature for 3 hours, the
reaction was acidified to pH 1 by adding 1N HCl. The solution was
concentrated in vacuo; the residue was partitioned between ethyl
acetate and brine. The organic phase was dried over sodium sulfate,
filtered, and concentrated to afford the title compound.
[1514] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.98 (6H, d, J=6.8
Hz), 1.03 (6H, d, J=6.8 Hz), 1.45 (3H, d, J=7.6 Hz), 1.46 (3H, d,
J=6.8 Hz), 1.88 (1H, d, J=8.8 Hz), 1.89 (1H, d, J=8.8 Hz), 2.29
(2H, m), 3.15 (1H, dd, J=6.4, 8.8 Hz), 3.18 (1H, dd, J=6.4, 8.8
Hz), 3.36 (6H, s), 4.71 (2H, m), 5.27 (2H, d, J=6.8 Hz), 6.95 (1H,
d, J=7.2 Hz), 7.02 (1H, d, J=7.2 Hz), 7.30-7.67 (18H, m).
[1515] MS calcd for C23H28N3O3S 426.18 (MH.sup.+), found 426.1.
Example 3-1
Preparation of
(S)-3-[(N'-(trans-Cinnamyl)-L-alaninyl)]amino-2,3-dihydro-1-
-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1516] Following General Procedure D above using trans-cinnamic
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 467 (M+H).
Example 3-2
Preparation of
3-[(N'-(trans-cinnamyl)-L-alaninyl)]amino]-2,3-dihydro-1-me-
thyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one
[1517] Following General Procedure C-J above using trans-cinnamic
acid and
3-[(N'-(trans-cinnamyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyri-
dyl)-1H-1,4-benzodiazepin-2-one, as described in Example C-AE, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 468 (M+H).
Example 3-5
Preparation of
5-{N'-(trans-cinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b, d]azepin-6-one
[1518] Following General Procedure C-P above using trans-cinnamic
acid and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
as described in Example 7-B, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 440
(M+H).
Example 4-1
Preparation of
(S)-3-[(N'-(2-phenoxybutyryl)-L-alaninyl)]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1519] Following General Procedure C-B above using 2-phenoxybutyric
acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 499 (M+H).
Example 4-2
Preparation of
(S)-3-[(N'-((R,S)-(-)-.alpha.-Methoxyphenylacetyl)-L-alanin-
yl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1520] Following General Procedure C-B above using
(R,S)-(-)-.alpha.-metho- xyphenylacetic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above,
the title compound was prepared. The molecular weight as determined
by mass spectrometry (FD) was: 485 (M+H).
Example 4-3
Preparation of
(S)-3-[(N'-(2-(4-Chlorophenoxy)-2-methylpropionyl)-L-alanin-
yl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1521] Following General Procedure C-B above using
2-(4-chlorophenoxy)-2-m- ethylpropionic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-pheny-
l-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above,
the title compound was prepared. The molecular weight as determined
by mass spectrometry (FD) was: 533 (M+H).
Example 4-4
Preparation of
(S)-3-[(N'-((R,S)-2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1522] Following General Procedure C-B above using
(R,S)-2-phenoxypropioni- c acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benz-
odiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 485 (M+H).
Example 4-5
Preparation of
3-[N'-(3,5-difluorophenyl-.alpha.-methoxyacetyl)-L-alaninyl-
]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one
A. Preparation of 3,5-difluorophenyl-.alpha.-methoxyacetic Acid
[1523] The title compound was prepared according to the general
procedure in Reeve, et al, J.A.C.S., 83: 2755 (1961). A solution of
3,5-difluorobenzaldehyde (Aldrich) and bromoform (1.2 eq.) In
methanol was cooled to -5.degree. C. and treated dropwise with
methanolic KOH. The reaction temperature was held below 6 C during
the addition. The mixture was slowly warmed to room temperature and
stirred overnight. The suspension was diluted with water and 50%
saturated aqueous brine. The mixture was extracted with ether, and
the aqueous layer was acidified to a pH around 3.5 and extracted
with ether. The latter organic phase was dried over sodium sulfate,
filtered and concentrated. The crude acid was purified via flash
chromatography eluting with 1:4:95 acetic acid/methanol/methylene
chloride to give a white solid. .sup.1H NMR (300 MHz. CDCl.sub.3)
.delta. 11.36 (1H, bs), 7.05 (1H, m), 6.81 (2H, tt, J=2.4, 8.8 Hz),
4.77 (1H, s), 3.47 (3H, s)/C9H8F2O3 (MW=202.17); mass spectroscopy
-202.
[1524] B. Following General Procedure D above using
3,5-difluorophenyl-.alpha.-methoxyacetic acid and
3-[(L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as
described in Example 8-B above, the title compound was prepared.
Anal. Calcd for C.sub.28H.sub.28F.sub.2N.sub.4O.sub.4 C, 64.61; H,
5.03; N, 10.76. Found: C, 64.36; H, 5.23; N, 10.53. MS calcd for
C.sub.28H.sub.28F.sub.2N.sub.4O- .sub.4 520.5, found 520.0.
Example 4-6
Preparation of
3-[N'-(3,5-difluorophenyl-.alpha.-methoxyacetyl)-L-alaninyl-
]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one
[1525] Following General Procedure D above using
3,5-difluorophenyl-.alpha- .-methoxyacetic acid (as described in
Example 4-5) and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin--
2-one, as described in Example 8-B above, the title compound was
prepared. Anal. Calcd for C.sub.28H.sub.28F.sub.2N.sub.4O.sub.4 C,
64.61; H, 5.03; N, 10.76. Found: C, 64.85; H, 5.18; N, 10.76. MS
calcd for C.sub.28H.sub.28F.sub.2N.sub.4O.sub.4 520.5, found
519.9.
Example 4-7
Preparation of
3-[(N'-(2-(4-hydroxyphenoxy)propionyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1526] Following General Procedure D above using
2-(4-hydroxyphenoxy)propi- onic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-b-
enzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 501 (M+H).
Example 4-8
Preparation of
(S)-3-[(N'-(2-(4-trifluorophenyoxy)propionyl)-L-alaninyl)]a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1527] Following one or more of the general procedures outlined
above, using 2-(4-trifluorophenyoxy)propionic acid and
3-[(L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described
in Example 8-B above, the title compound was prepared. The
molecular weight as determined by mass spectrometry (FD) was: 469
(M+H).
Example 4-9
Preparation of
(S)-3-[(N'-(2-(4-Biphenylyloxy)propionyl)-L-alaninyl)]amino-
-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1528] Following General Procedure D above using
2-(4-biphenylyloxy)propio- nic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-be-
nzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 561 (M+H).
Example 4-15
Preparation of
3-[(N'-(.alpha.-methoxyphenylacetyl)-L-alaninyl)]amino]-2,3-
-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2--
one
[1529] Following General Procedure C-J above using
.alpha.-methoxyphenylac- etic acid and
3-(L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-
-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one, as described in Example
C-AF, the title compound was prepared. The molecular weight as
determined by mass spectrometry (FD) was: 571 (M+H).
Example 4-16
25 Preparation of (S)-3-[(N'-(2-(4-Cyanophenoxy)-2-methyl
propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodi-
azepin-2-one
[1530] Following General Procedure D above using
2-(4-cyanophenoxy)-2-meth- yl propionic acid and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl--
1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 524 (M+H).
General Procedure 5-A1 for Urea Preparation
[1531] In a round bottom flask was added an amine (1.0 eq.) in THF
or CH.sub.2Cl.sub.2 followed by an isocyanate (1.0 eq.). The
reaction mixture was allowed to stir 2-20 hours at room temperature
under an atmosphere of nitrogen. The mixture was diluted with EtOAc
or CH.sub.2Cl.sub.2 and washed with saturated NaHCO.sub.3
(1.times.5 mL), H.sub.2O (1.times.5 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 either purified
by trituration or silica gel flash chromatography.
[1532] General Procedure (5-B1)--Urea Preparation
[1533]
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin--
6-one hydrochloride (1.0 eq) methylene chloride (CH.sub.2Cl.sub.2),
triethylamine (1.5 eq), and a suitable isocyanate (4 eq) are
combined in a brown glass vial and placed on an orbital shaker for
5-48 hours. At this time aminomethylated polystyrene resin
(Aldrich) (6 eq) is added and the mixture is shaken for an
additional 5-24 hours. The reaction mixture is then filtered, the
flask washed with an additional 15 mL CH.sub.2Cl.sub.2, and the
filtrate removed in vacuo. The remaining solid is then purified by
passing through a small silica gel plug with ethyl acetate (EtOAc).
The solvent is removed in vacuo to yield the product as a white
solid. The product is then analyzed by reverse phase HPLC (Waters
C18 mBondapak 3.9.times.300 mm column, eluent: 30% CH3CN in 0.1%
aqueous triflouroacetic acid, UV detection: 233 nm). Ionspray-MS is
also used to analyze the products.
[1534] General Procedure (5-C1)--Urea Preparation
[1535] A solution of
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one hydrochloride (Example 7B) (1.0 eq) in
dichloromethane is stirred at 0.degree. C. with aqueous saturated
sodium bicarbonate solution. After 15 minutes, the stirring is
stopped and the layers allowed to separate. A phosgene solution
(20% in toluene, Aldrich, 2.0 eq) is added to the organic layer,
and stirring is resumed. After 15 additional minutes of stirring at
0.degree. C., the layers are separated, and the organic layer is
washed with aqueous saturated sodium bicarbonate solution, dried
over anhydrous sodium sulfate and the solvents removed in vacuo to
yield a colorless oil. This oil is diluted with dichloromethane,
and transferred to a brown glass vial. A suitable amine (4 eq) is
added, and the vial is placed on an orbital shaker, and shaken for
3-28 hours. At this time, aminomethylated polystyrene resin (6 eq,
Aldrich) is added, and shaking continued for 4-28 hours. The
reaction mixture is filtered through a sintered glass funnel, the
solvents removed in vacuo to yield the product as a white solid.
The product is characterized by reverse phase HPLC (Waters
3.9.times.300 mBondapak column, eluent: 30% acetonitrile in 0.1%
aqueous triflouroacetic acid buffer, monitored by UV detection @
233 nm) and IEX-MS.
[1536] General Procedure (5-D1)--Urea Preparation
[1537] A solution of
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibe-
nz[b,d]azepin-6-one hydrochloride (Example 7B) (1.0 eq) in
dichloromethane is stirred at 0.degree. C. with aqueous saturated
sodium bicarbonate solution. After 15 minutes, the stirring is
stopped and the layers allowed to separate. A phosgene solution
(20% in toluene, Aldrich, 2.0 eq) is added to the organic layer,
and stirring is resumed. After 15 additional minutes of stirring at
0.degree. C., the layers are separated, and the organic layer is
washed with aqueous saturated sodium bicarbonate solution, dried
over anhydrous sodium sulfate and the solvents removed in vacuo to
yield a colorless oil. This oil is diluted with dichloromethane,
and a suitable amine is added (1.54 eq). The reaction mixture is
stirred for 17 hours, at which time the reaction mixture is washed
with 0.1N HCl. The organic layer is dried over anhydrous sodium
sulfate, and the solvents removed in vacuo. Purification by
chromatography provides the product as a white solid.
Example 5-1
Preparation of
(S)-3-[(N'-((trans-2-Phenylcyclopropyl)ureylenyl)-L-alaniny-
l)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1538] Following General Procedure (5-A1) using
trans-2-phenylcyclopropyl isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 495 (M+H).
Example 5-2
Preparation of
(S)-3-[(N'-((3,4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1539] Following General Procedure (5-A1) using 3,4-dichlorophenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B-above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 523 (M+H).
Example 5-3
Preparation of
(S)-3-[(N'-((2-propenyl)ureylenyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1540] Following General Procedure (5-A1) using 2-propenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: (M+H).
Example 5-4
Preparation of
(S)-3-[(N'-((R)-(-)-1-(1-Naphthyl)ethyl)ureylenyl)-L-alanin-
yl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1541] Following General Procedure (5-A1) using
(R)-(-)-1-(1-naphthyl)ethy- l isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1-
H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 533 (M+H).
