U.S. patent application number 10/101297 was filed with the patent office on 2002-12-05 for 1,4-benzodiazepinones and their uses as cck antagonists.
This patent application is currently assigned to Fujisawa Pharmaceutical Co., Ltd.. Invention is credited to Katsumi, Ikuyo, Mitsui, Hitoshi, Sato, Yoshinari, Tabuchi, Seiichiro, Yamamoto, Naoko.
Application Number | 20020183313 10/101297 |
Document ID | / |
Family ID | 3797154 |
Filed Date | 2002-12-05 |
United States Patent
Application |
20020183313 |
Kind Code |
A1 |
Sato, Yoshinari ; et
al. |
December 5, 2002 |
1,4-benzodiazepinones and their uses as CCK antagonists
Abstract
Benzodiazepine derivatives of the formula: 1 wherein R.sup.1 is
heterocyclic(lower)alkyl which may have one or more suitable
substituent(s), etc., R.sup.2 is lower alkyl, etc., R.sup.3 is
indolyl, etc., R.sup.4 is hydrogen, etc., or a pharmaceutically
acceptable salt thereof, which are useful as a medicament.
Inventors: |
Sato, Yoshinari; (Osaka-fu,
JP) ; Tabuchi, Seiichiro; (Hyogo-ken, JP) ;
Mitsui, Hitoshi; (Nara-ken, JP) ; Katsumi, Ikuyo;
(Osaka-fu, JP) ; Yamamoto, Naoko; (Hyogo-ken,
JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
Fujisawa Pharmaceutical Co.,
Ltd.
Osaka-shi
JP
|
Family ID: |
3797154 |
Appl. No.: |
10/101297 |
Filed: |
March 20, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10101297 |
Mar 20, 2002 |
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09897888 |
Jul 5, 2001 |
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09897888 |
Jul 5, 2001 |
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09269752 |
Apr 30, 1999 |
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6291452 |
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09269752 |
Apr 30, 1999 |
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PCT/JP97/03483 |
Sep 29, 1997 |
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Current U.S.
Class: |
514/221 ;
540/509 |
Current CPC
Class: |
C07K 5/0821 20130101;
C07D 243/18 20130101; C07D 243/14 20130101; C07K 5/0205 20130101;
C07K 5/06139 20130101; A61K 38/00 20130101; A61P 1/14 20180101;
A61P 25/18 20180101; A61P 1/12 20180101 |
Class at
Publication: |
514/221 ;
540/509 |
International
Class: |
A61K 031/5513; C07D
243/24 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 8, 1996 |
AU |
P0 2843/96 |
Claims
1. A Compound of the formula: 23Wherein R.sup.1 is (1) lower alkyl;
(2) hydroxy(lower)alkyl; (3) protected hydroxy(lower)alkyl; (4)
heterocyclic(lower)alkyl which may have one or more suitable
substituent(s); (5) aryl(lower)alkyl which may have one or more
suitable substituent(s); (6) carboxy(lower)alkyl; (7) protected
carboxy(lower)alkyl; or (8) 24[wherein A is lower alkylene and
R.sup.5 is (a) lower alkyl, (b) C.sub.3-C.sub.8 cycloalkyl, (c)
adamantyl, (d) aryl which may have one or more suitable
substituent(s), (e) amino which may have one or two suitable
substituent(s), (f) azabicyclo[3.2.2]nonyl, or (g) saturated
heteromonocyclic group containing at least one nitrogen atom, which
may have one or more suitable substituent(s)], R.sup.2 is (1) lower
alkyl, (2) C.sub.3-C.sub.8 cycloalkyl, (3) lower
alkoxy(lower)alkyl, (4) C.sub.3-C.sub.8 cycloalkyl(lower)alkyl, (5)
N, N-di(lower)alkylamino(lower)alkyl, (6) lower
alkylpiperazinyl(lower)alkyl- , (7) lower alkylthio(lower)alkyl,
(8) hydroxy(lower)alkyl, (9) protected hydroxy(lower)alkyl,
(10)azabicyclo[3.2.2]nonyl(lower)alkyl, (11) aryl which may have
one or more suitable substituent(s), (12) cyano, (13) lower
alkanoyl, (14) carboxy(lower)alkenyl, or (15) protected
carboxy(lower)alkenyl, R.sup.3 is indolyl or --NH--R.sup.6 [wherein
R.sup.6 is (1) aryl which may have one or more suitable
substituent(s), (2) pyridyl which may have one or more suitable
substituent(s), or (3)C.sub.3-C.sub.8 cycloalkyl], and R.sup.4 is
(1) hydrogen, (2) lower alkyl, (3) halogen, or (4)
di(lower)alkylamino, with proviso that when R.sup.4 is hydrogen,
then R.sup.2 is lower alkyl or C.sub.3-C.sub.8
cycloalkyl(lower)alkyl, or a pharmaceutically acceptable salt
thereof.
2. A Compound of claim 1, wherein R' is (1) lower alkyl; (2)
hydroxy(lower)alkyl; (3) acyloxy(lower)alkyl; (4)
heterocyclic(lower)alky- l which may have one or more
substituent(s) selected from the group consisting of lower alkyl
and acyl; (5) aryl(lower)alkyl which may have one or more acyl(s);
(6) carboxy(lower)alkyl; (7) esterified carboxy(lower)alkyl; or (8)
25[wherein A is lower alkylene and R.sup.5 is (a) lower alkyl, (b)
C.sub.3-C.sub.8 cycloalkyl, (c) adamantyl, (d) acyl which may have
one or more substituent(s) (e) selected from the group consisting
of lower alkyl, hydroxy, lower alkoxy, carboxy(lower)alkoxy,
protected carboxy(lower)alkoxy, nitro, amino and diacylamino, (e)
amino which may have one or two substituent(s) selected from the
group consisting of lower alkyl, hydroxy(lower)alkyl,
aryl(lower)alkyl and pyridyl, (f) azabicyclo[3.2.2]nonyl, or (g)
saturated heteromonocyclic group containing at least one nitrogen
atom, which may have one or more substituent(s) selected from the
group consisting of carbamoyl, acyl, hydroxy, oxo, aryl,
aryl(lower)alkyl, lower alkyl, hydroxy(lower)alkyl,
di(lower)alkylcarbamoyl, heterocyclic group, and
heterocycliccarbonyl(lower)alkyl], R.sup.2 is (1) lower alkyl, (2)
C.sub.3-C.sub.8 cycloalkyl, (3) lower alkoxy(lower)alkyl, (4)
C.sub.3-CS cycloalkyl(lower)alkyl, (5)
N,N-di(lower)alkylamino(lower)alky- l, (6) lower
alkylpiperazinyl(lower)alkyl, (7) lower alkylthio(lower)alkyl, (8)
hydroxy(lower)alkyl, (9) acyloxy(lower)alkyl,
(10)azabicyclo[3.2.2]nonyl(lower)alkyl, (11) aryl which may have
one or more halogen(s), (12) cyano, (13) lower alkanoyl, (14)
carboxy(lower)alkenyl, or (15) esterified carboxy(lower)alkenyl,
R.sup.3 is indolyl or --NH--R.sup.6 [wherein R.sup.6 is (1) aryl
which may have one or more substituent(s) selected from the group
consisting of lower alkyl, hydroxy, lower alkoxy, lower alkylthio,
hydroxy(lower)alkyl, acyl, halogen, carboxy, protected carboxy,
tetrazolyl, triphenyl(lower)alkyltet- razolyl,
hydroxyimino(lower)alkyl, sulfo(lower)alkyl, tetrazolyl(lower)alkyl
and di(lower)alkylamino, (2) pyridyl which may have one or more
lower alkyl(s), or (3) C.sub.3-C.sub.8 cycloalkyl], R.sup.4 is (1)
hydrogen, (2) lower alkyl, (3) halogen or (4) di(lower)alkylamino,
with proviso that when R.sup.4 is hydrogen, then R.sup.2 is lower
alkyl or C.sub.3-C.sub.5 cycloalkyl(lower)alkyl, or a
pharmaceutically acceptable salt thereof.
3. A compound of claim 1, wherein R' is (1) lower alkyl; (2)
hydroxy(lower)alkyl; (3) lower alkanoyloxy(lower)alkyl; (4)
heterocyclic(lower)alkyl which may have one or more substituent(s)
selected from the group consisting of lower alkyl and lower
alkanoyl; (5) aryl(lower)alkyl which may have one or more lower
alkanoyl(s); (6) carboxy(lower)alkyl; (7) lower
alkoxycarbonyl(lower)alkyl; or (8) 26[wherein A is lower alkylene
and R.sup.5 is (a) lower alkyl, (b) C.sub.3-Cl cycloalkyl, (c)
adamantyl, (d) aryl which may have one or more substituent(s)
selected from the group consisting of lower alkyl, hydroxy, lower
alkoxy, carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy,
nitro, amino and di(lower alkanoyl)amino, (e) amino which may have
one or two substituent(s) selected from the group consisting of
lower alkyl, hydroxy(lower)alkyl, phenyl(lower)alkyl and pyridyl,
(f) azabicyclo[3.2.2]nonyl, or (g) saturated heteromonocyclic group
containing at least one nitrogen atom, which may have one or more
substituent(s) selected from the group consisting of carbamoyl,
lower alkanoyl, hydroxy, oxo, phenyl, phenyl(lower)alkyl, lower
alkyl, hydroxy(lower)alkyl, di(lower)alkylcarbamoyl, piperidyl,
pyridyl, pyrimidinyl and pyrrolidinylcarbonyl(lower)alkyl, R.sup.2
is (1) lower alkyl, (2) C.sub.3-C.sub.8 cycloalkyl, (3) lower
alkoxy(lower)alkyl, (4) C.sub.3-C.sub.8 cycloalkyl(lower)alkyl, (5)
N,N-di(lower)alkylamino(lower)alkyl, (6) lower
alkylpiperazinyl(lower)alk- yl, (7) lower alkylthio(lower)alkyl,
(8) hydroxy(lower)alkyl, (9) lower alkanoyloxy(lower)alkyl, (10)
azabicyclo[3.2.2]nonyl(lower)alkyl, (11) aryl which may have one or
more halogen(s), (12) cyano, (13) lower alkanoyl, (14)
carboxy(lower)alkenyl, or (15) lower alkoxycarbonyl(lower)alkenyl,
R.sup.3 is indolyl or --NH--R.sup.6 [wherein R.sup.6 is (1)aryl
which may have one or more substituent(s) selected from the group
consisting of lower alkyl, hydroxy, lower alkoxy, lower alkylthio,
hydroxy(lower)alkyl, lower alkanoyl, halogen, carboxy, esterified
carboxy, tetrazolyl, triphenyl(lower)alkyltetrazolyl,
hydroxyimino(lower)alkyl, sulfo(lower)alkyl,
tetrazolyl(lower)alkyl, and di(lower)alkylamido, (2) pyridyl which
may have one or more lower alkyl(s), or (3) C.sub.3-C.sub.8
cycloalkyl], R.sup.4 is (1) hydrogen, (2) lower alkyl, (3) halogen
or (4) di(lower)alkylamino, with proviso that when R.sup.4 is
hydrogen, then R.sup.2 is lower alkyl or C.sub.3-C.sub.8
cycloalkyl(lower)alkyl, or a pharmaceutically acceptable salt
thereof.
4. A compound of claim 1, wherein R.sup.1 is (1) methyl, (2)
hydroxyethyl, (3) acetoxyethyl, (4) pyridylmethyl, imidazolylmethyl
or thienylmethyl, each of which may have one or more substituent(s)
selected from the group consisting of methyl and acetyl, (5) benzyl
which may have one or more substituent(s) selected from the group
consisting of acetyl, (6) carboxymethyl, (7) ethoxycarbonylmethyl
or t-butoxycarbonylmethyl, or (8) 27[wherein A is methylene, and
R.sup.5 is (a) methyl, ethyl or t-butyl, (b) cyclopropyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, (c) adamantyl,
(d) phenyl which may have one or more substituent(s) selected from
the group consisting of methyl, hydroxy, methoxy, carboxymethoxy,
ethoxycarbonylmethoxy, nitro, amino and diacetylamino, (e) amino
which may have one or two substituent(s) selected from the group
consisting of methyl, ethyl, t-butyl, isopropyl, hydroxyethyl,
isobutyl, 1-methyl-1-phenylethyl and pyridyl, (f)
azabicyclo[3.2.2]nonyl, or (g) pyrrolidinyl, piperidyl,
azacycloheptyl, azacyclooctyl, piperazinyl or morpholinyl, each of
which may have one or more substituent(s) selected from the group
consisting of carbamoyl, acetyl, hydroxy, oxo, phenyl, benzyl,
methyl, hydroxymethyl, hydroxyethyl, diethylcarbamoyl, piperidyl,
pyridyl, pyrimidinyl and pyrrolidinylcarbonylmethyl], R.sup.2 is
(1) methyl, ethyl, isopropyl, isobutyl, butyl or isopentyl, (2)
cyclopropyl or cyclohexyl, (3) methoxymethyl, (4) cyclohexylmethyl,
(5) N,N-dimethylaminomethyl, (6) methylpiperazinylmethyl, (7)
methylthiomethyl, (8) hydroxymethyl, (9) acetoxymethyl, (10)
(3-azabicyclo[3.2.2]non-3-yl)methyl, (11) phenyl which may have one
or more fluorine(s), (12) cyano, (13) formyl, (14) carboxyvinyl, or
(15) ethoxycarbonylvinyl, R.sup.3 is indolyl or --NH--R.sup.6
[wherein R.sup.6 is (1) phenyl which may have one or more
substituent(s) selected from the group consisting of methyl,
hydroxy, methoxy, methylthio, hydroxymethyl, formyl, acetyl,
chlorine, bromine, carboxy, t-butoxycarbonyl, tetrazolyl,
triphenylmethyltetrazolyl, hydroxyiminomethyl, hydroxyiminoethyl,
sulfoethyl, tetrazolylmethyl and N,N-dimethylamino, (2) pyridyl
which may have one or more methyl(s), or (3) cyclohexyl], R.sup.4
is (1) hydrogen, (2) methyl, ethyl or isopropyl, (3) chlorine, or
(4) N,N-dimethylamino, with proviso that when R.sup.4 is hydrogen,
then R.sup.2 is isopropyl, isobutyl, methyl, isopentyl, ethyl,
butyl or cyclohexylmethyl, or a pharmaceutically acceptable salt
thereof.
5. A compound of claim 1, which is a compound of the formula:
28wherein R.sup.2 is lower alkyl or C.sub.3-C.sub.8 cycloalkyl,
R.sup.4 is lower alkyl, R.sup.5 is C.sub.3-Cl cycloalkyl, R.sup.6
is lower alkylphenyl and A is lower alkylene, or a pharmaceutically
acceptable salt thereof.
6. A compound of claim 1, which is a compound of the formula:
29wherein R.sup.2 is lower alkyl or C.sub.3-C.sub.8 cycloalkyl,
R.sup.4 is lower alkyl, R.sup.5 is C.sub.3-C.sub.8 cycloalkyl,
R.sup.6 is lower alkylphenyl and A is lower alkylene, or a
pharmaceutically acceptable salt thereof.
7. A process for preparing a compound of the formula; 30Wherein R'
is (1) lower alkyl; (2) hydroxy(lower)alkyl; (3) protected
hydroxy(lower)alkyl; (4) heterocyclic(lower)alkyl which may have
one or more suitable substituent(s); (5) aryl(lower)alkyl which may
have one or more suitable substituent(s); (6) carboxy(lower)alkyl;
(7) protected carboxy(lower)alkyl; or (8) 31[wherein A is lower
alkylene and R.sup.5 is (a) lower alkyl, (b) C.sub.3-C.sub.8
cycloalkyl, (c) adamantyl, (d) aryl which may have one or more
suitable substituent(s), (e) amino which may have one or two
suitable substituent(s), (f) azabicyclo[3.2.2]nonyl, or (g)
saturated heteromonocyclic group containing at least one nitrogen
atom, which may have one or more suitable substituent(s)], R.sup.2
is (1) lower alkyl, (2) C.sub.3-C.sub.8 cycloalkyl, (3) lower
alkoxy(lower)alkyl, (4) C.sub.3-C.sub.8 cycloalkyl(lower)alkyl, (5)
N, N-di(lower)alkylamino(lower)alkyl, (.delta.) lower
alkylpiperazinyl(lower)alkyl, (7) lower alkylthio(lower)alkyl, (8)
hydroxy(lower)alkyl, (9) protected hydroxy(lower)alkyl, (10)
azabicyclo[3.2.2]nonyl(lower)alkyl, (11) aryl which may have one or
more suitable substituent(s), (12) cyano, (13) lower alkanoyl, (14)
carboxy(lower)alkenyl, or (15) esterified carboxy(lower)alkenyl,
R.sup.3 is indolyl or --NH--R.sup.6 [wherein R.sup.6 is (1) aryl
which may have one or more suitable substituent(s), (2) pyridyl
which may have one or more suitable substituent(s), or
(3)C.sub.3-C.sub.8 cycloalkyl], and R.sup.4 is (1) hydrogen, (2)
lower alkyl, (3) halogen, or (4) di(lower)alkylamino, with proviso
that when R.sup.4 is hydrogen, then R.sup.2 is lower alkyl or
C.sub.3-C.sub.8 cycloalkyl(lower)alkyl, or a salt thereof, which
comprises, (1) reacting a compound of the formula (II): 32wherein
R.sup.1, R.sup.2 and R.sup.4 are each as defined above, or its
reactive derivatives at the amino group or a salt thereof with a
compound of the formula (III): 33wherein R.sup.3 is each as defined
above, or its reactive derivative or a salt thereof to give a
compound of the formula (I): 34wherein R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are each as defined above, or a salt thereof, (2)
reacting a compound of the formula (IV): 35wherein R.sup.2,
R.sup.3, and R.sup.4 are each as defined above, or a salt thereof
with a compound of the formula (V): X--R' (V) wherein R.sup.1 is as
defined above, X is halogen,or a salt thereof to give a compound of
the formula (I): 36wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are each as defined above, or a salt thereof, (3) reacting a
compound of the formula (VI): 37wherein R.sup.2, R', R.sup.4 and A
are each as defined above, or its reactive derivative at the
carboxy group or a salt thereof with a compound of the formula
(VII): 38wherein 39is saturated heteromonocyclic group containing
at least one nitrogen atom, which may have one or more suitable
substituent(s) or its reactive derivative at the imino group or
salt thereof to give a compound of the formula (Ia): 40wherein
R.sup.2, R3, R', A and 41are each as defined above, or a salt
thereof, or (4) reacting a compound of the formula (VI): 42wherein
R.sup.2, R.sup.3, R.sup.4 and A are each as defined above, or its
reactive derivative at the carboxy group or a salt thereof with a
compound of the formula (VIII): 43wherein R.sup.7 is hydrogen,
lower alkyl, or hydroxy(lower)alkyl, R.sup.8 is lower alkyl,
hydroxy(lower)alkyl, aryl(lower)alkyl or pyridyl, or its reactive
derivative at the imino group or a salt thereof to give a compound
of the formula (Ib): 44wherein R.sup.2, R.sup.3, R.sup.4, R.sup.7,
R.sup.8 and A are each as defined above, or a salt thereof.
8. A pharmaceutical composition which comprises, as an active
ingredient, a compound of claim 1 or a pharmaceutically acceptable
salt thereof in admixture with pharmaceutically acceptable
carriers.
9. A use of compound of claim 1 or a pharmaceutically acceptable
salt thereof as a cholecystokinin antagonist.
10. A method for treating or preventing cholecystokinin-mediated
diseases which comprises administering a compound of claim 1 or a
pharmaceutically acceptable salt thereof to human or animals.
11. A process for preparing a pharmaceutical composition which
comprises admixing a compound of claim 1 or a pharmaceutically
acceptable salt thereof with a pharmaceutically acceptable carrier.
Description
TECHNICAL FIELD
[0001] This invention relates to new benzodiazepine derivatives or
a pharmaceutically acceptable salts thereof which are useful as a
medicament.
BACKGROUND ART
[0002] Some benzodiazepine derivatives have been known as
described, for example, in European Patent Application Publication
No. 349949 and International Publication No. WO 96/04254.
DISCLOSURE OF INVENTION
[0003] This invention relates to new benzodiazepine derivatives or
pharmaceutically acceptable salts thereof.
[0004] More particularly, it relates to new benzodiazepine
derivatives and pharmaceutically acceptable salts thereof which are
selective cholecystokinin-B (CCK-B) antagonists or
cholecystokinin-A and B (CCK-A/B) antagonists and therefore useful
as therapeutical and/or preventive agents for disorders of appetite
regulatory systems (e.g., anorexia, etc.), disorders associated
with intestinal smooth muscle hyperactivity (e.g., irritable bowel
syndrome, sphincter spasm, etc.), panic disorder, psychosis (e.g.,
schizophrenia, etc.), pancreatitis, etc. and also useful as
analgesics.
[0005] The benzodiazepine derivatives of this invention can be
represented by the following formula (I): 2
[0006] Wherein
[0007] R.sup.1 is
[0008] (1) lower alkyl;
[0009] (2) hydroxy(lower)alkyl;
[0010] (3) protected hydroxy(lower)alkyl;
[0011] (4) heterocyclic(lower)alkyl which may have one or more
suitable substituent(s);
[0012] (5) aryl(lower)alkyl which may have one or more suitable
substiluent(s);
[0013] (.delta.) carboxy(lower)alkyl;
[0014] (7) protected carboxy(lower)alkyl; or
[0015] (8) 3
[0016] [wherein
[0017] A is lower alkylene and
[0018] R.sup.5 is
[0019] (a) lower alkyl,
[0020] (b) C.sub.3-C.sub.8 cycloalkyl,
[0021] (c) adamantyl,
[0022] (d) aryl which may have one or more suitable
substituent(s),
[0023] (e) amino which may have one or two suitable
substituent(s),
[0024] (f) azabicyclo[3.2.2]nonyl, or
[0025] (g) saturated heteromonocyclic group containing at least one
nitrogen atom, which may have one or more suitable
substituent(s)],
[0026] R.sup.2 is
[0027] (1) lower alkyl,
[0028] (2) C.sub.3-C.sub.8 cycloalkyl,
[0029] (3) lower alkoxy(lower)alkyl,
[0030] (4) C.sub.3-C.sub.8 cycloalkyl(lower)alkyl,
[0031] (5) N, N-di(lower)alkylamino(lower)alkyl,
[0032] (.delta.) lower alkylpiperazinyl(lower)alkyl,
[0033] (7) lower alkylthio(lower)alkyl,
[0034] (8) hydroxy(lower)alkyl,
[0035] (9) protected hydroxy(lower)alkyl,
[0036] (10) azabicyclo [3.2.2]nonyl(lower)alkyl,
[0037] (11) aryl which may have one or more suitable
substituent(s),
[0038] (12) cyano,
[0039] (13) lower alkanoyl,
[0040] (14) carboxy(lower)alkenyl, or
[0041] (15) protected carboxy(lower)alkenyl,
[0042] R.sup.3 is indolyl or --NH--R.sup.6 [wherein R.sup.6 is
[0043] (1) aryl which may have one or more suitable
substituent(s),
[0044] (2) pyridyl which may have one or more suitable
substituent(s), or
[0045] (3) C.sub.3-C.sub.8 cycloalkyl], and
[0046] R.sup.4 is
[0047] (1) hydrogen,
[0048] (2) lower alkyl,
[0049] (3) halogen, or
[0050] (4) di(lower)alkylamino,
[0051] with proviso that when R.sup.4 is hydrogen, then R.sup.2 is
lower alkyl or C.sub.3-C.sub.8 cycloalkyl(lower)alkyl,
[0052] or a pharmaceutically acceptable salt thereof.
[0053] According to the present invention, the new benzodiazepine
derivatives (1) can be prepared by the processes which are
illustrated in the following scheme. 4
[0054] Process 2 5 6
[0055] Process 4 7
[0056] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and A are each
as defined above,
[0057] N is saturated heteromonocyclic group containing at least
one nitrogen atom, which may have one or more suitable
substituent(s),
[0058] X is halogen,
[0059] R.sup.7 is hydrogen, lower alkyl or hydroxy(lower)alkyl,
[0060] R.sup.8 is lower alkyl, hydroxy(lower)alkyl,
aryl(lower)alkyl or pyridyl.
[0061] The starting compounds (II), (IV) and (VI) can be prepared
by the following processes.
[0062] Process A 8 9
[0063] Process C 10
[0064] Process D 11
[0065] Process E 12
[0066] or its reactive derivative or its reactive derivative at the
amino group or a salt or a salt thereof thereof 13
[0067] or a salt thereof
[0068] wherein
[0069] R.sup.1, R.sup.2, R.sup.3, R.sup.4, X, N and A are each as
defined above,
[0070] R.sup.9 is protected amino, and
[0071] R.sup.10 is protected carboxy.
[0072] With regard to the object compound (I), in case that the
ompound (I) has the group of the formula 14
[0073] in R.sup.1, said group can also exist in the tautomeric form
and such tautomeric equilibrium can be represented by the following
scheme. 15
[0074] Both of the above tautomeric isomers are included within the
scope of the present invention. In the present specification and
claim, the compounds including the group of such tautomeric isomers
are represented for the convenient sake by one expression of the
group of the formula (A).
[0075] Further, in case that the compound (I) has the group of the
formula: 16
[0076] in R.sup.6, said group can also exist in the tautomeric from
and such tautomeric equilibrium can be represented by the following
scheme. 17
[0077] Both of the above tautomeric isomers are included within the
scope of the present invention. In the present specification and
claim, the compounds including the group of such tautomeric isomers
are represented for the convenient sake by one expression of the
group of the formula (C).
BEST MODE FOR CARRYING OUT THE INVENTION
[0078] Suitable pharmaceutically acceptable salts of the object
compound (I) are conventional non-toxic salts and include a metal
salts such as an alkali metal salt (e.g., sodium salt, potassium
salt, etc.) and an alkaline earth metal salt (e.g., calcium salt,
magnesium salt, etc.), an ammonium salt, an organic base salt
(e.g., trimethylamine salt, triethylamine salt, pyridine salt,
picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylene
diamine salt, etc.), an organic acid salt (e.g., acetate, maleate,
tartrate, methanesulfonate, benzcnesulfonate, formate,
toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt
(e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), a
salt with an amino acid (e.g., arginine, aspartic acid, glutamic
acid, etc.), and the like.
[0079] In the above and subsequent descriptions of the present
specification, suitable examples and illustrations of the various
definitions which the present invention include within the scope
thereof are explained in detail as follows.
[0080] The term "lower" is intended to mean 1 to 6 carbon atom(s),
unless otherwise indicated.
[0081] Suitable "lower alkyl" may include methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, t-butyl, 3-methylbutyl,
pentyl, t-pentyl, hexyl and the like.
[0082] Suitable "hydroxy protective group" in "protected
hydroxy(lower)alkyl" may include acyl, which includes aliphatic
acyl group and acyl group containing an aromatic or heterocyclic
ring.
[0083] And, suitable examples of the said acyl may be lower
alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl,
valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower
alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.);
lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl,
isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g.,
benzenesulfonyl, tosyl, etc.); aroyl (e.g., benzoyl, toluoyl,
xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.);
ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.);
ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl,
phenethyloxycarbonyl, etc.), and the like.
[0084] Suitable "heterocyclic group" may include saturated or
unsaturated, monocyclic or polycyclic heterocyclic group containing
at least one hetero-atom such as an oxygen, sulfur, nitrogen atom
and the like. And especially preferable heterocyclic group may be
heterocyclic group such as
[0085] unsaturated 3 to 8-membered heteromonocyclic group
containing 1 to 4 nitrogen atom(s), for example, pyrrolyl,
pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide,
pyperidyl, pyrimidinyl, pyrazinyl, dihydropyridazinyl,
tetrahydropyridazinyl, triazolyl (e.g., 1H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,
1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g.,
4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.),
etc.,
[0086] saturated 3 to 8-membered heteromonocyclic group containing
1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl,
piperidino, piperazinyl, azacycloheptyl, azacyclooctyl, etc.,
[0087] unsaturated condensed heterocyclic group containing 1 to 5
nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl,
isoindolinyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl,
indazolyl, benzotriazolyl, letrazolopyridyl, tetrazolopyridazinyl
(e.g.,tetrazolo[1,5-bJpyridazinyl, etc.,),
dihydrotriazolopyridazinyl, etc.,;
[0088] unsaturated 3 to 8-membered heteromonocyclic group
containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for
example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2,5-oxadiazolyl,
etc.,), etc.,; saturated 3 to 8-membered heteromonocyclic group
containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for
example, morpholinyl, etc.,;
[0089] unsaturated condensed heterocyclic group containing 1 to 2
oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
benzoxazolyl, benzoxadiazolyl, etc.,;
[0090] unsaturated 3 to 8-membered heteromonocyclic group
containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for
example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl
(e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,2,3-thiadiazolyl), etc.,;
[0091] saturated 3 to 8-membered heteromonocyclic group containing
1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiazolidinyl, etc.,;
[0092] unsaturated 3 to 8-membered heteromonocyclic group
containing an oxygen atom, for example furyl, etc.,
[0093] unsaturated 3 to 8-membered heteromonocyclic group
containing a sulfur atom, for example, thienyl, etc.,;
[0094] unsaturated condensed heteromonocyclic group containing 1 to
2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
benzothiazolyl, benzothiadiazolyl, etc., and the like.
[0095] Suitable "aryl" may include phenyl, naphthyl, and the
like.
[0096] Suitable "protected carboxy" may include esterified carboxy
and the like.
[0097] Suitable example of the ester moiety of an esterified
carboxy may be the ones such as lower alkyl ester (e.g. methyl
ester, ethyl ester, propyl ester, isopropyl ester, butyl ester,
isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.)
which may have at least one suitable substituent(s), for example,
lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester,
propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl
ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or
2)-acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl ester, 1 (or 2 or
3 or 4)-acetoxybutyl ester, 1 (or 2)-propionyloxyethyl ester, 1(or
2 or 3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester,
1(or 2)-isobutyryloxyethyl ester, 1(or 2)-pivaloyloxyethyl ester,
1(or 2)-hexanoyloxyethyl ester, iso-butyryloxymethyl ester,
2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester,
1(or 2)-pentanoyloxyethyl ester, etc.], lower
alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester, etc.),
mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester,
2,2,2-trichloroethyl ester, etc.), lower
alkoxycarbonyloxy(lower)alkyl ester (e.g. methoxycarbonyloxymethyl
ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl
ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl
ester, etc.), lower alkylthio(lower)alkyl ester (e.g.
methylthiomethyl ester, 1-(or 2-)methylthioethyl ester, 1-(or 2- or
3-)methylthiopropyl ester, 1-(or 2- or 3- or 4-)methylthiobutyl
ester, 1-(or 2- or 3- or 4- or 5-)methylthiopentyl ester, 1-(or 2-
or 3- or 4- or 5- or 6-)methylthiohexyl ester, ethyl-thiomethyl
ester, 1-(or 2-)ethylthioethyl ester, 1-(or 2- or
3-)ethylthiopropyl ester, propylthiomethyl ester, 1-(or
2-)propylthioethyl ester, 1-(or 2- or 3-)propylthiopropyl ester,
etc.), phthalidylidene(lower)alkyl ester, or (5-lower
alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
(5-ethyl-2-oxo-1,3-dioxol-4- -yl)methyl ester,
(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl
ester (e.g. vinyl ester, etc.); lower alkynyl ester (e.g. ethynyl
ester, propynyl ester, etc.); ar(lower)alkyl ester which may have
at least one suitable substituent(s) such as mono(or di or
tri)phenyl(lower)alkyl ester which may have at least one suitable
substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester,
4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl
ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,
4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which
may have at least one suitable substituent(s) (e.g. phenyl ester,
4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl
ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and
the like.
[0098] Suitable "lower alkylene" may include straight or branched
one having 1 to 6 carbon atom(s), such as methylene, ethylene,
trimethylene, tetramethylene, pentamethylene, hexamehylene, or the
like, preferably one having 1 to 4 carbon atom(s).