Example 5-5
Preparation of
(S)-3-[(N'-((2,6-Diisopropylphenyl)ureylenyl)-L-alaninyl)]a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1542] Following General Procedure (5-A1) using
2,6-diisopropylphenyl isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 539 (M+H).
Example 5-6
Preparation of
(S)-3-[(N'-((3-[(Trifluoromethyl)phenyl)ureylenyl)-L-alanin-
yl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1543] Following General Procedure (5-A1) using
3-[(trifluoromethyl)phenyl isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 523 (M+H)
Example 5-7
Preparation of
(S)-3-[(N'-((Phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydr-
o-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1544] Following General Procedure (5-A1) using phenyl isocyanate
and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 455 (M+H).
Example 5-8
Preparation of
(S)-3-[(N'-((4-ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1545] Following General Procedure (5-A1) using
4-ethoxycarbonylphenyl isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 527 (M+H).
Example 5-9
Preparation of
(S)-3-[(N'-((2-Bromophenyl)ureylenyl)-L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1546] Following General Procedure (5-A1) using 2-bromophenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzod-
iazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 534 (M+H).
Example 5-10
Preparation of
(S)-3-[(N'-((o-Tolyl)ureylenyl)-L-alaninyl)]amino-2,3-dihyd-
ro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1547] Following General Procedure (5-A1) using o-tolyl isocyanate
and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 469 (M+H).
Example 5-11
Preparation of
(S)-3-[(N'-((2-Ethyl-6-methylphenyl)ureylenyl)-L-alaninyl)]-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1548] Following General Procedure (5-A1) using
2-ethyl-6-methylphenyl isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 497 (M+H).
Example 5-12
Preparation of
(S)-3-[(N'-((2-Fluorophenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1549] Following General Procedure (5-A1) using 2-fluorophenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzod-
iazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 473 (M+H).
Example 5-13
Preparation of
(S)-3-[(N'-((2,4-difluorophenyl)ureylenyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1550] Following General Procedure (5-A1) using 2,4-difluorophenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 491 (M+H).
Example 5-14
Preparation of
(S)-3-[(N'-((2-Ethoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1551] Following General Procedure (5-A1) using 2-ethoxyphenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzod-
iazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 499 (M+H).
Example 5-15
Preparation of
(S)-3-[(N'-((3-Acetylphenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1552] Following General Procedure (5-A1) using 3-acetylphenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzod-
iazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 497 (M+H).
Example 5-16
Preparation of
(S)-3-[(N'-((3-[(cyano)phenyl)ureylenyl)-L-alaninyl)]amino--
2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1553] Following General Procedure (5-A1) using 3-[(cyano)phenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 501 (M+H).
Example 5-18
Preparation of
(S)-3-[(N'-((Phenethyl)ureylenyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1554] Following General Procedure (5-A1) using phenethyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 483 (M+H).
Example 5-19
Preparation of
(S)-3-[(N'-((4-n-Butylphenyl)ureylenyl)-L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1555] Following General Procedure (5-A1) using 4-n-butylphenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzod-
iazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 511 (M+H).
Example 5-20
Preparation of
(S)-3-[(N'-((Octyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1556] Following General Procedure (5-A1) using octyl isocyanate
and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 491 (M+H).
Example 5-21
Preparation of
(S)-3-[(N'-((4-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1557] Following General Procedure (5-A1) using 4-biphenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 531 (M+H).
Example 5-22
Preparation of
(S)-3-[(N'-((4-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-
-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1558] Following General Procedure (5-A1) using 4-isopropylphenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 497 (M+H).
Example 5-23
Preparation of
(S)-3-[(N'-((Hexyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-
-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1559] Following General Procedure (5-A1) using hexyl isocyanate
and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 463 (M+H).
Example 5-24
Preparation of
(S)-3-[(N'-((2-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-
-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1560] Following General Procedure (5-A1) using 2-isopropylphenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 513 (M+H).
Example 5-25
Preparation of
(S)-3-[(N'-((2,6-Difluorophenyl)ureylenyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1561] Following General Procedure (5-A1) using 2,6-difluorophenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 491 (M+H).
Example 5-26
Preparation of
(S)-3-[(N'-((Octadecyl)ureylenyl)-L-alaninyl)]amino-2,3-dih-
ydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1562] Following General Procedure (5-A1) using octadecyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 631 (M+H).
Example 5-27
Preparation of
(S)-3-[(N'-((4-(Trifluoromethoxy)phenyl)ureylenyl)-L-alanin-
yl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1563] Following General Procedure (5-A1) using
trifluoromethoxy)phenyl isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 539 (M+H).
Example 5-28
Preparation of
(S)-3-[(N'-((2,4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amin-
o-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1564] Following General Procedure (5-A1) using 2,4-dichlorophenyl
isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 524 (M+H).
Example 5-29
Preparation of
(S)-3-[(N'-((3-Ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1565] Following General Procedure (5-A1) using
ethoxycarbonylphenyl isocyanate and
(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-
-1,4-benzodiazepin-2-one, as described in Example 8-B above, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 527 (M+H).
Example 5-30
Preparation of
(S)-3-[(N'-((4-Chlorophenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1566] Following General Procedure (5-A1) using 4-chlorophenyl
isocyanate and
(S)-3-[(N'-((4-Chlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro--
1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in
Example 8-B above, the title compound was prepared. The molecular
weight as determined by mass spectrometry (FD) was: 489 (M+H).
Example 5-31
Preparation of
(S)-3-[(N'-((4-butoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,-
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1567] Following General Procedure (5-A1) using 4-butoxyphenyl
isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 547 (M+H).
Example 5-32
Preparation of
(S)-3-[(N'-((4-Phenoxyphenyl)ureylenyl)-L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1568] Following General Procedure (5-A1) using 4-phenoxyphenyl
isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 527 (M+H).
Example 5-33
Preparation of
(S)-3-[(N'-((1-Naphthyl)ureylenyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1569] Following General Procedure (5-A1) using naphthyl isocyanate
and
(S)-3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepi-
n-2-one, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: 505 (M+H).
Example 5-34
Preparation of
(S)-3-[(N'-((2-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-di-
hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1570] Following General Procedure (5-A1) using (2-phenyl)phenyl
isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
-benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 531 (M+H).
Example 5-35
Preparation of
(S)-3-[(N'-((2-(Methylthio)phenyl)ureylenyl)-L-alaninyl)]am-
ino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1571] Following General Procedure (5-A1) using
2-(methylthio)phenyl isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
-benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 501 (M+H).
Example 5-36
Preparation of
(S)-3-[(N'-((2-Ethylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-
-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1572] Following General Procedure (5-A1) using 2-ethylphenyl
isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 483 (M+H).
Example 5-37
Preparation of
(S)-3-[(N'-((3-Methoxyphenyl)ureylenyl)-L-alaninyl)]amino-2-
,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1573] Following General Procedure (5-A1) using 3-methoxyphenyl
isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 485 (M+H).
Example 5-38
Preparation of
(S)-3-[(N'-((3,4,5-Trimethoxyphenyl)ureylenyl)-L-alaninyl)]-
amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1574] Following General Procedure (5-A1) using
3,4,5-trimethoxyphenyl isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
-benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 545 (M+H).
Example 5-39
Preparation of
(S)-3-[(N'-((2,4,6-Trimethylphenyl)ureylenyl)-L-alaninyl)]a-
mino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1575] Following General Procedure (5-A1) using
2,4,6-trimethylphenyl isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
-benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: 497 (M+H).
Example 5-40
Preparation of
(S)-3-[(N'-((2-methyl-6-t-butylpenyl)ureylenyl)-L-alaninyl)-
]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1576] Following General Procedure (5-A1) using
2-methyl-6-t-butylphenyl isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-
-benzodiazepin-2-one, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: (M+H).
Example 5-41
Preparation of
(S)-3-[(N'-((2-(2-thiophene-yl)ethyl)ureylenyl)-L-alaninyl)-
]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1577] Following General Procedure (5-A1) using 2-thiophene-yl
isocyanate and
3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiaze-
pin-2-one, as described in Example 8-B above, the title compound
was prepared. The molecular weight as determined by mass
spectrometry (FD) was: (M+H).
Example 5-43
Preparation of
5-(S)-(N'-((2-(thiophen-2-yl)ethylureylenyl)-L-alaninyl)-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1578] Following General Procedure (5-A1) using 2-(thien-2-yl)ethyl
isocyanate and
5-(S)-(N'-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz-
[b,d]azepin-6-one, as described in Example 7-B, the title compound
was prepared as a white solid. The reaction was monitored by tlc
(R.sub.f=0.35 in 10% MeOH/CH.sub.2Cl.sub.2) and the product was
purified by silica gel chromatography using gradient elution of
MeOH/CH.sub.2Cl.sub.2 (1: 99-2:98).
[1579] NMR data was as follows:
[1580] .sup.1H-nmr (CDCl.sub.3): delta=7.86 (d, J=7.0 Hz, 1H),
7.51-7.24 (m, 10H), 7.06 (d, J=6.0 Hz, 1H), 6.87-6.84 (m, 1H),
6.72-6.71 (m, 1H), 5.20 (d, J=6.5 Hz, 1H), 4.55-4.53 (m, 1H), 3.27
(s, 3H), 3.20-3.05 (m, 2H) 2.75-2.70 (m, 2H), 1.25 (d, J=7.0 Hz,
3H).
[1581] C.sub.25H.sub.26N.sub.4O.sub.3S (MW=462.57); mass
spectroscopy (MH.sup.+) 463.6.
[1582] Anal Calcd for C.sub.25H.sub.26N.sub.4O.sub.3S, C, 64.91; H,
5.67; N, 12.11. Found: C, 65.12; H, 5.71; N, 12.10.
Example 5-44
Preparation of
5-(S)-(N'-((Phenethylureylenyl)-L-alaninyl)-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1583] Following General Procedure (5-A1) using phenethyl
isocyanate and
5-(S)-(N'-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-o-
ne, the title compound was prepared as a white solid. The reaction
was monitored by tlc (R.sub.f 0.53 in 10% MeOH/CH.sub.2Cl.sub.2)
and the product was purified by silica gel chromatography using
gradient elution of MeOH/CH.sub.2Cl.sub.2 (1: 99-3:97).
[1584] NMR data was as follows:
[1585] .sup.1H-nmr (CDCl.sub.3): .delta.=7.78 (d, J=6.6 Hz, 1H),
7.54-7.12 (m, 15H), 5.23 (d, J=6.7 Hz, 1H), 4.58-4.53 (m, 1H),
3.32-3.27 (m, 5H), 2.64 (t, J=7.4 Hz, 2H), 1.33 (d, J=7.0 Hz,
3H).
[1586] Optical Rotation: [.alpha.].sub.20=-80.3 @ 589 nm (c=1,
MeOH)
[1587] C.sub.27H.sub.28N.sub.4O.sub.3 (MW=456.5); mass spectroscopy
(MH.sup.+) 457.5
[1588] Anal Calcd for C.sub.27H.sub.18N.sub.4O.sub.3; C, 71.03; H,
6.18; N, 12.27. Found: C, 70.90; H, 6.38; N, 12.00.
Example 5-45
Preparation of
5-(S)-(N'-((Butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7--
dihydro-6H-dibenzo[b,d]azepin-6-one
[1589] Following General Procedure (5-A1) using butyl isocyanate
and
5-(S)-(N'-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-o-
ne, as described in Example 7-B, the title compound was prepared as
a white solid. The reaction was monitored by tlc (R.sub.f=0.49 in
10% MeOH/CH.sub.2Cl.sub.2) and the product was purified by silica
gel chromatography using gradient elution of MeOH/CH.sub.2Cl.sub.2
(1: 99-3:97).
[1590] NMR data was as follows:
[1591] .sup.1H-nmr (CDCl.sub.3): delta=7.74-7.33 (m, 1H), 5.24 (d,
J=6.7 Hz, 1H), 4.57-4.53 (m, 1H), 3.35 (s, 3H), 3.08-2.85 (m, 2H),
1.39-1.25 (m, 7H), 0.88 (t, J=7.0 Hz, 3H).