[0099] Suitable "C.sub.3-C.sub.8 cycloalkyl" may include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[0100] Suitable "saturated heteromonocyclic group containing at
least one nitrogen atom" may include
[0101] saturated 3 to 8-membered heteromonocyclic group containing
1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl,
piperidino, piperidyl, piperaziny], azacycloheptyl, azacyclooctyl,
etc.,;
[0102] saturated 3 to 8-membered heteromonocyclic group containing
1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
morpholinyl, etc.,;
[0103] saturated 3 to 8-membered heteromonocyclic group containing
1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiazolidinyl, etc., and the like.
[0104] Suitable "lower alkoxy" may include methoxy, ethoxy,
propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy,
hexyloxy, and the like.
[0105] Suitable "substituent" in the terms
"heterocyclic(lower)alkyl which may have one or more suitable
substituent(s)", "aryl(lower)alkyl which may have one or more
suitable substituent(s)", "aryl which may have one or more suitable
substituent(s)", "amino which may have one or more suitable
substituent(s)", "saturated heteromonocyclic group containing at
least one nitrogen atom, which may have one or more suitable
substituent(s)", and "pyridyl which may have one or more suitable
substituent(s)" may include lower alkyl (which is exemplified
above), acyl (which is exemplified above), hydroxy, lower alkoxy
(which is exemplified above), carboxy(lower)alkoxy, protected
carboxy(lower)alkoxy, nitro, amino, diacylamino,
hydroxy(lower)alkyl, aryl(lower)alkyl, carbamoyl, oxo, aryl (which
is exemplified above), mono or di substituted carbamoyl (which is
exemplified above), heterocyclic group (which is exemplified
below), heterocyclic carbonyl(lower)alkyl, halogen (e.g., chlorine,
bromine, fluorine and iodine), lower alkylthio (e.g., methylthio,
ethylthio, propylthio, butylthio, pentylthio, etc.), carboxy,
protected carboxy (which is exemplified above),
triphenyl(lower)alkyltetr- azolyl, hydroxyimino(lower)alkyl (e.g.,
hydroxyiminomethyl, hydroxyiminoethyl, etc.), sulfo(lower)alkyl
(e.g., sulfomethyl, sulfoethyl, etc.), tetrazolyl(lower)alkyl,
di(lower)alkylamino (e.g., N,N-dimethylamino, etc.), and the
like.
[0106] Suitable examples of the said mono or di substituted
carbamoyl may be mono or di(lower)alkylcarbamoyl (e.g.,
methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl,
diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, propylcarbamoyl,
dipropylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,
pentylcarbamoyl, hexylcarbamoyl, etc.), heterocyclic carbamoyl
(e.g., tetrazolylcarbamoyl, etc.,), mono or
di(carboxy)(lower)alkylcarbamoyl (e.g., carboxymethylcarbamoyl,
1-carboxyethylcarbamoyl, 2-carboxyethylcarbamoyl,
1,3-dicarboxypropylcarb- amoyl,etc.,), mono or di (lower
alkoxycarbonyl)(lower)alkylcarbamoyl (e.g.,
1,3-diethoxycarbonylpropylcarbamoyl,etc.), mono or di (protected
carboxy)(lower)alkylcarbamoyl (wherein "protected carboxy" is
exemplified above), mono or di
{(lower)alkyl~amino(lower)-alkylcarbamoyl (e.g.,
2-dimethylaminoethylcarbamoyl, etc.), and the like.
[0107] Suitable "lower alkanoyl" may include formyl, acetyl,
propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and
the like.
[0108] Suitable "lower alkenyl" may include vinyl, propenyl,
butenyl, pentenyl, hexenyl and the like.
[0109] Suitable "amino protective group" in "protected amino" may
include acyl (which is exemplified above) and the like.
[0110] The preferred embodiments of the object compound (I) are as
follows:
[0111] R.sup.1 is
[0112] (1) lower alkyl;
[0113] (2) hydroxy(lower)alkyl;
[0114] (3) acyloxy(lower)alkyl;
[0115] (4) heterocyclic(lower)alkyl which may have one or more
substituent(s) selected from the group consisting of lower alkyl
and acyl;
[0116] (5) aryl(lower)alkyl which may have one or more acyl(s);
[0117] (.delta.) carboxy(lower)alkyl;
[0118] (7) esterified carboxy(lower)alkyl; or
[0119] (8) 18
[0120] [wherein
[0121] A is lower alkylene and
[0122] R.sup.5 is
[0123] (a) lower alkyl,
[0124] (b) C.sub.3-C.sub.8 cycloalkyl,
[0125] (c) adamantyl,
[0126] (d) aryl which may have one or more substituent(s) selected
from the group consisting of lower alkyl, hydroxy, lower alkoxy,
carboxy(lower)alkoxy, protected carboxy(lower)alkoxy, nitro, amino
and diacylamino,
[0127] (e) amino which may have one or two substituent(s) selected
from the group consisting of lower alkyl, hydroxy(lower)alkyl,
aryl(lower)alkyl and pyridyl,
[0128] (f) azabicyclo[3.2.2]nonyl, or
[0129] (g) saturated heteromonocyclic group containing at least one
nitrogen atom, which may have one or more substituent(s) selected
from the group consisting of carbamoyl, acyl, hydroxy, oxo, aryl,
aryl(lower)alkyl, lower alkyl, hydroxy(lower)alkyl,
di(lower)alkylcarbamoyl, heterocyclic group, and
heterocycliccarbonyl(low- cr)alkyl],
[0130] R.sup.2 is
[0131] (1) lower alkyl,
[0132] (2) C.sub.3-C.sub.8 cycloalkyl,
[0133] (3) lower alkoxy(lower)alkyl,
[0134] (4) C.sub.3-C.sub.8 cycloalkyl(lower)alkyl,
[0135] (5) N,N-di(lower)alkylamino(lower)alkyl,
[0136] (.delta.) lower alkylpiperazinyl(lower)alkyl,
[0137] (7) lower alkylthio(lower)alkyl,
[0138] (8) hydroxy(lower)alkyl,
[0139] (9) acyloxy(lower)alkyl,
[0140] (10)azabicyclo[3.2.2]nonyl(lower)alkyl,
[0141] (11) aryl which may have one or more halogen(s),
[0142] (12) cyano,
[0143] (13) lower alkanoyl,
[0144] (14) carboxy(lower)alkenyl, or
[0145] (15) esterified carboxy(lower)alkenyl,
[0146] R.sup.3 is indolyl or --NH--R" [wherein R.sup.6 is
[0147] (1) aryl which may have one or more substituent(s) selected
from the group consisting of lower alkyl, hydroxy, lower alkoxy,
lower alkylthio, hydroxy(lower)alkyl, acyl, halogen, carboxy,
protected carboxy, tetrazolyl, triphenyl(lower)alkyltetrazolyl,
hydroxyimino(lower)alkyl, sulfo(lower)alkyl, tetrazolyl(lower)alkyl
and di(lower)alkylamino,
[0148] (2) pyridyl which may have one or more lower alkyl(s),
or
[0149] (3) C.sub.3-C.sub.8 cycloalkyl],
[0150] R.sup.4 is
[0151] (1) hydrogen,
[0152] (2) lower alkyl,
[0153] (3) halogen or
[0154] (4) di(lower)alkylamino,
[0155] with proviso that when R.sup.4 is hydrogen, then R.sup.2 is
lower alkyl or C.sub.3-C.sub.8 cycloalkyl(lower)alkyl, or a
pharmaceutically acceptable salt thereof.
[0156] The more preferred embodiments of the object compound (I )
are as follows:
[0157] R.sup.1 is
[0158] (1) lower alkyl;
[0159] (2) hydroxy(lower)alkyl;
[0160] (3) lower alkanoyloxy(lower)alkyl;
[0161] (4) heterocyclic(lower)alkyl which may have one or more
substituent(s) selected from the group consisting of lower alkyl
and lower alkanoyl;
[0162] (5) aryl(lower)alkyl which may have one or more lower
alkanoyl(s);
[0163] (.delta.) carboxy(lower)alkyl;
[0164] (7) lower alkoxycarbonyl(lower)alkyl; or
[0165] (8) 19
[0166] [wherein
[0167] A is lower alkylene and
[0168] R.sup.5 is
[0169] (a) lower alkyl,
[0170] (b) C.sub.3-C.sub.8 cycloalkyl,
[0171] (c) adamantyl,
[0172] (d) aryl which may have one or more substituent(s) selected
from the group consisting of lower alkyl, hydroxy, lower alkoxy,
carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, nitro,
amino and di(lower a]kanoyl)amino,
[0173] (e) amino which may have one or two substituent(s) selected
from the group consisting of lower alkyl, hydroxy(lower)alkyl,
phenyl(lower)alkyl and pyridyl,
[0174] (f) azabicyclo[3.2.2]nonyl, or
[0175] (g) saturated heteromonocyclic group containing at least one
nitrogen atom, which may have one or more substituent(s) selected
from the group consisting of carbamoyl, lower alkanoyl, hydroxy,
oxo, phenyl, phenyl(lower)alkyl, lower alkyl, hydroxy(lower)alkyl,
di(lower)alkylcarbamoyl, piperidyl, pyridyl, pyrimidinyl and
pyrrolidinylcarbonyl(lower)alkyl,
[0176] R.sup.2 is
[0177] (1) lower alkyl,
[0178] (2) C.sub.3-C.sub.8 cycloalkyl,
[0179] (3) lower alkoxy(lower)alkyl,
[0180] (4) C.sub.3-C.sub.8 cycloalkyl(lower)alkyl,
[0181] (5) N,N-di(lower)alkylamino(lower)alkyl,
[0182] (6) lower alkylpiperazinyl(lower)alkyl,
[0183] (6) lower alkylpiperazinyl(lower)alkyl,
[0184] (7) lower alkylthio(lower)alkyl,
[0185] (8) hydroxy(lower)alkyl,
[0186] (9) lower alkanoyloxy(lower)alkyl,
[0187] (10)azabicyclo[3.2.2]nonyl(lower)alkyl, or
[0188] (11)aryl which may have one or more halogen(s),
[0189] (12)cyano,
[0190] (13)lower alkanoyl,
[0191] (14)carboxy(lower)alkenyl, or
[0192] (15)lower alkoxycarbonyl(lower)alkenyl,
[0193] R.sup.3 is indolyl or --NH--R.sup.6 [wherein R.sup.6 is
[0194] (1) aryl which may have one or more substituent(s) selected
from the group consisting of lower alkyl, hydroxy, lower alkoxy,
lower alkylthio, hydroxy(lower)alkyl, lower alkanoyl, halogen,
carboxy, esterified carboxy, tetrazolyl,
triphenyl(lower)alkyltetrazolyl, hydroxyimino(lower)alkyl,
sulfo(lower)alkyl, tetrazolyl(lower)alkyl, and
di(lower)alkylamido,
[0195] (2) pyridyl which may have one or more lower alkyl(s),
or
[0196] (3) C.sub.3-C.sub.8 cycloalkyl],
[0197] R.sup.4 is
[0198] (1) hydrogen,
[0199] (2) lower alkyl,
[0200] (4) di(lower)alkylamino, with proviso that when R.sup.4 is
hydrogen, then R.sup.2 is lower alkyl or C.sub.3-C.sub.8
cycloalkyl(lower)alkyl,
[0201] or a pharmaceutically acceptable salt thereof.
[0202] And the more preferred embodiments of the object compound
(I) are as follows:
[0203] wherein R.sup.1 is
[0204] (1) methyl,
[0205] (2) hydroxyethyl,
[0206] (3) acetoxyethyl,
[0207] (4) pyridylmethyl, imidazolylmethyl or thienylmethyl, each
of which may have one or more substituent(s) selected from the
group consisting of methyl and acetyl,
[0208] (5) benzyl which may have one or more substituent(s)
selected from the group consisting of acetyl,
[0209] (.delta.) carboxymethyl,
[0210] (7) ethoxycarbonylmethyl or t-butoxycarbonylmethyl, or
[0211] (8) 20
[0212] [wherein
[0213] A is methylene, and
[0214] R.sup.5 is
[0215] (a) methyl, ethyl or t-butyl,
[0216] (b) cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or
cyclooctyl,
[0217] (c) adamantyl,
[0218] (d) phenyl which may have one or more substituent(s)
selected from the group consisting of methyl, hydroxy, methoxy,
carboxymethoxy, ethoxycarbonylmethoxy, nitro, amino and
diacetylamino,
[0219] (e) amino which may have one or two substituent(s) selected
from the group consisting of methyl, ethyl, t-butyl, isopropyl,
hydroxyethyl, isobutyl, 1-methyl-1-phenylethyl and pyridyl,
[0220] (f) azabicyclo[3.2.2]nonyl, or
[0221] (g) pyrrolidinyl, piperidyl, azacycloheptyl, azacyclooctyl,
piperazinyl or morpholinyl, each of which may have one or more
substituent(s) selected from the group consisting of carbamoyl,
acetyl, hydroxy, oxo, phenyl, benzyl, methyl, hydroxymethyl,
hydroxyethyl, diethylcarbamoyl, piperidyl, pyridyl, pyrimidinyl and
pyrrolidinylcarbonylmethyl],
[0222] R.sup.2 is
[0223] (1) methyl, ethyl, isopropyl, isobutyl, butyl or
isopentyl,
[0224] (2) cyclopropyl or cyclohexyl,
[0225] (3) methoxymethyl,
[0226] (4) cyclohexylmethyl,
[0227] (5) N,N-dimethylaminomethyl,
[0228] (.delta.) methylpiperazinylmethyl,
[0229] (7) methylthiomethyl,
[0230] (8) hydroxymethyl,
[0231] (9) acetoxymethyl,
[0232] (10) (3-azabicyclo[3.2.2]non-3-yl)methyl,
[0233] (11) phenyl which may have one or more fluorine(s),
[0234] (12) cyano,
[0235] (13) formyl,
[0236] (14) carboxyvinyl, or
[0237] (15) ethoxycarbonylvinyl,
[0238] R.sup.3 is indolyl or --NH--R.sup.6 [wherein R.sup.6 is
[0239] (1) phenyl which may have one or more substituent(s)
selected from the group consisting of methyl, hydroxy, methoxy,
methylthio, hydroxymethyl, formyl, acetyl, chlorine, bromine,
carboxy, t-butoxycarbonyl, tetrazolyl, triphenylmethyltetrazolyl,
hydroxyiminomethyl, hydroxyiminoethyl, sulfoethyl, tetrazolylmethyl
and N,N-dimethylamino,
[0240] (2) pyridyl which may have one or more methyl(s), or
[0241] (3) cyclohexyl],
[0242] R.sup.4 is
[0243] (1) hydrogen,
[0244] (2) methyl, ethyl or isopropyl,
[0245] (3) chlorine, or
[0246] (4) N,N-dimethylamino, with proviso that when R.sup.4 is
hydrogen, then R.sup.2 is isopropyl, isobutyl, methyl, isopentyl,
ethyl, butyl or cyclohexylmethyl,
[0247] or a pharmaceutically acceptable salt thereof.
[0248] And the more preferred embodiments of the object compound
(I) are as follows: 21
[0249] wherein R.sup.2 is lower alkyl or C.sub.3-C.sub.5
cycloalkyl,
[0250] R.sup.4 is lower alkyl,
[0251] R.sup.5 is C.sub.3-C.sub.8 cycloalkyl,
[0252] R.sup.6 is lower alkylphenyl and
[0253] A is lower alkylene,
[0254] or a pharmaceutically acceptable salt thereof.
[0255] And the most preferred embodiments of the object compound
(I) are as follows: 22
[0256] wherein R.sup.2 is lower alkyl or C.sub.3-C.sub.8
cycloalkyl,
[0257] R.sup.4 is lower alkyl,
[0258] R.sup.5 is C.sub.3-C.sub.8 cycloalkyl,
[0259] R.sup.6 is lower alkylphenyl and
[0260] A is lower alkylene,
[0261] or a pharmaceutically acceptable salt thereof.
[0262] The processes for preparing the object compound (1) and the
starting compounds of the present invention are explained in detail
in the following.
[0263] Process 1:
[0264] The compound (I) or a salt thereof can be prepared by
reacting the compound (II) or its reactive derivative at the amino
group or a salt thereof with the compound (III) or its reactive
derivative or a salt thereof.
[0265] Suitable reactive derivative at the amino group of the
compound (II) may include Schiff's base type imino or its
tautomeric enamine type isomer formed by the reaction of the
compound (II) with a carbonyl compound such as aldehyde, ketone or
the like; a silyl derivative formed by the reaction of the compound
(II) with a silyl compound such as
N,N-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the
like; a derivative formed by the reaction of the compound (II) with
phosphorus trichloride or phosgene and the like.
[0266] Suitable reactive derivative of the compound (III) may
include an acid halide, an acid anhydride, an activated amide, an
activated ester, isocyanate, and the like. The suitable example may
be an acid chloride, an acid azide; a mixed acid anhydride with an
acid such as substituted phosphoric acid (e.g., dialkylphosphoric
acid, phenylphosphoric acid, diphenylphosphoric acid,
dibenzylphosphoric acid, halogenated phosphoric acid, etc.),
dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,
alkanesulfonic acid (e.g., methanesulfonic acid, cthanesulfonic
acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic
carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic
acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic
carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid
anhydride; an activated amide with imidazole, 4-substituted
imidazole, dimethylpyrazole, triazole or tetrazole; an activated
ester (e.g., cyanomethyl ester, methoxymethyl ester,
dimethyliminomethyl [(CH.sub.3).sub.2N.sup.+.dbd.CH] ester, vinyl
ester, propargyl ester, phenyl ester, p-nitrophenyl ester,
2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl
ester, mesylphenyl ester, phenylazophenyl ester, pyranyl ester,
pyridyl ester, piperidyl ester, etc.); an ester with a N-hydroxy
compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1
H)-pyridone, N-hydroxy-succinimide, N-hydroxybenzotriazole,
N-hydroxyphtalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.);
isocyanate of the formula: R.sup.3--N.dbd.C.dbd.O (in which R.sup.3
is as defined above), and the like. These reactive derivatives can
optionally be selected according to the kind of the compound (III)
to be used.
[0267] Suitable salts of the compounds (II) and (III) can be
referred to the ones as exemplified for the compound (I).
[0268] The reaction is usually carried out in a conventional
solvent such as water, acetone, dioxane, acetonitrile, chloroform,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl
acetate, N,N-dimethylformamide, pyridine or any other organic
solvents which do not adversely affect the reaction. These
conventional solvents may also be used in a mixture with water.
[0269] When the compound (III) is used in free acid form or its
salt form in the reaction, the reaction is preferably carried out
in the presence of a conventional condensing agent such as
N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylam- inocyclohexyl)carbodiimide;
N,N-diethylcarobodiimide, N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiim- ide;
N,N'-carbonylbis-(2-methylimidazole); N,N'-carbonyldiimidazolc,
pentamethyleneketene-N-cyclohexylimine;
diphenylketenc-N-cyclohexylimine; ethoxyacetylene;
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
chloride); phosphorus trichloride; thionyl chloride; oxalyl
chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium
salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide
intra-molecular salt;
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called
Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide
with thionyl chloride, phosgene, phosphorus oxychloride, etc.; or
the like.
[0270] The reaction may also be carried out in the presence of an
inorganic or organic base such as an alkali metal bicarbonate,
tri(lower)alkylamine, pyridine, N-(lower)aklylmorphorine,
N,N-di(lower)alkylbenzylamine, or the like. The reaction
temperature is not critical, and the reaction is usually carried
out under cooling to heating.
[0271] The compound (III) or its reactive derivative, or a salt
thereof can be prepared in accordance with the method disclosed in
the Preparations described later or similar manners thereto.
[0272] Process 2
[0273] The compound (I) or a salt thereof can be prepared by
reacting the compound (IV) or a salt thereof with a compound (V) or
a salt thereof.
[0274] This reaction can be referred to that of Examples
3,6,8-10.
[0275] Process 3
[0276] The compound (Ia) or a salt thereof can be prepared by
reacting the compound (VI) or its reactive derivative at the
carboxy group or a salt thereof with the compound (VII) or its
reactive derivative at the imino group or a salt thereof.
[0277] Suitable reactive derivative at the carboxy group of the
compound (VI) may include the same one as illustrated in the
explanation of the Process 1.
[0278] Suitable reactive derivative at the imino group of the
compound (VII) may be adequately selected from the reactive
derivative at the amino group that is illustrated in the
explanation for the Process 1.
[0279] Suitable salts of the compounds (VI) and (VII) can be
referred to the ones as exemplified for the compound (I).
[0280] The reaction is usually carried out in the presence of
base.
[0281] Suitable base may include an inorganic base such as alkali
metal hydride (e.g., sodium hydride, etc.), alkali metal hydroxide
(e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth
metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide,
etc.), alkali metal carbonate (e.g., sodium carbonate, potassium
carbonate, etc.), alkaline earth metal carbonate (e.g., magnesium
carbonate, calcium carbonate, etc.), alkali metal bicarbonate
(e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali
metal acetate (e.g., sodium acetate, potassium acetate, etc.),
alkaline earth metal phosphate (e.g., magnesium phosphate, calcium
phosphate, etc.), alkali metal hydrogen phosphate (e.g., disodium
hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the
like, and an organic base such as trialkylamine (e.g.,
trimethylamine, triethylamine etc.), picoline, N-methylpyrrolidine,
N-methyl-morpholine, or the like.
[0282] The reaction is usually carried out in a solvent such as
alcohol (e.g., methanol, ethanol, etc.), benzene,
N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other
solvent which does not adversely affect the reaction.
[0283] The reaction temperature is not critical and the reaction is
usually carried out under cooling to heating.
[0284] Process 4
[0285] The compound (Ib) or a salt thereof can be prepared by
reacting the compound (VI) or its reactive derivative at the
carboxy group or a salt thereof with the compound (VIII) or its
reactive derivative at the imino group or a salt thereof.
[0286] Suitable reactive derivative at the carboxy group of the
compound (VI) and suitable reactive derivative at the imino group
of the compound (VIII) may include the same one as illustrated in
the explanation of the Process 1.
[0287] Suitable salts of the compounds (VI) and (VIII) can be
referred to the ones as exemplified for the compound (1).
[0288] The reaction can be referred to that of the aforementioned
Process 3.
[0289] It is to be noted that the compound (I) may include one or
more stereoisomers due to asymmetric carbon atoms, and all of such
isomers and mixture thereof are included within the scope of this
invention. It is also to be noted that the compound (I) may include
a solvate, e.g., hydrate, etc.
[0290] Process A
[0291] The compound (X) or a salt thereof can be prepared by
reacting the compound (IX) or a salt thereof with the compound (V)
or a salt thereof. This reaction can be referred to that of
aforementioned Process 2.
[0292] Process B
[0293] The compound (Xa) or a salt thereof can be prepared by
reacting the compound (XI) or its reactive derivative at the
carboxy croup or a salt thereof with the compound (VII) or its
reactive derivative at the imino group or a salt thereof. This
reaction can be referred to that of Preparation 59-5.
[0294] Process C
[0295] The compound (II) or a salt thereof can be prepared by
subjecting the compound (X) or a salt thereof to elimination
reaction of the amino protective group. This elimination reaction
can be referred to that of Preparations 13-4, 15-2, 16-11 and
17-4.
[0296] Process D
[0297] The compound (VI) or a salt thereof can be prepared by
subjecting the compound (XII) or a salt thereof to elimination
reaction of the carboxy protective group. This elimination reaction
can be referred to that of Preparation 59-4.
[0298] Process E
[0299] The compound (IV) or a salt thereof can be prepared by
reacting the compound (XIII) or its reactive derivative at the
amino group or a salt thereof with the compound (III) or its
reactive derivative or a salt thereof.
[0300] The reaction can be referred to that of the aforementioned
Process 1.
[0301] The compound (XIII) or its reactive derivative at the amino
group or a salt thereof can be prepared in accordance with the
method disclosed in the Preparations described later or similar
manners thereto.
[0302] The object compound (I) and pharmaceutically acceptable
salts thereof are selective CCK-B antagonists or CCK-A/B
antagonists.
[0303] Further, it is expected that the object compound (I) and
pharmaceutically acceptable salts thereof have gastrin antagonism
and are useful as therapeutical and/or preventive agents for ulcers
such as gastric ulcer, duodenal ulcer, excess gastric secretion,
zollinger-Ellison Syndrome, non-ulcer dyspepsia, gastroesophageal
reflux disease, etc.
[0304] In order to show the utility of the object compound (1),
pharmacological activity of the representative compound thereof is
shown in the following.
[0305] Experiment 1
[0306] [I] Test Compound
[0307]
(1)N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihyd-
ro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylthiophenyl)ure-
a
[0308]
(2)N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihyd-
ro-5-acetoxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylp-
henyl)urea
[0309] [II] Test:
[0310] [.sup.125I]CCK-8 binding to guinea-pig cerebral cortical
membranes
[0311] Test Method
[0312] (i) Membrane Preparation
[0313] Guinea-pigs were killed by decapitation and bled to death.
Cerebral cortex was removed, minced in a small quantity of 50 mM
Tris-HCl buffer (pH 7.4), and homogenized in 20 vol. of the buffer
by a glass-teflon homogenizer. The homogenate was centrifuged at
30000.times. g (16000 rpm) for 10 minutes. The pellet was then
resuspended in the same buffer by a glass-teflon homogenizer and
recentrifuged at 30000.times. g for 10 minutes. This procedure
(washings) was repeated twice more. The final pellet (membrane) was
suspended in incubation medium (see below) so as to obtain a final
protein concentration of 4 mg/ml and frozen at -80.degree. C. All
manipulations were done at 0-4.degree. C.
[0314] (ii) Receptor Binding Assay
[0315] The composition of incubation medium was as follows:
[0316] 10 mM HEPES (pH 6.5), 5 mM MgCl.sub.2, 1 mM EGTA, 130 mM
NaCI and 0.25 mg/ml bacitracin. Frozen membranes were thawed and
aliquots (400 .mu.g, protein) were incubated for 60 minutes under
shaking at 37.degree. C. in plastic tubes in 500 .mu.L of
incubation medium with 50 pM .sup.125I-CCK-8 in the presence or
absence of test compound (1.times.10.sup.-8 M). To determine the
non-specific binding, CCK-8 at 1 .mu.M was added. Each assay was
performed in duplicate. Reaction mixture was filtered through a
Whatman GF/B glass filter to stop the reaction. After washing the
filter with 50 mM Tris-HCl (pH 7.4) buffer containing 0.1% BSA, the
radioactivity of the filter was countered. Non-specific binding was
subtracted from total binding to yield specific binding. The effect
of the test compound was expressed as % inhibition of specific
'.sup.125I-CCK-8 binding.
[0317] Test Result
[0318] Inhibition (%)
[0319] test compound(1): 97.3%
[0320] test compound(2): 97%
[0321] Experiment 2
[0322] [I] Test Compound
[0323] (A)
N-[(3RS)-1-cyclohexylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2--
oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[0324] (B)
N-[(3RS)-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-ethyl-9-methy-
l-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[0325] (C)
N-[(3R)-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2-oxo-2,3-d-
ihydro-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[0326] (D)
N-[(3RS)-1-cyclohexylcarbonylmethyl-5-cyclopropyl-2,3-dihydro-9-
-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-met
hylphenyl)urea
[0327] [II] Tests:
[0328] Receptor binding studies and gastric emptying in mice
[0329] Test Method
[0330] The tests were carried out in accordance with the method
described at pages 571 to 572 in the following literature;
[0331] Harunobu Ito, Hajime Sogabe et al., The Journal of
Pharmacology and Experimental Therapeutics, 571, No.2, Vol.268
(1994).
[0332] Test results are shown in the table 1.
1TABLE 1 Biological evaluation results Com- IC.sub.50 (nM)
IC.sub.50 (nM) selectivity Gastric emptying pound for CCK-B for
CCK-A A/B ID.sub.50 (mg/Kg) (A) 3.7 1.1 0.30 0.4 (B) 1.6 0.9 0.56
0.4 (C) 1.0 0.3 0.30 0.23 (D) 1.1 2.0 1.82 1.8
[0333] The object compound (I) or pharmaceutically acceptable salts
thereof can usually be administered to mammals including human
being in the form of a conventional pharmaceutical composition such
as capsule, micro-capsule, tablet, granule, powder, troche, syrup,
aerosol, inhalation, solution, injection, suspension, emulsion,
suppository or the like.
[0334] The pharmaceutical composition of this invention can contain
various organic or inorganic carrier materials, which are
conventionally used for pharmaceutical purpose, such as excipient
(e.g., sucrose, starch, mannit, sorbit, lactose, glucose,
cellulose, talc, calcium phosphate, calcium carbonate, etc.),
binding agent (cellulose, methyl cellulose, hydroxypropyl
cellulose, polypropylpyrrolidone, gelatin, gum arabic,
polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g.,
starch, carboxymethyl cellulose, calcium salt of carboxymethyl
cellulose, hydroxypropylstarch, sodium glycole-starch, sodium
bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant
(e.g., magnesium stearate, talc, sodium lauryrsulfate, etc.),
flavoring agent (e.g., citric acid, menthol, glycine, orange
powders, etc.), preservative (e.g., sodium benzoate, sodium
bisulfite, methylparaben, propylparaben, etc.), stabilizer (e.g.,
citric acid, sodium citrate, acetic acid, etc.), suspending agent
(e.g., methyl cellulose, polyvinylpyrrolidone, aluminum stearate,
etc.), dispersing agent, aqueous diluting agent (e.g., water), base
wax (e.g., cacao butter, polyethyleneglycol, white petrolatum,
etc.).
[0335] The effective ingredient may usually be administered with a
unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However,
the above dosage may be increased or decreased according to age,
weight, conditions of the patient or the administering method.
[0336] The following Preparations and Examples are given only for
the purpose of illustrating the present invention in more
detail.
[0337] Preparation 1-1
[0338] To a suspension of magnesium turnings (7.53 g) in dry ether
(100 ml) was added dropwise a solution of isopropyl bromide (36.87
g) in dry ether (5 ml) at reflux temperature for 1 hour. The
mixture was heated at the same temperature for 1 hour and then
allowed to cool to 5.about.10.degree. C. in an ice bath. To the
mixture was added dropwise a solution of 2-aminobenzonitrile (11.81
g) in dry tetrahydrofuran (100 ml) at the same temperature for 1
hour. The mixture was stirred additionally 1 hour and then heated
under reflux for 3 hours. The reaction mixture was allowed to cool
to 5.about.10.degree. C. in an ice bath. A 3N aqueous hydrochloric
acid was added dropwise to the mixture for 1 hour and then heated
under reflux for 3 hours. The resultant mixture was concentrated in
vacuo to remove the organic solvent. The residue was extracted with
chloroform (2.times.300 ml). The extracts were combined and washed
with a brine (2.times.100 ml). Dryness over magnesium sulfate and
evaporation gave a crude product. The product was purified by
column chromatography on silica gel with chloroform. The fractions
containing the desired product were combined and evaporated in
vacuo to afford a pure 2-isopropylcarbonylaniline (15.35 g) as a
colorless oil. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.20 (6H, d,
J=6.8 Hz), 3.56-3.60 (1H, m), 6.30 (2H, br), 6.63-6.67 (2H, m),
7.22-7.27 (1H, m) 7.77 (1H, d, J=12 Hz)
[0339] Preparation 1-2
[0340] The following compound was prepared according to the method
of katrisky [J. Org, Chem, 55, 2206 (1990)] in 84.6% yield.
[0341] 2-(1-benzotriazolyl)-2-benzyloxycarbonylaminoacetic acid
[0342] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 5.01-5.13 (3H, m),
7.20-7.60 (7H, m), 8.00 (1H, d, J=8.0 Hz), 8.08 (1H, d, J=8.8 Hz),
9.39 (1H, d, J=8.8 Hz)
[0343] Preparation 1-3
[0344] To a suspension of 2-isopropylcarbonyl aniline (15.26 g) and
2-(1-benzotriazolyl)-2-benzyloxycarbonylamino acetic acid (30.70 g)
in dry methylene chloride (200 ml) was added dropwise a solution of
dicyclohexyl carbodiimide (23.23 g) in dry methylene chloride (160
ml) at 20.about.25.degree. C. for 1 hour. The mixture was stirred
at the same temperature for 1 hour. The resultant mixture was
filtered by suction to remove an insoluble material. The filtrate
was concentrated in vacuo and the residue was recrystallized from
ethyl acetate and isopropyl ether to give 2-isopropylcarbonyl
N-{2-(1-benzotriazolyl)-2-benzyloxycarbonylamino- }- acetylaniline
(40.5 g) as a pale yellow powder.