[1592] Optical Rotation: [.alpha.].sub.20=-97.1 @ 589 nm (c=1,
MeOH)
[1593] C.sub.23H.sub.28N.sub.4O.sub.3 (MW=408.5); mass spectroscopy
(MH.sup.+) 409.4
[1594] Anal Calcd for C.sub.23H.sub.28N.sub.4O.sub.3; C, 67.63; H,
6.91; N, 13.72. Found: C, 67.46; H, 6.93; N, 13.64.
Example 5-46
Preparation of
5-(S)-(N'-((Benzylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b, d]azepin-6-one
[1595] Following General Procedure (5-A1) using benzyl isocyanate
and
5-(S)-(N'-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-o-
ne, as described in Example 7-B, the title compound was prepared as
a white solid. The reaction was monitored by tlc (R.sub.f=0.63 in
10% MeOH/CH.sub.2Cl.sub.2) and the product was purified by
trituration from EtOAc and Hex.
[1596] NMR data was as follows:
[1597] .sup.1H-nmr (CDCl.sub.3): .delta.=7.86 (d, J=6.7 Hz, 1H),
7.46-7.09 (m, 15H), 5.21 (d, J=6.7 Hz, 1H), 4.59-4.40 (m, 1H),
4.38-4.00 (m, 2H), 3.27 (s, 3H), 1.29 (d, J=7.1 Hz, 3H).
[1598] C.sub.26H.sub.26N.sub.4O.sub.3 (MW=442.52); mass
spectroscopy (MH.sup.+) 443.3.
[1599] Anal Calcd for C.sub.16H.sub.26N.sub.4O.sub.3; C, 70.57; H,
5.92; N, 12.66. Found: C, 70.36; H, 6.05; N, 12.47.
Example 5-47
Preparation of
5-(S)-(N'-((Ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1600] Following General Procedure (5-A1) using ethyl isocyanate
and
5-(S)-(N'-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-o-
ne, as described in Example 7-B, the title compound was prepared as
a white solid. The reaction was monitored by tlc (R.sub.f=0.35 in
10% MeOH/CH.sub.2Cl.sub.2) and the product was purified by silica
gel chromatography using gradient elution of MeOH/CH.sub.2Cl.sub.2
(1:99-4:96).
[1601] NMR data was as follows:
[1602] 1H-nmr (CDCl.sub.3): .delta.=7.84 (d, J=6.8 Hz, 1H),
7.56-7.30 (m, 10H), 5.23 (d, J=6.7 Hz, 1H), 4.60-4.53 (m, 1H), 3.33
(s, 3H), 3.00-2.87 (m, 2H), 1.30 (d, 7.0 Hz, 3H), 0.85 (t, J=7.1
Hz, 3H).
[1603] C.sub.21H.sub.24N.sub.4O.sub.3 (MW=380.45); mass
spectroscopy (MH.sup.+) 381.3.
[1604] Anal Calcd for C.sub.21H.sub.24N.sub.4O.sub.3; C, 66.30; H,
6.36; N, 14.73. Found: C, 66.14; H, 6.58; N, 14.49.
Example 5-48
Preparation of
5-(R/S)-(N'-(2-hydroxy-2-phenethylureylenyl)-L-alaninyl)-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1605] Following General Procedure (5-D1) above using
5-(R/S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e hydrochloride (Example 7B) and 2-(R/S)-amino-1-phenylethanol
(Sigma) the title compound was prepared. The final product was
purified by flash chromatography (5% CH.sub.3OH in 2:1
CH.sub.2Cl.sub.2:EtAc) to give a mixture of diastereomers.
[1606] C27H28N4O4 (MW=472.54), mass spectroscopy (MH.sup.+) 473.
Anal. Calcd for C27H28N4O4, C, 68.63; H, 5.97; N, 11.86. Found C,
68.14; H, 5.98; N, 11.50.
Example 5-49
Preparation of
5-(S)-(N'-((hexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1607] Following General Procedure (5-B1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and hexyl isocyanate (Aldrich) the title
compound was prepared.
[1608] C25H32N4O3 (MW=436.56); mass spectroscopy (MH+) 437.
[1609] Retention time; 11.0 minutes.
Example 5-50
Preparation of
5-(S)-(N'-((cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1610] Following General Procedure (5-B1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and cyclohexyl isocyanate (Aldrich) the
title compound was prepared.
[1611] C25H30N4O3 (MW=434.54); mass spectroscopy (MH+) 435.
[1612] Retention time; 8.2 minutes.
Example 5-51
Preparation of
5-(S)-(N'-((isopropylureylenyl)-L-alaninyl)-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1613] Following General Procedure (5-B 1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and isopropyl isocyanate (Aldrich) the
title compound was prepared.
[1614] C22H26N4O3 (MW=394.48); mass spectroscopy (MH+) 395.
[1615] Retention time; 5.3 minutes.
Example 5-52
Preparation of
5-(S)-(N'-((tert-butylureylenyl)-L-alaninyl)-amino-7-methyl-
-5,7-dihydro-6H-dibenz[b, d]azepin-6-one
[1616] Following General Procedure (5-B1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and tert-butyl isocyanate (Aldrich) the
title compound was prepared.
[1617] C23H28N4O3 (MW=408.50); mass spectroscopy (MH+) (409).
[1618] Retention time; 6.9 minutes.
Example 5-53
Preparation of
5-(S)-(N'-((1-adamantylureylenyl)-L-alaninyl)-amino-7-methy-
l-5,7-dihydro-6H dibenz[b,d]azepin-6-one
[1619] Following General Procedure (5-B1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 1-adamantyl isocyanate (Aldrich) the
title compound was prepared.
[1620] C29H34N4O3 (MW=486.62); mass spectroscopy (MH+) 487.
[1621] Retention time; 20.3 minutes.
Example 5-54
Preparation of
5-(S)-(N'-((2-methylpropylureylenyl)-L-alaninyl)-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1622] Following General Procedure (5-C1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and isobutylamine (Aldrich) the title
compound was prepared.
[1623] C23H28N4O3 (MW=408.50); mass spectroscopy (MH+) 409.
[1624] HPLC retention time: 6.592 minutes.
Example 5-55
Preparation of
5-(S)-(N'-(R/S)-3-hydroxy-3-phenylethylureylenyl)-L-alaniny-
l)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1625] Following General Procedure (5-C1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 2-(R/S)-amino-1-phenylethanol
(Sigma) the title compound was prepared.
[1626] C27H28N4O4 (MW=472.55); mass spectroscopy (MH+) 473.
[1627] HPLC retention time: 5.707 minutes.
Example 5-56
Preparation of
5-(S)-(N'-((3-methylbutylureylenyl)-L-alaninyl)-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1628] Following General Procedure (5-C1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and isoamylamine (Aldrich) the title
compound was prepared.
[1629] C24H30N4O3 (MW=422.53); mass spectroscopy (MH+) 423.
[1630] HPLC retention time: 8.575 minutes.
Example 5-57
Preparation of
5-(S)-((N'-(S)-1-hydroxymethyl-3-methylbutylureylenyl)-L-al-
aninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b, d]azepin-6-one
[1631] Following General Procedure (5-D1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and (S)-leucinol (Aldrich) the title
compound was prepared.
[1632] C25H32N4O4 (MW=452.56); mass spectroscopy (MH+) 453.
[1633] Anal. Calcd for C.sub.25H.sub.32N.sub.4O.sub.4; C, 66.35; H,
7.13; N, 12.38. Found: C, 66.02; H, 7.03; N, 11.84.
Example 5-58
Preparation of
5-(S)-((N'-(1S)-(2S)-1-hydroxymethyl-2-methylbutylureylenyl-
)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1634] Following General Procedure (5-D1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and (L)-isoleucinol (Aldrich) the title
compound was prepared.
[1635] C25H32N4O4 (MW=452.56); mass spectroscopy (MH+) 453.
[1636] Anal. Calcd for C.sub.25H.sub.32N.sub.4O.sub.4; C, 66.35; H,
7.13; N, 12.38. Found: C, 66.31; H, 6.93; N, 12.21.
Example 5-59
Preparation of
5-(S)-(N'-(3-chloropropylureylenyl)-L-alaninyl)-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1637] Following General Procedure (5-B1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 3-chloropropyl isocyanate (Aldrich)
the title compound was prepared.
[1638] C22H25ClN4O3 (MW=428.92); mass spectroscopy (MH+) 429.
[1639] Retention time; 6.0 minutes.
Example 5-60
Preparation of
5-(S)-(N'-octylureylenyl)-L-alaninyl)-amino-1-methyl-5,7-di-
hydro-6H-dibenz[b,d]azepin-6-one
[1640] Following General Procedure (5-B1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and octyl isocyanate (Aldrich) the title
compound was prepared.
[1641] C27H36N4O3 (MW=464.61); mass spectroscopy (MH+) 465.
[1642] Retention time; 29.7 minutes.
Example 5-61
Preparation of
5-(S)-(N'-1,1,3,3-tetramethylbutylureylenyl)-L-alaninyl)-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1643] Following General Procedure (5-B1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 1,1,3,3-tetramethylbutyl isocyanate
(Aldrich) the title compound was prepared.
[1644] C27H36N4O3 (MW=464.61); mass spectroscopy (MH+) 465.
[1645] Retention time; 20.3 minutes.
Example 5-62
Preparation of
5-(S)-(N'-(R/S)-1-methylbutylureylenyl)-L-alaninyl)-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1646] Following General Procedure (5-C1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 1-(R/S)-methylbutylamine (Aldrich)
the title compound was prepared.
[1647] C24H30N4O3 (MW=422.53); mass spectroscopy (MH+) 423.
[1648] HPLC retention time: 8.0 minutes.
Example 5-63
Preparation of
5-(S)-((N'-(R/S)-1-hydroxymethylbutylureylenyl)-L-alaninyl)-
-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1649] Following General Procedure (5-C1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 2-(R/S)-amino-1-pentanol (Aldrich)
the title compound was prepared.
[1650] C24H30N4O4 (MW=438.53); mass spectroscopy (MH+) 439.
[1651] HPLC retention time: 4.6 minutes.
Example 5-64
Preparation of
5-(S)-((N'-(R/S)-1,3-dimethylbutylureylenyl)-L-alaninyl)-am-
ino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1652] Following General Procedure (5-C1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and (R/S)-1,3-dimethylbutylamine
(Aldrich) the title compound was prepared.
[1653] C25H32N4O3 (MW=436.56); mass spectroscopy (MH+) 437.
[1654] HPLC retention time: 10.6 minutes.
Example 5-65
Preparation of
5-(S)-((N'-(R)-1-hydroxymethyl-3-methylbutylureylenyl)-L-al-
aninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1655] Following General Procedure (5-C1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and (R)-Leucinol (Aldrich) the title
compound was prepared.
[1656] C25H32N4O4 (MW=452.56); mass spectroscopy (MH+) 453.
[1657] HPLC retention time: 5.0 minutes.
Example 5-66
Preparation of
5-(S)-((N'-(R/S)-2-methylbutylureylenyl)-L-alaninyl)-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1658] Following General Procedure (5-C1) above using
5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 2-(R/S)-methylbutylamine (Aldrich)
the title compound was prepared.
[1659] C24H30N4O3 (MW=422.53); mass spectroscopy (MH+) 423.
[1660] HPLC retention time: 8.1 minutes.
Example 5-67
Preparation of
5-(S)-(N'-morpholinoureylenyl)-L-alaninyl)-amino-7-methyl-5-
,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1661] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and morpholine (Aldrich) the title
compound was prepared.
[1662] C23H26N4O4 (MW=422.48); mass spectroscopy (MH+) 423.
[1663] Retention time; 4.5 minutes.
Example 5-68
Preparation of
5-(S)-(N'-(2-(2-hydroxyethoxy)-ethylureylenyl)-L-alaninyl)--
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1664] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 2-(2-aminoethoxy)ethanol (Aldrich)
the title compound was prepared.