[0345] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.05 (6H, d, J=8.8 Hz),
3.60-3.70 (1H, m), 5.63 (2H, d, J=12.8 Hz), 5.23 (1H, d, J=12.8
Hz), 7.27-7.66 (9H, m), 7.97-8.11 (3H, m), 8.37 (1H, d, J=8.4 Hz),
9.65 (1H, d, J=8.0 Hz), 12.08 (1H, s)
[0346] Preparation 1-4
[0347] A suspension of
2-isopropylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzy-
loxycarbonylamino}acetylaniline (40.5 g) in methanol (150 ml) was
treated with a saturated solution of ammonia in methanol (150 ml)
at 0.about.5.degree. C. in an ice bath for 1 hour and then at room
temperature for 1 hour. The mixture was concentrated. The residue
was treated with a 10% solution of ammonium acetate in acetic acid
(300 ml) at room temperature for 2 hours. The resultant mixture was
evaporated in vacuo and the residue was partitioned between ethyl
acetate (100 ml) and IN aqueous sodium hydroxide (1 OOml). The
organic layer was washed with a saturated sodium hydrogen carbonate
(100 ml) and a brine (100 ml). Dryness over magnesium sulfate and
evaporation afforded a crude product. The crude product was
recrystallized from ethyl acetate and isopropyl ether to give
(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1-
,4-benzodiazepin-2-one (26.88 g).
[0348] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.92 (3H, d, J=6.8 Hz),
1.28 (3H, d, J=6.8 Hz), 3.07-3.17 (1H, m), 5.12 (2H, s), 5.17 (1H,
d, J=8.4 Hz), 6.46(1H, d, J=8.4 Hz), 7.11 (1H, d, J=8.4 Hz),
7.22-7.40 (6H, m), 7.46 (1H, t, J=7.2 Hz), 7.59 (1H, d, J=7.6 Hz),
9.13 (1H, s)
[0349] Preparation 1-5
[0350] To a suspension of sodium hydride (0.123 g of a 65%
dispersion in mineral oil) in dry N, N-dimethylformamide (lOmI) was
added dropwise a solution of
(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-
-benzodiazepin-2-one (1.00 g) in dry N, N-dimethylformamide (5 ml)
under cooling in an ice-bath. The mixture was stirred at the same
temperature for 1 hour and then at room temperature for 1 hour. To
the mixture was added dropwise a solution of
N-bromomethylcarbonyl-3-azabicyclo[3.2.2]non- ane (0.77 g) in dry
N, N-dimethylformamide (5 ml) and stirred at the same condition for
2 hours. The reaction mixture was concentrated in vacuo and the
residue was taken up with ethyl acetate (100 ml) and a saturated
aqueous sodium hydrogen carbonate (100 ml). The organic layer was
washed with a brine (50 ml) and dried over anhydrous magnesium
sulfate. Filtration and evaporation gave
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)car-
bonylmethyl]-3-benzyloxy-carbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benz-
odiazepin-2-one.
[0351] .sup.1H-NMR (CDCl.sub.3, .delta.) 0.98 (3H, d, J=7.2 Hz),
1.00-1.40 (2H, m), 1.31 (3H, d, J=7.2 Hz), 1.60-1.80 (6H, m),
2.04-2.16 (2H, m), 3.10-3.22 (1H, m), 3.44-3.86 (4H, m), 4.34 (1H,
d, J=17.2 Hz), 4.94 (1H, d, J=17.2 Hz), 5.04-5.20 (2H, m), 5.10
(1H, d, J=8.0 Hz), 6.60 (1H, d, J=8.0 Hz), 7.20-7.60 (9H, m)
[0352] Preparation 1-6
[0353] Pd-C (5 wt %, 0.10 g) was added to a suspension of
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonyl-
amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.718 g)
in methanol (20 ml) and then anmonium formate (0.351 g) at room
temperature. The mixture was stirred at the same condition for 4
hours and filtered on Celite.RTM. to remove the catalyst. The
filtrate was concentrated in vacuo and the residue was taken up
with ethyl acetate (100 ml) and a saturated aqueous sodium hydrogen
carbonate (50 ml). The organic layer was washed with a brine (50
ml) and dried over anhydrous sodium sulfate. Filtration and
evaporation gave (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non--
3-yl)carbonylmethyl]-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one
(0.39 g) which was used in a following reaction step without
further purification.
[0354] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.97 (3H, d, J=7.2 Hz),
1.30-1.40 (2H, m), 1.31 (3H, d, J=7.2 Hz), 1.60-1.80 (6H, m),
2.00-2.20 (4H, m), 3.07-3.16 (1H, m), 3.47-3.89 (4H, m), 4.24 (AH,
d, J=16.4 Hz), 4.42 (1H, s), 5.00 (1H, d, J=16.4 Hz), 7.20-7.53
(4H, m)
[0355] Preparation 2-1
[0356] To a suspension of Pd-C (5 wt %, 1.60 g) in methanol (60 ml)
was added dropwise a solution of
(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-
-isopropyl-1H-1,4-benzodiazepin-2-one (8.00 g) in methanol (60 ml)
and then ammonium formate (5.56 g) at room temperature. The
reaction mixture was stirred at the same temperature for 1 hour.
The catalyst was filtered on Celite.RTM.. The filtrate was
concentrated in vacuo. The residue was taken up with ethyl acetate
(100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml).
The organic layer was washed with a brine (100 ml). Dryness over
sodium sulfate and evaporation gave
(3RS)-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one
(4.21 g). The product was used in a following reaction step without
further purification.
[0357] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.79 (3H, d, J=7.2 Hz),
1.20 (3H, d, J=7.2 Hz), 3.16-3.24 (1H, m), 3.20-3.50 (2H, br), 4.02
(1H, s), 7.14 (1H, d, J=8.0 Hz), 7.19 (1H, t, J=7.2 Hz), 7.48 (1H,
t, J=7.2 Hz), 7.69 (1H, d, J=7.2 Hz), 10.44 (1H, s)
[0358] Preparation 2-2
[0359] To a solution of
(3RS)-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzo- diazcpin-2-one
(3.98 g) in N, N-dimethylformamide (100 ml) was added
4-dimethylaminopyridine (0.20 g) and then dropwise a solution of
di-tert-butyl dicarbonate (4.09 g) in N,N-dimethylformamide (20 ml)
at room temperature. The mixture was stirred at ambient temperature
overnight and concentrated in vacuo to dryness. The residue was
taken up with ethyl acetate (100 ml) and 1N aqueous hydrochloric
acid (100 ml). The aqueous layer was separated, basified with
sodium hydrogen carbonate and extracted with ethyl acetate
(2.times.100 ml). The extracts were combined, dried over sodium
sulfate and evaporated in vacuo to afford
(3RS)-3-tert-butoxycarbonylamino-+B2,3-dihydro-5-isopropyl-1H-1,4-benzodi-
azepin-2-one (4.05 g). The product was used in a following reaction
step without further purification.
[0360] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.93 (3H, d, J=6.8 Hz),
1.30 (3H, d, J=6.8 Hz), 1.45 (9H, s), 3.12-3.19 (1H, m), 5.15 (1H,
d, J-8.4 Hz), 6.22 (1H, d, J=8.4 Hz), 7.12 (1H, d, J=8.0 Hz), 7.23
(1H, t, J=8.0 Hz), 7.46 (1H, t, J=8.0 Hz), 7.58 (1H, d, J=8.0 Hz),
8.97 (1H, br)
[0361] Preparation 2-3
[0362] To a suspension of sodium hydride (0.065 g of a 65%
dispersion in mineral oil) in dry N, N-dimethylformamide (Smi) was
added dropwise a solution of
(3RS)-3-tert-buloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1-
,4-benzodiazepin-2-one (0.508 g) in dry N, N-dimethylformamide (5
ml) under cooling in an ice-bath. The mixture was stirred under the
same condition for 30 minutes and then at ambient temperature for 2
hours. To the mixture was added dropwise a solution of
2-acetyl-3-bromomethylthioph- ene (0.420 g) in dry N,
N-dimethylformamide under cooling in an ice-bath. After completion
of the addition, the mixture was stirred under the same condition
for 30 minutes and then at ambient temperature overnight. The
resultant mixture was concentrated in vacuo. The residue was
treated with ethyl acetate (100 ml), washed with water (50 ml) and
dried over anhydrous sodium sulfate. Filtration and evaporation
gave a crude product. The product was purified by column
chromatography on silica gel with an eluent of a mixture of
chloroform and ethyl acetate (10:1) to give
(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-
-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.380 g).
[0363] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.86 (3H, d, J=6.0 Hz),
1.28 (3H, d, J=6.0 Hz), 1.46 (9H, s), 3.10-3.20 (1H, m), 5.22 (1H,
d, J=9.6 Hz), 5.33 (1H, d, J=17.2 Hz), 5.66 (1H, d, J=17.2 Hz),
6.31 (1H, d, J=8.8 Hz), 6.93 (1H, d, J=4.8 Hz), 7.20-7.30 (3H, m),
7.37-7.43 (2H, m), 7.50 (1H, d, J=8.0 Hz)
[0364] Preparation 2-4
[0365] A solution of
(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxyca-
rbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one
(0.370 g) in ethyl acetate (50 ml) was treated with gaseous
hydrogen chloride at 5-10.degree. C. in an ice-bath for 30 minutes.
The resultant mixture was extracted with 3N aqueous hydrochloric
acid (2.times.10 ml). The aqueous layer was basified with sodium
hydrogen carbonate and extracted with ethyl acetate (2.times.50
ml). The extracts were combined, over sodium sulfate, filtered and
concentrated in vacuo to afford
(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-amino-2,3-dihydro-5-isopropyl-1H--
1,4-benzodiazepin-2-one (0.230 g), which was used in a following
reaction step without further purification.
[0366] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.88 (3H, d, J=6.8 Hz),
1.29 (3H, d, J=6.8 Hz), 2.50 (3H, s), 3.08-3.18 (1H, m), 3.25 (1H,
br), 4.43 (1H, s), 5.37 (1H, d, J=17.2 Hz), 5.67 (1H, d, J=17.2
Hz), 6.92 (1H, d, J=5.2 Hz), 7.20-7.50 (6H, m)
[0367] Preparation 3
[0368] To a solution of
(3RS)-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzo- diazepin-2-one
(0.536 g) in methylene chloride (30 ml) was added dropwise a
solution of 3-methylphenyl isocyanate (0.361 g) in methylene
chloride (5 ml) at room temperature for 10 minutes. The mixture was
stirred at the same condition for 2 hours. The resultant
precipitate was collected by suction to afford
N-[(3RS)-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiaz-
epin-3-yl]-N'-(.sup.3-methylphenyl)urea (0.600 g). The filtrate was
concentrated in vacuo and the residue was treated with isopropyl
cther to give the second crop of the desired compound (0.170
g).
[0369] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.81 (3H, d, J=6.8 Hz),
1.18 (3H, d, J=6.8 Hz), 2.23 (3H, s), 3.20-3.30 (1H, m), 4.49 (1H,
d, J=8.0 Hz), 6.72 (1H, d, J=8.0 Hz), 7.06-7.22 (6H, m), 7.55 (1H,
t, J=7.2 Hz), 7.77 (1H, d, J=7.2 Hz), 8.88 (1H, s), 10.69 (1H,
s)
[0370] Preparation 4
[0371] To a solution of 3-aminoacetophenone (2.049 g) and pyridine
(1.286 g) in tetrahydrofuran (35 ml) was added dropwise a solution
of 4-nitrophenylchloroformate (3.288 g) in tetrahydrofuran (10 ml)
under cooling in an ice bath. After completion of the addition, the
mixture was allowed to stand to ambient temperature and stirred
over night. Water was added to the mixture. The resultant
precipitate was collected by suction filtration, washed with water
and dried in vacuo at 80.degree. C. to afford 4-nitrophenyl
N-(3-acetylphenyl)carbamate (3.31 g).
[0372] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.57 (3H, s), 7.50-7.59
(3H, m), 7.71 (1H, d, J=8.0 Hz), 7.76 (1H, d, J=8.0 Hz), 8.13 (1H,
s), 8.32 (2H, d, J=9.0 Hz), 10.67 (1H, s)
[0373] Preparation 5
[0374] The following compound was prepared in a similar manner to
that of preparation 4.
[0375] 4-nitrophenyl N-{3-(tetrazol-5-yl)phenyl}carbamate
[0376] Preparation 6-1
[0377] The following compound was prepared in a similar manner to
that of Preparation 1-1.
[0378] 2-(2-methyl)propylcarbonylaniline
[0379] .sup.1H-NMR (CDCl.sub.3, .delta.) 0.93 (6H, q, J=8 Hz),
2.04-2.12 (1H, m), 2.93 (2H, d, J=8 Hz), 6.26 (2H, br), 6.60 (2H,
d, J=8 Hz), 7.24 (1H, t, J=8 Hz), 7.74 (1H, d, J=8 Hz)
[0380] Preparation 6-2
[0381] The following compound was prepared in a similar manner to
that of Preparation 1-3.
[0382]
2-(2-methyl)propylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzyloxylcarb-
onylamino} acetylaniline
[0383] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.83 (6H, q, J=8 Hz),
2.02-2.10 (1H, m), 2.70 (2H, d, J=8 Hz), 5.04-5.14 (3H, m), 6.95
(1H, br), 7.13-7.45 (9H, m), 7.84 (2H, d, J=8 Hz), 8.08 (1H, d, J=8
Hz), 8.62 (1H, d, J=8 Hz). 12.40 (1H, br)
[0384] Preparation 6-3
[0385] A solution of
2-(2-methyl)propylcarbonyl-N-{2-(1-benzotriazolyl)-2--
benzloxycarbonylamino}acetylaniline (31.7 g) in methanol (100 ml)
was treated with a saturated solution of ammonia in methanol (200
ml) at 0.degree. C. in a dry ice-acetone bath for 1 hour and then
stirred overnight at ambient temperature. The resultant mixture was
concentrated and the residue was treated with a 0.5N aqueous sodium
hydroxide and chloroform. The organic layer was dried over sodium
sulfate, filtered and concentrated in vacuo to give a crude
compound. The crude compound was purified by a column
chromatography on silica gel with a mixture of chloroform and ethyl
acetate to give (3RS)-3-benzyloxycarbonylamino-2,3-d-
ihydro-5-(2-methylpropyl)-1H-1,4-benzodiazepin-2-one as a colorless
powder.
[0386] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.71 (3H, d, J=8 Hz),
0.83 (3H, d, J=8 Hz), 1.21-1.76 (1H, m), 2.45 (1H, dd, J=16 Hz,
J=16 Hz), 2.85 (1H, dd, J=8 Hz, J=16 Hz), 5.07-5.21 (3H, m), 6.68
(1H, d, J=8 Hz), 7.14-7.53 (9H, m), 7.87 (1H, d, J=8 Hz)
[0387] Preparation 6-4
[0388] The following compound was prepared in a similar manner to
that of Preparation 2-1.
[0389] (3RS)-3-amino-2, 3-dihydro-5-(2-methylpropyl)-1H-1,
4-benzodiazepin-2-one
[0390] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.76 (3H, d, J=8 Hz),
0.84 (3H, d, J=8 Hz), 1.74-1.83 (1H, m), 2.20 (2H, br), 2.46 (1H,
dd, J=16 Hz, J=16 Hz), 2.85 (1H, dd, J=8 Hz, J=16 Hz), 4.32 (1H,
s), 7.14 (1H, d, J=8 Hz), 7.24 (1H, t, J=8 Hz), 7.46 (1H, d, J=8
Hz), 7.56 (1H, d, J=8 Hz), 9.04 (1H, s)
[0391] Preparation 6-5
[0392] The following compound was prepared in a similar manner to
that of Preparation 3.
[0393]
N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-2-oxo-1H-1,4-benzodiazepin--
3-yl]-N '-(3-met hylphenyl)urea
[0394] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.68 (3H, d, J=8 Hz),
0.84 (3H, d, J=8 Hz), 1.66-1.70 (1H, m), 2.23 (3H, s), 2.34 (1H,
dd, J=16 Hz, J=16 Hz), 2.94 (1H, dd, J=8 Hz, J=16 Hz), 4.99 (1H, d,
J=14 Hz), 6.72 (1H, d, J=8 Hz), 7.07-7.30 (7H, m), 7.55 (1H, t, J=8
Hz), 7.76 (1H, d, J=14 Hz), 8.85 (1H, s)
[0395] Preparation 7-1
[0396] The following compound was prepared in a similar manner to
that of Preparation 2-2.
[0397] (3RS)-3-tert-butoxycarbonylamino-2,
3-dihydro-5-(2-methylpropyl)-1H- -1,4-benzodiazepin-2-one
[0398] .sup.1H-NMR (CDC.sub.3, .delta.): 0.72 (3H, d, J=8 Hz), 0.86
(3H, d, J=8 Hz), 1.45 (9H, s), 1.78-1.82 (1H, m), 2.64 (1H, d, J=16
Hz), 2.88 (1H, d, J=8 Hz, 16 Hz), 5.14 (1H, d, J=8 Hz), 6.35 (1H,
d, J=8 Hz), 7.21-7.57 (4H, m), 9.71 (1H, s)
[0399] Preparation 7-2
[0400] The following compound was prepared in a similar manner to
that of Preparation 2-3.
[0401]
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxy-
carbonylamino-2,3-dihydro-5-(2-methylpropyl)-1H-1,4-benzodiazepin-2-one
[0402] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.76 (3H, d, J=8 Hz),
0.88 (3H, d, J=8 Hz), 1.42 (9H, s), 1.61-1.88 (9H, m), 2.10 (2H,
br), 2.48 (1H, dd, J=16 Hz, J=16 Hz), 2.89 (1H, dd, J=8 Hz, J=16
Hz), 3.44-3.96 (4H, m). 4.14 (1H, d, J=18 Hz), 5.02 (1H, d, J=18
Hz), 5.25 (1H, d, J=8 Hz), 6.43 (1H, d, J=8 Hz), 7.24-7.54 (4H,
m)
[0403] Preparation 7-3
[0404] The following compound was prepared in a similar manner to
that of Preparation 2-4.
[0405]
(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-d-
ihydro-5-(2-methylpropyl)-1H-1, 4-benzodiazepin-2-one
[0406] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.77 (3H, d, J=8 Hz),
0.88 (3H, d, J=8 Hz), 1.70-2.11 (13H, m), 2.50 (1H, dd, J=16 Hz,
J=16 Hz), 2.88 (1H, dd, J=8 Hz, J=16 Hz), 3.46-3.92 (4H, m). 4.10
(1H, d, J=18 Hz), 4.43 (1H, s), 5.06 (1H, d, J=18 Hz), 7.21-7.51
(4H, m)
[0407] Preparation 8-1
[0408] The following compound was prepared in a similar manner to
that of Preparation 1-3.
[0409]
2-methylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzyloxycarbonylamino}
acetylaniline
[0410] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.53 (3H, s), 5.04-5.26
(3H, m), 7.07-7.52 (10H, m), 7.78-7.87 (2H, m), 8.05 (1H, d, J=8
Hz), 8.62 (1H, d, J=8 Hz), 12.36 (1H, s)
[0411] Preparation 8-2
[0412] The following compound was prepared in a similar manner to
that of Preparation 6-3.
[0413]
(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-methyl-1H-1,4-benzodia-
zepin-2-one
[0414] .sup.1H-NMR (CDC.sub.3, .delta.): 2.42 (3H, s), 5.05-5.15
(3H, m), 6.82 (1H, d, J=8 Hz), 7.08 (1H, d, J=8 Hz), 7.08-7.34 (7H,
m), 7.52 (1H, d, J=8 Hz), 10.13 (1H, s)
[0415] Preparation 8-3
[0416] The following compound was prepared in a similar manner to
that of Preparation 2-1.
[0417]
(3RS)-3-amino-2,3-dihydro-5-methyl-1H-1,4-benzodiazepin-2-one
[0418] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.35-2.64 (2H, br), 2.45
(3H, s), 4.32 (1H, s), 7.18 (1H, d, J=8 Hz), 7.21 (1H, t, 3=8 Hz),
7.45 (1H, t, J=8 Hz), 7.58 (1H, d, J=8 Hz), 9.60 (1H, br)
[0419] Preparation 8-4
[0420] The following compound was prepared in a similar manner to
that of Preparation 3.
[0421]
N-[(3RS)-2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(-
3-methylphenyl)urea
[0422] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.23 (3H, s), 2.40 (3H,
s), 4.95 (1H, d, J=8 Hz), 6.72 (1H, d, J=8 Hz), 7.08-7.31 (6H, m),
7.56 (1H, t, J=8 Hz), 7.78 (1H, d, J=8 Hz), 8.88 (1H, s), 10.77
(1H, s)
[0423] Preparation 9-1
[0424] The following compound was prepared in a similar manner to
that of Preparation 1-1.
[0425] 2-(3-methyl)butylcarbonylaniline
[0426] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.94 (6H, q, J=8 Hz),
1.62 (2H, q, J=8 Hz), 2.06-2.10 (1H, m), 2.93 (2H, t, J=8 Hz), 6.26
(2H, br), 6.63 (2H, d, J=8 Hz), 7.24 (1H, t, J=8 Hz), 7.74 (1H, d,
J=8 Hz)
[0427] Preparation 9-2
[0428] The following compound was prepared in a similar manner to
that of Preparation 1-3.
[0429]
2-(3-methyl)butylcarbonyl-N-[2-(1-benzotriazolyl)-2-benzyloxylcarbo-
nylamino]acetylaniline
[0430] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.88 (6H, q, J=8 Hz),
1.44 (2H, q, J=8 Hz), 1.80-1.84 (1H, m), 2.40 (2H, t, J=8 Hz),
5.05-5.28 (3H, m), 6.97 (1H, br), 7.26-7.57 (9H, m), 7.85 (2H, d,
J=8 Hz), 8.08 (1H, d, J=8 Hz), 8.63 (1H, d, J=8 Hz), 12.40 (1H,
br)
[0431] Preparation 9-3
[0432] The following compound was prepared in a similar manner to
that of Preparation 6-3.
[0433]
(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(3-methylbutyl)-1H-1,4-
-benzodiazepin-2-one
[0434] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.83-0.86 (6H, m),
1.29-1.53 (3H, m), 2.74-2.79 (2H, m), 4.69 (1H, s), 5.08-5.17 (3H,
m), 6.52 (1H, d, J=8 Hz), 7.09 (1H, d, J=8 Hz), 7.23-7.36 (SH, m),
7.44 (1H, t, J=8 Hz), 7.57 (1H, d, J=8 Hz), 9.26 (1H, s)
[0435] Preparation 9-4
[0436] The following compound was prepared in a similar manner to
that of Preparation 2-1.
[0437]
(3RS)-3-amino-2,3-dihydro-5-(3-methylbutyl)-1H-1,4-benzodiazepin-2--
one
[0438] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.83 (3H, dd, J=3.5 Hz,
J=4.9 Hz), 0.88 (3H, dd, J=1.4 Hz, J=2.8 Hz), 1.30-1.42 (1H, m),
1.45-1.60 (2H, m), 2.72-2.76 (2H, m), 3.40-3.78 (2H, br), 4.23 (1H,
s), 7.02-7.75 (4H, m), 9.70 (1H, br)
[0439] Preparation 9-5
[0440] The following compound was prepared in a similar manner to
that of Preparation 3.
[0441]
N-[(3RS)-2,3-dihydro-5-(3-methylbutyl)-2-oxo-1H-1,4-benzodiazepin-3-
-yl]-N'-(3-methylphenyl)urea
[0442] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.73 (6H, t, J=8 Hz),
1.15-1.40 (3H, m), 2.25 (3H, s), 2.6-2.72 (2H, m), 5.35 (1H, d,
J=16 Hz), 6.78 (1H, d, J=8 Hz), 7.07-7.32 (7H, m), 7.50 (1H, d, J=8
Hz), 7.78 (1H, d, J=14 Hz), 8.80 (1H, br)
[0443] Preparation 10-1
[0444] The following compound was prepared in a similar manner to
that of Preparation 1-1.
[0445] 2-ethylcarbonylaniline
[0446] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.20 (3H, t, J=7.0 Hz),
2.97 (2H, q, J=7.0 Hz), 6.27 (2H, br), 6.62-6.66 (2H, m), 7.22-7.27
(1H, m), 7.75 (11H, d, J=8 Hz)
[0447] Preparation 10-2
[0448] The following, compound was prepared in a similar manner to
that of Preparation 1-3.
[0449]
2-ethylcarbonyl-N-12-(1-benzoiriazolyl)-2-benzyloxvcarbonylamino }
acetylaniline
[0450] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.06 (3H, t, J=7.0 Hz),
2.94 (2H, q, J=7.0 Hz), 5.06-5.25 (3H, m), 6.96 (1H, br), 7.14-7.42
(7H, m), 7.52-7.56 (2H, m), 7.86-7.88 (2H, m), 8.93 (1H, d, J=8.0
Hz), 8.63 (1H, d, J=8.0 Hz), 12.45 (1H, s)
[0451] Preparation 10-3
[0452] The following compound was prepared in a similar manner to
that of Preparation 6-3.
[0453]
(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-1H-1,4-benzodiaz-
epin-2-one
[0454] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.08 (3H, t, J=7.0 Hz),
2.74-2.86 (2H, m), 5.08-5.16 (2H, m), 5.18 (1H, d, J=8.0 Hz), 6.52
(1H, d, J=8.0 Hz), 7.12 (1H, d, J=8.0 Hz), 7.23-7.38 (6H, m), 7.47
(1H, t, J=8.0 Hz), 7.58 (1H, d, J=8.0 Hz), 9.27 (1H, s)
[0455] Preparation 10-4
[0456] The following compound was prepared in a similar manner to
that of Preparation 2-1.
[0457]
(3RS)-3-amino-2,3-dihydro-5-ethyl-1H-1,4-benzodiazepin-2-one
[0458] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.10 (3H, t, J=7.0 Hz),
2.00 (2H, br), 2.73-2.83 (2H, m), 4.33 (1H, s), 7.10 (1H, d, J=8.0
Hz), 7.23 (1H, t, J=8.0 Hz), 7.46 (1H, t, J=8.0 Hz), 7.57 (1H, d,
J=8.0 Hz), 8.74 (1H, s)
[0459] Preparation 10-5
[0460] The following compound was prepared in a similar manner to
that of Preparation 3.
[0461]
N-[(3RS)-2,3-dihydro-5-ethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N
'-(3-methylphenyl)urea
[0462] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.99 (3H, t, J=7.0 Hz),
2.23 (3H, s), 2.66-2.72 (1H, m), 2.84-2.88 (1H, m), 5.00 (1H, d,
J=8.0 Hz), 6.72 (1H, d, J=7.0 Hz), 7.07-7.30 (6H, m), 7.55 (1H, d,
J=7.0 Hz), 7.78 (1H, d, J=8.0 Hz), 8.88 (1H, s), 10.73 (1H, s)
[0463] Preparation 11-1
[0464] The following compound was prepared in a similar manner to
that of Preparation 1-1.
[0465] 2-(3-butenyl)carbonylaniline
[0466] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.46-2.50 (2H, m), 3.03
(2H, t, J=7 Hz), 5.01 (1H, d, J=13.0 Hz), 5.09 (1H, d, J=18.8 Hz),
5.86-5.98 (1H, m), 6.26 (2H, br), 6.62-6.66 (2H, m), 7.25 (1H, t,
J=8.4 Hz), 7.75 (1H, d, J=8.0 Hz)
[0467] Preparation 11-2
[0468] The following compound was prepared in a similar manner to
that of Preparation 1-4 and Preparation 1-5.
[0469]
(3RS)-3-benzyloxycarbonylamino-5-(3-butenyl)-2,3-dihydro-1H-1,4-ben-
zodiazepin-2-one
[0470] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.24-2.36 (2H, m), 2.88
(2H, t, J=7.6 Hz), 4.90-5.19 (5H, m), 5.71-5.80 (1H, m), 6.65 (1H,
d, J=8.0 Hz), 7.12 (1H, d, J=7.6 Hz), 7.25-7.36 (6H, m), 7.49 (1H,
t, J=7.6 Hz), 7.59 (1H, d, J=7.6 Hz), 9.17 (1H, br)
[0471] Preparation 11-3
[0472] The following compound was prepared in a similar manner to
that of Preparation 1-6.
[0473]
(3RS)-3-amino-5-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
[0474] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.82 (3H, t, J=7.2 Hz),
1.16-1.20 (2H, m), 1.26-1.40 (2H, m), 2.40 (2H, br), 2.60-2.68 (1H,
m), 2.76-2.81 (1H, m), 3.27 (1H, s), 7.14 (1H, d, J=8.0 Hz), 7.19
(1H, t, J=8.0 Hz), 7.48 (1H, t, J=8.0 Hz), 7.67 (1H, d, J=8.0 Hz),
10.47 (1H, br)
[0475] Preparation 11-4
[0476] The following compound was prepared in a similar manner to
that of Preparation 2-2.
[0477] (3RS)-3-tert-butoxycarbonylamino-5-butyl-2,3-dihydro-1H
1,4-benzodiazepin-2-one
[0478] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.84 (3H, t, J=7.6 Hz),
1.24-1.29 (2H, m), 1.40-1.47 (2H, m), 1.44 (9H, s), 2.73-2.90 (2H,
m), 5.14 (1H, d, J=8.0 Hz), 6.28 (1H, d, J=8.0 Hz), 7.11 (1H, d,
J=8.0 Hz), 7.24 (1H, t, J=8.0 Hz), 7.47 (1H, t, J=8.0 Hz), 7.57
(1H, d, J=8.0 Hz), 8.97 (1H, br)
[0479] Preparation 11-5
[0480] The following compound was prepared in a similar manner to
that of Preparation 2-3.
[0481]
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxy-
carbonylamino-5-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
[0482] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.86 (3H, t, J=7.6 Hz),
1.24-1.31 (2H, m), 1.42 (9H, s), 1.42-1.52 (2H, m), 1.60-1.80 (8H,
m), 2.05-2.15 (2H, m), 2.70-2.90 (2H, m), 3.45-3.90 (4H, m), 4.27
(1H, d, J=16.0 Hz), 4.94 (1H, d, J=16.0 Hz), 5.24 (1H, d, J=8.0
Hz), 6.41 (1H, d, J=8.0 Hz), 7.23-7.54 (4H, m)
[0483] Preparation 11-6
[0484] The following compound was prepared in a similar manner to
that of Preparation 2-4.
[0485]
(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-but-
yl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
[0486] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.86 (3H, t, J=7.6 Hz),
1.24-1.31 (2H, m), 1.44-1.80 (12H, m), 2.00-2.15 (2H, m), 2.70-2.90
(2H, m), 3.40-3.90 (4H, m), 4.26 (1H, d, J=16.0 Hz), 4.40 (1H, s),
4.94 (1H, d, J=16.0 Hz), 7.20-7.60 (4H, m)
[0487] Preparation 12-1
[0488] The following compound was prepared in a similar manner to
that of Preparation 1-1.
[0489] 2-cyclohexylmethylcarbonylaniline
[0490] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.80-1.40 (6H, m),
1.60-1.80 (4H, m), 1.85-2.00 (1H, m), 2.77 (2H, d, J=6.8 Hz), 6.28
(1H, br), 6.62-6.67 (2H, m), 7.23-7.27 (1H, m), 7.73 (1H, d, J=8.4
Hz)
[0491] Preparation 12-2
[0492] The following compound was prepared in a similar manner to
that of Preparation 1-2.
[0493]
2-cyclohexylmethylcarbonyl-N-{2-(1-benzotriazolyl)-2-benzyloxycarbo-
nylamino} acetylaniline
[0494] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.80-1.80 (11H,'m), 2.69
(2H, d, J=6.8 Hz), 5.00-5.30 (3H, m), 6.91 (1H, br), 7.10-7.50 (7H,
m), 7.54 (2H, m), 7.83 (2H, d, J=8.0 Hz), 8.09 (1H, d, 3=8.0 Hz),
8.61 (1H, d, J=8.0 Hz), 12.40 (1H, br)
[0495] Preparation 12-3
[0496] The following compound was prepared in a similar manner to
that of Preparation 6-3.
[0497] (3RS)-3-benzyloxycarbonylamino-5-cyclohexylmethyl-2,
3-dihydro-1H-1,4-benzodiazepin-2-,one
[0498] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.80-1.80 (l1H, m),
2.49-2.55 (1H, m), 2.82-2.88 (1H, m), 5.10-5.20 (3H, m), 6.49 (1H,
d, J=8.0 Hz), 7.08 (1H, d, J=8.0 Hz), 7.30-7.50 (6H, m), 7.46-7.50
(1H, m), 7.58 (1H, d, J=8.0 Hz), 8.33 (1H, s)
[0499] Preparation 12-4
[0500] The following compound was prepared in a similar manner to
that of Preparation 1-5.
[0501]
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxyca-
rbonylamino-5-cyclohexylmethyl-2,3-dihydro-1
H-1,4-benzodiazepin-2-one
[0502] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.80-1.80 (19H, m), 2.10
(2H, br), 2.51-2.57 (1H, m), 2.82-2.88 (1H, m), 3.43-3.48 (1H, m),
3.56-3.60 (1H, m), 3.67-3.72 (1H, m), 3.85-3.89 (1H, m),4.18 (1H,
d, J=16 Hz), 4.97 (1H, d, J=16 Hz), 5.04-5.16 (2H, m), 6.65 (1H, d,
J=8.0 Hz), 7.2-7.6 (9H, m)
[0503] Preparation 12-5
[0504] To a solution of
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmeth-
yl]-3-benzyloxycarbonylamino-5-cyclohexylmethyl-2,3-dihydro-1H-1,4-benzodi-
azepin-2-one (0.396 g) in methanol (15 ml) was added Peariman's
catalyst (0.111 g). The mixture was stirred under H.sub.2
atmosphere over night. The catalyst was filtered off by suction
filtration on Celite.RTM.. The filtrate was concentrated in vacuo
to give (3RS)-3-amino-1-[(3-azalicyclo-
[3.2.2]non-3-yl)carbonylmethyl]-5-cyclohexylmethyl-2,3-dihydro-1H-1,4-benz-
odiazepin-2-one (0.298 g), which was used in a following reaction
step without further purification.
[0505] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.80-1.20 (4H, m),
1.4-1.9 (15H, m), 2.00-2.20 (4H, br), 2.57-2.63 (1H, m), 2.78-2.83
(1H, m), 3.50-3.90 (4H, m), 4.13 (1H, d, J=16H), 4.42 (1H, s), 5.05
(1H, d, J=16 Hz), 7.22-7.30 (2H, m), 7.43-7.51 (2H, m)
[0506] Preparation 13-1
[0507] 2-(2-Fluorobenzoyl)-6-methylaniline was prepared in a
similar manner to that of Preparation 50-1.
[0508] mp: 65.5-67.5.degree. C.
[0509] IR (Nujol, cm.sup.-1): 3470, 3350, 1610, 1580, 1551, 1375,
1320, 1280, 1218, 1088, 1002, 956, 830, 752
[0510] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.20 (3H, s), 6.38 (2H,
br), 6.52 (1H, , J=7.6 Hz), 7.08-7.46 (6H, m) APCI-MS (m/z): 230
(M.sup.++1)
[0511] Preparation 13-2
[0512]
(3RS)-3-Benzyloxycarbonylamino-5-(2-fluorophenyl)-9-methyl-2,3-dihy-
dro-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 45-2.
[0513] mp: 222.5-225.degree. C.
[0514] IR (Nujol, cm.sup.-1): 3200, 1715, 1690, 1608, 1530, 1374,
1051, 860, 750
[0515] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.40 (3H, s), 5.05 (1H,
d, J=8.9 Hz), 5.08 (2H, s), 7.0-7.62 (12H, m), 8.43 (1H, d, J=8.9
Hz), 10.28 (1H, s)
[0516] APCI-MS (m/z): 418 (M.sup.++1)
[0517] Preparation 13-3
[0518]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1-(2--
methoxylphenacyl)-9-methyl-1H-1,4-benzodiazepin-2-one was prepared
in a similar manner to that of Preparation 59-3.
[0519] IR (Nujol, cm.sup.-1) 1710, 1660
[0520] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.46 (3H, s), 3.94 (3H,
s), 4.60 (1H, d, 18.1 Hz), 5.06 (2H, br, s), 5.24 (1H, d, J=8.6
Hz), 5.44 (1H, d, J=18.1 Hz), 6.9-7.8 (15H, m), 8.4-8.6 (1H, m)
[0521] Mass (APCI): 566 (M.sup.++1)
[0522] Preparation 13-4
[0523]
(3RS)-3-Amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methoxyp-
henacyl)-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-6.
[0524] IR (Nujol, cm.sup.-1): 1675
[0525] .sup.1H-NMR(CDCl.sub.3, .delta.): 2.45 (3H, s), 3.93 (3H,
s), 4.59 (7H, d, J=18.0 Hz), 4.65 (1H, d, J=7.6 Hz), 5.52 (1H, d,
J=18.0 Hz), 6.9-7.5 (9H, m), 7.7-8.0 (2H, m)
[0526] Mass (APCI): 432 (M.sup.++1)
[0527] Preparation 14
[0528] To a solution of
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmeth-
yl]-3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-b-
enzodiazepin-2-one (1.9 g) in ethanol (40 ml) was added 1N-sodium
hydroxide solution (7 ml) under stirring at ambient temperature.
The mixture was stirred for 20 minutes under the same conditions.
After removal of the solvent water was added into the mixture,
which was adjusted to pH 4 with a diluted hydrochloric acid and
extracted with ethyl acetate twice. The combined extract was washed
with water and dried over magnesium sulfate. Removal of the solvent
gave
(3RS)-1-[(3-azabicyclo[3.2.2)non-3-yl)carbonylmethyl]-3-benzyloxycarbonyl-
amino-5-hydroxymethyl-9-methyl-2,3-dihydro-1
H-1,4-benzodiazepin-2-one as an amorphous mass (1.68 g, 95.3%).
[0529] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.4-1.75 (8H, m), 1.9-2.1
(2H, m), 2.36 (3H, s), 3.19-3.34 (2H, m), 3.55-3.89 (2H, m), 4.51
(2H, dd, J=15.8 Hz, 298.4 Hz), 4.75 (2H, dd, J=14.7 Hz, J=27.6 Hz),
5.10 (2H, s), 5.41 (1H, d, J=8.8 Hz), 6.54 (1H, d, J=8.8 Hz),
7.25-7.47 (8H, m)
[0530] APCI-MS (m/z): 519 (M.sup.++1)
Preparation 15-1
[0531]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-met-
hyl-1-(2-nitrophenacyl)-1H-1,4-benzodiazepin-2-one was prepared in
a similar manner to that of Preparation 59-3.
[0532] IR (Nujol, cm.sup.-1) 1710, 1675
[0533] .sup.1H-NMR (DMSO-d,(5): 2.43 (3H, s), 4.66 (1H, d, J=18.1
Hz), 5.06 (2H, m), 5.26 (1H, d, J=9.1 Hz), 5.45 (1H, d, J=18.0 Hz),
7.07 (1H, d, J=7.7 Hz), 7.2-8.0 (14H, m), 8.0-8.2 (1H, m), 8.4-8.6
(1H, m)
[0534] Mass (APCI): 581 (M.sup.++1)
[0535] Preparation 15-2
[0536]
(3RS)-3-Amino-1-(2-aminophenacyl)-2,3-dihydro-5-(2-fluorophenyl)-9--
methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar manner
to that of Preparation 59-6.
[0537] mp: 139.7-147.0.degree. C.
[0538] IR (Nujol, cm.sup.-1): 1680, 1660
[0539] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.46 (3H, s), 4.10 (1H,
s), 4.49 (1H, d, J=16.8 Hz), 5.74 (1H, d, J=16.8 Hz), 6.0 (2H, m),
6.5-6.7 (2H, m), 7.0-7.3 (7H, m), 7.3-7.6 (2H, m), 7.6-7.7 (1H, m),
7.7-7.9 (1H, m)
[0540] Mass (APCI): 417 (M.sup.++1)
[0541] Preparation 16-1
[0542] 2-Amino-3-methyl-2'-fluorobenzophenone was prepared in a
similar manner to that of Preparation 50-1.
[0543] mp: 52.2-55.2.degree. C.
[0544] IR (Nujol, cm.sup.-1): 3470, 3330. 1620
[0545] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.21 (3H, s), 6.6-6.8
(3H, m), 7.0-7.7 (5H,m)
[0546] Mass (APCI): 230 (M.sup.++1)
[0547] Preparation 16-2
[0548] 2-Bromoacetylamino-3-methyl-2'-fluorobenzophenone was
prepared in a similar manner to that of Preparation 29-2.
[0549] mp: 100.1-103.2.degree. C.
[0550] IR (Nujol, cm.sup.-1) 1660
[0551] .sup.1H-NMR (DMSO-d.sub.6, .delta.):2.26 (3H, s), 3.70 (2H,
s), 7.2-7.4 (4H, m), 7.4-7.8 (3H, m), 9.96 (1H, br, s)
[0552] Mass (APCI): 352 (M.sup.++1), 350 (M.sup.+-1)
[0553] Preparation 16-3
[0554]
5-(2-Fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one--
4-oxide was prepared in a similar manner to that of Preparation
19-3.
[0555] mp: 204.4-205.1.degree. C.
[0556] IR (Nujol, cm.sup.-1): 1690
[0557] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.48 (3H, s), 4.70 (2H,
s), 6.9-7.0 (1H, m), 7.0-7.6 (6H, m), 9.31 (1H, br, s)
[0558] Mass (APCI m/z): 285 (M.sup.++1)
[0559] Preparation 16-4
[0560]
3-Acetoxy-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiaze-
pin-2-one was prepared in a similar manner to that of Preparation
19-4.
[0561] IR (Nujol, cm.sup.-1): 1745
[0562] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.32 (3H, s), 2.44 (3H,
s), 5.97 (1H, s), 7.0-7.2 (3H, m), 7.2-7.3 (1H, m), 7.3-7.5 (2H,
m), 7.6-7.8 (1H, m), 8.62 (1H, br, s)
[0563] Mass (APCI): 327 (M.sup.++1)
[0564] Preparation 16-5
[0565]
(3RS)-3-Phthalimido-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4--
benzodiazepin-2-one was prepared in a similar manner to that of
Preparation 20-5.
[0566] mp: >250.degree. C.
[0567] NMR (CDCl.sub.3, .delta.): 2.44 (3H, s), 5.93 (1H, s),
6.9-8.0 (11H, m)
[0568] Mass (APCI): 414 (M.sup.++1)
[0569] Preparation 16-6
[0570]
(3RS)-3-Amino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzod-
iazepin-2-one was prepared in a similar manner to that of
Preparation 19-6.
[0571] mp: 102.2-112.2.degree. C.
[0572] IR (Nujol, cm.sup.-1): 1685
[0573] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.42 (3H, s), 4.49 (1H,
s), 7.0-7.8 (7H, m), 8.64 (1H, m)
[0574] Mass (APCI): 284 (M.sup.++1)
[0575] Preparation 16-7
[0576]
(3RS)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-methyl-2,3-di-
hydro-1H-1,4-benzodiazepin-2-one was prepared in a similar manner
to that of Preparation 20-7.
[0577] mp: 183.2-186.6.degree. C.
[0578] .sup.1H-NMR (CDC.sub.3, .delta.): 1.48 (9H, s), 2.41 (3H,
s), 5.31 (1H, d, J=8.7 Hz), 6.39 (1H, d, J=8.7 Hz), 7.0-7.2 (3H,
m), 7.2-7.3 (1H, m), 7.3-7.6 (2H, m), 7.6-7.8 (1H, m), 8.26 (1H,
br, s)
[0579] Mass (APCI): 384 (M.sup.++1)
[0580] Preparation 16-8
[0581]
(3RS)-1-Ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluoro-
phenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-3.
[0582] .sup.1H-NMR (CDCl .sub.3, .delta.): 1.46 (9H, s), 2.40 (3H,
s), 3.91(1H, d, J=16.8 Hz), 3.8-4.2 (2H, m), 4.83 (1H, d, J=16.8
Hz), 5.40 (1H, d, J=8.9 Hz), 6.41 (1H, d, J=8.8 Hz), 7.0-7.4 (4H,
m), 7.3-7.6 (2H, m), 7.7-7.9 (1H, m)
[0583] Mass (APCI): 470 (M.sup.++1)
[0584] Preparation 1 6-9
[0585]
(3RS)-1-Carboxymethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-
-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Example 48-2.
[0586] mp: 132.1-149.3.degree. C.
[0587] IR (Nujol, cm.sup.-1): 1700
[0588] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.45 (9H, s), 2.36 (3H,
s), 3.89 (1H, d, J=17.2 Hz), 4.82 (1H, d, J=17.2 Hz), 5.38 (1H, d,
J=8.9 Hz), 6.40 (1H, d, J=8.9 Hz), 6.9-7.8 (7H, m)
[0589] Mass (APCI): 442 (M.sup.++1)
[0590] Preparation 16-10
[0591]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxy-
carbonylamino-5-(2-fluorophenyl)-9-methyl-2.3-dihydro-1H-1,4-benzodiazepin-
-2-one was prepared in a similar manner to that of Preparation
59-5.
[0592] mp: 108.1-113.9.degree. C.
[0593] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.45 (9H, s), 1.3-2.2 (10
H, m), 2.45(3H, s), 3.2-3.9 (4H, m), 4.04 (1H, d, J=15.5 Hz), 5.05
(1H, d, J=15.SHz), 5.42 (1H, d, J=8.9 Hz), 6.40 (1H, d, J=lOHz),
6.9-7.3 (4H, m), 7.3-7.5 (2H, m), 7.7-7.9 (1H, m)
[0594] Mass (APCl): 549 (M.sup.++1)
[0595] Preparation 16-11
[0596]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-(2--
fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 30-2.
[0597] mp: 102.3-113.4.degree. C.
[0598] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.41
(3H, s), 3.0-3.4 (2H, m), 3.6-3.9 (2H, m), 4.06 (1H, d, J=16.2 Hz),
4.36 (1H, s), 5.06 (1H, d, J=16.2 Hz), 6.9-7.0 (1H, m), 7.1-7.4
(3H, m), 7.4-7.6 (2H, m), 7.6-7.8 (1H, m) Mass (APCI): 449
(M.sup.++1)
[0599] Preparation 17-1
[0600] To a solution of o-toluidine (27.98 g) and
cyclohexanecarbonitrile (14.25 g) in toluene (200 ml) was added
dropwise lN-borontrichloride toluene solution (131 ml) under
stirring and cooling in an ice-bath below 5.degree. C. After the
addition was completed, the mixture was stirred at ambient
temperature for 0.5 hour. The mixture was cooled again and aluminum
chloride (17.40 g) was added portionwise. The mixture was gradually
warmed to ambient temperature and then refluxed under stirring for
7.5 hours. The reaction mixture was cooled in an ice-bath and
2N-hydrochloric acid (180 ml) was added dropwise under stirring.
The resultant mixture was refluxed again for 2.5 hours. The
reaction mixture was cooled under stirring and the resultant
precipitate was filtered off. The filtrate and washings with ethyl
acetate were combined and extracted with ethyl acetate. The organic
extract was washed with 1N-hydrochloric acid twice and brine
successively and dried over magnesium sulfate. Removal of the
solvent in vacuo gave an oil, which was subjected to column
chromatography on silica gel eluting with a mixture of n-hexane and
methylene chloride (2:1). The fractions containing the desired
product were combined and evaporated in vacuo to give
2-cyclohexylcarbonyl-6-methylaniline (27.9 g, 98.4% yield) as a
light yellow oil.
[0601] IR (Film, cm.sup.-1) 3470, 3320, 1638, 1608, 1580, 1550,
1424, 1380, 1310, 1240, 1218, 1150, 1004, 980, 891, 740
[0602] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-1.95 (8H, m), 2.16
(3H, s), 3.23-3.36 (1H, m), 6.4 (1H, br), 6.60 (1H, t, J=7.3 Hz),
7.18 (1H, d, J=7.3 Hz), 7.68 (1H, d, J=7.3 Hz)
[0603] APCI-MS (m/z): 218 (M.sup.++1)
[0604] Preparation 17-2
[0605] To a solution of
N-benzyloxycarbonyl-2-(benzotriazol-1-yl)glycine (3.59 g) in dry
tetrahydrofuran (THF, 30 ml) was added oxalyl chloride (1.05 ml) at
0-5.degree. C. under stirring and nitrogen stream. After one drop
of dimethylformamide was added, the mixture was stirred for 2 hours
under the same conditions. To the reaction mixture was added
dropwise a mixture of 2-cyclohexycarbonyl-6-methylaniline (2.17 g)
and N-methylmorpholine (2.23 g) in dry THF for 20 minutes under the
same conditions. The mixture was allowed to warm to ambient
temperature and stirred for 1 hour. THF was removed in vacuo to
afford a residue, which was dissolved in ethyl acetate and washed
with diluted aqueous sodium bicarbonate, water and brine
successively. After drying over magnesium sulfate, the solvent was
removed in vacuo to give an amorphous mass (5.77 g), which was
dissolved in methanol (4 ml). To the solution was added 9M
methanolic ammonia (22 ml) and the mixture was stirred at ambient
temperature overnight. The mixture was evaporated in vacuo to give
a residue, which was dissolved in ethyl acetate and washed with
IN-sodium hydroxide aqueous solution and water. The organic layer
was dried over magnesium sulfate and evaporated in vacuo to give a
residue, which was dissolved in acetic acid (60 ml). Ammonium
acetate (4.0 g) was added to the solution and the mixture was
stirred for 1.5 hour at ambient temperature. Acetic acid was
removed in vacuo to give a residue, which was dissolved in ethyl
acetate and washed with diluted sodium hydroxide aqueous solution
and water successively. After drying over magnesium sulfate, the
solvent was removed in vacuo to give a crystalline mass, which was
pulverized in a mixture of diisopropyl ether and n-hexane and
collected by filtration to give
(3RS)-3-benzyloxycarbonylamino-5-cyclohex-
yl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (2.36 g, 58.3%
yield) as a crystalline powder.
[0606] mp: 171-173.degree. C.
[0607] IR (Nujol, cm.sup.-1) 3490 (sh), 3300, 3200, 1710, 1685,
1620, 1520, 1370, 1056, 987, 793, 749, 696
[0608] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.8-2.0 (8H, m), 2.33
(3H, s), 2.91-1 (1H, br, t), 4.86 (1H, d, J=8.7 Hz), 5.03 (2H, s),
7.16-7.60 (8H, m), 8.11 (1H, d, J=8.7 Hz), 9.96 (1H, s)
[0609] APCI-MS (m/z): 406 (M.sup.++1)
[0610] Preparation 17-3
[0611]
(3RS)-3-1Benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-1,9-dimeth-
yl-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 59-3.
[0612] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.0-2.0 (8H, m), 2.34 (3H,
s), 2.75-2.80 (1H, m), 3.16 (3H, s), 5.01-5.15 (2H, m), 5.18 (1H,
d, J=8.5 Hz), 6.54 (1H, d, J=8.4 Hz), 7.2-7.4 (8H, m)
[0613] Mass (APCI): 420 (M'+1)
[0614] Preparation 17-4
[0615] (3RS)-3-Amino-5-cyclohexyl-2,3-dihydro-1,
9-dimethyl-1H-1,4-benzodi- azepin-2-one was prepared in a similar
manner to that of Preparation 59-6.
[0616] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.8-2.0 (10 H, m), 2.34
(3H, s), 2.7-2.9 (1H, m), 3.16 (3H, s), 4.34 (1H, br, s), 7.1-7.5
(3H, m)
[0617] Mass (APCI): 286 (M.sup.++1)
[0618] Preparation 18-1
[0619]
(3RS)-1-(2-methylphenacyl)-3-tert-butoxycarbonylamino-5-(2-fluoroph-
enyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was prepared
in a similar manner to that of Preparation 59-3.
[0620] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.47 (9H, s), 2.35 (3H,
s), 2.44 (3H, s), 4.36 (1H, d, J=17.2 Hz), 5.49 (1H, d, J=17.2 Hz),
5.51 (1H, d, J=7.3 Hz), 6.42 (1H, d, J=8.9 Hz), 7.0-7.5 (9H, m),
7.5-7.7 (1H, m), 7.8-8.0 (1H, m)
[0621] Mass (APCI): 516 (M.sup.++1)
[0622] Preparation 18-2
[0623]
(3RS)-3-Amino-1-(2-methylphenacyl)-5-(2-fluorophenyl)-9-methyl-2,3--
dihydro-1H-1,4-benzodiazepin-2-one was prepared in a similar manner
to that of Preparation 30-2.
[0624] mp: 198.1-202.6.degree. C.
[0625] IR (Nujol, cm.sup.-1): 1695, 1665
[0626] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.26 (31H, s), 2.44
(3H, s), 4.44 (1H, s), 4.60 (1H, d, J=17.4 Hz), 5.40 (1H, d, J=17.4
Hz), 7.0 (1H, m), 7.2-8.0 (11H, m)
[0627] Mass (APCI) 416 (M.sup.++1)
[0628] Preparation 19-1
[0629] 2-Amino-3-ethyl-2'-fluorobenzophenone was prepared in a
similar manner to that of Preparation 50-1.
[0630] IR (Neat, cm.sup.-1): 1620
[0631] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.30 (3H, t, J=7.5 Hz),
2.55 (2H, q, J=7.5 Hz), 6.5-6.7 (3H, m), 7.0-7.7 (5H, m)
[0632] Mass (APCI): 244 (M.sup.++1)
[0633] Preparation 19-2
[0634] 2-Bromoacetylamino-3-ethyl-2'-fluorobenzophenone was
prepared in a similar manner to that of Preparation 29-2.
[0635] mp: 90.2-91.6.degree. C.
[0636] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.26 (3H, t, J=7.5 Hz),
2.69 (2H, q, J=7.5 Hz), 3.87 (2H, s), 7.0-7.4 (4H, m), 7.4-7.7 (3H,
m), 9.02 (1H, br, s)
[0637] Mass (APCI):366 (M.sup.++2), 364 (M.sup.+)
[0638] Preparation 19-3
[0639] A mixture of
2-bromoacetylamino-3-ethyl-2'-fluorobenzophenone (12.0 g),
hydroxylamine hydrochloride (17.65 g), sodium hydroxide (8.58 g) in
ethanol was stirred at 30-40.degree. C. for 4.5 hours. Concentrated
aqueous hydrochloric acid (14.8 ml) was added to the reaction
mixture, which was stirred at room temperature overnight. The
mixture was evaporated in vacuo to afford precipitates. Water was
added to the resultant mixture. The precipitate was collected by
filtration and washed with water to afford
5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzod-
iazepin-2-one-4-oxide (9.25 g, 94.2%).
[0640] mp: 170.9-176.2.degree. C.
[0641] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.30 (3H, t, J=7.4 Hz),
2.82 (2H, q, J=7.4 Hz), 4.69 (2H, s), 6.8-7.0 (1H, m), 7.0-7.6 (6H,
m), 9.05 (1H, br, s)
[0642] Mass (APCI): 299 (M.sup.++1)
[0643] Preparation 19-4
[0644] A mixture of
9-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodia-
zepin-2-one-4-oxide (9.0 g) and acetic anhydride (32 ml) in
chloroform (32 ml) was stirred at room temperature overnight. The
reaction mixture was evaporated to remove chloroform. Diisopropyl
ether was added to the residue to afford powder, which was
collected by filtration and washed with diisopropyl ether to give
(3RS)-3-acetoxy-5-(2-fluorophenyl)-9-ethyl-
-2,3-dihydro-1H-1,4-benzodiazepin-2-one (6.30 g, 61.3%).
[0645] mp: 225.8-228.1.degree. C.
[0646] IR (Nujol, cm.sup.-1): 1730, 1680
[0647] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.18 (3H, t, J=7.4 Hz),
2.20 (3H, s), 2.6-2.8 (1H, m), 2.8-3.1 (1H, m), 5.67 (1H, s),
7.0-7.8 (7H, m)
[0648] Mass (APCI): 341 (M.sup.++1)
[0649] Preparation 19-5
[0650]
(3RS)-9-Ethyl-3-phthalimido-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-b-
enzodiazepin-2-one was prepared in a similar manner to that of
Preparation 20-5.
[0651] IR (Nujol, cm.sup.-1) 1710, 1670
[0652] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-1.3 (3H, m),
2.6-2.9 (1H, m), 2.9-3.2 (1H, m), 5.67 (1H, s), 7.0-7.1 (1H, m),
7.1-7.5 (3H, m), 7.5-7.8 (3H, m), 7.8-8.1 (4H, m)
[0653] Mass (APCI): 428 (M.sup.++1)
[0654] Preparation 19-6
[0655] A mixture of
(3RS)-3-phthalimido-9-ethyl-5-(2-fluorophenyl)-2,3-dih-
ydro-1H-1,4-benzodiazepin-2-one (6.0 g) and hydrazine hydrate (1.05
g) in a mixture of methanol and tetrahydrofuran (1:1, 60 ml) was
refluxed with stirring for 3 hours. The reaction mixture was
allowed to cool to room temperature, and the resultant precipitates
were filtered off. The filtrate and the washings were combined and
evaporated in vacuo to give a residue, which was dissolved in ethyl
acetate and washed with a saturated aqueous solution of sodium
bicarbonate, water and brine successively. The solvent was dried
over sodium sulfate and evaporated in vacuo to afford a pale yellow
powder, which was washed with diisopropyl ether and collected by
filtration to give
(3RS)-3-amino-9-ethyl-5-(2-fluorophenyl)-2,3-dihydr-
o-1H-1,4-benzodiazepin-2-one (3.37 g, 81.0%).
[0656] mp: 178.2-180.6.degree. C.
[0657] IR (Nujol, cm.sup.-1): 1620
[0658] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.18 (3H, t, J=7.5 Hz),
2.6-3.1 (2H, m), 4.22 (1H, s), 7.0-7.7 (7H, m)
[0659] Mass (APCI) 298 (M.sup.++1)
[0660] Preparation 19-7
[0661]
(3RS)-3-Tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-ethyl-2,3-dih-
ydro-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 20-7.
[0662] mp: 88.1-92.1.degree. C.
[0663] IR (Nujol, cm.sup.-1): 1670, 1720
[0664] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.2-1.4 (3H, m), 1.48 (9H,
s), 2.6-2.9 (2H, m), 5.31 (1H, d, J=8.6 Hz), 6.40 (1H, d, J=8.6
Hz), 7.0-7.4 (4H, m), 7.4-7.6 (2H, m), 7.6-7.8 (1H, m), 8.16 (1H,
br, s)
[0665] Mass (APCI): 398 (M.sup.++1)
[0666] Preparation 19-8
[0667]
(3RS)-1-Ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluoro-
phenyl)-9-ethyl-2,3-dihydro-1 H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-3.
[0668] IR (Nujol, cm.sup.-1): 1750, 1680
[0669] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.33 (3H, t, J=6.0 Hz),
0.99 (3H, t, J=7.1 Hz), 1.46 (3H, s), 2.6-2.8 (2H, m), 3.7-4.1 (3H,
m), 4.88 (1H, d, J=16.6 Hz), 5.39 (1H, d, J=8.8 Hz), 6.42 (1H, d,
J=8.8 Hz), 7.0-7.2 (2H, m), 7.2-7.4 (2H, m), 7.4-7.6 (2H, m),
7.7-7.9 (1H, m)
[0670] Mass (APCI): 484 (M.sup.++1)
[0671] Preparation 19-9
[0672]
(3RS)-1-Carboxymethyl-3-tert-butoxycarbonylamino-5-(2-fluoropheny])-
-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Example 48-2.
[0673] IR (Nujol, cm.sup.-1) 1720, 1680
[0674] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.25 (3H, t, J=7.1 Hz),
1.45 (9H, s), i2.6-2.8 (2H, m), 3.85 (1H, d, J=17.2 Hz), 4.87 (1H,
d, J=17.2 Hz), 5.37 (1H, d, J=8.8 Hz), 6.40 (1H, d, J=8.8 Hz),
7.0-7.9 (7H, m)
[0675] Mass (APCI): 456 (M.sup.++1)
[0676] Preparation 19-10
[0677]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxy-
carbonylamino-5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin--
2-one was prepared in a similar manner to that of Preparation
59-5.
[0678] IR (Nujol, cm.sup.-1): 1720, 1650
[0679] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.34 (3H, t, J=7.5 Hz),
1.45 (9H, s), 1.4-2.2 (10 H, m), 2.7-2.9 (2H, m), 3.2-3.8 (4H, m),
3.96 (1H, d, J=15.5 Hz), 5.01 (1H, d, J=15.5 Hz), 5.41 (1H, br, s),
7.0-7.1 (2H, m), 7.1-7.3 (2H, m), 7.3-7.5 (2H, m), 7.7-7.9 (1H,
m)
[0680] Mass (APCI): 563 (M.sup.++1)
[0681] Preparation 19-11
[0682]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-(2--
fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 30-2.
[0683] mp: 160.4-164.8.degree. C.
[0684] .sup.1H-NMR (DMSO-d.sub.6, .delta.):1.26 (3H, t, J=7.4 Hz),
1.3-2.2 (1OH, m), 2.75 (2H, q, J=7.4 Hz), 3.0-3.4 (2H, m), 3.4-3.9
(2H, m), 3.97 (1H, d, J=16.1 Hz), 4.36 (1H, br, s), 5.13 (1H, d,
J=16.1 Hz), 6.8-7.0 (1H, m), 7.2-7.4 (3H, m), 7.4-7.6 (2H, m),
7.6-7.8 (1H, m)
[0685] Mass (APCI): 160.4-164.8.degree. C.
[0686] Preparation 20-1
[0687] 2-Amino-3-isopropyl-2'-fluorobenzophenone was prepared in a
similar manner to that of Preparation 50-1.
[0688] IR (Neat, cm.sup.-1) 1620
[0689] .sup.1H-NMR (CDCl.sub.31, 6): 1.26 (3H, d, J=6.8 Hz), 1.30
(3H, d, J=6.8 Hz), 2.7-3.1 (1H, m), 3.64 (1H, br), 6.5-7.6 (7H,
m)
[0690] Mass (APCI): 258 (M.sup.++1)
[0691] Preparation 20-2
[0692] 2-Bromoacetylamino-3-isopropyl-2-fluorobenzophenone was
prepared in a similar manner to that of Preparation 29-2.
[0693] mp: 125.8-126.3.degree. C.
[0694] IR (Nujol, cm.sup.-1): 1660
[0695] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.27 (6H, d, J=6.8 Hz),
3.0-3.3 (1H, m), 3.86 (2H, s), 7.0-7.4 (4H, m), 7.4-7.8 (3H, m),
8.86 (1H, s)
[0696] Mass (APCI): 380 (M.sup.++2), 378 (M.sup.+)
[0697] Preparation 20-3
[0698]
5-(2-Fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-o-
ne-4-oxide was prepared in a similar manner to that of Preparation
19-3.
[0699] mp: 205.5-207.7.degree. C.
[0700] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.32 (6H, d, J=6.7 Hz),
3.2-3.4 (1H, m), 4.70 (2H, s), 6.8-7.0 (1H, m), 7.0-7.3 (3H, m),
7.3-7.5 (3H, m), 8.91 (1H, br, s)
[0701] Mass (APCI): 313 (M.sup.++1)
[0702] Preparation 20-4
[0703]
(3RS)-3-acetoxy-5-(2-fluoropheyl)-9-isopropyl-2,3-dihydro-1H-1,4-be-
nzodiazepin-2-onc was prepared in a similar manner to that of
Preparation 19-4.
[0704] mp: 243.2-247.1.degree. C.