[1665] C23H28N4O5 (MW=440.50); mass spectroscopy (MH+) 441.
[1666] Retention time; 3.8 minutes.
Example 5-69
Preparation of
5-(S)-(N'-piperidinylureylenyl)-L-alaninyl)-amino-7-methyl--
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1667] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B), piperidine (Aldrich), and
diisopropylethylamine (Aldrich) (1.5 eq) the title compound was
prepared.
[1668] C24H28N4O3 (MW=420.51); mass spectroscopy (MH+) 421.
[1669] Retention time; 6.9 minutes.
Example 5-70
Preparation of
5-(S)-(N'-(N"-methyl-N'-butylureylenyl)-L-alaninyl)-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1670] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and N-methyl-butylamine (Aldrich) the
title compound was prepared.
[1671] C24H30N4O3 (MW=422.53); mass spectroscopy (MH+) 423.
[1672] Retention time; 8.8 minutes.
Example 5-71
Preparation of
5-(S)-(N'-(1-(R/S)-hydroxymethylcyclopentylureylenyl)-L-ala-
ninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1673] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 1-aminocyclopentane methanol
(Aldrich) the title compound was prepared.
[1674] C25H30N4O4 (MW=450.54); mass spectroscopy (MH+) 451.
[1675] Retention time; 5.3 minutes.
Example 5-72
Preparation of
5-(S)-(N'-(4-hydroxybutylureylenyl)-L-alaninyl)-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1676] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 4-aminobutanol (Aldrich) the title
compound was prepared.
[1677] C23H28N4O4 (MW=424.50); mass spectroscopy (MH+) 425.
[1678] Retention time; 3.9 minutes.
Example 5-73
Preparation of
5-(S)-(N'-(1-(R/S)-hydroxymethyl-2-methylpropylureylenyl)-L-
-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1679] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 2-amino-3-methylbutanol (Aldrich)
the title compound was prepared.
[1680] C24H30N4O4 (MW=438.53); mass spectroscopy (MH+) 439.
[1681] Retention time; 4.7 minutes.
Example 5-74
Preparation of
5-(S)-(N'-(2-(R/S)-hydroxycyclohexylureylenyl)-L-alaninyl)--
amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1682] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B), 2-aminocyclohexanol (Janssen), and
diisopropylethylamine (Aldrich) (1.5 eq) the title compound was
prepared.
[1683] C25H30N4O4 (MW=450.54); mass spectroscopy (MH+) 451.
[1684] Retention time; 4.9 minutes.
Example 5-75
Preparation of
5-(S)-(N'-(isopropyl-hydroxyureylenyl)-L-alaninyl)-amino-7--
methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1685] Following General Procedure (5-D1) above using
5-(R/S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e hydrochloride (Example 7B) and N-isopropylhydroxylamine
hydrochloride (Aldrich), in the presence of diisopropylethylamine
(Aldrich) the title compound was prepared. The final product was
purified by flash chromatography (ethyl acetate) to give a mixture
of diastereomers.
[1686] C22H26N4O4 (MW=410.471), mass spectroscopy (MH+) 411.
[1687] 1H NMR (CD3OD, 400 MHz, d) 7.64-7.36 (m, 8H), 5.17 (s, 1H),
4.48-4.38 (m, 1H), 4.35-4.25 (m, 1H), 3.29 (s, 3H), 1.40 (d, J=7.3
Hz, 3H), 1.12-1.09 (m, 6H).
Example 5-76
Preparation of
5-(S)-(N'-(benzyl-hydroxyureylenyl)-L-alaninyl)-amino-7-met-
hyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1688] Following General Procedure (5-D1) above using
5-(R/S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-on-
e hydrochloride (Example 7B) and N-benzylhydroxylamine
hydrochloride (Aldrich), in the presence of diisopropylethylamine
(Aldrich) the title compound was prepared. The final product was
purified by flash chromatography (ethyl acetate) to yield a mixture
of diastereomers.
[1689] C26H26N4O4 (MW=458.52), mass spectroscopy (MH+) 459.
[1690] 1H NMR (CD3OD, 460 MHz, d) 7.65-7.12 (m, 13H), 5.19 (s, 1H),
4.70-4.58 (m, 2H), 4.51-4.44 (m, 1H), 3.32 (s, 3H), 1.44-1.41 (m,
3H).
Example 5-77
Preparation of
5-(S)-(N'-(thiomorpholinylureylenyl)-L-alaninyl)-amino-7-me-
thyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1691] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and thiomorpholine (Aldrich) the title
compound was prepared.
[1692] C23H26N4O3S (MW=438.55); mass spectroscopy (MH+) 439.
[1693] Retention time; 5.9 minutes.
Example 5-78
Preparation of
5-(S)-(N'-(2(R/S)-hydroxybutylureylenyl)-L-alaninyl)-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1694] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 2-(R/S)-hydroxybutylamine
(Transworld) the title compound was prepared.
[1695] C23H28N4O4 (MW=424.50); mass spectroscopy (MH+) 425.
[1696] Retention time; 4.2 minutes.
Example 5-79
Preparation of
5-(S)-(N'-2,2,2-trifluoroethylureylenyl)-L-alaninyl)-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1697] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 2,2,2-triflouroethylamine (Aldrich)
the title compound was prepared.
[1698] C21H21F3N4O3 (MW=434.42); mass spectroscopy (MH+) 435.
[1699] Retention time; 6.0 minutes.
Example 5-80
Preparation of
5-(S)-(N'-(4R/S)-cyclohexylureylenyl)-L-alaninyl)-amino-7-m-
ethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1700] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and 4-aminocyclohexanol (Fluka) the
title compound was prepared.
[1701] C25H30N4O4 (MW=450.54); mass spectroscopy (MH+) 451.
[1702] Retention time; 4.0 minutes.
Example 5-81
Preparation of
5-(S)-(N'-(1R)-hydroxymethyl-3-methylthiopropylureylenyl)-L-
-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1703] Following General Procedure (5-C1) above using
5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
hydrochloride (Example 7B) and L-methioninol (Lancaster) the title
compound was prepared.
[1704] C24H30N4O4S (MW=470.60); mass spectroscopy (MH+) 471.
[1705] Retention time; 4.6 minutes.
Example 6-1
Preparation of
5-{N'-(benzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihy-
dro-6H-dibenz[b, d]azepin-6-one
[1706] To
5-(L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6--
one hydrochloride (Example 7B) (0.1500 g, 0.434 mmol) in THF (4 ml)
were added pyridine (0.088 ml, 1.09 mmol) and benzenesulfonyl
chloride (Aldrich) (0.061 ml, 0.477 mmol), stirred at RT for 2
days. The reaction mixture was evaporated to dryness. Water and
CH.sub.2Cl.sub.2 were added. CH.sub.2Cl.sub.2 layer was dried over
MgSO.sub.4. Evaporation and flash chromatography (silica, 5-6%
MeOH/CH.sub.2Cl.sub.2) gave a residue, which was crystallized in
CHCl.sub.3/hexane and washed with Et.sub.2O to give the title
compound (0.027 g, 14%) as a white solid.
[1707] C24H23N3O4S (MW=449.529); mass spectroscopy (MH+) 448.
[1708] Anal. Calcd for C24H23N3O4S: C, 64.13; H, 5.16; N, 9.35.
Found: C, 63.99; H, 5.05; N, 9.24.
Example 6-2
Preparation of
5-{N'-(3-fluorobenzenesulfonyl)-L-alaninyl}-amino-7-methyl--
5,7-dihydro-6H-dibenz[b, d]azepin-6-one
[1709] To
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one hydrochloride (Example 7B) (0.1500 g, 0.434 mmol) in THF (4
ml) was added pyridine (0.088 ml, 1.09 mmol) and
3-fluorobenzenesulfonyl chloride (Fluorochem Limited) (0.0928 ml,
0.477 mmol), stirred at RT overnight. The reaction mixture was
evaporated to dryness. Water was added, filtered. The solid was
purified with flash chromatography (silica, 6%.
MeOH/CH.sub.2Cl.sub.2, crystallized with CH.sub.2Cl.sub.2/hexane
and washed with Et.sub.2O/hexane (1:1, v/v) to give the title
compound (0.0580 g, 29%) as a white solid.
[1710] C24H22FN3O4S (MW=467.519); mass spectroscopy (MH.sup.+)
468.
[1711] Anal. Calcd for C24H22FN3O4S: C, 61.66; H, 4.74; N, 8.99.
Found: C, 61.76; H, 4.93; N, 8.76.
Example 6-3
Preparation of
5-{N'-(benzylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihyd-
ro-6H-dibenz[b,d]azepin-6-one
[1712] To
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one (Example 7B) (0.2050 g, 0.66 mmol) in DMF (5 ml) was added
benzylsulfonyl chloride (Aldrich) (0.0632 g, 0.33 mmol), stirred at
RT for 3.5 days. The reaction mixture was evaporated to dryness.
Water was added, extracted with CH.sub.2Cl.sub.2, washed with
brine, dried over MgSO.sub.4. Evaporation and flash chromatography
(silica, 5% MeOH/CH.sub.2Cl.sub.2), gave a residue, which was
washed with Et.sub.2O/hexane (1:2, v/v) to give the title compound
(0.0531 g, 35%) as a light yellow solid.
[1713] C25H25N3O4S (MW=463.555); mass spectroscopy (MH.sup.+)
464.
[1714] Anal. Calcd for C.sub.25H.sub.25N.sub.3O.sub.4S: C, 64.78;
H, 5.44; N, 9.06. Found: C, 64.83; H, 5.17; N, 8.86.
Example 6-4
Preparation of
5-{N'-(butylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1715] To
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added
pyridine (0.059 ml, 0.728 mmol) and 1-butanesulfonyl chloride
(Aldrich) (0.063 ml, 0.485 mmol), stirred at RT overnight. The
reaction mixture was evaporated to dryness. Water was added,
extracted with EtOAc, washed with brine, dried over MgSO.sub.4.
Evaporation and flash chromatography (silica, 5%
MeOH/CH.sub.2Cl.sub.2), gave the title compound (0.0714 g, 34%) as
a yellow solid.
[1716] C22H27N3O4S (MW=429.538); mass spectroscopy (MH.sup.+)
430.
[1717] Anal. Calcd for C22H27N3O4S: C, 61.52; H, 6.34; N, 9.78.
Found: C, 61.78; H, 6.40; N, 9.51.
Example 6-5
Preparation of
5-{N'-(octylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one
[1718] To
5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-
-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added
pyridine (0.059 ml, 0.728 mmol) and 1-octanesulfonyl chloride
(Aldrich) (0.095 ml, 0.485 mmol), stirred at RT overnight. The
reaction mixture was evaporated to dryness. Water was added,
extracted with EtOAc, washed with brine, dried over MgSO.sub.4.
Evaporation and flash chromatography (silica, 5%
MeOH/CH.sub.2Cl.sub.2), gave the title compound (0.0805 g, 34%) as
a yellow solid.
[1719] C26H35N3O4S (MW=485.646); mass spectroscopy (MH+) 486.
[1720] Anal. Calcd for C26H35N3O4S: C, 64.30; H, 7.26; N, 8.65.
Found: C, 64.14; H, 7.13; N, 8,48.
Example 7-1
Preparation of 5-(S)-(N'-(3,5-difuorophenyl-.alpha.-aminoacetyl)-L
valinyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1721] Following General Procedure D above using
N-boc-3,5-difluorophenylg- lycine and
5-(S)-(L-valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azep-
in-6-one hydrochloride (Example 7B), the protected intermediate was
prepared as a colorless oil. The Boc-group was removed using 5.0 M
HCl in dioxane and the resulting free-base purified by flash
chromatography using 98:2 CHCl.sub.3/MeOH yielding the title
compound.
[1722] NMR data was as follows:
[1723] .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).
[1724] C.sub.28H.sub.28F.sub.2N.sub.4O.sub.3 (MW=506); mass
spectroscopy (MH.sup.+) 506.9
[1725] Anal Calcd for C.sub.28H.sub.28F.sub.2N.sub.4O.sub.3; C,
66.39; H, 5.57; N, 11.06. Found: C, 66.33; H, 5.67; N, 10.89.