[0705] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.12 (3H, d, J=6.7 Hz),
1.31 (1H, d, J=8.0 Hz), 2.20 (3H, s), 3.3-3.6 (1H, m), 5.65 (1H,
s), 7.0-7.1 (1H, m), 7.1-7.5 (3H, m), 7.5-7.7 (3H, m), 10.40 (1H,
br, s)
[0706] Mass (APCI): 355 (M.sup.++1)
[0707] Preparation 20-5
[0708] A mixture of
(3RS)-3-acetoxy-5-(2-fluorophenyl)-9-isopropyl-2,3-dih-
ydro-1H-1,4-benzodiazepin-2-one (2.73g), sodium iodide (11.5 g) and
phthalimide potassium salt (2.14 g) in N,N-dimethylformamide (18ml)
was stirred at 90.degree. C. for 1.3 hours. The hot reaction
mixture was poured into an ice with stirring to afford
precipitates, which were collected by filtration, washed with water
and air dried at room temperature to afford
(3RS)-3-phthalimido-5-(2-fluorophenyl)-9-isopropyl--
2,3-dihydro-1H-1 ,4-benzodiazepin-2-one (3.08 g, 90.6%) as a
crystalline powder.
[0709] mp: 247.6-252.2.degree. C.
[0710] IR (Nujol, cm.sup.-1): 1680
[0711] .sup.1H-NMR (DMSO-d.sub.6, .delta.):1.12 (3H, d, J=6.7 Hz),
1.33 (3H, d, J=6.6 Hz), 3.3-3.7 (1H, m), 5.65 (1H, s), 7.0-7.2 (1H,
m), 7.2-7.5 (3H, m), 7.5-7.8 (3H, m), 7.8-8.1 (4H, m)
[0712] Mass (APCI): 442 (M.sup.++1)
[0713] Preparation 20-6
[0714]
(3RS)-3-Amino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-ben-
zodiazepin-2-one was prepared in a similar manner to that of
Preparation 19-6.
[0715] mp: 192.3-198.6.degree. C.
[0716] IR (Nujol, cm.sup.-1): 1690
[0717] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.11 (3H, d, J=6.7 Hz),
1.29 (1H, d, 3=6.7 Hz), 3.3-3.6 (1H, m), 4.20 (1H, s), 6.9-7.7 (7H,
m)
[0718] Mass (APCI): 312 (M.sup.++1)
[0719] Preparation 20-7
[0720] A mixture of
(3RS)-3-amino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihyd-
ro-1H-1,4-benzodiazepin-2-one (1.5 g), a catalytic amount of
hydroxylamine hydrochloride, trielhylamine (731mg) and
di-tert-butyl dicarbonate (1.57 g) in methylene chloride (30 ml)
was stirred at room temperature for 1.5 hours. Chloroform and water
were added to the reaction mixture. The separated organic layer was
washed with water twice and dried over magnesium sulfate. The
solvent was evaporated in vacuo to afford a crude paste, which was
dissolved in diisopropyl ether, and allowed to stand at room
temperature to afford a pale yellow powder. The powder was
collected by filtration and washed with diisopropyl ether to afford
(3RS)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihyd-
ro-1H-1,4-benzodiazepin-2-one (1.55 g, 78.1%).
[0721] mp: 196.0-199.2.degree. C.
[0722] IR (Nujol, cm.sup.-1):1715, 1665
[0723] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.32 (3H, t, J=6.6 Hz),
1.48 (9H, s), 3.1-3.3 (1H, m), 5.32 (1H, d, J=8.6 Hz), 6.41 (1H, d,
J=8.6 Hz), 7.0-7.4 (4H, m), 7.4-7.6 (2H, m), 7.6-7.8 (1H, m), 8.15
(1H, br, s)
[0724] Mass (APCI): 412 (M.sup.++1)
[0725] Preparation 20-8
[0726]
(3RS)-1-Ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluoro-
phenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-3.
[0727] IR (Nujol, cm.sup.-1) 1750, 1720, 1670
[0728] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.99 (1H, t, J=7.1 Hz),
1.20 (3H, d, J=6.7 Hz), 1.4-1.6 (3H, m), 1.46 (9H, s), 3.7-4.2 (3H,
m), 3.0-3.2 (1H, m), 4.94 (1H, d, J=16.5 Hz), 5.39 (1H, d, J=8.7
Hz), 6.41 (1H, d, 3=8.7 Hz), 7.0-7.2 (2H, m), 7.2-7.4 (2H, m),
7.4-7.6 (2H, m), 7.7-7.9 (1H, m)
[0729] Mass (APCI): 498 (M.sup.++1)
[0730] Preparation 20-9
[0731]
(3RS)-1-Carboxymethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-
-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was prepared in
a similar manner to that of Example 48-2.
[0732] IR (Nujol, cm.sup.-1) 1720, 1690
[0733] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.14 (3H, d, J=7.6 Hz),
1.39 (3H, d, J=6.8 Hz), 1.45 (9H, s), 2.9-3.1 (1H, m), 3.81 (1H, d,
J=17.1 Hz), 4.95 (1H, d, I=17.1 Hz), 5.37 (1H, d, J=8.8 Hz), 6.39
(1H, d, J=8.8 Hz), 7.0-7.6 (6H, m), 7.6-7.8 (1H, m)
[0734] Mass (APCI): 470 (M.sup.++1)
[0735] Preparation 20-10
[0736]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-tert-butoxy-
carbonylamino-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiaze-
pin-2-one was prepared in a similar manner to that of Preparation
59-5.
[0737] IR (Nujol, cm.sup.-1) 1720, 1650
[0738] .sup.1H-NMR (CDCl.sub.3 , .delta.): 1.21 (3H, d, J=6.6 Hz),
1.41 (3H, d, J=6.6 Hz), 1.45 (9H, s), 1.4-2.2 (10H, m), 3.1-3.42
(2H, m), 3.42-3.6 (1H, m), 3.7-3.9 (1H, m), 3.92 (1H, d, J=15.4
Hz), 5.16 (1H, d, J=15.4 Hz), 5.41 (1H, d, J=8.9 Hz), 6.39 (1H, d,
J=8.9 Hz), 7.0-7.2 (2H, m), 7.2-7.35 (2H, m), 7.35-7.6 (2H, m),
7.7-7.9 (1H, m)
[0739] Mass (APCI): 577 (M.sup.++1)
[0740] Preparation 20-11
[0741]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-d-
ihydro-5-(2-fluorophenyl)-9-isopropyl-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 30-2.
[0742] mp: 211.6-214.2.degree. C.
[0743] IR (Nujol, cm.sup.-1): 1080, 1640
[0744] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.10 (3H, d, J=6.6 Hz),
1.38 (1H, d, J=6.6 Hz), 1.4-2.2 (10 H, m), 3.0-3.4 (2H, m), 3.6-3.8
(2H, m), 3.84 (1H, d, J=16.3 Hz), 4.36 (1H, br, s), 5.22 (1H, d,
J=16.3 Hz), 6.8-7.0 (1H, m), 7.2-7.4 (3H, m), 7.4-7.8 (3H, m)
[0745] Mass (APCI): 477 (M'+1)
[0746] Preparation 21-1
[0747]
(3RS)-1-(2-Acetoxyethyl)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3--
dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-3.
[0748] IR (Nujol, cm.sup.-1):1720, 1675, 1610
[0749] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.2-2.2 (10 H, m), 2.32
(3H, s), 2.84 (1H, m), 3.39 (1H, d, I, J=6.0 Hz and J=14.2 Hz),
3.9-4.0 (2H, m), 4.60 (1H, d, t, J=5.4 Hz and J=14.2 Hz), 5.0-5.2
(3H, m), 6.53 (1H, d, J=8.5 Hz), 7.2-7.5 (8H, m)
[0750] Mass (APCI): 492 (M.sup.++1)
[0751] Preparation 21-2
[0752]
(3RS)-3-Amino-1-(2-acetoxyethyl)-5-cyclohexyl-2,3-dihydro-9-methyl--
1H-1,4-henzodiazepin-2-one was prepared in a similar manner to that
of Preparation 59-6.
[0753] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-2.2 (10 H, m), 2.33
(3H, s), 2.7-2.9 (1H, m), 3.3-3.5 (1H, m), 3.8-4.1 (2H, m), 4.29
(1H, br, s), 4.61 (1H, dt, J=5.3 Hz and J=14.1 Hz), 7.2-7.5 (3H,
m)
[0754] Mass (APCI): 358 (M.sup.++1)
[0755] Preparation 22
[0756] A mixture of
(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonyl-
methyl]-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
(1.0 g) and 1,1'-carbonyldiimidazole (723 mg) in tetrahydrofuran
(20 ml) was stirred at room temperature overnight. Ethyl acetate
and water were added to the reaction mixture. The separated organic
layer was washed with water twice, brine and dried over magnesium
sulfate. The solvent was evaporated in vacuo to afford
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbo-
nyimethyl]-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-3-(imidazol-1-yl)carbon-
ylamino-1H-1,4-benzodiazepin-2-one (1.27 g) as a crystalline
powder.
[0757] mp: 107.3-118.2.degree. C.
[0758] IR (Nujol, cm.sup.-1): 1680, 1645
[0759] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10 H, m), 2.45
(3H, s), 2.9-3.4 (2H, m), 3.7-4.0 (2H, m), 4.12 (1H, d, J=16.0 Hz),
5.18 (1H, d, J=16.0 Hz), 5.48 (1H, d, J=7.4 Hz), 6.9-7.1 (2H, br,
m), 7.2-7.4 (2H, m), 7.5-7.7 (2H, m), 7.7-7.8 (1H, m), 7.91 (1H,
br, s), 8.43 (1H, br, s), 9.84 (1H, d, J=7.4 Hz)
[0760] Mass (APCI): 475 (M.sup.++1)
[0761] Preparation 23-1
[0762]
(3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-1-ethoxycarbonyl-methyl-
-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-3.
[0763] JR (Nujol, cm.sup.-1):1750, 1720, 1670
[0764] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.1-2.2 (10H, m), 1.21
(3H, t, J=7.1 Hz), 2.33 (3H, s), 2.7-2.9 (1H, m), 3.82 (1H, d,
J=16.7 Hz), 4.12 (2H, q, 1=7.1 Hz), 4.68 (1H, d, J=16.7 Hz),
5.0-5.2 (2H, br, m), 5.22 (1H, d, J=8.6 Hz), 6.47 (1H, d, J=8.6
Hz), 7.1-7.5 (8H, m)
[0765] Mass (APCI): 492 (M.sup.++1)
[0766] Preparation 23-2
[0767]
(3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-1-carboxyme-
thyl-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Example 48-2.
[0768] IR (Nujol, cm.sup.-1): 1720, 1680
[0769] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.1-2.2 (IOH, m), 2.33
(3H, s), 2.81 (1H, m), 3.84 (1H, d, J=17.1 Hz), 4.72 (1H, d, J=17.1
Hz), 4.9-5.2 (2H, br, m), 5.21 (1H, d, 1=8.6 Hz), 6.52 (1H, d,
J=8.7 Hz), 7.2-7.5 (8H, m)
[0770] Mass (APCI): 464 (M.sup.++1)
[0771] Preparation 23-2
[0772]
(3RS)-1-[(3-Azabicyclo[3.2.2)non-3-yl)carbonylmethyl]-3-benzyloxyca-
rbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-5.
[0773] IR (Nujol, cm.sup.-1): 1720, 1660
[0774] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.1-2.2 (20H, m), 2.35
(3H, s), 2.7-3.0 (1H, m), 3.3-3.9 (4H, m), 3.88 (1H, d, J=15.5 Hz),
4.96 (1H, d, J=15.5 Hz), 4.9-5.2 (2H, m), 5.23 (1H, d, J=8.6 Hz),
6.50 (1H, d, J=8.7 Hz), 7.2-7.6 (8H, m)
[0775] Mass (APCI): 571 (M'+1)
[0776] Preparation 23-4
[0777]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyc-
lohexyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 49-2.
[0778] IR (Nujol, cm.sup.-1) 1660
[0779] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.1-2.2 (10H, m), 2.41
(3H, s), 2.7-3.0 (1H, br, s), 3.3-3.8 (4H, m), 3.91 (1H, d, J=15.8
Hz), 5.09 (1H, d, J=5.2 Hz), 5.14 (1H, d, J=15.8 Hz), 7.2-7.5 (3H,
m)
[0780] Mass (APCI): 437 (M.sup.++1)
[0781] Preparation 24-1
[0782] (3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-9-
methyl-1-(2-methylphenacyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-3.
[0783] IR (Nujol, cm.sup.-1):1720, 1660
[0784] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.1-2.2 (10H, m), 2.35
(3H, s), 2.38 (3H, s), 2.8-3.0 (1H, m), 4.22 (1H, d, J=17.0 Hz),
5.0-5.2 (2H,-br, m), 5.28 (1H, d, J=8.7 Hz), 5.40 (1H, d, J=17.0
Hz), 6.51 (1H, d, J=8.6 Hz), 7.2-7.6 (l1H, m), 7.6-7.7 (1H, m)
[0785] Mass (APCI): 538 (M.sup.++1)
[0786] Preparation 24-2
[0787]
(3RS)-3-Amino-5-cyclohexyl-2,3-dihydro-9-methyl-1-(2-methylphenacyl-
)-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 49-2.
[0788] IR (Nujol, cm.sup.-1): 1680
[0789] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-2.3 (10H, m), 2.38
(3H, s). 2.39 (3H, s), 2.85 (1H, m), 4.22 (1H, d, J=17.1 Hz), 4.66
(1H, br, s), 5.45 (1H, d, J=17.1 Hz), 7.2-7.5 (6H, m), 7.5-7.7 (1H,
m)
[0790] Mass (APCI): 404 (M.sup.++1)
[0791] Preparation 25-1
[0792] To a solution of 2-chloroacetyl-6-methylaniline (1.84 g) in
methanol (50 ml) was added a 15% aqueous solution of sodium
methanthiolate (14.01 g, 3 eq.mol) under stirring and cooling in an
ice-bath. The mixture was stirred at ambient temperature for 2.5
hours. From the reaction mixture methanol was removed in vacuo and
dissolved in ethyl acetate. The solution was washed with water and
brine successively and dried over magnesium sulfate. Removal of the
solvent in vacuo oave an oil (2.26 g), which was subjected to
column chromatography on silica gel eluting with a mixture of
n-hexane and chloroform (10:1). The fractions containing the
desired product were combined and evaporated to give
2-methylthioacetyl-6-methylaniline (1.75 g, 89.7%) as an oil.
[0793] IR (Film, cm.sup.-1): 3470, 3340, 1635, 1610, 1583, 1555,
1459, 1430, 1380, 1310, 1281, 1250, 1218, 1127, 1030, 980, 740
[0794] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.18 (6H, s), 3.80 (2H,
s), 6.35 (1H, br), 6.59 (1H, t, J=7.2 Hz), 7.21 (1H, d, J=7.2 Hz),
7.62 (1H, d, J=7.2 Hz)
[0795] APCI-MS (m/z): 196 (M.sup.++1)
[0796] Preparation 25-2
[0797]
(3RS)-3-Benzyloxycarbonylamino-5-methylthiomethyl-9-methyl-2,3-dihy-
dro-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 45-2.
[0798] mp: 152.6-153.8.degree. C.
[0799] IR (Nujol, cm.sup.-1): 3250 (sh), 3200, 1720, 1695, 1680
(sh), 1460, 1375, 1059, 762, 700
[0800] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.01 (3H, s), 2.37 (3H,
s), 3.72 (2H, dd, J=13.7 Hz, J=44.6 Hz), 5.11 (2H, dd, J=12.3 Hz,
J=14.3 Hz), 5.20 (1H, d, J=8.2 Hz), 6.54 (1H, d, J=8.2 Hz),
7.16-7.59 (8H, m), 7.98 (1H, s)
[0801] APCI-MS (m/z): 384 (M.sup.++1)
[0802] Preparation 25-3
[0803]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl--
9-methyl-5-methylthiomethyl-1H-1,4-benzodiazepin-2-one was prepared
in a similar manner to that of Preparation 59-3.
[0804] .sup.1H-NMR(CDC.sub.3, .delta.): 1.1-1.3 (3H, m), 2.18 (3H,
s), 2.35 (3H, s), 3.6-4.0 (2H, m), 4.08 (2H, q, J=7.1 Hz), 4.71
(1H, d, J=16.9 Hz), 5.0-5.2 (2H, br, m), 5.30 (1H, d, J=8.6 Hz),
6.55 (1H, d, J=8.5 Hz), 7.2-7.5 (7H, m), 7.74 (1H, d, J=7.5 Hz)
[0805] Mass (APCI): 470 (M.sup.++1)
[0806] Preparation 25-4
[0807]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-9-methyl-
-5-methylthio methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-4.
[0808] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.0-2.2 (3H, m), 2.2-2.4
(3H, m), 3.6-4.0 (2H, m), 4.6-5.0 (1H, br), 5.6-5.2 (3H, m), 5.28
(1H, d, J=8.4 Hz), 7.2-7.6 (7H, m), 7.75 (1H, d, J=6.7 Hz)
[0809] Mass (APCI): 442 (M.sup.++1)
[0810] Preparation 25-5
[0811]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxyca-
rbonylamino-2,3-dihydro-9-methyl-5-methylthiomethyl-1H-1,4-benzodiazepin-2-
-one was prepared in a similar manner to that of Preparation
59-5.
[0812] IR (Nujol, cm.sup.-1) 1725, 1675, 1640
[0813] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.5-1.9 (8H, br), 1.9-2.1
(2H, br), 2.30 (3H, s), 2.36 (3H, s), 3.2-3.4 (2H, m), 3.5-3.7 (1H,
m), 3.7-3.9 (4H, m), 5.02 (1H, d, J=14.7 Hz), 5.09 (2H, m), 5.32
(1H, d, J=8.5 Hz), 6.54 (1H, d, J=8.5 Hz), 7.2-7.5 (7H, m), 7.76
(1H, d, J=6.5 Hz)
[0814] Mass (APCI): 549 (M.sup.++1)
[0815] Preparation 26-1
[0816]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-[[(S)-N-(te-
rt-butoxycarbonyl)phenylalanylIamino]-5-(2-fluolophenyl)-9-methyl-2,3-dihy-
dro-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 59-5.
[0817] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.38 (18H, s), 1.4-2.2
(20H, m), 2.44 (6H, s), 3.1-3.6 (8H, m), 3.6-4.1 (4H, m), 4.56 (2H,
m), 4.9-5.2 (4H, m), 5.62 (1H, d, J=8.2 Hz), 5.64 (1H, d, J=8.1
Hz), 7.0-7.5 (16H, m), 7.5-7.9 (4H, m)
[0818] Mass(FAB): 696(M.sup.++1)
[0819] Preparation 26-2
[0820] A mixture of
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-
-3-[[(S)-N-(tert-butoxycarbonyl)phenylalanyl]aminol-5-(2-fluolophenyl)-9-m-
ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (900 mg) and
4N-hydrochloric acid in ethyl acetate (6 ml) was stirred at ambient
temperature for 1.5 hours. Ethyl acetate and saturated aqueous
sodium bicarbonate were added to the reaction mixture at 0.degree.
C. The separated organic layer was washed with brine and dried over
sodium sulfate. The solvent was evaporated in vacuo to afford a
crude white amorphous powder (672mg) composing two
diastereoisomers, which were separated by high-pressure liquid
chromatography.
[0821] Each fraction containing the respective diastereoisomers was
evaporated in vacuo and dissolved in ethyl acetate. Each solution
was washed with aqueous sodium hydrogen carbonate respectively. The
respective separated organic layer was dried over sodium sulfate
and evaporated in vacuo to afford each diastereoisomer of (3R)-and
(3S)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-[(S)-phenylalanyla-
mino]-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
respectively. (S)-isomer: 257mg, 33.4% yield. and (R)-isomer:
251mg, 32.7% yield.
[0822] (S)-isomer
[0823] Mass (APCI): 596 (M.sup.++1)
[0824] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.3-2.2 (10 H, m), 2.45
(3H, s), 2.78 (1H, dd, J=9.1 Hz and 13.7 Hz), 3.2-3.6 (4H, m),
3.6-3.9 (2H, m), 4.01 (1H, d, J=15.5 Hz), 5.10 (1H, d, J=15.5 Hz),
5.68 (1H, d, J=8.6 Hz), 7.0-7.6 (l1H, m), 7.7-7.9 (1H, m), 8.92
(1H, d, J=8.6 Hz) (R)-isomer
[0825] .sup.1H-NMR (CDCl.sub.3, .delta.):1.4-2.2 (10H, m), 2.46
(3H, s), 2.66 (1H, dd, J=10.4 Hz and 13.7 Hz), 3.3-3.6 (4H, m),
3.6-3.9 (2H, m), 4.03 (1 H, d, J=15.5 Hz), 5.11 (1H, d, J=15.5 Hz),
5.67 (1H, d, J=8.5 Hz), 7.0-7.6 (11H, m), 7.7-7.9 (1H, m), 8.91
(1H, d, J=8.4 Hz)
[0826] Mass (APCI): 596 (M.sup.++1)
[0827] Preparation 26-3
[0828] A mixture of
(3S)-1-[(3-azabicyclo[3.2.2]non-.sup.3-y])-carbonylmet-
hyl]-3-[(S)-phenylalanylamino]-5- (2- fluorophenyl)-9
methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (235 mg) and
triethylamine (42 mg) in tetrahydrofuran (2.0 ml) was stirred at
room temperature. Phenylisothioisocyanate (109 mg) was added
dropwise to the reaction mixture, stirred for 30 minutes. The
mixture was evaporated in vacuo to dryness. A mixture of the
residue and trifluoroacetic acid (1.0 ml) was stirred at 50.degree.
C. for 45 minutes. The mixture was evaporated in vacuo to afford an
oily residue. The oily residue was separated by column
chromatography on silica gel to afford either of (3R) or
(3S)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-(2-fluorop-
henyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
trifluoroacetate (165 mg, 74.4% yield).
[0829] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.44
(3H, s), 2.9-3.1 (1H, m), 3.1-3.4 (1H, m), 3.6-4.0 (2H, m), 4.18
(2H, d, J=16.2 Hz), 5.17 (1H, d, J=16.2 Hz), 5.21 (1H, br, s),
7.0-7.1 (1H, m), 7.2-7.5 (3H, m), 7.5-7.8 (3H, m), 8.98 (2H, m)
[0830] Mass (APCI): 449 (M'+1)
[0831] Preparation 27
[0832]
(3R)-3-amino-1-[(3-azabicyclo[3.2.2]non-.sup.3-yl)carbonylmethyl]-5-
-(2-fluorophenyl)-9-methyl-2,3-dihydro-1 H-1,4-benzodiazepin-2-one
trifluoroacetate was prepared in a similar manner to that of
Preparation 26-3.
[0833] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (1H, m), 2.44
(3H, s), 2.9-3.1 (1H, m), 3.1-3.4 (1H, m), 3.6-4.0 (4H, m), 4.18
(1H, d, J=16.3 Hz), 5.17 (1H, d, J=16.3 Hz), 5.21 (1H, br, s),
7.0-7.1 (1H, m), 7.2-7.5 (3H, m), 7.5-7.8 (3H, m), 8.98 (2H, m)
[0834] Mass (APCI): 449 (M.sup.++1)
[0835] Preparation 28-1
[0836]
(3RS)-2,3-Dihydro-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-9-m-
ethyl-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-3.
[0837] IR (Nujol, cm.sup.-1): 1720, 1680
[0838] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.47 (9H, s), 2.52 (3H,
s), 4.53 (1H, d, J=15.1 Hz), 5.37 (1H, d, J=8.7 Hz), 5.71 (1H, d,
J=15.1 Hz), 6.45 (1H, d, J=8.6 Hz), 6.9-7.5 (9H, m), 7.5-7.7 (1H,
m), 8.2-8.3 (1H, m)
[0839] Mass (APCI): 475 (M.sup.++1)
[0840] Preparation 28-2
[0841]
(3RS)-3-Amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(pyridin-2--
yl)methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 30-2.
[0842] IR (Nujol, cm.sup.-1) 1670
[0843] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.52 (3H, s), 4.50 (1H,
d, J=15.0 Hz), 4.60 (1H, s), 5.73 (1H, d, J=15.0 Hz), 7.0-7.7 (10H,
m), 8.2-8.4 (1H, m)
[0844] Mass (APCI): 375 (M.sup.++1)
[0845] Preparation 29-1
[0846] 2-Chloro-6-(2-fluorobenzoyl)aniline was prepared in a
similar manner to that of Preparation 50-1.
[0847] mp 86-87.5.degree. C.
[0848] IR (Nujol, cm.sup.-1): 3400, 3290, 1620, 1600
[0849] .sup.1H-NMR (CDCl.sub.3, .delta.): 6.54 (1H, t, J=7.8 Hz),
6.8-7.0 (2H, br), 7.0-7.4 (3H, br, m), 7.4-7.6 (3H, br, m)
[0850] Mass (APCI): 250 (M.sup.++1)
[0851] Preparation 29-2
[0852] To a solution of 2-amino-3-chloro-2'-fluorobenzophenone
(4.80 g) and pyridine (3.04 g) in methylene chloride (100 ml) was
added dropwise bromoacetyl bromide (3.42 ml) under stirring and
cooling in an ice-bath. After the addition was completed, the
mixture was stirred at ambient temperature for 0.5 hour and
refluxed for 0.5 hour. The mixture was allowed to stand to cool to
ambient temperature and evaporated in vacuo to give a residue,
which was dissolved in ethyl acetate and washed with water three
times and brine successively. After drying, over magnesium sulfate
and treating with active carbon, the solvent was removed in vacuo
to give a crystalline mass. Pulverization in diisopropyl ether and
collection by filtration afforded
2-(bromoacetylamino)-3-chloro-2'-fluoro- benzophenone (5.86 g,
82.4% yield) as a white crystalline powder.
[0853] IR (Nujol, cm.sup.-1): 3270, 1679 (sh), 1670, 1608, 1594,
1512, 1375, 1304, 1138, 1100, 975, 945, 826, 775, 752, 694
[0854] .sup.1H-NMR (CDCl.sub.3, .delta.): 3.83 (2H, s), 7.08-7.81
(7H, m), 8.84 (1H, s)
[0855] APCI-MS (m/z): 371 (M.sup.++1)
[0856] Preparation 29-3
[0857] Sodium hydroxide (pellet, 2.82 g) was dissolved in a mixture
of methanol (15 ml) and water (25 ml) under stirring. To the
mixture was added hydroxylamine hydrochloride (5.50 g). To the
clear solution prepared above was portionwise added a suspension of
2-bromoacetylamino-3-chloro-2'-fluorobenzophenone (5.80 g) in
methanol (30 ml) under stirring at 30-35.degree. C. After the
addition was completed, the mixture was refluxed under stirring for
3 hours. Methanol was removed in vacuo and the residual mixture was
extracted with ethyl acetate. The extract was washed with water
three times and dried over magnesium sulfate. The solvent was
removed in vacuo to afford an oil (5.0 g), which was pulverized in
a mixture of diisopropyl ether and ethyl acetate. The resultant
crystalline mass was collected by filtration and dried to give
9-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzod-
iazepin-4-oxide (1.74 g, 36.5% yield) as a white crystalline
powder.
[0858] IR (Nujol, cm.sup.-1): 3350, 1700, 1610, 1490 (sh), 1478,
1350, 1298, 1265, 1230, 1200, 1154, 1100, 992, 860, 819, 792, 750,
730
[0859] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 4.66 (2H, br, s),
6.9-7.7 (7H, m), 10.73 (1H, s)
[0860] APCI-MS (m/z): 305 (M'+1), 307 (M.sup.++3)
[0861] Preparation 29-4
[0862] A suspension of
9-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,-
4-benzodiazepin-4-oxide (1.475 g) in acetic anhydride (12 ml) was
refluxed for 0.5 hour. The resultant clear solution was cooled in
an ice-bath to afford precipitate. To the cooled suspension was
added diisopropyl ether (20 ml) and the mixture was cooled further.
The resultant precipitate was collected by filtration and washed
with diisopropyl ether to give
(3RS)-3-acetoxy-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiaze-
pin-2-one (0.84 g, 50.0% yield) as a colorless crystalline
powder.
[0863] IR (Nujol, cm.sup.-1) 3200, 3125, 1736, 1688, 1610, 1593,
1484, 1371, 1322, 1212, 1091, 1060, 926, 794, 770, 748, 705
[0864] .sup.1H-NMR (DMSO-d, .delta.): 2.21 (3H, s), 5.79 (1H, s),
7.18-7.83 (7H, m), 10.72 (1H, s)
[0865] APCI-MS (m/z): 347 (M.sup.++1), 349 (M.sup.++3)
[0866] Preparation 29-5
[0867] A mixture of
(3RS)-3-acetoxy-5-(2-fluorophenyl)-9-chloro-2,3-dihydr-
o-1H-1,4-benzodiazepin-2-one (3.60 g), sodium iodide (15.59 g) and
potassium phthalimide (2.89 g) in dimethylformamide (25 ml) was
stirred at 100.degree. C. for 1 hour. The reaction mixture was
poured into ice-water and the resultant precipitate was collected
by filtration. After washing with water several times and dried
over phosphorus pentoxide under reduced pressure, the crude powder
was subjected to column chromatography on silica gel eluting with a
mixture of chloroform and methanol (100:1). The fractions
containing the desired product were combined and evaporated in
vacuo to give (3RS)-3-phthalimido-5-(2-fluorop-
henyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.82 g,
18.9% yield) as a crystalline powder.
[0868] IR (Nujol, cm.sup.-1) 3350, 1780, 1720, 1710, 1380, 1125,
886, 746, 712
[0869] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 5.77 (1H, s), 7.20-8.02
(11H, m), 10.70 (1H, s)
[0870] APCI-MS (m/z): 434 (M.sup.++1), 436 (M.sup.++3)
[0871] Preparation 29-6
[0872] To a suspension of
(3RS)-3-phthalimido-5-(2-fluorophenyl)-9-chloro--
2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.8 g) in a mixed solvent
of tetrahydrofuran and methanol (1:1, 8 ml) was added hydrazine
hydrate (0.11 ml) under stirring at ambient temperature. The
mixture was stirred at ambient temperature for 0.5 hour and
refluxed for 0.5 hours. After allowing to cool to ambient
temperature, the resultant precipitate was filtered off and washed
with cold methanol. The filtrate and the washings were combined and
evaporated in vacuo to afford a residue, which was subjected to
column chromatography on silica gel eluting with a mixture of
chloroform and methanol (50:1). The fractions containing the
desired product were combined and evaporated in vacuo to give a
crystalline mass, which was pulverized in diisopropyl ether and
collected by filtration to give
(3RS)-3-amino-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodi-
azepin-2-one (0.54 g, 96.6% yield).
[0873] IR (Nujol, cm.sup.-1) 3350, 3300, 1686, 1608, 1484, 1374,
1320, 1215, 1130, 1018, 968, 830, 746, 715
[0874] .sup.1H-NMR (CDCl.sub.3, .delta.):2.27 (2H, br, s), 4.50(1H,
s), 7.03-7.68 (7H, m), 8.04 (1H, br, s)
[0875] APCI-MS (m/z): 304 (M.sup.++1), 306 (M.sup.++3)
[0876] Preparation 29-7
[0877] To a suspension of
(3RS)-3-amino-5-(2-fluorophenyl)-9-chloro-2,3-di-
hydro-1H-1,4-benzodiazepin-2-one (538.8mg), triethylamine (269.2
mg) and a catalytic amount of hydroxylamine hydrochloride in
methylene chloride was added dropwise a solution of di-t-butyl
dicarbonate (580.5 g) in methylene chloride (1 ml) at ambient
temperature under stirring. After the mixture was stirred for 3.5
hours under the same conditions, triethylamine (89.7 mg) and
di-t-butyl dicarbonate (193.0 mg) was added. The mixture was
stirred overnight at ambient temperature. Methylene chloride was
removed in vacuo to afford a residue, which was dissolved in ethyl
acetate and washed with water twice. After drying over magnesium
sulfate, the-solvent was removed in vacuo to give an oil (1.10 g),
which was subjected to column chromatography on silica gel eluting
with chloroform. Fractions containing the desired product were
combined and evaporated in vacuo to give
(3RS)-9-chloro-5-(2-fluorophenyl)-3-t-butoxyc-
arbonylamino-2,3-dihydro-1H-1,4-benzodiazepin-2-one (566.1 mg,
79.2% yield) as a white crystalline powder.