Example 7-2
Preparation of
5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-tert-l-
eucinyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1726] Following General Procedure D above using
N-boc-3,5-difluorophenylg- lycine and
5-(S)-(L-tert-leucinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,-
d]azepin-6-one hydrochloride, the protected intermediate was
prepared as a colorless oil. The Boc-group was removed using 5.0 M
HCl in dioxane and the resulting free-base purified by flash
chromatography using 98:2 CHCl.sub.3/MeOH yielding the title
compound.
[1727] C.sub.29H.sub.30F.sub.2N.sub.3O.sub.4 (MW=520.57); mass
spectroscopy (MH.sup.+) 521
[1728] Anal Calcd for C.sub.29H.sub.30F.sub.2N.sub.3O.sub.4; C,
66.91; H, 5.81; N, 10.76. Found: C, 66.66; H, 5.70; N, 10.55.
Example 7-3
Preparation of
5-(S)-(N'-(valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6-
H-dibenz[b,d]azepin-6-one
[1729] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and L-Boc-Valine (Aldrich), the protected intermediate
was prepared. This was purified by flash chromatography using
CHCl.sub.3/MeOH (99:1). The Boc-group was removed using 5.0 M HCl
in dioxane and the resulting free-base purified by flash
chromatography CHCl.sub.3/MeOH (95:5) yielding the title
compound.
[1730] C23H28N4O3 (MW=408.499); mass spectroscopy (MH+) 409.
[1731] Anal. Calcd for C23H28N4O3; C, 67.63; H, 6.91; N, 13.72.
Found: C, 67.48; H, 7.01; N, 13.70.
Example 7-4
Preparation of
5-(S)-(N'-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-di-
hydro-6H-diben[b,d]azepin-6-one
[1732] Following General Procedure F above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and the acid fluoride of L-Boc-phenylglycine (Carpino,
et. al., J. Org. Chem., (1991), 56, 2611-2614), the protected
intermediate was prepared. This was purified by flash
chromatography using CHCl.sub.3/MeOH (99:1). The Boc-group was
removed using 5.0 M HCl in dioxane and the resulting hydrochloride
purified by flash chromatography CHCl.sub.3/MeOH (99:1) yielding
the title compound.
[1733] C26H26N4O3 (MW=442.516); mass spectroscopy (MH+) 443.
[1734] Anal. Calcd for C26H26N4O3.HCl; C, 65.79; H, 5.68; N, 11.69.
Found: C, 65.69; H, 5.63; N, 11.42.
Example 7-5 and 7-6
Preparation of 5-(S)-(N'-(R and
S)-3,5-difluorophenyl-.alpha.-aminoacetyl)-
-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1735] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and D/L-Boc-3,5-difluorophenylglycine, the protected
intermediate was prepared. The Boc-group was removed using 5.0 M
HCl in dioxane and the resulting free-base diastereomers were
purified by flash chromatography CHCl.sub.3/MeOH (98:2) yielding
the title compounds.
[1736] Isomer A: C26H24F2N4O3 (MW=478.497); mass spectroscopy (MH+)
479.
[1737] Anal. Calcd for C26H24F2N4O3. 0.6681 mol H.sub.2O; C, 63.66;
H, 5.20; N, 11.42. Found: C, 63.65; H, 5.35; N, 11.56.
[1738] Isomer B: C26H24F2N4O3 (MW=478.497); mass spectroscopy (MH+)
479.
[1739] Anal. Calcd for C26H24F2N4O.sub.3. 0.5146 mol H.sub.2O; C,
64.02; H, 5.17N, 11.49. Found: C, 64.04; H, 5.01; N, 11.30.
Example 7-8
Preparation of
5-(S)-(N'-(D-valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-
-6H-dibenz[b,d]azepin-6-one
[1740] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and D-Boc-Valine (Aldrich), the protected intermediate
was prepared. This was purified by flash chromatography using
CHCl.sub.3/MeOH (99:1). The Boc-group was removed using 5.0 M HCl
in dioxane and the resulting free-base purified by flash
chromatography CHCl.sub.3/MeOH (95:5) yielding the title
compound.
[1741] C23H28N4O3 (MW=408.499); mass spectroscopy (MH+) 409.
[1742] Anal. Calcd for C23H28N4O3; C, 67.63; H, 6.91; N, 13.72.
Found: C, 68.18; H, 6.88; N, 13.79.
Example 7-9
Preparation of
5-(S)-(N'-(].sub.p-phenylglycinyl)-L-alaninyl-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1743] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7-B) and D-boc-phenylglycine (Aldrich), the protected
intermediate was prepared. The Boc-group was removed using 5.0 M
HCl in dioxane and the resulting free-base purified by flash
chromatography CHCl.sub.3/MeOH (95:5) yielding the title
compound.
[1744] C26H26N4O3 (MW=442.516); mass spectroscopy (MH+) 443.
[1745] Anal. Calcd for C26H26N4O3; C, 70.57; H, 5.92; N, 12.66.
Found: C, 70.39; H, 5.93; N, 12.43.
Example 7-10
Preparation of
5-(S)-(N'-(3,5-difluorophenyl-.alpha.-aminoacetyl)-L-alanin-
yl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1746] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7-B) and N-boc-3,5-difluorophenylglycine, the protected
intermediate was prepared. The Boc-group was removed using 5.0 M
HCl in dioxane and the resulting free-base purified by flash
chromatography yielding the title compound. The molecular weight as
determined by mass spectrometry (FD) was: (M+H).
Example 7-11
Synthesis of
5-(S)-[N'-(L-Trifluoromethylphenylglycinyl)-L-alaninyl]-amino-
-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1747] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and (S)-2-Phenyl-N-(trifluoroacetyl)glycine (Aldrich),
the title compound was prepared. The product was purified by flash
chromatography using CHCl3/MeOH (99:1).
[1748] C28H25F3N4O4 (MW=538.524); mass spectroscopy (MH+) 539.
[1749] Anal. Calcd for C28H25F3N4O4; C, 62.45; H, 4.68; N, 10.40.
Found: C, 62.33; H, 4.78; N, 10.16.
Example 7-12
Synthesis of
5-(S)-[N'-(L-N-Methyl-valinyl)-L-alaninyl]-amino-7-methyl-5,7-
-dihydro-6H-dibenz[b,d]azepin-6-one
[1750] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and L-N-Methyl-Boc-Valine (Aldrich), the protected
intermediate was prepared. This was purified by flash
chromatography using CHCl.sub.3/MeOH (98:2). The Boc-group was
removed using 5.0 M HCl in dioxane and the resulting free-base
purified by flash chromatography CHCl.sub.3/MeOH (98:2) yielding
the title compound.
[1751] C24H30N4O3 (MW=422.526); mass spectroscopy (MH+) 423.
[1752] Anal. Calcd for C24H30N4O3. 0.6269 mol H.sub.2O; C, 66.44;
H, 7.26; N, 12.91. Found: C, 66.50; H, 7.47; N, 12.70.
Example 7-13
Synthesis of
5-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-7-methyl-5,7--
dihydro-6H-dibenz[b,d]azepin-6-one
[1753] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and Boc-Hexafluorovaline (Aldrich), the protected
intermediate was prepared. This was purified by flash
chromatography using CHCl.sub.3/MeOH (98:2). The Boc-group was
removed using 5.0 M HCl in dioxane and the resulting free-base
purified by flash chromatography CHCl.sub.3/MeOH (97:3) yielding
the title compound.
[1754] C23H22F6N4O3 (MW=516.44); mass spectroscopy (MH+) 517.
[1755] Anal. Calcd for C23H22F6N4O3; C, 51.68; H, 4.49; N, 10.47.
Found: C, 51.46; H, 4.22; N, 9.94.
Example 7-15
Preparation of
5-(S)-(N'-(L-valinyl)-L-alaninyl-)]amino-2,3-dihydro-1-meth-
yl-5-phenyl-1H-1,4-benzodiazepin-2-one
[1756] Following General Procedure D above using N-boc-L-valine and
5-(S)-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazep-
in-2-one hydrochloride (Example 8-B), the protected intermediate
was prepared. The Boc-group was removed using 5.0 M HCl in dioxane
and the resulting free-base purified by flash chromatography
yielding the title compound. Anal. Calc'd for C24H29N5O3: C, 66.19;
H, 6.71; N, 16.08. Found: C, 66.50; H, 6.68; N, 15.87. MS Found
(M+H) 436.
Example 7-17
Preparation of
5-(S)-(N"-(S)-phenylglycinyl)-N'-L-alaninyl]amino-1-methyl--
5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
Step A--Preparation of
3-[(N'"-t-butoxycarbonyl)-N"-(S)-phenylglycinyl)-N'-
-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepi-
n-2-one
[1757] To a solution of
3-[(N'-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5--
tetrahydro-2H-1,5-benzodiazepin-2-one (Example 8M) (300 mg, 0.89
mmol) in THF (30 mL) was added L-Boc-phenylglycine (246 mg, 0.98
mmol, NovaBioChem) and
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (242 mg, 0.98 mmol,
Aldrich). The resulting mixture was stirred at ambient temperature
under nitrogen overnight. The mixture was diluted with EtOAc (500
mL) and washed with water (1.times.100 mL) and brine (1.times.100
mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified by HPLC eluting with
hexanes/EtOAc (1:1) to yield the title intermediate (230 mg).
Step B--Synthesis of
5-(S)-(N"-(S)-phenylglycinyl)-N'-L-alaninyl]amino-1-m-
ethyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
[1758] Through a solution of the product from step A (230 mg, 0.40
mmol) in 1,4-dioxane (50 mL) was passed a stream of HCl gas for 10
minutes. The resulting solution was capped and stirred overnight at
ambient temperature, then concentrated. The residue was dissolved
in water (100 mL) and washed with Et.sub.2O (1.times.100 mL). Then,
the aqueous layer was basified to pH 9 with 1 M aq. NaOH, and the
product extracted into EtOAc (100 mL). The EtOAc extract was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by HPLC eluting with CH.sub.2Cl.sub.2/MeOH (95:5) to yield
the title compound (114 mg) as a white solid.
[1759] C.sub.27H.sub.29N.sub.5O.sub.3 (MW 471.56) mass spectroscopy
(MH.sup.+) 472.3, (MH.sup.-) 470.3
[1760] HRMS. Calcd. for C.sub.27H.sub.30N.sub.5O.sub.3: 472.2348.
Found: 472.2352.
Example 7-18
Preparation of
5-(S)-[(N"-L-valinyl)-N'-L-alaninyl]amino-1-methyl-5-phenyl-
-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
Step A--Synthesis of
3-[(N'"-t-butoxycarbonyl)-N"-(S)-valinyl)-N'-L-alanin-
yl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
[1761] To a solution of
3-[(N'-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5--
tetrahydro-2H-1,5-benzodiazepin-2-one (Example 8M) (300 mg, 0.89
mmol) in THF (30 mL) was added L-Boc-valine (212 mg, 0.98 mmol,
NovaBioChem) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
(242 mg, 0.98 mmol, Aldrich). The resulting mixture was stirred at
ambient temperature under nitrogen overnight. The mixture was
diluted with EtOAc (500 mL) and washed with water (1.times.100 mL)
and brine (1.times.100 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by HPLC eluting with hexanes/EtOAc (1:1) to yield the
title intermediate (240 mg).
Step B--Synthesis of
5-(S)-(N'-L-alaninyl-N"-L-valinyl]amino-1-methyl-5-ph-
enyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
[1762] Through a solution of the product from step A (240 mg, 0.44
mmol) in 1,4-dioxane (50 mL) was passed a stream of HCl gas for 10
minutes. The resulting solution was capped and stirred overnight at
ambient temperature, then concentrated. The residue was dissolved
in water (100 mL) and washed with Et.sub.2O (1.times.100 mL). Then,
the aqueous layer was basified to pH 9 with 1 M aq. NaOH, and the
product extracted into EtOAc (100 mL). The EtOAc extract was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by HPLC eluting with CH.sub.2Cl.sub.2/MeOH (95:5) to yield
the title compound (180 mg) as a white solid.