[0878] mp: 187.1-188.6.degree. C.
[0879] IR (Nujol, cm.sup.-1): 3210, 3150 (sh), 1700 (sh), 1689,
1604, 1532, 1365, 1327, 1270, 1254, 1170, 1059, 1020, 957, 945,
880, 834, 763, 746, 680
[0880] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.32 (2H, br, s),
1.41(9H, s), 5.03(1H, d, J=8.6 Hz), 7.17-7.82 (7H, m), 7.91 (1H, d,
J=8.6 Hz), 10.56 (1H, s)
[0881] APCI-MS (m/z): 404 (M.sup.++1), 406 (M.sup.++3)
[0882] Preparation 29-8
[0883]
(3RS)-9-Chloro-2,3-dihydro-3-tert-butoxycarbonylamino-1-ethoxycarbo-
nylmethyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-3.
[0884] IR (Nujol, cm.sup.-1) 1680
[0885] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.00 (3H, t, J=7.1 Hz),
1.46 (9H, s), 3.8-4.2 (2H, m), 4.25 (1H, d, J=17.2 Hz), 4.95 (1H,
d, J=17.2 Hz), 5.39 (1H, d, J=8.8 Hz), 6.42 (1H, d, J=8.7 Hz),
7.0-7.2 (1H, br, s), 7.2-7.4 (3H, m), 7.4-7.6 (1H, br, s), 7.6-7.7
(1H, m), 7.7-7.9 (1H, m)
[0886] Mass (APCI): 490 (M.sup.++1)
[0887] Preparation 29-9
[0888]
(3RS)-9-Chloro-2,3-dihydro-3-tert-butoxycarbonylamino-5-(2-fluoroph-
enyl)-1-carboxymethyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Example 48-2.
[0889] IR (Nujol, cm.sup.-1): 1745, 1675
[0890] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.48 (9H, s), 4.31 (1H,
d, J=17.5 Hz), 5.01 (1H, d, J=17.5 Hz), 5.39 (1H, d, J=8.8 Hz),
6.41 (1H, d, J=8.9 Hz), 6.9-7.9 (7H, m)
[0891] Mass (APCI): 462 (M.sup.++1)
[0892] Preparation 29-10
[0893]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-9-chloro-2,3--
dihydro-5-(2-fluorophenyl)-3-tert-butoxycarbonylamino-1H-1,4-benzodiazepin-
-2-one was prepared in a similar manner to that of Preparation
59-5.
[0894] IR (Nujol, cm.sup.-1): 1660
[0895] .sup.1H-NMR(CDCL .sub.3, .delta.): 1.46 (9H, s), 1.4-2.2
(10H, br), 3.2-3.5(2H, m), 3.5-4.0 (2H, m), 4.36 (1H, d, J=16.1
Hz), 5.24 (1H, d, J=16.1 Hz), 5.42 (1H, d, J=9.0 Hz), 6.39 (1H, d,
J=8.9 Hz), 7.0-7.3 (3H, m), 7.3-7.5 (1H, m), 7.5-7.7 (1H, m),
7.7-7.9 (1H, m), 8.01 (1H, br, s)
[0896] Mass (APCI): 596 (M.sup.++1)
[0897] Preparation 29-11
[0898] A mixture of
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]--
9-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-tert-butoxycarbonylamino-1H-1,4--
benzodiazepin-2-one (660mg) and 4N aqueous hydrochloric acid in
ethyl acetate (3 ml) was stirred at 0.degree. C. for 5.5 hours. A
saturated aqueous solution of sodium bicarbonate and ethyl acetate
were added to the reaction mixture. The separated organic layer was
washed with water and brine, and then dried over sodium sulfate.
The solvent was evaporated in vacuo to afford
(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonyl-
methyl]-9-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one
(549.0 mg) as a crystalline powder.
[0899] IR (Nujol, cm.sup.-1): 1680, 1650
[0900] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.4-2.2 (10H, m), 3.2-3.5
(2H, m), 3.5-4.0 (2H, m), 4.36 (1H, d, J=16.1 Hz), 4.61 (1H, br,
s), 5.29 (1H, d, J=16.1 Hz), 7.0-7.4 (4H, m), 7.4-7.5 (1H, m),
7.5-7.7 (1H, m), 7.7-7.9 (1H, m)
[0901] Mass (APCI): 469 (M.sup.++1)
[0902] Preparation 30-1
[0903]
(3RS)-2,3-Dihydro-1-tert-butylcarbonylmethyl-3-tert-butoxy-carbonyl-
amino-5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-3.
[0904] IR (Nujol, cm.sup.-1): 1720, 1700, 1635
[0905] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.13 (9H, s), 1.45 (9H,
s), 2.39 (3H, s), 4.03 (1H, d, J=17.1 Hz), 5.09 (1H, d, J=17.1 Hz),
5.40 (1H, d, J=9.0 Hz), 6.36 (1H, d, J=9.0 Hz), 7.0-7.6 (6H, m),
7.7-7.9 (1H, m)
[0906] Mass (APCI): 482 (M.sup.++1)
[0907] Preparation 30-2
[0908] A mixture of
(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-tert-butylcarbo-
nylmethyl-3-tert-butoxycarbonylamino-9-methyl-1H-1,4-benzodiazepin-2-one
(130mg) and 4N HCl in ethyl acetate (1 ml) was stirred at 0.degree.
C. for 5 hours. Ethyl acetate and a saturated aqueous solution of
sodium bicarbonate were added to the reaction mixture. The
separated organic layer was washed with water and brine, and then
dried over sodium sulfate. The solvent was evaporated in vacuo to
afford
(3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-tert-butylcarbonylmethyl-9-
-methyl-1H-1,4-benzodiazepin-2-one (100mg, 97.1%) as a crystalline
powder.
[0909] IR (Nujol, cm.sup.-1): 1720, 1670
[0910] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.14 (9H, s), 2.39 (3H,
s), 3.99 (1H, d, J=17.1 Hz), 4.65 (1H, br, s), 5.16 (1H, d, J=17.1
Hz), 7.0-7.6 (6H, m), 7.7-7.9 (1H, m).
[0911] Mass (APCI): 382 (M.sup.++1)
[0912] Preparation 31-1
[0913]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonylmethyl-5-
,9-dimethyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-3.
[0914] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.19 (3H, t, J=7.1 Hz),
2.33 (3H, s), 2.56 (3H, s), 3.78 (1H, d, J=16.9 Hz), 4.08 (2H, q,
J=7.1 Hz), 4.92 (1H, d, J=16.9 Hz), 5.0-5.2 (2H, m), 5.2-5.3 (1H,
m), 6.50 (1H, d, J=8.6 Hz), 7.2-7.5 (8H, m)
[0915] Mass (APCI): 424 (M.sup.++1)
[0916] Preparation 31-2
[0917]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-5,9-dime-
thyl-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 59-4.
[0918] IR (Nujol, cm.sup.-1): 1720, 1690, 1618
[0919] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.29 (3H, s), 2.46 (3H,
s), 3.72 (1H, d, J=17.1 Hz), 4.91 (1H, d, J=17.1 Hz), 5.0-5.1 (2H,
m), 5.25 (1H, d, J=7.6 Hz), 6.73 (1H, d, J=8.7 Hz), 7.2-7.5 (8H,
m), 7.90 (1H, m)
[0920] Mass (APCI): 396 (M.sup.++1)
[0921] Preparation 31-3
[0922]
(3RS)-3-Benzyloxycarbonylamino-1-[(3-azabicyclo[3.2.2]non-3-yl)carb-
onylmethyl]-2,3-dihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-5.
[0923] IR (Nujol, cm.sup.-1): 1720, 1675, 1650
[0924] .sup.1H-NMR (CDCl.sub.3, .delta.) 1.5-1.9 (8H, m), 1.9-2.1
(2H, m), 2.35 (3H, s), 2.60 (3H, s), 3.2-3.4 (2H, m), 3.60 (1H, dd,
J=4.7 Hz and J=13.7 Hz), 3.77 (1H, d, J=15.8 Hz), 3.87 (1H, d,
J=5.0 Hz and J=13.7 Hz), 5.0-5.1 (2H, m), 5.19 (1H, d, J=15.8 Hz),
5.2-5.4 (1H, m), 6.52 (1H, d, I=8.7 Hz), 7.2-7.5 (8H, m)
[0925] Mass (APCI): 503 (M.sup.++1)
[0926] Preparation 31-4
[0927]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-d-
ihydro-5,9-dimethyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-6.
[0928] IR (Nujo], cm.sup.-1) 3350, 3270, 1665, 1620
[0929] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.4-1.9 (8H, m), 1.9-2.1
(2H, m), 2.35 (3H, s), 2.58 (3H, s), 3.2-3.5 (2H, m), 3.5-3.9 (2H,
br, m), 4.42 (1H, s), 5.23 (1H, d, J=15.6 Hz), 7.2-7.5 (3H, m)
[0930] Mass (APCI): 369 (M.sup.++1)
[0931] Preparation 31-5
[0932]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5,9-dimethyl--
2,3-dihydro-3-(imidazol-1-yl)carbonylamino-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 22.
[0933] IR (Nujol, cm.sup.-1) 1720, 1685, 1650
[0934] Mass (APCI): 427 (M.sup.++1)
[0935] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.39
(3H, s), 2.49 (3H, s), 2.9-3.4 (2H, m), 3.6-3.9 (2H, m), 3.95 (1H,
d, J=16.2 Hz), 5.13 (1H, d, J=16.2 Hz), 5.2-5.3 (1H, m), 7.0-7.1
(1H, m), 7.2-7.7 (3H, m), 7.86 (1H, br, s), 8.40 (]H, br, s), 9.71
(1H, d, J=7.2 Hz)
[0936] Preparation 32
[0937] To a suspension of
N-{(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbon-
ylmethyl]-2,3-dihydro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl}-N'-(3--
methylphenyl)urea (140.5mg) in methylene chloride (5 ml) was added
m-chloroperbenzoic acid (m-CPBA, 72.5mg, 1.5eq.mol) portionwise
under stirring at ambient temperature. After stirring for 5.5
hours, an additional m-CPBA (48 mg) was added and the stirring was
continued for 3.5 hours further. From the clear reaction mixture,
methylene chloride was removed in vacuo and the residue was
dissolved in ethyl acetate. The solution was washed with an aqueous
solution of sodium bicarbonate, water and brine. The organic layer
was dried over magnesium sulfate and evaporated to afford a reddish
oil, which was subjected to preparative thin layer chromatography
on silica gel (60F254, 0.5 mm, 20.times.20 cm Merck) developed with
a mixture of chloroform and methanol (10:1) to give
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5,9-di-
methyl-2-oxo-1H-1,4-benzodiazepin-4-oxido-3-yl]-N'-(3-methylphenyl)urea
as a while crystalline powder (69.5mg, 48.0%).
[0938] mp: 244.1-245.6.degree. C. (dec.)
[0939] .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD, .delta.): 1.53-1.73 (8H,
m), 1.94 (1H, br, s), 2.05 (1H, br, s), 2.25 (3H, s), 2.41 (3H, s),
2.56 (3H, s), 3.20-3.36 (2H, m), 3.54-3.81 (2H, m), 4.56 (2H, dd,
J=15.8 Hz, J=255.0 Hz), 5.97 (1H, s), 6.76-7.45 (9H, m)
[0940] APCI-MS (m/z): 518 (M'+1)
[0941] Preparation 33-1
[0942] 2'-Amino-3'-(N,N-dimethylamino)acetophenone was prepared in
a similar manner to that of Preparation 50-1.
[0943] IR (Nujol, cm.sup.-1): 3450, 3320, 1640
[0944] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.60 (3H, s), 2.64 (3H,
s), 6.59 (1H, dd, J=7.7 Hz and J=8.1 Hz), 7.13 (1H, dd, J=1.3 Hz
and J=7.5 Hz), 7.48 (1H, dd, J=1.3 Hz and J=8.2 Hz), 6.6-7.0 (2H,
m)
[0945] Mass (APCI): 179 (M.sup.++1)
[0946] Preparation 33-2
[0947]
(3RS)-3-Benzyloxycarbonylamino-5-methyl-9-(N,N-dimethylamino)-2,3-d-
ihydro-1H-1,4-benzodiazepin-2-one was prepared in a similar manner
to that of Preparation 45-2.
[0948] IR (Nujol, cm.sup.-1): 1710, 1680
[0949] .sup.1H-NMR(CDCl.sub.3, .delta.): 2.46 (3H, s), 2.67 (6H,
s), 5.0-5.2 (2H, m), 6.56 (1H, d, J=8.1 Hz), 7.1-7.4 (8H, m), 8.26
(1H, br, s)
[0950] Mass (APCI): 367 (M.sup.++1)
[0951] Preparation 33-3
[0952] To a solution of
(3RS)-3-benzyloxycarbonylamino-5-methyl-9-(N,N-dim-
ethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (820 mg) in
N,N-dimethylformamide (5 ml) was added portionwise 60% sodium
hydride suspended in oil (94 mg) under nitrogen stream and cooling
in an icc-bath. The mixture was stirred under the same conditions
for 3 hours. N-Bromoacetyl-3-azabicyclo[3.2.2]nonane (578 g) was
added to the reaction mixture at 0.degree. C. The resultant mixture
was stirred at room temperature overnight. Ethyl acetate and water
were added to the mixture. The separated organic layer was washed
with water twice and brine, and then dried over sodium sulfate. The
solvent was evaporated in vacuo to afford a pale yellow residue,
which was subjected to column chromatography on silica gel eluting,
with a mixture of toluene and ethyl acetate (2:1).
[0953] The fractions containing the desired product were combined
and evaporated in vacuo to give
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbony-
lmethyl]-3-benzyloxycarbonylamino-5-methyl-9-(N,N-dimethylamino)-2,3-dihyd-
ro-1H-1,4-benzodiazepin-2-one (510 mg, 42.8% yield) as a
crystalline powder.
[0954] IR (Nujol, cm.sup.-1): 1715, 1680, 1650
[0955] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.3-2.2 (IOH, m), 2.58
(3H, s), 2.74 (6H, s), 3.2-3.4 (2H, m), 3.4-3.8 (2H, m), 4.70 (1H,
d, J=16.1 Hz), 5.09 (1H, d, J=16.1 Hz), 5.0-5.2 (2H, m), 5.2-5.4
(1H, m), 6.48 (1H, d, J=8.5 Hz), 7.0-7.4 (8H, m)
[0956] Mass (APCI): 532 (M.sup.++1)
[0957] Preparation 33-4
[0958]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-met-
hyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-6.
[0959] IR (Nujol, cm.sup.-1): 1680, 1640
[0960] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.3-2.2 (10H, m), 2.35
(2H, m), 2.57 (3H, s), 2.74 (6H, s), 3.2-3.8 (4H, m), 4.46 (1H, br,
s), 4.69 (1H, d, J=16.1 Hz), 5.13 (1H, d, J=16.1 Hz), 7.0-7.4 (3H,
m)
[0961] Mass (APCI): 398 (M.sup.++1)
[0962] Preparation 34-1
[0963]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-met-
hyl-1-tert-butoxycarbonylmethyl-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-3.
[0964] IR (Nujol, cm.sup.-1) 1720, 1680
[0965] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.28 (9H, s), 2.36 (3H,
s), 3.81 (1H, d, J=16.6 Hz), 4.70 (1H, d, J=16.6 Hz), 5.0-5.3 (2H,
m), 5.42 (1H, d, J=8.6 Hz), 6.67 (1H, d, J=8.6 Hz), 7.0-7.6 (11H,
m), 7.7-7.9 (1H, m)
[0966] Mass (APCI): 532 (M.sup.++1)
[0967] Preparation 34-2
[0968]
(3RS)-3-Amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-tert-butoxy-
carbonylmethyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-6.
[0969] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.29 (9H, s), 2.38 (3H,
s), 3.79 (1H, d, J=16.6 Hz), 4.58 (1H, s), 4.73 (1H, d, J=16.6 Hz),
7.0-7.6 (6H, m), 7.7-7.9 (1H, m)
[0970] Mass (APCI): 398 (M.sup.++1)
[0971] Preparation 35-1
[0972]
(3RS)-1-(Adamantan-1-yl)carbonylmethyl-3-benzyloxycarbonyl-amino-2,-
3-dihydro-5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-3.
[0973] IR (Nujol, cm.sup.-1): 1710, 1670
[0974] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.5-2.0 (1SH, m), 2.40
(3H, s), 4.06 (1H, d, J=17.4 Hz), 5.04 (2H, br, s), 5.16 (1H, d,
J=8.5 Hz), 5.21 (1H, d, J=17.5. Hz), 7.03 (1H, d, J=8.7 Hz),
7.0-7.8 (12H, m)
[0975] Mass (APCI): 594 (M.sup.++l)
[0976] Preparation 35-2
[0977]
(3RS)-1-(Adamantan-1-yl)carbonylmethyl-3-amino-5-(2-fluorophenyl)-2-
,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-6.
[0978] IR (Nujol, cm.sup.-1): 1710, 1670
[0979] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.5-2.3 (15H, m), 2.38
(3H, s), 3.95 (1H, d, J=17.1 Hz), 4.59 (1H, s), 5.14 (1H, d, J=17.1
Hz), 7.0-7.5 (6H, m), 7.7-7.9 (1H, m)
[0980] Mass (APCI): 460 (M+1)
[0981] Preparation 36-1
[0982]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1,5,9-trimethyl-1H-1,4-b-
enzodiazepin-2-one was prepared in a similar manner to that of
Preparation 59-3.
[0983] IR (Nujol, cm.sup.-1): 1710, 1665, 1620
[0984] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.35 (31H, s), 2.43 (3H,
s), 3.19 (31H, s), 5.06 (1H, d, J=12.3 Hz), 5.13 (1H, d, J=12.3
Hz), 5.1-5.2 (1H, m), 6.60 (1H, d, J=8.3 Hz), 7.1-7.5 (8H, m)
[0985] Mass (APCI): 352 (M.sup.++1)
[0986] Preparation 36-2
[0987]
(3RS)-3-Amino-2,3-dihydro-1,5,9-trimethyl-1H-1,4-benzodiazepin-2-on-
e was prepared in a similar manner to that of Preparation 59-6.
[0988] IR (Neat, cm.sup.-1): 3350, 1685, 1615
[0989] .sup.1H-NMR(CDCl.sub.3, .delta.):2.36 (3H, s), 2.47 (3H, s),
3.18 (3H, s), 4.31 (1H, d, J=1.3 Hz), 7.1-7.4 (3H, m)
[0990] Mass (APCI): 218 (M.sup.++1)
[0991] Preparation 37-1
[0992]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5,9-dimethyl-1-(2-methyl-
phenacyl)-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-3.
[0993] IR (Nujol, cm.sup.-1): 1715, 1670
[0994] .sup.1H-NMR (CDCl.sub.3, .delta.):2.29 (3H, s), 2.39 (3H,
s), 2.51 (3H, s), 4.20 (1H, d, J=17.0 Hz), 5.0-5.2 (2H, m), 5.28
(1H, dd, J=1.5 Hz and 8.7 Hz), 5.61 (1H, d, J=17.0 Hz), 6.52 (1H,
d, J=8.7 Hz), 7.2-7.5 (11H, m), 7.5-7.6 (1H, m)
[0995] Mass (APCI): 470 (M.sup.++1)
[0996] Preparation 37-2
[0997]
(3RS)-3-Amino-1-(2-methylphenacyl)-2,3-dihydro-5,9-dimethyl-1H-1,4--
benzodiazepin-2-one was prepared in a similar manner to that of
Preparation 59-6.
[0998] IR (Nujol, cm .sup.1) 1670, 1615
[0999] .sup.1H-NMR(CDCl.sub.3, .delta.):2.28 (3H, s), 2.41 (3H, s),
2.47 (3H, s), 4.18 (1H, d, J=16.9 Hz), 4.4 (1H, m), 5.64 (1H, d,
J=16.9 Hz), 7.1-7.6 (7H, m)
[1000] Mass (APCI): 336 (M.sup.++1)
[1001] Preparation 38
[1002]
(3RS)-1-(Adamantan-1-yl)carbonylmethyl-3-amino-2,3-dihydro-5,9-dime-
thyl-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 59-6.
[1003] IR (Nujol, cm .sup.-1): 1700, 1670
[1004] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.6-2.3 (15H, br), 2.32
(3H, s), 2.61 (3H, s), 3.74 (1H, d, J=17.2 Hz), 4.4 (1H, m), 5.28
(1H, d, J=17.2 Hz), 7.1-7.5 (3H, m)
[1005] Mass (APCI): 380 (M'+1)
[1006] Preparation 39-1
[1007]
(3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-2,3-dihyd-
ro-5,9-dimethyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-3.
[1008] IR (Neat, cm.sup.-1) 1720, 1670
[1009] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.1-2.0 (10H, m), 2.2-2.4
(1H, m), 2.32 (3H, s), 2.61 (3H, s), 3.74 (1H, d, J=17.2 Hz),
5.0-5.2 (3H, m), 5.24 (1H, d, J=7.3 Hz), 6.46 (1H, d, J=8.8 Hz),
7.1-7.5 (8H, m) Mass (APCI): 462 (M.sup.++1)
[1010] Preparation 39-2
[1011]
(3RS)-3-Amino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1-
H-1,4-benzodiazepin-2-one was prepared in a similar -manner to that
of Preparation 59-6.
[1012] IR (Neat, cm.sup.-1) 1715, 1670
[1013] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.1-2.0 (10H, m), 2.0-2.4
(1H, m), 2.32 (3H, s), 2.60 (3H, s), 3.72 (1H, d, J=17.2 Hz), 4.4
(1H, m), 5.13 (1H, d, J=17.2 Hz), 7.1-7.5 (3H, m) Mass (APCI): 328
(M.sup.++1)
[1014] Preparation 40-1
[1015]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-met-
hyl-1-methylcarbonylmethyl-1H-1,4-benzodiazepin-2-one was prepared
in a similar manner to that of Preparation 59-3.
[1016] IR (Nujol, cm.sup.-1) 1705, 1660
[1017] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.00 (3H, s), 2.38 (3H,
s), 4.23 (1H, d, J=17.6 Hz), 4.91 (1H, d, J=17.6 Hz), 5.05 (2H, br,
s), 5.18 (1H, d, J=8.5 Hz), 7.04 (1H, d, J=7.6 Hz), 7.1-7.7 (11H,
m), 8.42 (1H, d, J=8.5 Hz)
[1018] Mass (APCI): 474 (M.sup.++1)
[1019] Preparation 40-2
[1020]
(3RS)-3-Amino-5-(2-fluorophenyl)-2,3-dihydro-9-methyl-1-methylcarbo-
nylmethyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-6.
[1021] IR (Nujol, cm.sup.-1): 1720, 1670
[1022] .sup.1H-NMR(CDCl.sub.3, .delta.): 2.07 (3H, s), 2.39 (3H,
s), 3.87 (1H, d, J=17.0 Hz), 4.60 (1H, s), 4.96 (1H, d, J=17.0 Hz),
7.0-7.6 (6H, m), 7.7-7.9 (1H, m)
[1023] Mass (APCI): 340 (M.sup.++1)
[1024] Preparation 41
[1025]
(3RS)-3-Amino-2,3-dihydro-1-tert-butylcarbonylmethyl-5,9-dimethyl-1-
H-1,4-benzodiazepin-2-one was prepared in a similar manner to that
of Preparation 59-6.
[1026] IR (Nujol, cm.sup.-1): 1710, 1670, 1615
[1027] .sup.1H-N MR(CDCl.sub.3, .delta.): 1.13 (9H, s), 2.32 (3H,
s), 2.61 (3H, s), 3.79 (1H, d, J=17.2 Hz), 4.4 (1H, m), 5.29 (1H,
d, 3=17.2 Hz), 7.1-7.5 (3H, m)
[1028] Mass (APCI):302 (M.sup.++1)
[1029] Preparation 42-1
[1030] (3RS)-3-
Benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-9-me-
thyl-1-(3-nitrophenacyl)-1H-1,4-benzodiazepin-2-one was prepared in
a similar manner to that of Preparation 59-3.
[1031] mp: 86.1-89.0.degree. C.
[1032] IR (Nujol, cm.sup.-1): 1700, 1670
[1033] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 4.51 (1H, d, J=17.0
Hz), 5.52 (1H, d, J=8.6 Hz), 5.72 (1H, d, J=17.0 Hz), 6.61 (1H, d,
3=8.7 Hz), 7.0-7.8 (12H, m), 7.8-8.0 (1H, m), 8.1-8.3 (1H, m),
8.3-8.5 (1H, m), 8.68 (1H, m)
[1034] Mass (APCI): 581 (M'+1)
[1035] Preparation 42-2
[1036]
(3RS)-3-Amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(.sup.3-nit-
rophenacyl)-1H-1,4-benzodiazepin-2-one hydrobromide was prepared in
a similar procedure to that of Preparation 43.
[1037] IR (Nujol, cm.sup.-1): 1678
[1038] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.50 (3H, s), 5.04 (1H,
d, J=17.9 Hz), 5.30 (1H, s ), 5.91 (1H, d, J=17.9 Hz), 7.12 (1H, d,
J=7.6 Hz), 7.3-7.5 (3H, m), 7.5-8.0 (4H, m), 8.3-8.5 (2H, m), 8.65
(1H, m), 9.05 (2H, m)
[1039] Mass (APCI): 447 (free, M.sup.++1)
[1040] Preparation 43
[1041] A mixture of
(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(2-fluoro-
phenyl)-9-methyl-1-(2-nitrophenacyl)-1H-1,4-benzodiazepin-2-one
(300 mg) and 30% hydrobromic acid in acetic acid (3 ml) was stirred
at room temperature for 4.5 hours. Water and ice were added to the
reaction mixture to afford powder, which was collected by
filtration, and washed with water to give
(3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-9-methyl--
1-(2-nitrophenacyl)-1H-1,4-benzodiazepin-2-one hydrobromide (227mg,
81.8%).
[1042] IR (Nujol, cm.sup.-1): 1670
[1043] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.43 (3H, s), 4.79 (1H,
d, J=18.3 Hz), 5.32 (1H, s), 5.56 (1H, d, J=18.3 Hz), 7.12 (1H, d,
J=7.6 Hz), 7.2-7.4 (3H, m), 7.5-7.7 (3H, br), 7.-7-8.0 (3H, m),
8.12 (1H, d, J=7.8 Hz), 9.04 (2H, m)
[1044] Mass (APCI): 447 (free, M.sup.++1)
[1045] Preparation 44-1
[1046]
(3RS)-3-Benzyloxycarbonylamino-2,3-dithydro-1-ethylcarbonylmethyl-5-
,9-dimethyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-3.
[1047] IR (Nujol, cm.sup.-1): 1715, 1670, 1620
[1048] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.00 (3H, t, J=7.3 Hz),
2.32 (3H, s), -2.3-2.5 (2H, m), 2.60 (3H, s), 3.72 (1H, d, J=17.2
Hz), 5.0-5.2 (3H, m), 5.25 (1H, dd, J=1.4 Hz and J=8.7 Hz), 6.46
(1H, d, J=8.6 Hz), 7.2-7.5 (8H, m)
[1049] Mass (APCI): 408 (M.sup.++1)
[1050] Preparation 44-2
[1051]
(3RS)-3-Amino-2,3-dihydro-1-ethylcarbonylmethyl-5,9-dimethyl-1H-1,4-
-benzodiazepin-2-one was prepared in a similar manner to that of
Preparation 59-6.
[1052] IR (Neat, cm.sup.-1): 1720
[1053] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.00 (3H, t, J=7.3 Hz),
2.32 (3H, s), 2.3-2.6 (2H, br, m), 2.60 (3H, s), 3.70 (1H, d,
J=17.1 Hz), 4.40 (1H, m), 5.06 (1H, d, J=17.1 Hz), 7.1-7.5 (3H,
m)
[1054] Mass (APCI): 274 (M.sup.++1)
[1055] Preparation 45-1
[1056] 2-Isobutyryl-6-methylaniline was prepared in a similar
manner to that of Preparation 50-1.
[1057] mp: 47-49.degree. C.
[1058] IR (Nujol, cm.sup.-1) 3470, 3320, 1638, 1607, 1580, 1550,
1422, 1380, 1230, 1094, 1011, 984, 745
[1059] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.21 (6H, d, J=6.8 Hz),
2.16 (3H, s), 3.62 (1H, hept, J=6.8 Hz), 6.4 (1H, br), 6.60 (JH, I,
J=7.3 Hz), 7.19 (1H, d, J=7.3 Hz), 7.69 (1H, d, J=7.3 Hz)
[1060] APCI-MS (m/z): 178 (M.sup.++1)
[1061] Preparation 45-2
[1062] To a solution of
N-benzyloxycarbonyl-2-(benzotriazol-1-yl)glycine (10.77 g) in dry
tetrahydrofuran (80 ml) were added oxalyl chloride (2.88 ml) and
one drop of dimethylformamide at 0.degree. C. under stirring and
nitrogen stream. The mixture was stirred for 2 hours under the same
conditions. To the reaction mixture was added dropwise a mixture of
2-isobutyryl-6-methylaniline (5.32 g) and N-methylmorpholine (6.68
g) in dry tetrahydrofuran (30 ml) for 20 minutes under the same
conditions. After the addition was completed, the mixture was
stirred at ambient temperature for 0.5 hour. The resultant
precipitate was filtered off and the filtrate and washings were
combined and evaporated in vacuo. The residue was dissolved in 20%
methanolic ammonia (80 ml) and stirred at ambient temperature
overnight. The resultant precipitate was collected by filtration
and washed with cold methanol to give the first crop of the desired
product (3.25 g, 29.6%). The filtrate and the washings were
combined and evaporated in vacuo to afford a residue; which was
dissolved in ethyl acetate and washed with 1N--NaOH aqueous
solution and water. The organic layer was dried over magnesium
sulfate and evaporated to give a residual oil, which was dissolved
in acetic acid (70 ml) and treated with ammonium acetate (7.0 g)
for 4 hours at ambient temperature. After removal of acetic acid in
vacuo, the residue was dissolved in ethyl acetate and washed with
diluted hydroxide aqueous solution and water successively. The
organic layer was dried over magnesium sulfate and evaporated in
vacuo to give an orange oil, which was triturated in methanol
overnight to afford the second crop of the desired product (1.01 g,
9.2%),
(3RS)-3-benzyloxycarbonylamino-5-isopropyl-9-methyl-2,3-dihydro-
-1H-1,4-benzodiazepin-2-one.
[1063] mp: 169.1-172.8.degree. C.
[1064] IR (Nujol, cm.sup.-1): 3300 (sh), 3200, 1710, 1690, 1614,
1514, 1398, 1367, 1055, 990, 798, 750, 687
[1065] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.91 (3H, d, J=7.0 Hz),
1.27 (3H, d, J=7 Hz), 2.36 (3H, s), 3.13 (1H, hept, J=7.0 Hz), 5.11
(2H, s), 5.15 (1H, d, J=8.4 Hz), 6.46 (1H, d, J=8.4 Hz), 7.1-7.45
(8H, m), 8.59 (1H, s)
[1066] APCI-MS (m/z): 366 (M-+1)
[1067] Preparation 45-3
[1068]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl--
5-isopropyl-9-methyl-1H-1,4-benzodiazepin-10-2-one was prepared in
a similar manner to that of Preparation 59-3.
[1069] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.1-1.4 (3H, m), 2.34
(3H, s), 3.1-3.4 (1H, m), 3.82 (1H, d, J=16.7 Hz), 4.12 (2H, q,
J=7.1 Hz), 4.72 (1H, d, J=16.7 Hz), 5.0-5.2 (2H, m), 5.2-5.3 (1H,
m), 6.49 (1H, d, J=8.6 Hz), 7.2-7.5 (8H, m)
[1070] Mass (APCI): 452 (M-+1)
[1071] Preparation 45-4
[1072]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-5-isopro-
pyl-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-4.
[1073] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.0-1.4 (6H, m), 2.32
(3H, br, s), 3.1-3.3 (1H, m), 3.84 (1H, d, J=17.0 Hz), 4.76 (1H, d,
J=17.0 Hz), 5.0-5.2 (2H, m), 5.22 (1H, d, J=8.1 Hz), 6.54 (1H, d,
J=8.7 Hz), 7.2-7.5 (8H, m)
[1074] Mass (APCI): 424 (M.sup.++1)
[1075] Preparation 45-5
[1076]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxyca-
rbonylamino-2,3-dihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-5.
[1077] IR (Nujol, cm.sup.-1): 1720, 1650
[1078] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.22 (3H, d, J=7.1 Hz),
1.33 (3H, d, J=6.6 Hz), 1.4-1.9 (8H, m), 1.9-2.1 (2H, m), 2.36 (3H,
br, s), 3.1-3.9 (SH, m), 3.86 (1H, d, J=15.5 Hz), 5.0-5.2 (2H, m),
5.24 (1H, d, J=8.2 Hz), 6.50 (1H, d, J=8.7 Hz), 7.2-7.5 (8H, m)
[1079] Mass (APCI): 531 (M.sup.++1)
[1080] Preparation 45-6
[1081]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-d-
ihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-one was prepared
in a similar manner to that of Preparation 59-6.
[1082] IR (Nujol, cm.sup.-1) 3330, 3250, 1660, 1630
[1083] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-1.3 (3H, m), 1.34
(3H, d, J=6.6 Hz), 1.5-2.3 (1OH, m), 2.36 (3H, s), 3.21 (1H, m),
3.4-3.9 (4H, m), 3.87 (1H, d, J=15.5 Hz), 4.38 (1H, s), 5.02 (1H,
d, J=15.5 Hz), 7.1-7.5 (3H, m)
[1084] Mass (APCI): 397 (M.sup.++1)
[1085] Preparation 46-1
[1086]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5,9-dimethyl-1-methylcar-
bonylmethyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-3.
[1087] IR (Neat, cm.sup.-1): 1720, 1670
[1088] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.06 (3H, s), 2.32 (3H,
s), 2.60 (3H, s), 3.75 (1H, d, J=17.4 Hz), 5.0-5.2 (3H, m), 5.25
(1H, dd, J=1.4 Hz and 8.7 Hz), 6.47 (1H, d, J=8.6 Hz), 7.2-7.5 (8H,
m)
[1089] Mass (APCI): 394 (M.sup.++1)
[1090] Preparation 46-2
[1091]
(3RS)-3-Amino-2,3-dihydro-5,9-dimethyl-1-methylcarbonylmethyl-1H-1,-
4-benzodiazepin-2-one was prepared in a similar manner to that of
Preparation 59-6.
[1092] IR (Neat, cm.sup.-1): 1720, 1650
[1093] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.07 (3H, s), 2.32 (3H,
s), 2.59 (3H, s), 3.72 (1H, d, J=17.4 Hz), 5.4 (1H, m), 5.08 (1H,
d, J-17.3 Hz), 7.1-7.5 (3H, m)
[1094] Mass (APCI): 260 (M.sup.++1)
[1095] Preparation 47-1
[1096]
(3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-1-cyclopropyl-carbonylm-
ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was prepared
in a similar manner to that of Preparation 59-3.
[1097] .sup.1H-NMR(CDCl.sub.3, .delta.): 0.8-1.2 (4H, m), 1.2-2.0
(1H, m), 2.0-2.2 (1H, m), 2.34 (3H, br, s), 2.84 (1H, m), 4.01 (1H,
d, J=17.1 Hz), 4.96 (1H, d, J=17.1 Hz), 5.0-5.2 (2H, m), 5.21 (1H,
d, J=8.2 Hz), 6.49 (1H, d, J=8.7 Hz), 7.2-7.5 (8H, m)
[1098] Mass (APCI): 488 (M.sup.++1)
[1099] Preparation 47-2
[1100]
(3RS)-3-Amino-5-cyclohexyl-1-cyclopropylcarbonylmethyl-2,3-dihydro--
9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-6.
[1101] IR (Nujol, cm.sup.-1): 1675
[1102] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.8-2.0 (14H, m), 2.0-2.2
(1H, m), 2.34 (3H, s), 2.7-2.9 (1H, m), 4.01 (1H, d, J=17.1 Hz),
4.39 (1H, br, s), 4.95 (1H, d, J=17.1 Hz), 7.1-7.5 (3H, m)
[1103] Mass (APCI): 354 (M'+1)
[1104] Preparation 48
[1105]
(3RS)-3-Amino-2,3-dihydro-1-ethoxycarbonylmethyl-5,9-dimethyl-1H-1,-
4-benzodiazepin-2-one was prepared in a similar manner to that of
Preparation 59-6.
[1106] IR (Neat, cm.sup.-1): 3380, 3300, 1738, 1680, 1620
[1107] .sup.1H-NMR(CDCl.sub.3, .delta.):1.19 (3H, t, J=7.1 Hz),
2.24 (2H, m), 2.33 (3H, s), 2.55 (3H, s), 3.75 (1H, d, J=16.9 Hz),
4.09 (2H, q, J=7.1 Hz), 4.40 (1H, br, s ), 4.94 (1H, d, J=16.9 Hz),
7.1-7.7 (3H, m)
[1108] Mass (APCI): 290 (M.sup.++1)
[1109] Preparation 49-1
[1110]
(3RS)-3-Benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1--
(1-triphenylmethylimidazol-4-yl)methyl-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-3.
[1111] IR (Nujol, cm.sup.-1) 720, 1675
[1112] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.0-2.2 (10H, m), 2.35
(3H, br, s), 2.67 (1H, m), 4.23 (1H, d, J=14.5 Hz), 5.0-5.2 (3H,
br), 5.32 (1H, d, J=14.4 Hz), 6.51 (1H, d, J=8.3 Hz), 6.77 (1H, br,
s), 6.9-7.5 (24H, m)
[1113] Mass (FAB): 728 (M'+1)
[1114] Preparation 49-2
[1115] A mixture of
(3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydr-
o-9-methyl-1-(1-triphenylmethylimidazol-4-yl)methyl-1H-1,4-benzodiazepin-2-
-one (0.5 g) and 30% hydrobromic acid in acetic acid (2.0 ml) was
stirred at room temperature overnight. The reaction mixture was
poured into a mixture of an ice and ethyl acetate under stirring.
The separated water layer was washed with ethyl acetate once, and
neutralized with a saturated aqueous solution of sodium
bicarbonate. The resultant aqueous mixture was extracted with ethyl
acetate and the extract was dried over sodium sulfate. Removal of
the solvent in vacuo afforded
(3RS)-3-amino-5-cyclohexyl-2,3-dihydro-1-(imidazol-4-yl)methyl-9-methyl-1-
H-1,4-benzodiazepin-2-one (174mg, 72.1%) as a crystalline
powder.
[1116] IR (Nujol, cm.sup.-1): 1670, 1610
[1117] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.9-2.0 (10H, m), 2.42
(3H, s), 2.5-2.7 (1H, m), 4.19 (1H, d, J=14.7 Hz), 4.29 (1H, br,
s), 5.31 (1H, d, J=14.7 Hz), 6.73 (1H, br, s), 7.1-7.5 (6H, m)
[1118] Mass (APCI): 352 (M.sup.++1)
[1119] Preparation 50-1
[1120] To a mixture of 2-toluidine (32.8 g, 0.30 ml) and
acetonitrile (6.22 g, 0.15 mol) in dry toluene (200 ml) was added
1N-solution of boron trichloride in toluene (150 ml) dropwise under
stirring and Gooling in an ice-bath for 2 hours. After the addition
was completed, the mixture was stirred for 1 hour at ambient
temperature and cooled again. To the cooled mixture was added
aluminum chloride (20.0 g, 0.15 mol) portionwise. The resultant
mixture was stirred at ambient temperature for 1 hour and refluxed
for 5 hours. After cooling the reaction mixture in an ice-bath,
2N-HCl (200 ml) was added. The mixture was then refluxed for 2.5
hours. After cooling the mixture, ethyl acetate was added. The
separated organic layer was washed with water twice and dried over
magnesium sulfate. Removal of the solvent in vacuo gave crystals,
which was washed with n-hexane with stirring and collected by
filtration to give 2-acetyl-6-methylaniline as a yellow crystal
(8.91 g, 39.8%).
[1121] mp 51.1-52.9.degree. C.
[1122] IR (Nujol, cm.sup.-1): 3410, 3300, 1630 (sh), 1610, 960,
740
[1123] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.16 (3H, s), 2.59 (3H),
6.4 (1H, br), 6.59 (1H, t, J=7.9 Hz), 7.19 (1H, d, J=7.9 Hz), 7.63
(1H, d, J=7.9 Hz)
[1124] APCI-MS (m/z): 150 (M.sup.++1)
[1125] Preparation 50-2
[1126] To a solution of
N-benzyloxycarbonyl-2-(benzotriazol-1-yl)glycine (14.11 g) in dry
tetrahydrofuran (100 ml) were added oxalyl chloride (3.77 ml) and
dimethylformamide (3 drops) under stirring at 0.degree. C. in an
ice-salt bath under nitrogen stream. After the mixture was stirred
under the same conditions for 2 hours, a mixture of
2-acetyl-6-methylaniline (4.30 g) and N-methylmorpholine (8.74 g)
in tetrahydrofuran (20 ml) was added dropwise for 20 minutes. After
the addition was completed, the mixture was allowed to warm to
ambient temperature with stirring. Tetrahydrofuran was removed in
vacuo and the residue was dissolved in ethyl acetate. The mixture
was washed with water twice and dried over magnesium sulfate.
Removal of the solvent gave an intermediate product as an oil, to
which was added 20% methanolic ammonia (75 ml) and stirred at
ambient temperature overnight. The resultant precipitate was
collected by filtration and washed with cold methanol and
diisopropyl ether successively, and dried to give
(3RS)-3-benzyloxycarbon-
ylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one as a
white crystalline powder (6.17 g, 63.5%).
[1127] mp 238-239.5.degree. C.
[1128] IR (Nujol, cm.sup.-1): 3210, 1718, 1690, 1678, 1628, 1059,
742, 699
[1129] .sup.1H-NMR (CDCL .sub.3, .delta.) 2.36 (3H, s), 2.46 (3H,
s), 5.11 (2H, s), 5.14 (1H, d, J=8.3 Hz), 6.50 (1H, d, J=8.3 Hz),
7.13-7.47 (8H, m), 8.48 (1H, s)
[1130] APCI-MS (m/z):338 (M.sup.++1)
[1131] Preparation 50-3
[1132] To a suspension of
(3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3--
dihydro-1H-1,4-benzodiazepin-2-one (3.22 g) in methylene chloride
(50 ml) was added m-chloroperbenzoic acid (2.50 g, 1.5 eq.mol)
portionwise under stirring at ice-bath cooling. The mixture was
stirred for 3 days at ambient temperatures. From the reaction
mixture methylene chloride was removed in vacuo and to the residue
was added an aqueous solution of sodium bicarbonate and stirred for
several minutes. The mixture was extracted with ethyl acetate twice
and the combined extract was washed with aqueous sodium
bicarbonate, water twice and brine. The organic layer was dried
over magnesium sulfate and evaporated in vacuo to afford an
amorphous mass, which was triturated in methanol and collected by
filtration to give
(3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydr-
o-1H-1,4-benzodiazepin-2-one-4-oxide (2.59 g) as a crystalline
powder. From the mother liquid, the second crop (0.25 g) of the
desired powder was prepared by crystallization in a mixture of
methanol and diisopropyl ether (3:1).
[1133] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.38 (6H, s), 5.08 (2H,
dd, J=12.9 Hz, 14.8 Hz), 5.45 (1H, d, J=9.3 Hz), 7.15-7.52 (8H, m),
7.89 (1H, d, J=9.3 Hz), 10.49 (1H, s)
[1134] APCI-MS (m/z): 354 (M.sup.++1)
[1135] Preparation 50-4
[1136] A mixture of
(3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydr-
o-1H-1,4-benzodiazepin-2-one-4-oxide (2.83 g) and acetic anhydride
(7.6 ml, 10 eq.mol) in methylene chloride (60 ml) was stirred for 4
days. From the reaction mixture methylene chloride was removed in
vacuo. To the residue was added a mixture (60 ml) of diisopropyl
ether and n-hexane (1:1). The resultant crystalline powder was
collected by filtration and washed with diisopropyl ether to give
(3RS)-3-benzyloxycarbonylamino-5-ac-
etoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepine-2-one (2.26
g, 71.1%) as a crystalline powder.
[1137] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.01 (3H, s), 2.36 (3H,
s), 4.95-5.29 (5H, m), 6.48 (1H, d, J=8.3 Hz), 7.12-7.47 (8H, m),
7.94 (1H, s)
[1138] APCI-MS (m/z): 396 (M.sup.++1)
[1139] IR (Nujol, cm.sup.-1) 3200, 1740, 1686
[1140] Preparation 50-5
[1141] To a solution of
(3RS)-3-benzyloxycarbonylamino-5-acetoxymethyl-9-m-
ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (2.24 g) in
dimethylformamide (40 ml) was added portionwise sodium hydride (60%
suspension in mineral oil, 0.227 g) under stirring and ice-bath
cooling. After the addition was completed, the suspension was
stirred for 1 hour at ambient temperature. Then to the mixture
after ice-bath cooling again was added dropwisc a solution of
t-butyl bromoacetate (1.11 g) in dimethylformamide (5 ml). The
mixture was .stirred for 10 minutes under cooling and for 3.5 hours
at ambient temperature.
[1142] The reaction mixture was poured into ice-water and extracted
with ethyl acetate. The extract was washed with water three times
and dried over magnesium sulfate. Removal of the solvent afforded
(3RS)-3-benzyloxycarbonylamino-1-t-butoxycarbonylmethyl-5-acetoxymethyl-9-
-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one 2.75 g, 95.2%) as an
amorphous mass which was used in a following reaction without
further purification.
[1143] .sup.1H-NMR (CDCl.sub.3 , .delta.): 1.37 (9H, s), 2.09 (3H,
s), 2.34 (3H, s), 4.22 (2H, dd, J=16.8 Hz, 210.1 Hz), 5.09 (2H, s),
5.20 (2H, s), 5.29 (1H, d, J=8.6 Hz), 6.52 (1H, d, J=8.6 Hz),
7.25-7.52 (8H, m)
[1144] APCI-MS (m/z): 510 (M.sup.++1)
[1145] Preparation 50-6
[1146] To a solution of
(3RS)-3-benzyloxycarbonylamino-1-t-butoxycarbonylm-
ethyl-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
(3.02 g) in methylene chloride (45 ml) was added trifluoroacetic
acid (4.6 ml) under stirring at ambient temperature. The mixture
was stirred for 20 hours under the same conditions. Methylene
chloride was removed in vacuo and the residue was dissolved in
ethyl acetate. The solution was washed with water four times and
dried over magnesium sulfate. Removal of the solvent afforded an
amorphous mass (2.82 g), which was subjected to column
chromatography on silica gel eluting with a mixture of chloroform
and methanol (30:1). The fractions containing the desired product
were combined and evaporated to give
(3RS)-3-benzyloxycarbonylamino-1-carboxym-
ethyl-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
(1.89 g, 70.3%) as a crystalline powder.
[1147] IR (Nujol, cm.sup.-1): 3300, 2800-2200 (br), 1740 (sh),
1720, 1690, 1375, 1230, 1060, 750
[1148] .sup.1H-NMR (DMSO-d.sub.6, .delta.):2.04 (3H, s), 2.33 (3H,
s), 4.25 (2H, dd, J=17.0 Hz, 139.4 Hz), 4.96 (1H, d, J=8.32 Hz),
5.02 (2H, s), 5.17 (2H, dd, J=14.4 Hz, 57.4 Hz), 7.3-7.65 (8H, m),
8.31 (1H, d, J=8.32 Hz)
[1149] APCI-MS (m/z): 454 (M.sup.++1)
[1150] Preparation 50-7
[1151] A mixture of
(3RS)-3-benzyloxycarbonylamino-1-carboxymethyl-5-aceto-
xymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (343.Omg),
3-azabicyclo[3.2.2]nonane (106.3mg), 1-hydroxybenzotriazole (HOBT,
112.4mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (WSCD, 160.3 mg) and triethylamine (84.1 mg) in
dimethylformamide (7 ml) was stirred for 12 hours at ambient
temperature. The reaction mixture was poured into water and the
mixture was extracted with ethyl acetate twice. The organic extract
was washed with water three times and dried over magnesium sulfate.
Removal of the solvent afforded an oil (0.45 g), which was
pulverized in diisopropyl ether and collected by filtration to give
(3RS)-3-benzyloxycarbonylamino-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmet-
hyl-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
(339.Omg, 80.0%) as a light yellow crystalline powder.
[1152] IR (Nujol, cm.sup.-1): 3370, 1751, 1729, 1677, 1642, 1508,
1230, 1056, 760
[1153] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-1.8 (8H, m),
1.85-2.15 (2H, m), 2.07 (3H, s), 2.37 (3H, s), 3.04-3.31 (2H, m),
3.60-3.82 (2H, m), 4.68 (2H, dd, J=14.7 Hz, 288.3 Hz), 4.90-5.14
(5H, m), 7.34-7.62 (8H, m), 8.26 (1H, d, J=8.6 Hz)
[1154] APCI-MS (m/z): 561 (M.sup.++1)
[1155] Preparation 50-8
[1156] A mixture of
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]--
3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzo-
diazepin-2-one (320 mg), ammonium formate (144 mg) and 10%
Pd-C(wet) (80 mg) in 99% ethanol (5 ml) was stirred for 4 hours.
The catalyst was removed by filtration through Celite and the
filtrate and the washings were combined and evaporated in vacuo to
afford a residue, which was subjected to column chromatography on
silica gel eluting with a mixture of chloroform and methanol
(20:1). The fractions containing the desired product were combined
and evaporated to give (3RS)-3-amino-1-[(3-azabicyc-
lo[3.2.2]non-3-yl)carbonylmethyl]-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodia-
zepin-2-one as an amorphous mass (178.8mg, 85.1%).
[1157] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.55-1.77 (8H, m),
1.95-2.17 (2H, m), 2.35 (3H, s), 2.57 (3H, m), 3.29(2H, br, s),
3.36 (2H, m), 3.56-3.86 (2H, m), 4.44 (1H, s), 4.50 (2H, dd, J=15.7
Hz, 295.5 Hz), 7.18-7.40 (3H, m)
[1158] APCI-MS (m/z): 369 (M.sup.++1)
[1159] Preparation 51-1
[1160]
(3RS)-1-(2-Acetylbenzyl)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3--
dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-3.
[1161] IR (Nujol, cm.sup.-1): 1660
[1162] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-2.2 (10H, m), 2.38
(3H, s), 2.41 (3H, s), 2.8-3.0 (1H, m), 4.21 (1H, d, J=17.1 Hz),
5.0-5.2 (2H, m), 5.28 (1H, d, J=8.2 Hz), 5.40 (1H, d, J=17.1 Hz),
6.51 (1H, d, J=8.6 Hz), 7.2-7.5 (11H, m), 7.60 (1H, d, J=77 Hz)
[1163] Mass (APCI): 538 (M.sup.++1)
[1164] Preparation 51-7
[1165]
(3RS)-1-(2-Acetylbenzyl)-3-amino-5-cyclohexyl-2,3-dihydro-9-methyl--
1H-1,4-benzodiazepin-2-one was prepared in a similar manner to that
of Preparation 59-6.
[1166] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-2.3 (10H, m), 2.37
(3H, s), 2.38 (3H, s), 2.8-3.0 (1H, m), 4.21 (1H, d, J=17.0 Hz),
4.43 (1H, br, s), 5.39 (1H, d, J=17.0 Hz), 5.2-5.6 (6H, m), 7.6-7.7
(1H, m)
[1167] Mass (APCI): 404 (M.sup.++1)
[1168] Preparation 52-1
[1169] To a solution of 3-azabicyclo[3.2.2]nonane (1.1 g) and
triethylamine (0.88 g) in methylene chloride (25 ml) was added
portionwise 2-chloroacetyl-6-methylaniline (1.47 g) under stirring
and cooling in an ice-bath. After the addition was completed, the
mixture was stirred at ambient temperature overnight. Removal of
the solvent afforded a residue, which was dissolved in ethyl
acetate and washed with water and brine. The organic layer was
dried over magnesium sulfate and evaporated in vacuo to give a
crystalline mass, which was pulverized in a mixture of n-hexane and
diisopropyl ether. A dark yellow crystal was collected by
filtration to give
2-[(3-azabicyclo[3.2.2]non-3-yl)acetyl]-6-methylanilin- e (1.92 g,
88.2%).
[1170] IR (Nujol, cm.sup.-1) 3440, 3325, 1630, 1608, 1580, 1552,
1374, 1312, 1136, 1000, 944, 868, 857, 749
[1171] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.48-1.9 (10H, m), 2.16
(3H, s), 2.68 (4H, d, J=4.2 Hz), 3.68 (2H, s), 6.38 (1H, br), 6.58
(1H, t, J=7.3 Hz), 7.19 (1H, d, J=7.3 Hz), 8.10 (1H, d, J=7.3
Hz)
[1172] APCI-MS (m/z): 273 (M.sup.++1)
[1173] Preparation 52-2
[1174]
(3RS)-3-Benzyloxycarbonylamino-5-(3-azabicyclo[3.2.2]non-3-yl)methy-
l-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 45-2.
[1175] mp: 149.2-151.4.degree. C.
[1176] IR (Nujol, cm.sup.-1): 3400 (sh), 3220, 1718, 1700, 1681,
1532, 1374, 1058, 980, 778, 749, 691
[1177] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-1.8 (10H, m), 2.36
(3H, s), 2.35-2.7 (4H, m), 3.45 (1H, br, d, J=14.3 Hz), 3.90 (1H,
d, J=14.3 Hz), 5.11 (2H, s), 5.19 (1H, d, J=8.2 Hz), 6.54 (1H, d,
J=8.2 Hz), 7.1-7.8 (8H, m), 8.02 (1H, s)
[1178] APCI-MS (m/z): 461 (M.sup.++1)
[1179] Preparation 52-3
[1180]
(3RS)-5-[(3-Azabicyclo[3.2.2]non-3-yl)methyl]-3-benzyloxycarbonylam-
ino-2,3-dihydro-1,9-dimethyl-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-3.
[1181] IR (Nujol, cm.sup.-1): 1720, 1670, 1620
[1182] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-1.8 (10H, m), 2.35
(3H, s), 2.4-2.7 (4H, m), 3.15 (3H, s), 3.3-3.5 (1H, br, s),
3.9-4.1 (1H, br, s), 5.0-5.2 (2H, m), 5.23 (1H, d, J=8.4 Hz), 6.64
(1H, d, J=8.5 Hz), 7.2-7.6 (8H, m)
[1183] Mass (APCI): 475 (M.sup.++1)
[1184] Preparation 52-4
[1185]
(3RS)-3-Amino-5-[(3-azabicyclo[3.2.2]non-3-yl)methyl]-2,3-dihydro-1-
,9-dimethyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-6.
[1186] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-1.8 (10H, m), 2.35
(3H, s), 2.3-2.6 (4H, m), 3.15 (3H, s), 3.2-3.4 (1H, m), 3.9-4.1
(1H, br, s), 4.40 (1H, m), 3.2-3.6 (3H, m)
[1187] Mass (APCI): 341 (M.sup.++1)
[1188] Preparation 53-1
[1189] To a solution of 2-chloroacetyl-6-methylaniline (1.84 g) in
methanol (50 ml) was added 28% methanolic sodium methoxide (5.79 g,
3 eq.mol.) under stirring and cooling in an ice-bath. The mixture
was stirred for 0.5 hour under cooling and at ambient temperature
overnight. Methanol was removed in vacuo to afford a residue, which
was dissolved in ethyl acetate and washed with water and brine
successively. The organic layer was dried over magnesium sulfate
and evaporated in vacuo to give an oil which was subjected to
column chromatography on silica gel eluting with chloroform. The
fractions containing the desired product were combined and
evaporated to give 2-methoxyacetyl-6-methylaniline (1.07 g, 59.7%
yield) as an oil.
[1190] IR (Film, cm.sup.-1) 3410, 3340, 1655, 1620 (sh), 1610,
1585, 1560, 1460, 1429, 1380, 1235, 1200, 1120, 1025, 982, 963,
930, 770 (sh), 744
[1191] .sup.1H-NMR (CDCl.sub.3, .delta.):2.17 (3H, s), 3.51 (3H,
s), 4.70 (2H, s), 6.41 (1H, br), 6.58 (1H, t, J=7.3 Hz), 7.19 (1H,
d, J=7.3 Hz), 7.49 (1H, d, J=7.3 Hz)
[1192] APCI-MS (m/z): 180 (M.sup.++1)
[1193] Preparation 53-2
[1194]
(3RS)-3-Benzyloxycarbonylamino-5-methoxymethyl-9-methyl-2,3-dihydro-
-1H-1,4-benzodiazepin-2-one was prepared in a similar manner to
that of Preparation 45-2.
[1195] IR (Nujol, cm.sup.-1): 3250 (sh), 3210, 1719, 1696, 1685
(sh), 1530, 1394, 1374, 1085, 1060, 985, 970, 780, 750
[1196] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.37 (3H, s), 3.31 (3H,
s), 4.50 (2H, dd, J=13.5 Hz, J=49.8 Hz), 5.11 (2H, s), 5.18 (1H,
br, d), 6.58 (1H, br, d), 7.15-7.6 (8H, m), 8.30 (1H, s)
[1197] APCI-MS (m/z): 368 (M.sup.++1)
[1198] Preparation 53-3
[1199]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl--
5-methoxymethyl-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in
a similar manner to that of Preparation 59-3.
[1200] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.22 (3H, t, J=7.1 Hz),
2.34 (3H, br, s), 3.46-3.48 (3H, m), 3.6-4.0 (2H, m), 4.12 (2H, q,
J=7.1 Hz), 4.0-4.3 (1H, br), 4.8-5.1 (1H, br, s), 5.1-5.3 (2H, m),
5.3-5.7 (1H, m), 6.5-6.8 (1H, m), 7.2-7.6 (8H, m)
[1201] Mass (APCI): 454 (M.sup.++1)
[1202] Preparation 53-4
[1203]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-9-methyl-
-5-methoxymethyl-1 H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-4.
[1204] IR (Neat, cm.sup.-1): 1720, 1680
[1205] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.34 (3H, s), 3.4-3.9
(6H, m), 5.0-5.3 (2H, m), 5.4-5.7 (1H, m), 6.6-6.8 (1H, m), 7.2-7.6
(8H, m)
[1206] Mass (APCI): 426 (M.sup.++1)
[1207] Preparation 53-5
[1208]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxyca-
rbonylamino-2,3-dihydro-5-methoxymethyll-9-methyl-1H-1,4-benzodiazepin-2-o-
ne was prepared in a similar manner to that of Preparation
59-5.
[1209] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.4-1.9 (8H, m), 1.9-2.2
(2H, m), 2.36 (3H, s), 3.2-3.4 (2H, m), 3.49 (3H, s), 3.5-3.7 (2H,
br), 3.7-3.9 (2H, m), 4.6-4.8 (1H, m), 5.1-5.3 (3H, m), 5.3-5.4
(1H, m), 6.5-6.6 (1H, br), 7.2-7.6 (8H, m)
[1210] Mass (APCI): 533 (M.sup.++1)
[1211] Preparation 53-6
[1212]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-y1)carbonylmethyl]-2,3-d-
ihydro-5-methoxymethyl-9-methyl-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-6.
[1213] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.4-2.1 (10H, m), 2.35
(3H, s), 3.2-3.5 (2H, m), 3.61 (3H, s), 3.6-3.9 (4H, m), 4.5-4.8
(2H, m), 5.21 (1H, d, J=15.6 Hz), 7.1-7.6 (3H, m)
[1214] Mass (APCI): 399 (M'+1)
[1215] Preparation 54-1
[1216] To a solution of
(3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-di-
hydro-9-methyl-1-[N-methyl-N-(2-pyridyl)amino]carbonyimethyl-1H-1,4-benzod-
iazepin-2-one (400 mg) in tetrahydrofuran (4 ml) was added
cyclohexyl magnesium chloride (1.08 ml) under stirring, at
0.degree. C. The mixture was stirred for twenty minutes under the
same conditions and at room temperature overnight. Ethyl acetate
and a saturated aqueous solution of ammonium chloride were added to
the reaction mixture. The separated organic layer was washed with
0.1N aqueous hydrochloric acid, water, a saturated aqueous sodium
bicarbonate solution and brine successively and dried under
magnesium sulfate. The solvent was removed in vacuo to afford a
residue, which was subjected to column chromatography on silica gel
eluting with a mixture of toluene and ethyl acetate (20:1) to give
(3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-1cyclohexylcarbonylmethyl-2,3-
-dihydro-9-methyl1H-1R,4-benzodiazepin-2-one.
[1217] .sup.1H-NMR (CDC.sub.3, .delta.): 1.1-2.0 (20H, m), 2.0-2.2
(1H, m), 2.31 (3H, s), 2.85 (JH, br, s), 3.81 (1H, d, J=17.0 Hz),
4.88 (1H, d, J=17.0 Hz), 5.07-5.08 (2H, m), 5.19 (1H, d, J=9 Hz),
6.42 (1H, d, J=9 Hz), 7.1-7.5 (8H, br, m)
[1218] Mass (APCI): 530 (M.sup.++1)
[1219] Preparation 54-2
[1220]
(3RS)-3-Amino-5-cyclohexyl-1-cyclohexylcarbonylmethyl-2,3-dihydro-9-
-methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar manner
to that of Preparation 59-6.
[1221] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.1-2.2 (10H, m), 2.31
(3H, s), 2.3-2.5 (1H, br, s), 3.82 (1H, d, J=16.9 Hz), 4.35 (1H,
s), 4.86 (1H, d, J=16.9 Hz), 7.2-7.5 (3H, m)
[1222] Mass (APCI): 396 (M'+1)
[1223] Preparation 55-1
[1224] 2-Chloroacetyl-6-methylaniline was prepared in a similar
manner to that of Preparation 50-1.
[1225] IR (Nujol, cm.sup.-1): 3400, 3340, 1655, 1610, 1587, 1560,
1380, -788, 738, 700
[1226] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.17 (3H, s), 4.70 (2H,
s), 6.2 (1H, br), 6.60 (1H, t, J=7.2 Hz), 7.22 (1H, d, J=7.2 Hz),
7.53 (1H, d, J=7.2 Hz)
[1227] APCI-MS (m/z): 184 (M.sup.++1), 186 (M.sup.++3)
[1228] Preparation 55-2
[1229] To a solution of 2-chloroacetyl-6-methylaniline (2.0 g) in
methylene chloride (20 ml) was added 1-methylpiperazine (2.29 g)
under stirring and cooling in an ice-bath. The mixture was stirred
overnight at ambient temperature. Methylene chloride was removed in
vacuo and to the residue were added ethyl acetate and diluted
aqueous solution of sodium bicarbonate. From the aqueous layer the
desired product was extracted with ethyl acetate five times and
combined organic extract was washed with brine. After drying over
magnesium sulfate, the solvent was removed in vacuo to give
2-[(4-methylpiperazin-1-yl)acetyl]-6-methylaniline (2.07 g, 76.9%
yield) as a crystalline mass.
[1230] IR (Nujol, cm.sup.-1) 3380, 3280, 1654, 1610, 1588, 1562,
1375, 1280, 1141, 1005, 974, 780, 740
[1231] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.16 (3H, s), 2.31 (3H,
s), 2.55 (4H, br, m), 2.65 (4H, br, m), 3.79 (2H, s), 6.41 (1H, br,
s), 6.57 (1H, t, J=7.3 Hz), 7.20 (1H, d, J=7.3 Hz), 7.72 (1H, d,
J=7.3 Hz)
[1232] APCI-MS (m/z): 248 (M.sup.++1)
[1233] Preparation 55-3
[1234]
(3RS)-3-Benzyloxycarbonylamino-5-(4-methylpiperazin-1-yl)methyl-9-m-
ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 45-2.