[1763] C.sub.24H.sub.31N.sub.5O.sub.3 (MW 437.54) mass spectroscopy
(MH.sup.+) 438.2, (MH.sup.-) 436.5
[1764] HRMS. Calcd. for C.sub.24H.sub.31N.sub.5O.sub.3: 438.2505.
Found: 438.2502.
Examples 7-19 and 7-20
Preparation of
3-(N"-(3,5-difluorophenylglycinyl)-N'-L-alaninyl]amino-2,4--
dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepine
Hydrochloride
Step A--Preparation of
3-[((N"-t-butoxycarbonyl)-N'-(3,5-difluorophenylgly-
cinyl)-N'-L-alaninyl]amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro--
2H-1,5-benzodiazepine Hydrochloride
[1765] To a solution of
3-(N'-L-alaninyl)-amino-2,4-dioxo-1-methyl-5-pheny-
l-2,3,4,5-tetrahydro-2H-1,5-benzodiazepine (Example 8-N) (500 mg,
1.28 mmol) in THF (15 mL) was added
N-t-boc-D,L-3,5-difluorophenylglycine (404 mg, 1.41 mmol),
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (270
mg, 1.41 mmol), 1-hydroxybenzotriazole hydrate (190 mg, 1.41 mmol),
followed by N,N-diisopropylethylamine (490 .mu.L, 2.82 mmol).
[1766] The resulting mixture was stirred at ambient temperature
under nitrogen overnight. The mixture was diluted with EtOAc (200
mL) and washed with water (1.times.200 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by HPLC eluting with hexanes/EtOAc (1:1) to
yield the title intermediate as two separated diastereomers
(labeled isomer 1 as the less polar intermediate (280 mg), and
isomer 2 as the more polar intermediate (316 mg)).
[1767] Data for Isomer 1:
[1768] C.sub.32H.sub.33N.sub.5O.sub.6F.sub.2 (MW 621.64) mass
spectroscopy (MH.sup.+) 622.5, (MH.sup.-) 620.7
[1769] Anal. Calcd. for C.sub.32H.sub.33N.sub.5O.sub.6F.sub.2: C,
61.83; H, 5.35; N, 11.27. Found: C, 61.58; H, 5.23; N, 10.97.
[1770] Data for Isomer 2:
[1771] C.sub.32H.sub.33N.sub.5O.sub.6F.sub.2 (MW 621.64) mass
spectroscopy (MH.sup.+) 622.5, (MH.sup.-) 620.7
[1772] Anal. Calcd. for C.sub.32H.sub.33N.sub.5O.sub.6F.sub.2: C,
61.83; H, 5.35; N, 11.27. Found: C, 61.95; H, 5.24; N, 10.98.
Step B--Preparation of
3-[(N"-(3,5-difluorophenylglycinyl)-N'-L-alaninyl]a-
mino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepine
Hydrochloride
[1773] Through a solution of isomer 1 from step A (250 mg, 0.40
mmol) in 1,4-dioxane (80 mL) was passed a stream of HCl gas for 5
minutes. The resulting solution was capped and stirred overnight at
ambient temperature, then concentrated. The title compound was
isolated (161 mg) as a white solid by trituration with
hexanes/EtOAc.
[1774] Data for the Title Compound from Isomer 1:
[1775] C.sub.27H.sub.25N.sub.5O.sub.4F.sub.2 HCl (FW 557.98) mass
spectroscopy (MH.sup.+, --HCl) 523.4, (MH.sup.-, --HCl) 520.3
[1776] HRMS. Calcd. for C.sub.27H.sub.26N.sub.5O.sub.4F.sub.2:
522.1953. Found: 522.1949.
[1777] Optical rotation: [ ].sup.20D=73.02 (c 0.5, MeOH)
[1778] m.p. 218-219 C.
[1779] Isomer 2 (280 mg, 0.45 mmol) was processed in the same
manner as isomer 1, except using 90 mL of 1,4-dioxane. Yielding 200
mg of the title compound as a white solid.
[1780] Data for the Title Compound from Isomer 2:
[1781] C.sub.27H.sub.25N.sub.5O.sub.4F.sub.2 HCl (FW 557.98) mass
spectroscopy (MH.sup.+, --HCl) 523.4, (MH.sup.-, --HCl) 520.3
[1782] HRMS. Calcd. for C.sub.27H.sub.26N.sub.5O.sub.4F.sub.2:
522.1953. Found: 522.1959.
[1783] optical rotation: [ ].sup.20.sub.D=134.28 (c 0.5, MeOH)
[1784] m.p. at 184 C the white solid became a foam.
Example 7-21
Preparation of
5-(S)-[N'-(2-Amino-3,3,3-trifluoromethylbutyryl)-L-alaninyl-
]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1785] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and D/L-Boc4,4,4-trifluorovaline (Oakwood), the
protected intermediate was prepared. This was purified by flash
chromatography using CHCl.sub.3/MeOH (99:1). The Boc-group was
removed using 5.0 M HCl in dioxane and the resulting free-base
purified by flash chromatography CHCl.sub.3/MeOH (98:2) yielding
the title compounds.
[1786] Isomer 1:
[1787] C.sub.23HF.sub.3N.sub.4O.sub.3 (MW=462.47); mass
spectroscopy (MH.sup.+) 463.
[1788] Anal. Calcd for C.sub.23H.sub.25F.sub.3N.sub.4O.sub.3.0.95
mol H.sub.2O; C, 57.59; H, 5.65; N, 11.62. Found: C, 57.64; H,
5.77; N, 11.52.
[1789] Isomer 2:
[1790] C.sub.23H.sub.25F.sub.3N.sub.4O.sub.3 (MW 462.47); mass
spectroscopy (MH+) 463.
[1791] Anal. Calcd for C.sub.23H.sub.25F.sub.3N.sub.4O.sub.3.0.91
mol H.sub.2O; C, 57.67; H, 5.65; N, 11.70. Found: C, 57.69; H,
5.65; N, 11.40.
Example 7-22
Preparation of
5-(S)-[N'-(2-amino-5,5,5-trifluoropentanyl)-L-alaninyl]-ami-
no-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1792] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and D/L-Boc-5,5,5-trifluoronorvaline (Oakwood), the
protected intermediate was prepared. This was purified by flash
chromatography using CHCl.sub.3/MeOH (9:1). The Boc-group was
removed using 5.0 M HCl in dioxane and the resulting free-base
purified by flash chromatography CHCl.sub.3/MeOH (95:5) yielding
the title compounds.
[1793] Isomer 1:
[1794] C.sub.23H.sub.25F.sub.3N.sub.4O.sub.3 (MW=462.47); mass
spectroscopy (MH+) 463.
[1795] Anal. Calcd for C.sub.23H.sub.25F.sub.3N.sub.4O.sub.3.0.4295
mol H.sub.2O; C, 58.75; H, 5.54; N, 11.91. Found: C, 58.81; H,
5.38; N, 11.53.
[1796] Isomer 2:
[1797] C.sub.23H.sub.25F.sub.3N.sub.4O.sub.3 (MW=462.47); mass
spectroscopy (MH+) 463.
[1798] Anal. Calcd for C.sub.23H.sub.25F.sub.3N.sub.4O.sub.3.0.2318
mol H.sub.2O; C, 59.19; H, 5.50; N, 12.00. Found: C, 59.27; H,
5.55; N, 11.67.
Example 7-23
Preparation of
5-(S)-[N'-(2-amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amin-
o-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1799] Following General Procedure D above using
5-(S)-[L-alaninyl]-amino--
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 7B) and D/L-(2-N-Boc-amino)-4,4,4-trifluorobutyric acid
(Oakwood), the protected intermediate was prepared. The Boc-group
was removed using 5.0 M HCl in dioxane and the resulting free-base
purified by flash chromatography CHCl.sub.3/MeOH (95:5) yielding
the title compounds.
[1800] Isomer 1:
[1801] C.sub.22H.sub.23F.sub.3N.sub.4O.sub.3 (MW=448.443); mass
spectroscopy (MH+) 449.
[1802] Anal. Calcd for C.sub.22H.sub.23F.sub.3N.sub.4O.sub.3.0.7377
mol H.sub.2O; C, 57.23; H, 5.34; N, 12.13. Found: C, 57.27; H,
5.13; N, 11.82.
[1803] Isomer 2:
[1804] C.sub.22H.sub.23F.sub.3N.sub.4O.sub.3 (MW=448.443); -mass
spectroscopy (MH+) 449.
[1805] Anal. Calcd for CH.sub.23F.sub.3N.sub.4O.sub.3.0.6657 mol
H.sub.2O; C, 57.39; H, 5.32; N, 12.17. Found: C, 57.42; H, 5.19; N,
11.95.
Example 7-24
Preparation of
1-(S)-[N'-(2-Amino-3,3,3-trifluorobutyryl)-L-alaninyl]-amin-
o-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[1806] Following General Procedure D above using
1-(S)-[L-alaninyl]-amino--
3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one hydrochloride
(Example 7-30, below) and D/L-N-Boc4,4,4-trifluorovaline (Oakwood),
the protected intermediate was prepared. This was purified by flash
chromatography using CHCl.sub.3/MeOH (99:1). The Boc-group was
removed using 5.0 M HCl in dioxane and the resulting free-base
purified by flash chromatography CHCl.sub.3/MeOH (95:5) yielding
the title compounds.
[1807] Isomer 1 (Single Diastereomer):
[1808] C.sub.19H.sub.25F.sub.3N.sub.4O.sub.3 (MW=414.426); mass
spectroscopy (MH+) 415
[1809] Anal. Calcd for C.sub.19H.sub.25F.sub.3N.sub.4O.sub.3; C,
55.07; H, 6.08; N, 13.52. Found: C, 55.18; H, 6.11; N, 13.49.
[1810] Isomer 2 (Single Diastereomer):
[1811] C.sub.19H.sub.25F.sub.3N.sub.4O.sub.3 (MW=414.426); mass
spectroscopy (MH+) 415
[1812] Anal. Calcd for C.sub.19H.sub.25F.sub.3N.sub.4O.sub.3; C,
55.07; H, 6.08; N, 13.52. Found: C, 54.82; H, 6.06; N, 13.35.
[1813] Isomer 3 (Mixture of Two Diastereomers):
[1814] C.sub.19H.sub.25F.sub.3N.sub.4O.sub.3 (MW=414.426); mass
spectroscopy (MH+) 415
[1815] Anal. Calcd for C.sub.19H.sub.25F.sub.3N.sub.4O.sub.3; 0.255
mol H.sub.2O, C, 54.46; H, 6.14; N, 13.37. Found: C, 54.54; H,
6.14; N, 13.05.
Example 7-25
Preparation of
1-(S)-[N'-(2-Amino-5,5,5-trifluoropentanoyl)-L-alaninyl]-am-
ino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[1816] Following General Procedure D above using
1-(S)-[L-alaninyl]-amino--
3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one hydrochloride
(Example 7-30, below) and D/L-N-Boc-5,5,5-trifluoronorvaline
(Oakwood), the protected intermediate was prepared. The Boc-group
was removed using 5.0 M HCl in dioxane and the resulting free-base
purified by flash chromatography CHCl.sub.3/MeOH (95:5) yielding
the title compounds.
[1817] Isomer 1 (Single Diastereomer):
[1818] C.sub.19H.sub.25F.sub.3N.sub.4O.sub.3 (MW=414.1967); High
resolution MS (MH+) 415.1957
[1819] 400 MHZ .sup.1H NMR (CDCl.sub.3) d=6.17 ppm (d, 1H), 4.61
(m, 1H), 3.01 (s, 3H), 1.49 (d, 3H).
[1820] Isomer 2 (Single Diastereomer):
[1821] C.sub.19H.sub.25F.sub.3N.sub.4O.sub.3 (MW=414.1967); High
resolution MS (MH+) 415.1946
[1822] 400 MHZ .sup.1H NMR (CDCl.sub.3) d=6.18 ppm (d, 1H), 4.64
(m, 1H), 3.01 (s, 3H), 1.48 (d, 3H).
Example 7-26
Preparation of
1-(S)-[N'-(2-Amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amin-
o-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[1823] Following General Procedure D above using
1-(S)-[L-alaninyl]-amino--
3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one hydrochloride
(Example 7-30, below) and 2-(N-Boc-amino)-4,4,4-trifluorobutyric
acid (Oakwood), the protected intermediate was prepared. The
Boc-group was removed using 5.0 M HCl in dioxane and the resulting
free-base purified by flash chromatography CHCl.sub.3/MeOH (97.3)
yielding the title compounds.
[1824] Isomer 1 (Single Diastereomer):
[1825] C.sub.18H.sub.23F.sub.3N.sub.4O.sub.3 (MW=400.399); mass
spectroscopy (MH+) 401
[1826] Anal. Calcd for C.sub.18H.sub.23F.sub.3N.sub.4O.sub.3; C,
53.99; H, 5.79N, 13.99. Found: C, 54.08; H, 5.90; N, 13.70.
[1827] Isomer 2 (Single Diastereomer):
[1828] C.sub.18H.sub.23F.sub.3N.sub.4O.sub.3 (MW=400.399); high
resolution MS (MH+) 401.1800
[1829] 400 MHZ .sup.1H NMR (CDCl.sub.3) d=6.18 ppm (d, 1H), 4.61
(m, 1H), 3.01 (s, 3H), 2.22 (m, 2H), 1.48 (d, 3H).
Example 7-27
Preparation of
1-(S)-[N'-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6-
,7-tetrahydro-2H-3-benzazepin-2-one
[1830] Following General Procedure D above using
1-(S)-[L-alaninyl]-amino--
3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one hydrochloride
(Example 7-30, below) and 2-(L-N-Boc-amino)butyric acid (Aldrich),
the protected intermediate was prepared. The Boc-group was removed
using 5.0 M HCl in dioxane and the resulting free-base purified by
chromatography CHCl.sub.3/MeOH (95:5) yielding the title
compound.
[1831] C.sub.18H.sub.26N.sub.4O.sub.3 (MW=346.428); mass
spectroscopy (MH+) 347
[1832] Anal. Calcd for C.sub.18H.sub.26N.sub.4O.sub.3; C, 62.41; H,
7.56; N, 16.17. Found: C, 62.46; H, 7.73; N, 15.98.
Example 7-28
Preparation of
1-(S)-[N'-(Hexafluorovalinyl)-L-alaninyl]-amino-3-methyl-4,-
5,6,7-tetrahydro-2H-3-benzazepin-2-one
[1833] Following General Procedure D above using
1-(S)-[L-alaninyl]-amino--
3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one hydrochloride
(Example 7-30, below) and N-Boc-hexafluorovaline (Aldrich), the
protected intermediate was prepared. The Boc-group was removed
using 5.0 M HCl in dioxane and the resulting free-base purified by
chromatography CHCl.sub.3/MeOH (95:5) yielding the title compound
as a mixture of diastereomers.
[1834] C.sub.19H.sub.22F.sub.6N.sub.4O.sub.3 (MW=468.396); mass
spectroscopy (MH+) 469
[1835] Anal. Calcd for C.sub.19H.sub.22F.sub.6N.sub.4O.sub.3; C,
48.72; H, 4.73; N, 11.96. Found: C, 48.56; H, 4.73; N, 11.83.
Example 7-29
Preparation of
1-(S)-[N'-(L-2-Aminobutyryl)-L-alaninyl]-amino-3-(2-methylp-
ropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[1836] Following General Procedure D above using
1-(S)-[L-alaninyl]-amino--
3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
hydrochloride (Example 7-31, below) and L-2-(N-Boc)-aminobutyric
acid (Aldrich), the protected intermediate was prepared. The
Boc-group was removed using 5.0 M HCl in dioxane and the resulting
free-base purified by chromatography CHCl.sub.3/MeOH (95:5)
yielding the title compound as a mixture of diastereomers.
[1837] C.sub.21H.sub.32N.sub.4O.sub.3 (MW=388.509); mass
spectroscopy (MH+) 389
[1838] Anal. Calcd for C.sub.21H.sub.32N.sub.4O.sub.3; C, 64.92; H,
8.30; N, 14.42. Found: C, 64.62; H, 8.12; N, 14.29.
Example 7-30
Preparation of
1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-b-
enzazepin-2-one Hydrochloride
Step A: Synthesis of
1-hydroxyimino-3-methyl-4,5,6,7-tetrahydro-2H-3-benza-
zepin-2-one
[1839] Following the procedure described for Example 7-A (Step B)
and using 3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one (CS#
73644-95-8),
1-hydroxyimino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
was prepared.
[1840] C.sub.11H.sub.12N.sub.2O.sub.2(MW=204.1); mass spectroscopy
(MH+) 205
Step B: Synthesis of
(R/S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzaz-
epin-2-one
[1841] The compound isolated above was reduced following General
Procedure 7-A (Step C),
(R/S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2- -one
was prepared.
[1842] C.sub.11H.sub.4N.sub.2O (MW=190.1); mass spectroscopy (MH+)
191
Step C: Resolution of
(S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzaze- pin-2-one
[1843] The amine isolated above was resolved as described in
General Procedure 7-C using Di-p-Toluoyl-L-tartaric acid (Aldrich,
CAS# 32634-66-5). Enantiomeric excess (ee) was determined by
Capillary Electrophoresis using a Beckman Place MDQ and 5% sulfated
.alpha.-cyclodrextrin, 20 mM (Et.sub.3N)(NH.sub.4)PO.sub.4 (pH=2.5)
on a 50 m capillary @ 15 kVolts and the detector set at 20.degree.
C.m (200 nM). The desired enantiomer had a migration time of 7.4
minutes relative to the undesired enantiomer (migration time=6.83
minutes).
[1844] [a]=-72 (c=1, MeOH) as tartarate salt. ee=97%.
Step D: Synthesis of
1-(S)-[N-t-Boc-L-alaninyl]-amino-3-methyl-4,5,6,7-tet-
rahydro-2H-3-benzazepin-2-one
[1845] Using the amine isolated above and following the procedure
described in Example 7-B (Step A) the title compound was
isolated.
[1846] C.sub.14H.sub.27N.sub.3O.sub.4 (MW=362.19); mass
spectroscopy (MH+) 362
[1847] Anal. Calcd for C.sub.19H.sub.27N.sub.3O.sub.4; C, 63.14; H,
7.53; N, 11.62. Found: C, 63.01; H, 7.44; N, 11.59.
[1848] [a]=+16.22 (c=1, CH.sub.2Cl.sub.2)
Step E: Synthesis of
1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro--
2H-3-benzazepin-2-one Hydrochloride
[1849] The compound isolated above was treated as described in
Example 7-B (Step B).
[1850] C.sub.14H.sub.19N.sub.3O.sub.2 HCl (MW=297.78); mass spec
(MH+, free base) 262
[1851] Anal. Calcd for C.sub.14H.sub.19N.sub.3O.sub.2 HCl; C,
56.47; H, 6.77; N, 14.11. Found: C, 56.27; H, 6.56; N,
13.63.[a]=+38.99 (c=0.5, MeOH)
Example 7-31
Preparation of
1-(S)-[L-alaninyl]-amino-3-(2-methylpropyl)-4,5,6,7-tetrahy-
dro-2H-3-benzazepin-2-one Hydrochloride
Step A: Synthesis of
3-(2-methylpropen-2-yl)-4,5,6,7-tetrahydro-2H-3-benza-
zepin-2-one
[1852] A solution of 4,5,6,7-tetrahydro-2H-3-benzazepin-2-one (61
g, 0.379 mol) in DMF was cooled to 0.degree. C. and treated with a
solution of LiHMDS (1.0 M, 398 ml, 0.391 mols) over 30 minutes.
Methallyl bromide (42 ml, 0.041 mols) was added neat and the
reaction allowed to stir for 2 hours at 0.degree. C. under nitrogen
atmosphere. Most of the solvent was removed under reduced pressure,
the residue diluted into CH.sub.2Cl.sub.2 and washed with two
portions of 1.0 N HCl. The organics were washed 0.2 M LiCl, dried
over Na.sub.2SO.sub.4 and chromatographed over SiO.sub.2 using 9:1
CHCl.sub.3/MeOH. The appropriate fractions were pooled, evaporated
to an oil which was recrystallized from hexanes/EtOAc yielding 17 g
of a tan solid.
[1853] C.sub.14H.sub.17NO (MW=215); mass spectroscopy (MH+) 216
[1854] 400 MHZ .sup.1H NMR (CDCl.sub.3) d=7.18-7.05 ppm (m, 4H),
4.88 (s, 1H), 4.79 (s, 1H), 3.98 (s, 2H), 3.93 (s, 2H), 4.67 (m,
2H), 3.09 (m, 2H), 1.66 (s, 3H).
[1855] Anal. Calcd for C.sub.14H.sub.17NO; C, 78.10; H, 7.97; N,
6.51. Found: C, 78.40; H, 8.08; N, 6.54.
Step B. Synthesis of
3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin- -2-one
[1856] The compound isolated above was hydrogenated over 10% Pd/C
at 35 psi in a Parr shaker for 2 h at room temperature. The
catalyst was filtered and the titled compound isolated as a yellow
oil.
[1857] C.sub.14H.sub.19NO (MW=217); mass spectroscopy (MH+) 218
[1858] Anal. Calcd for C.sub.14H.sub.19NO; C, 77.38; H, 8.81; N,
6.45. Found: C, 77.04; H, 8.81; N, 6.43.
Step C: Synthesis of
1-hydroxyimino-3-(2-methylpropyl)-4,5,6,7-tetrahydro--
2H-3-benzazepin-2-one
[1859] Following the procedure described for Example 7-A (Step B)
and using
3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one,
1-hydroxyimino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one
was prepared.
[1860] C.sub.14H.sub.18N.sub.2O.sub.2 (MW=246.3); mass spectroscopy
(MH+) 247
Step D: Synthesis of
(R/S)-1-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2-
H-3-benzazepin-2-one
[1861] The compound isolated above was reduced following General
Procedure 7-A (Step C),
(R/S)-1-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-be-
nzazepin-2-one was prepared.
[1862] C.sub.14H.sub.20N.sub.2O (MW=232.14); mass spectroscopy
(MH+) 233
Step E: Resolution of
(S)-1-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-
-3-benzazepin-2-one
[1863] The amine isolated above was resolved as described in
General Procedure 7-C using Di-p-Toluoyl-L-tartaric acid (Aldrich,
CAS# 32634-66-5). Enantiomeric excess (ee) was determined by
Capillary Electrophoresis using a Beckman Place MDQ and 5% sulfated
a-cyclodrextrin, 20 mM (Et.sub.3N)(NH.sub.4)PO.sub.4 (pH=2.5) on a
50 m capillary @ 15 kVolts and the detector set at 20.degree. C.m
(200 nM). The desired enantiomer had a migration time of 6.95
minutes relative to the undesired enantiomer (migration time=6.51
minutes).
[1864] [a]=-78 (c=1, MeOH) as tartarate salt. ee=99%.
Step F: Synthesis of
1-(S)-[N-t-Boc-L-alaninyl]-amino-3-(2-methylpropyl)-4-
,5,6,7-tetrahydro-2H-3-benzazepin-2-one
[1865] Using the amine isolated above and following the procedure
described in Example 7-B (Step A) the title compound was
isolated.
[1866] C.sub.22H.sub.33N.sub.3O.sub.4 (MW=403.52); mass
spectroscopy (MH+) 404
[1867] Anal. Calcd for C.sub.12H.sub.33N.sub.3O.sub.4; C, 65.48; H,
8.24; N, 10.41. Found: C, 65.40; H, 7.99; N, 10.66.
[1868] [a]=-9.7 (c=0.5, MeOH)
Step G: Synthesis of
1-(S)-[L-alaninyl]-amino-3-(2-methylpropyl)-4,5,6,7-t-
etrahydro-2H-3-benzazepin-2-one Hydrochloride
[1869] The compound isolated above was treated as described in
Example 7-B (Step B).
[1870] C.sub.17H.sub.25N.sub.3O.sub.2 HCl (MW=339.864); mass spec
(MH+, free base) 304
[1871] [a]=+29.5 (c=1, MeOH)
Example 7-32
Synthesis of
5-[N'-(S)-2-(4-methylpentyl)amino-3-methylbutyryl-L-alaninyl]-
-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Step A: Synthesis of
5-[N'-(S)-2-tert-Boc-amino-3-methylbutyryl-L-alaninyl-
]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1872] Following General Procedure D using N-tert-Boc-L-valine and
(S)- and
(R)-5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6--
one (Example 3-B), the title compound was prepared.
[1873] C.sub.28H.sub.36N.sub.4O.sub.5 (MW=508.615); mass
spectroscopy (MH.sup.+) 509.
Step B: Synthesis of
5-[N'-(S)-2-amino-3-methylbutyryl-L-alaninyl]-amino-7-
-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1874] Following General Procedure 4-N using the compound made
above, the title compound was prepared after passing through an SCX
column [5% MeOH(7N NH.sub.3)/CH.sub.2Cl.sub.2]
[1875] C.sub.23H.sub.28N.sub.4O.sub.3 (MW=408.499); mass
spectroscopy (MH.sup.+) 409.
Step C: Synthesis of
5-[N'-(S)-2-(4-methylpentyl)amino-3-methylbutyryl-L-a-
laninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1876] To a solution of the compound made above (2.00 eq.) in MeOH
was added a few drops of HCl-MeOH, 4-methyl-1-pentanal (1.00 eq.)
(made by following the procedure described in Tetrahedron Letter,
No. 31, 1975, pp 2647, incorporated herein by reference) and
molecular sieves. NaBH.sub.3CN (0.67 eq.) was added. The pH of the
reaction mixture was maintained at 5-6 by adding HCl-MeOH. The
reaction mixture was stirred at RT overnight. The reaction mixture
was basified, extracted with EtOAc, dried over Na.sub.2SO.sub.4.
Concentration and flash chromatography [silica gel, 5% MeOH (7 N
NH.sub.3)/CH.sub.2Cl.sub.2] gave the title compound.
[1877] C.sub.29H.sub.40N.sub.4O.sub.3 (MW=492.660); mass
spectroscopy (MH.sup.+) 493.
[1878] Anal. Calcd for C.sub.29H.sub.40N.sub.4O.sub.3: C, 70.70; H,
8.18; N, 11.37; Found: C, 70.92; H, 8.21 N 11.41.
Example 8-1
Preparation of
3-[N'-3,5-difluorophenyl-.alpha.-azidoacetyl)-L-alaninyl]-3-
-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine
[1879] Following general procedure D using
3,5-difluorophenyl-.alpha.-azid- oacetic acid and
3-(L-alaninyl)-3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-
,4-benzodiazepine, as described in Example 8-B above, the title
compound was prepared. The molecular weight as determined by mass
spectrometry (FD) was: (M+H).
Examples 9-1 and 9-2
Preparation of
3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-ace-
tyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
Step A--Preparation of
2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-ac- etic Acid
Ethyl Ester
[1880] Through a solution of 3-isochromanone (1.00 g, 6.75 mmol,
Aldrich) in absolute EtOH (100 mL) was passed a stream of HBr gas
for 10 minutes, during which time the temperature rose to 40 C.
Alanine ethyl ester hydrochloride (1.036 g, 6.75 mmol, Aldrich) was
then added and the reaction mixture heated to reflux for 2 hours.
The mixture was allowed to cool, then concentrated. The residue was
dissolved in absolute EtOH (100 ml), and K.sub.2CO.sub.3 (3.66 g,
27 mmol) was added and the mixture heated to reflux for 18 hours.
The mixture was allowed to cool, then concentrated. The residue was
dissolved in EtOAc (200 mL) and washed with water (1.times.100 mL).
The organic phase was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by HPLC, eluting with
hexanes/EtOAc (1:1) to yield the title intermediate (204 mg).
[1881] C.sub.14H.sub.17N.sub.1O.sub.3 (MW 247.30) mass spectroscopy
(MH.sup.+) 248.2, (MH.sup.-) 246.4
[1882] Anal. Calcd. for C.sub.14H.sub.17N.sub.1O.sub.3: C, 68.02;
H, 6.88; N, 5.67. Found: C, 68.12; H, 6.88; N, 5.40.
Step B--Preparation of
2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-ac- etic Acid
[1883] To the intermediate from step A (170 mg, 0.688 mmol) in
1,4-dioxane (3 mL) and water (1 mL) was added LiOH (57.7 mg, 1.38
mmol) and the resulting mixture was stirred at ambient temperature
for 2.5 hours. The mixture was diluted into EtOAc (100 mL) and
carboxylate extracted into water (100 mL). The aqueous extract was
acidified with 0.1 M aq. HCl and the product extracted into EtOAc.
The EtOAc extract was dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give the title intermediate as a white solid (150
mg). C.sub.12H.sub.13N.sub.1O.sub.3 (MW 219.24) mass spectroscopy
(MH.sup.+) 220.2, (MH.sup.-) 218.4
[1884] Anal. Calcd. for C.sub.12H.sub.13N.sub.1O.sub.3: C, 65.75;
H, 5.94; N, 6.39. Found: C, 66.22; H, 6.01; N, 6.03.
Step C--Preparation of
3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-me-
thyl-acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-on-
e
[1885] To the intermediate from step B (112 mg, 0.511 mmol) in THF
(5 mL) was added
3-(S)-(amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-
-2-one (136 mg, 0.511 mmol),
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimid- e hydrochloride (98
mg, 0.511 mmol), 1-hydroxybenzotriazole hydrate (70 mg, 0.511
mmol), and N,N-diisopropylethylamine (88 .mu.L, 0.511 mmol). The
resulting mixture was stirred overnight at ambient temperature,
then diluted into EtOAc (100 mL) and washed with 10% aqueous citric
acid (1.times.50 mL), brine (1.times.50 mL), and 1M aqueous
K.sub.2CO.sub.3 (1.times.50 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, concentrated, and the residue purified
by HPLC eluting with hexanes/EtOAc (1:1 gradient to 1:3) to provide
the two separated isomers.
[1886] Isomer 1 (60 mg): C.sub.8H.sub.26N.sub.4O.sub.3 (MW 466.54)
mass spectroscopy 466.05
[1887] Anal. Calcd. for C.sub.28H.sub.26N.sub.4O.sub.3:.degree. C.,
72.10; H, 5.58; N, 12.02. Found: C, 71.99; H, 5.80; N, 11.73.
[1888] optical rotation: [ ].sup.20.sub.D=18.52 (c 0.5, MeOH)
[1889] m.p. 125-126 C.
[1890] Isomer 2 (76 mg): C.sub.28H.sub.26N.sub.4O.sub.3 (MW 466.54)
mass spectroscopy 466.02
[1891] Anal. Calcd. for C.sub.28H.sub.26N.sub.4O.sub.3: C, 72.10;
H, 5.58; N, 12.02. Found: C, 72.38; H, 5.50; N, 11.72.
[1892] optical rotation: [ ].sup.20.sub.D=-137.9 (c 0.5, MeOH)
[1893] m.p. 209-210 C.
Example 10-1
Preparation of
3-[N'-3,5-difluorophenyl-acetamido)-L-alaninyl]-3-amino-2,3-
-dihydrol-methyl-5-phenyl-1H-1,4-benzodiazepine
[1894] Following general procedure D, using difluorophenylacetamido
and
3-(L-alaninyl)-3-amino-2,3-dihydrol-methyl-5-phenyl-1H-1,4-benzodiazepine-
, as described in Example 8-B above, the title compound was
prepared. The molecular weight as determined by mass spectrometry
(FD) was: (M+H).
Example 10-2
Preparation of
5-{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methy-
l-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
[1895] Following one or more of the general procedures outlined
above, using acetyl-N-phenylglycine and
5-(L-alaninyl)-amino-7-methyl-5,7-dihydr-
o-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the
title compound was prepared. The molecular weight as determined by
mass spectrometry (FD) was: 485 (M+H).
[1896] 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.-amino lactam to provide for compounds of the formulas:
113
[1897] where R.sup.1--(NR.sup.5).sub.2).sub.l--C(X)--NR.sup.5--Y,
R.sup.1-Z-NR.sup.5--Y, --R.sup.1--SO.sub.2--NR.sup.5--Y,
R.sup.1-Z-NR.sup.5--NR.sup.5--C(O)--NR.sup.5--Y and 114
[1898] are the residues of the associated carboxylic acids (i.e.,
R.sup.1, R.sup.2, R.sup.5, X, X', X", Z, l and n are defined
above), Y=--CHR.sup.2--C(O)--, and W" is selected from the
following structures:
1151161171181191201211221231241251261271281291301311321331341351361371381-
39140141142143144145146147148149150151152153154155156157158159160161162163-
16416516616716816917017117217317417517617717817918018118218318418518618718-
8189190191192193194195196197198199
200201202203204205206207208209210211212-
21321421521621721821922022122222322422522622722822923023123223323423523623-
72382392402412422432442452462472482492502512522532542552562572582592602612-
62263264265266267268269270271272273274275276277278279
2802812822832842852862872882892902912922932942952962972982993003013023033-
04305306307308309310311312313314315316317318319320321322323324325326327328-
329330
3313323333343353363373383393403413423433443453463473483493503513523-
53354355356357358359360361362363364365366367368369370371372373374
Example Bio-1
Cellular Screen for the Detection of Inhibitors of .beta.-Amyloid
Production
[1899] Numerous compounds described 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.651, Met.sub.652 to Asn.sub.651,
LeU.sub.652 (APP751 numbering) in the manner described in
International Patent Application Publication No. 94/10569.sup.8 and
Citron et al. 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
(around 0.2 to 2.5 ng per mL). 15
[1900] Following overnight incubation at 37.degree. C. in an
incubator equilibrated with 10% carbon dioxide, media were removed
and replaced with 200 microliters of a compound described above
(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%.
[1901] 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 .alpha.L of conditioned
media or appropriate dilutions thereof were transferred into an
ELISA plate pre-coated 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.
[1902] 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 microliters of a
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
(Sigma, St. Louis, Mo.) stock solution (5 mg/mL) to a final
concentration of 1 mg/mL. Cells were incubated at 37 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.
[1903] 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.
[1904] 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 described
herein 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
[1905] 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-ethyl-cellulose (Sigma Chemical Co., St. Louis Mo.).
[1906] 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.
[1907] 1. Brain Assay
[1908] 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 1.0 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 peptide.
[1909] The brain homogenates are diluted 1:10 with ice-cold casein
buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium
azide, 20 micrograms/ml aprotinin, 5 mM EDTA, pH 8.0, 10
micrograms/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 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 (1-40 or 1-42 amino acids) were prepared
such that the final composition equaled 0.5 M guanidine in the
presence of 0.1% bovine serum albumin (BSA).
[1910] The total .beta.-amyloid sandwich ELISA, quantitating both
.beta.-amyloid (aa 140) and .beta.-amyloid (aa 142) includes two
monoclonal antibodies (mAb) to .alpha.-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
serves 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 crossreactivity
to the endogenous murine .beta.-amyloid peptide at concentrations
up to 1 ng/ml.
[1911] 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 around 125 pg/ml
(28 pM).
[1912] The 266 and 21F12 capture mAbs are coated at 10
micrograms/ml into 96 well immunoassay plates (Costar, Cambidge
CIA) 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 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
C. The plates are washed 3 or more times with wash buffer between
each step of the assay. The biotinylated 3D6, diluted to 0.5
micrograms/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 calorimetric 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.
[1913] 2. Blood Assay
[1914] The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/l
sodium phosphate-H.sub.2 0 (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.
[1915] 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.
[1916] 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.
* * * * *