[1235] .sup.1H-NMR (CDCl.sub.3, 5): 2.25 (3H, s), 2.35 (3H, s),
2.2-2.5 (8H, m), 3.58 (2H, dd, J=13.7 Hz, 45.9 Hz), 5.10 (2H, s),
5.16 (1H, d, J=8.2 Hz), 6.56 (1H, d, J=8.2 Hz), 7.1-7.73 (8H, m),
8.05 (1H, s)
[1236] APCI-MS (m/z):436 (M.sup.++1)
[1237] Preparation 55-4
[1238]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1,9-dimethyl-5-(4-methyl-
piperazin-1-yl)methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-3.
[1239] IR (Nujol, cm.sup.-1):1710, 1680
[1240] .sup.1H-NMR(CDCl.sub.3, .delta.): 2.27 (3H, s), 2.35 (3H,
s), 3.17 (3H, s), 2.4-2.6 (8H, m), 3.40 (1H, d, J=13.5 Hz), 3.81
(1H, d, J=13.5 Hz), 5.0-5.3 (3H, br, m), 6.63 (1H, d, J=8.2 Hz),
7.2-7.6 (8H, m)
[1241] Mass (APCI): 450 (M.sup.++1)
[1242] Preparation 56-1
[1243] Dimethylamine aqueous solution (50%, 5.41 g) was added to a
solution of 2-chloroacetyl-6-methylaniline (3.67 g) in methanol (50
ml) under stirring and cooling in an ice-bath. The mixture was
stirred for 3 hours at ambient temperature. Methanol was removed in
vacuo to give a residue, which was dissolved in ethyl acetate and
washed with water. From the organic layer a basic subrtance was
extracted with 1N-hydrochloric acid twice. The aqueous extract was
washed with ethyl acetate and basidified with 1N-sodium hydroxide
aqueous solution. The mixture was extracted with ethyl acetate
twice and washed with water and brine. The organic extract was
dried over magnesium sulfate and evaporated in vacuo to afford an
oil (2.58 g), which was pulverized in a mixture of n-hexane and
diisopropyl ether (1:1) and collected by filtration to give
2-(N,N-dimethylamino)acetyl-6-methylaniline (2.03 g, 52.8% yield)
as a yellow crystalline powder.
[1244] IR (Nujol, cm.sup.-1): 3410, 3300, 1640, 1612, 1585, 1552,
1378, 1008, 983, 862, 770, 745
[1245] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.16 (3H, s), 2.37 (6H,
s), 3.71 (2H, s), 6.41 (1H, br), 6.58 (1H, dd, J=7.2 Hz, 8.1 Hz)
7.18 (1H, d, J=7.2 Hz), 7.71 (1H, d, J=7.2 Hz)
[1246] APCI-MS (m/z): 193 (M.sup.++1)
[1247] Preparation 56-2
[1248]
(3RS)-.sup.3-Benzyloxycarbonylamino-5-(N,N-dimethylamino)methyl-9-m-
ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 45-2.
[1249] mp: 204.1-205.2.degree. C.
[1250] IR (Nujol, cm.sup.-1): 3250 (sh), 3200, 1718, 1695, 1685,
1615, 1530, 1391, 1370, 1058, 855, 785, 752, 690
[1251] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.18 (6H, s), 2.34 (3H,
s), 3.52 (2H, dd, J=13.7 Hz, 101.6 Hz), 5.11 (2H, s), 5.19 (1H, d,
J=8.4 Hz), 6.53 (1H, d , J=8.4 Hz), 7.18-7.4 (7H, m), 7.58 (1H, d,
J=7.8 Hz), 8.07 (1H, s)
[1252] APCI-MS (m/z): 381 (M.sup.++1)
[1253] Preparation 56-3
[1254]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonyl-methyl--
5-(N,N-dimethylamino)methyl-.sup.9-methyl-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-3.
[1255] IR (Neat, cm.sup.-1):1750, 1720, 1675, 1620
[1256] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.20 (3H, t, J=7.1 Hz),
2.34 (3H, s), 2.35 (6H, s), 3.59 (2H, s), 3.82 (1H, d, J=16.9 Hz),
4.09 (2H, q, J=7.1 Hz), 4.76 (1H, d, J=16.9 Hz), 5.29 (1H, d, J=8.7
Hz), 6.54 (1H, d, J=8.6 Hz), 7.2-7.5 (8H, m)
[1257] Mass (APCI): 467 (M.sup.++1)
[1258] Preparation 56-4
[1259]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-9-methyl-
-5-(N,N-dimethylamino)methyl-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-4.
[1260] IR (Nujol, cm.sup.-1):1715, 1685, 1600
[1261] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.27 (3H, s), 2.31 (3H,
s), 2.46 (3H, s), 3.5-3.8 (3H, m), 3.42 (1H, d, J=16.5 Hz), 4.98
(1H, d, J=9.6 Hz), 5.01 (2H, s), 7.1-7.4 (5H, m), 7.45 (1H, d,
J=7.1 Hz), 7.76 (1H, d, J=7.3 Hz), 8.07 (1H, d, J=8.6 Hz), 8.31
(1H, s)
[1262] Mass (APCI) 439 (M.sup.++1)
[1263] Preparation 56-5
[1264]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxyca-
rbonylamino-2,3-dihydro-9-methyl-5-(N,N-dimethylamino)-methyl-1H-1,4-benzo-
diazepin-2-one was prepared in a similar manner to that of
Preparation 59-5.
[1265] IR (Neat, cm.sup.-1) 1735, 1655, 1625
[1266] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.5-1.9 (8H, m), 1.9-2.2
(2H, m), 2.22 (3H, s), 2.34 (6H, s), 3.1-3.5 (4H, m), 3.6-3.8 (2H,
m), 3.82 (1H, d, J=15.5 Hz), 4.97-5.31 (4H, m), 7.1-7.5 (7H, m),
7.7-7.9 (1H, m)
[1267] Mass (APCI):546 (M.sup.++1)
[1268] Preparation 56-6
[1269]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-d-
ihydro-5-(N,N-dimethylamino)methyl-9-methyl-1H-1,4-bcnzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-6.
[1270] IR (Neat, cm .sup.1): 3320, 1645
[1271] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.2-2.6 (19H, m), 3.2-4.0
(6H, m), 4.13 (1H, m), 4.47 (1H, m), 5.10 (1H, m), 7.25 (2H, m),
7.70 (1H, m)
[1272] Mass (APCI):412 (M.sup.++1)
[1273] Preparation 57-1
[1274] 2-(4-chlorobutanoyl)-6-methylaniline was prepared in a
similar manner to that of Preparation 50-1.
[1275] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.16 (3H, s), 2.20 (2H,
m), 3.15 (2H, t, J=7.0 Hz), 3.66 (2H, t, J=6.3 Hz), 6.38 (1H, br,
s), 6.5-6.7 (1H, m), 7.1-7.3 (1H, m), 7.6-7.8 (1H, m)
[1276] Mass (APCI): 212 (M.sup.++1)
[1277] Preparation 57-2
[1278] A mixture of 2-(4-chlorobutanoyl)-6-methylaniline (538 mg)
and potassium t-butoxide (285 mg) in tetrahydrofuran (8 ml) was
stirred at room temperature for 1.5 hour. Ethyl acetate and 0.1N
aqueous hydrochloric acid were added to the reaction mixture. The
separated organic layer was washed with water, saturated aqueous
sodium bicarbonate and brine successively and dried over magnesium
sulfate. Removal of the solvent in vacuo gave
2-cyclopropylcarbonyl-6-methylaniline (445 mg, 100.0%) as a
crystalline powder.
[1279] IR (Nujol, cm.sup.-1) 3450, 3300, 1610
[1280] .sup.1H-NMR (CDC'.sub.3, .delta.): 0.90-1.00 (2H, m),
1.14-1.21 (3H, m), 2.17 (3H, s), 2.5-2.8 (1H, m), 6.25 (2H, m),
6.64 (1H, t, J=7.2 Hz), 7.22 (1H, t, J=7.2 Hz), 7.88(1H, d, J=8.2
Hz)
[1281] Mass (APCI): 176 (M.sup.++1)
[1282] Preparation 57-3
[1283]
(3RS)-3-Benzyloxycarbonylamino-5-cyclopropyl-2,3-dihydro-9-methyl-1-
H-1,4-benzodiazepin-2-one was prepared in a similar manner to that
of Preparation 45-2.
[1284] IR (Nujol, cm.sup.-1): 1715, 1675, 1620
[1285] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.7-1.2 (4H, m), 2.03
(1H, m), 2.34 (3H, s), 4.79 (1H, d, J=8.6 Hz), 5.02 (2H, br, s),
7.1-7.5 (6H, m), 7.6-7.8 (1H, m), 7.9-8.2 (1H, m), 9.96 (1H, br,
s)
[1286] Mass (APCI): 364 (M.sup.++1)
[1287] Preparation 57-4
[1288]
(3RS)-3-Benzyloxycarbonylamino-5-cyclopropyl-2,3-dihydro-1-ethoxyca-
rbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-3.
[1289] IR (Neal, cm.sup.-1): 1750, 1700, 1630
[1290] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.83-0.94 (2H, m),
0.98-1.10 (2H, m), 1.19 (3H, t, J=7.1 Hz), 1.9-2.4 (1H, m), 2.33
(3H, s), 3.80 (1H, d, J=16.8 Hz), 4.10 (2H, q, J=7.1 Hz), 4.85 (1H,
d, J=16.8 Hz), 5.01-5.14 (2H, m), 5.18 (1H, d, J=8.7 Hz), 6.36 (1H,
d, J=8.6 Hz), 7.2-7.4 (7H, m), 7.63-7.68 (1H, m)
[1291] Mass (APCI): 450 (M.sup.++1)
[1292] Preparation 57-5
[1293]
(3RS)-3-Benzyloxycarbonylamino-5-cyclopropyl-2,3-dihydro-1-carboxym-
ethy)-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-4.
[1294] IR (Nujol, cm.sup.-1): 1730, 1680, 1610
[1295] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.82-0.90 (2H, m),
0.96-1.07 (2H, m), 1.26 (3H, t, J=7.1 Hz), 1.90-2.04 (1H, m), 2.31
(3H, s), 3.80 (1H, d, J=17.3 Hz), 4.89 (1H, d, J=17.3 Hz),
4.93-5.12 (2H, m), 5.18 (1H, d, J=8.7 Hz), 6.40 (1H, d, J=8.7 Hz),
7.2-7.4 (7H, m), 7.5-7.6 (1H, m)
[1296] Mass (APCI): 422 (M.sup.++1)
[1297] Preparation 57-6
[1298]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxyca-
rbonylamino-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-5.
[1299] IR (Nujol, cm.sup.-1) 1725, 1675, 1650, 1615
[1300] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.87-1.09 (4H, m),
1.25-1.73 (8H, m), 2.03-2.15 (3H, m), 2.36 (3H, s), 3.31-3.80 (4H,
m), 3.84 (1H, d, J=15.5 Hz), 5.10 (2H, m), 5.14 (1H, d, J=15.5 Hz),
5.19 (1H, d, J=8.7 Hz), 6.38 (1H, d, J=8.6 Hz), 7.2-7.5 (7H, m),
7.6-7.7 (1H, m)
[1301] Mass (APCI): 529 (M.sup.++1)
[1302] Preparation 57-7
[1303]
(3RS)-3-Amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyc-
lopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was
prepared in a similar manner to that of Preparation 59-6.
[1304] IR (Nujol, cm.sup.-1): 1675, 1645, 1600
[1305] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.85-1.06 (4H, m),
1.4-1.8 (8H, m), 1.9-2.2 (2H, m), 2.23 (1H, br, s), 2.37 (3H, s),
3.35-3.67 (4H, m), 3.86 (1H, d, J=15.SHz), 4.34 (1H, s), 5.17 (1H,
d, J=15.5 Hz), 7.1-7.4 (2H, m), 7.6-7.7 (1H, rn)
[1306] Mass (APCI): 395 (M'+1)
[1307] Preparation 58-1
[1308] 2-methyl-6-isovalerylaniline was prepared in a similar
manner to that of Preparation 50-1.
[1309] IR (Nujol, cm.sup.-1) 3475, 3330, 1638, 1610, 1580, 1555,
1025, 951, 742
[1310] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.99 (6H, d, J=6.6 Hz),
2.17 (3H, s), 2.27 (1H, m), 2.81 (2H, d, J=6.9 Hz), 6.4 (1H, br),
6.59 (1H, dd, J=7.3 Hz, J=8.0 Hz), 7.16-7.3 (2H, m), 7.66 (1H, d,
J=8.0 Hz)
[1311] APCI-MS (m/z): 192 (M.sup.++1)
[1312] Preparation 58-2
[1313]
(3RS)-3-Benzyloxycarbonylamino-5-isobutyl-9-methyl-2,3-dihydro-1H-1-
,4-benzodiazepin-2-one was prepared in a similar manner to that of
Preparation 45-2.
[1314] mp: 208.4-209.1.degree. C.
[1315] IR (Nujol, cm.sup.-1) 3250 (sh), 3200, 1718, 1690 (sh),
1680, 1526, 1390, 1367, 1057, 983, 761, 698
[1316] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.75 (3H, d, J=6.6 Hz),
0.86 (3H, d, J=6.6 Hz), 1.79 (1H, m), 2.36 (3H, s), 2.46 (1H, dd,
J=9.4 Hz, J=13.9 Hz), 2.87 (1H, dd, 3=3.9 Hz, J=13.9 Hz), 5.10 (2H,
s), 5.15 (1H, d, J=8.4 Hz), 6.48 (1H, d, J=8.4 Hz), 7.12-7.45 (8H,
m), 8.24 (1H, br, s)
[1317] APCI-MS (m/z): 380 (M.sup.++1)
[1318] Preparation 58-3
[1319]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-ethoxycarbonylmethyl-5-
-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation of 59-3.
[1320] IR (Neat, cm.sup.-1): 1750, 1720, 1620
[1321] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.96 (6H, d, J=6.6 Hz),
1.21 (3H, t, J=7.1 Hz), 2.13-2.28 (1H, m), 2.35 (3H, s), 2.57-2.88
(2H, m), 3.89 (1H, d, J=16.9 Hz), 4.12 (2H, q, J=7.1 Hz), 4.64 (1H,
d, J=16.9 Hz), 5.06 (1H, d, J=12.4 Hz), 5.13 (1H, d, J=12.4 Hz),
5.25 (1H, d, J=8.6 Hz), 6.50 (1H, d, J=8.6 Hz), 7.2-7.4 (8H, m)
[1322] Mass (APCI): 466 (M.sup.++1)
[1323] Preparation 58-4
[1324]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-carboxymethyl-5-isobut-
yl-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a similar
manner to that of Preparation 59-4.
[1325] IR (Nujol, cm.sup.-1): 1715, 1680, 1610
[1326] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.91 (3H, d, J=6.6 Hz),
0.93 (3H, d, J=6.6 Hz), 2.1-2.2 (1H, m), 2.34 (3H, s), 2.55-2.73
(2H, m), 3.91 (1H, d, J=17.2 Hz), 4.68 (1H, d, J=17.2 Hz), 5.04
(1H, d, J=12.4 Hz), 5.12 (1H, d, J=12.4 Hz), 6.56 (1H,-d, J=8.6
Hz), 5.24 (1H, d, J=8.6 Hz), 7.2-7.4 (8H, m)
[1327] Mass (APCI): 438 (M.sup.++1)
[1328] Preparation 58-5
[1329]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxyca-
rbonylamino-2,3-dihydro-9-methyl-5-isobutyl-1H-1,4-benzodiazepin-2-one
was prepared in a similar manner to that of Preparation 59-5.
[1330] IR (Nujol, cm.sup.-1):1710, 1675, 1650
[1331] .sup.1H-NMR(CDCl.sub.3, .delta.): 0.15 (6H, d, J=6.6 Hz),
1.5-1.8 (8H, br), 1.9-2.2 (2H, m), 2.2-2.3 (1H, m), 2.36 (3H, s),
2.58-2.95 (2H, m), 3.31-3.40 (2H, m), 3.53-3.82 (2H, m), 3.91 (1H,
d, J=15.7 Hz), 4.95 (1H, d, J=15.7 Hz), 5.05 (1H, d, J=12.4 Hz),
5.12 (1H, d, J=12.4 Hz), 5.27 (1H, d, J=8.6 Hz), 6.51 (1H, d, J=8.6
Hz), 7.1-7.5 (8H, m)
[1332] Mass (APCI): 545 (M.sup.++1)
[1333] Preparation 58-6
[1334]
(3RS)-3-Amino-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-iso-
butyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was prepared
in a similar manner to that of Preparation 59-6.
[1335] IR (Nujol, cm.sup.-1): 3380, 1680, 1650
[1336] .sup.1H-NMR(CDCl.sub.3, .delta.): 0.98 (3H, d, J=6.5 Hz),
0.99 (3H, d, J=6.5 Hz), 1.5-1.8 (8H, m), 1.9-2.1 (2H, m), 2.2-2.3
(1H, m), 2.36 (3H, s), 2.56-2.68 (1H, m), 2.77-2.88 (1H, m),
3.35-3.44 (2H, m), 3.53-3.63 (1H, m), 3.77-3.85 (1H, m), 3.82 (1H,
d, J=15.7 Hz), 4.41(1H, s), 4.97 (1H, d, J=15.7 Hz), 7.1-7.4 (3H,
m)
[1337] Mass (APCI): 411 (M.sup.++1)
[1338] Preparation 59-1
[1339] 2-Propanoyl-6-methylaniline was prepared in a similar manner
to that of Preparation 50-1.
[1340] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.21 (3H, l, J=7.3 Hz),
2.16 (3H, s), 2.98 (2H, q, J=7.3 Hz), 6.40 (2H, m), 6.5-6.6 (1H,
m), 7.18 (1H, d, J=7.1 Hz), 7.66 (1H, d, J=8.1 Hz)
[1341] Mass (APCI): 164 (M.sup.++1)
[1342] Preparation 59-2
[1343]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-ethyl-9-methyl-1H-1,4--
benzodiazepin-2-one was prepared in a similar manner to that of
Preparation 50-2.
[1344] IR (Nujol, cm.sup.-1) 1705, 1675, 1610
[1345] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.99 (3H, t, J=7.4 Hz),
2.34 (3H, s), 2.65-2.90 (2H, m), 4.86 (1H, d, J=8.6 Hz), 5.03 (2H,
s), 7.1-7.5 (7H, m), 7.58 (1H, d, J=7.9 Hz), 8.09 (1H, d, J=8.6
Hz), 9.95 (1H, s)
[1346] Mass (APCI): 352 (M.sup.++1)
[1347] Preparation 59-3
[1348] A mixture of
(3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-9-m-
ethyl-1H-1,4-benzodiazepin-2-one (1.0 g) and 60% sodium hydride
(120 mg) in N,N-dimethylformamide was stirred at 0.degree. C. for 1
hour and at room temperature for 3 hours. To the resultant mixture
was added dropwise ethyl bromoacetate (476 mg) under cooling at
0-5.degree. C. in an ice-bath. The mixture was stirred for 5.5
hours under the same conditions. The reaction mixture was poured
into 0.1 N aqueous hydrochloric acid and extracted with ethyl
acetate. The extract was washed with water twice, saturated aqueous
sodium bicarbonate and brine successively and dried over magnesium
sulfate. The solvent was evaporated in vacuo to afford
(3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-1-e-
thoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.55 g) as
an oil.
[1349] IR (Neat, cm.sup.-1): 1750, 1720, 1622
[1350] .sup.1H-NMR (CDCl.sub.3.delta.): 1.0-1.35 (6H, m), 2.33 (3H,
s), 3.78 (1H, d, J=16.8 Hz), 2.75-2.98 (2H, m), 4.85 (1H, d, J=16.8
Hz), 4.10 (2H, q, J=7.1 Hz), 5.06 (1H, d, J=12.3 Hz), 5.13 (1H, d,
J=12.3 Hz), 5.27 (1H, d, J=8.7 Hz), 6.49 (1H, d, J=8.6 Hz), 7.2-7.4
(8H, m)
[1351] Mass (APCI): 438 (M.sup.++1)
[1352] Preparation 59-4
[1353] A mixture of
(3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-1-e-
thoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.55g) and
1N sodium hydroxide (7.0 ml) in 1,2-dimethoxyethane (10 ml) was
stirred at room temperature overnight. The reaction mixture was
evaporated in vacuo to afford a residue, which was dissolved in a
mixture of ethyl acetate and 1N aqueous hydrochloric acid. The
separated organic layer was washed with water and brine, and then
dried over magnesium sulfate. The solvent was evaporated in vacuo
to afford a residue, which was triturated in diisopropyl ether and
collected by filtration to give
(3RS)-3-bcnzyloxycarbonylamino-5-ethyl-1-carboxymethyl-2,3-dihydro-9-meth-
yl-1H-1,4-benzodiazepin-2-one (1.22 g, 84.2% yield) as a white
crystalline powder.
[1354] IR (Nujol, cm.sup.-1) 1720, 1670, 1615
[1355] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.14 (3H, 1, J=7.4 Hz),
2.31 (3H, s), 2.74-2.95 (2H, m), 3.79 (1H, d, J=17.1 Hz), 4.86 (1H,
d, J=17.1 Hz), 5.03 (1H, d, J=12.4 Hz), 5.01 (1H, d, J=12.4 Hz),
5.26 (1H, d, J=8.7 Hz), 6.62 (1H, d, J=8.7 Hz), 7.2-7.4 (8H, m).
7.87 (1H, br)
[1356] Mass (APCI):410 (M.sup.++1)
[1357] Preparation 59-5
[1358] A mixture of
(3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-1-c-
arboxymethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.22 g),
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
(642mg), 1-hydroxybenzotriazole (453mg), 3-azabicyclo[3.2.2]nonane
(419mg) and triethylamine (1.55 ml) in N,N-dimethylformamide (30
ml) was stirred at room temperature overnight. Ethyl acetate and
0.1 N aqueous hydrochloric acid were added to the reaction mixture,
which was stirred for several minutes. The separated organic layer
was washed with 1N aqueous hydrochloric acid, water twice, a
saturated aqueous solution of sodium bicarbonate and brine,
successively, and then dried over magnesium sulfate. The solvent
was evaporated in vacuo, and the residue was triturated in
diisopropyl ether and collected by filtration to afford
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonyl-
amino-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one
(1.23gi, 79.9%) as a crystalline powder.
[1359] IR (Nujol, cm.sup.-1): 1718, 1675, 1650
[1360] .sup.1H-NMR (CDCL .sub.3, .delta.): 1.26 (3H, t, J=7.4 Hz),
1.5-1.8 (10H, m), 2.34 (3H, s), 2.90 (2H, q, J=7.4 Hz), 3.29-3.36
(2H, m), 3.55-3.64 (1H, m), 3.79 (1H, d, J=15.6 Hz), 3-7-3.86 (1H,
m), 5.05 (1H, d, J=12.4 Hz), 5.12 (1H, d, J=12.4 Hz), 5.14 (1H, d,
J=15.6 Hz), 5.28 (1H, d, J=8.7 Hz), 6.50 (1H, d, J=8.7 Hz), 7.2-7.4
(8H, m)
[1361] Mass (APCI): 517 (M.sup.++1)
[1362] Preparation 59-6
[1363] A mixture of
(3RS)-3-benzyloxycarbonylamino-1-[(3-azabicyclo[3.2.2]-
non-3-yl)-carbonylmethyl]-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepi-
n-2-one (1.23 g), 10% palladium on carbon (50% wet, 250 mg) and
ammonium formate (600 mg) in ethanol (15 ml) was stirred at room
temperature for 1 hour. The catalyst was filtered off and the
filtrate was evaporated in vacuo to afford a residue, which was
dissolved in ethyl acetate and washed with saturated aqueous sodium
bicarbonate, water and brine successively. After drying over sodium
sulfate, the solvent was evaporated in vacuo to afford a residue,
which was triturated in diisopropyl ether and collected by
filtration to give
(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-ethyl-2,3-
-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (792mg, 87.0% yield)
as a crystalline powder.
[1364] IR (Nujol, cm.sup.-1): 3360, 3370, 1680, 1655
[1365] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.27 (3H, 1, J=7.3 Hz),
1.5-1.8 (8H, m), 1.8-2.1 (2H, m), 2.35 (3H, s), 2.89 (2H, q, J=7.3
Hz), 3.3-3.42 (2H, m), 3.5-3.6 (2H, m), 3.79 (1H, d, J=15.5 Hz),
4.41 (1H, s), 5.17 (1H, d, J=15.5 Hz), 7.1-7.4 (3H, m) Mass
(APCI):383 (M.sup.++1)
[1366] Preparation 60-1
[1367]
(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-1-cthoxycarbonyl-methyl--
5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-2-one was prepared
in a similar manner to that of Preparation 59-3.
[1368] IR (Nujol, cm.sup.-1) 1720, 1675 .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 0.97 (3H, t, J=7.1 Hz), 2.39 (3H, s), 3.89 (2H, q, J=7.1
Hz), 4.21 (1H, d, J=16.7 Hz), 4.68 (1H, d, J=16.7 Hz), 5.05 (1H,
br, s), 5.20 (H, d, J=8.6 Hz), 7.06 (1H, d, J=7.6 Hz), 7.2-7.8
(11H, m), 8.4-8.6 (1H, m)
[1369] Mass (APCI): 504 (M.sup.++1)
[1370] Preparation 60-2
[1371]
(3RS)-3-Benzyloxycarbonylamino-2,3-dibydro-5-(2-fluorophenyl)-1-car-
boxymethyl-9-methyl-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Example 48-2.
[1372] IR (Nujol, cm.sup.-1): 1720, 1680
[1373] .sup.1H-NMR(CDCl.sub.3, .delta.): 2.35 (3H, s), 3.88 (1H, d,
J=17.2 Hz), 4.84 (1H, d, J=17.2 Hz), 5.0-5.3 (2H, m), 5.42 (1H, d,
J=8.7 Hz), 6.67 (1H, d, J=8.7 Hz), 6.9-7.5 (11H, m), 7.6-7.8 (1H,
m)
[1374] Mass (FAB): 476 (M'+1)
[1375] Preparation 61-1
[1376]
(3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-2,3-dihyd-
ro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one was obtained in a
similar manner to that of Preparation 59-3.
[1377] IR (Nujol, cm.sup.-1) 3350, 1710, 1670, 1620
[1378] .sup.1H-NMR (CDCl.sub.3, .delta.):1.27 (3H, t, J=7.4 Hz),
1.1-2.0 (10H, m), 2.2-2.4 (1H, m), 2.32 (3H, s), 2.92 (2H, q, J=7.4
Hz), 3.75 (1H, d, J=17 Hz), 5.05 (1H, d, J=17 Hz), 5.0-5.2 (2H, m),
5.25 (1H, d, J=8.7 Hz), 6.45 ((1H, d, J=8.6 Hz), 7.1-7.5 (8H,
m)
[1379] Mass (APCI)(e/z): 476 (M.sup.++1)
[1380] Preparation 61-2
[1381]
(3RS)-3-Amino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-ethyl-9-meth-
yl-1H-1,4-benzodiazepin-2-one was obtained in a similar manner to
that of Preparation 59-6.
[1382] IR (Neat, cm.sup.-1): 3380, 3320, 1720, 1680
[1383] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.29 (3H, t, J=7.1 Hz),
1.1-1.4 (5H, m), 1.5-2.0 (5H, m), 2.0-2.2 (2H, m), 2.2-2.4 (1H, m),
2.32 (3H, s), 2.8-3.0 (2H, m), 3.74(1H, d, J=17.0 Hz), 4.39 (1H, 1,
J=1.5 Hz), 5.06 (1H, d, J=17.0 Hz), 7.1-7.4 (3H, m)
[1384] Mass (APCI)(e/z): 342 (M.sup.++1)
[1385] Preparation 62-1
[1386]
(3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-2,3-dihyd-
ro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-one was obtained in
a similar manner to that of Preparation 59-3.
[1387] IR (Nujol, cm.sup.-1): 3350, 1720, 1670, 1610
[1388] .sup.1H-NMR(CDCl.sub.3, .delta.): 1.19 (3H, d, J=7.1 Hz),
1.33 (3H, d, J=6.6 Hz), 1.1-2.0 (10H, m), 2.32 (3H, s), 2.2-2.4
(1H, m), 3.1-3.3 (1H,m), 3.79 (1H, d, J=17.0 Hz), 4.93 (1H, d,
J=17.0 Hz), 5.05 (1H, d, J=12.6 Hz)(5.12, d, J=12.6 Hz), 5.20 (1H,
d, J=8.7 Hz), 6.42 (1H, d, J=8.6 Hz), 7.1-7.5 (8H, m)
[1389] Mass (APCI)(e/z): 490 (M.sup.++1)
[1390] Preparation 62-2
[1391]
(3RS)-3-Amino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-isopropyl-9--
methyl-1H-1,4-benzodiazepin-2-one was obtained in a similar manner
to that of Preparation 59-6.
[1392] IR (Neat, cm.sup.-1) 3380, 3320, 1725, 1680, 1620
[1393] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.21 (3H, d, J=7.0 Hz),
1.35 (3H, d, J=6.6 Hz), 1.1-1.5 (5H, m), 1.5-2.2 (5H, m), 2.2-2.4
(1H, m), 2.35 (3H, s), 3.1-3.3 (1H, m), 3.80(1H, d, J=17.0 Hz),
4.34 (1H, s), 4.92 (1H, d J=17,0 Hz), 7.1-7.4 (3H, m)
[1394] Mass (APCI)(e/z): 356 (M.sup.++1)
[1395] Preparation 63-1
[1396]
(3RS)-3-Benzyloxycarbonylamino-1-cycloheptylcarbonylmethyl-2,3-dihy-
dro-5,9-dimethyl-1H-1,4-benzodiazepin-2-one was obtained in a
similar manner to that of Preparation 54-1.
[1397] IR (Nujol, cm.sup.-1): 3400, 1720, 1670, 1620
[1398] Mass (APCI)(e/z): 476 (M.sup.++1)
[1399] .sup.1H-NMR(CDC.sub.3, .delta.): 1.3-2.0 (12H, m), 2.32 (3H,
s), 2.4-2.6 (1H, m), 2.61 (3H,s), 3.75 (1H, d, J=17 Hz), 5.10 (1H,
d, J=17 Hz), 5.0-5.2 (2H, m), 5.24 (1H, d, J=8.7 Hz), 6.48 (1H, d,
J=8.7 Hz), 7.1-7.5 (8H, m)
[1400] Preparation 63-2
[1401]
(3RS)-3-Amino-1-cycloheptylcarbonylmethyl-2,3-dihydro-5,9-dimethyl--
1H-1,4-benzodiazepin-2-one was obtained in a similar manner to that
of Preparation 59-6.
[1402] IR (Nujol, cm.sup.-1): 3360, 3320, 1720, 1670, 1620
[1403] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.3-2.3 (12H, br), 2.32
(3H, s), 2.4-2.6 (1H, m), 2.60 (3H, s), 3.74 (1H, d, J=17 Hz), 4.39
(1H, s), 5.12 (1H, d, J=17 Hz), 7.1-7.5 (3H, m)
[1404] Mass (APCI)(e/z): 342 (M'+1)
[1405] Preparation 64-1
[1406]
(3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-5-cyclopr-
opyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was obtained
in a similar manner to that of Preparation 59-3.
[1407] IR (Nujol, cm.sup.-1): 3300, 1715, 1665, 1605
[1408] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.8-1.5 (10H, m), 1.5-1.9
(4H, m), 2.0-2.2 (1H, m), 2.2-2.4 (1H, m), 2.32 (3H, s), 3.78 (1H,
d, J=17.0 Hz), 5.01 (1H, d, J=17.0 Hz), 5.0-5.2 (2H, m), 5.17 (1H,
d, J=9 Hz), 6.33 (1H, d, J=9 Hz), 7.1-7.4 (7H, m), 7.6-7.7 (1H,
m)
[1409] Mass (APCI)(e/z): 488 (M.sup.++1)
[1410] Preparation 64-2
[1411]
(3RS)-3-Amino-1-cyclohexylcarbonylmethyl-5-cyclopropyl-2,3-dihydro--
9-methyl-1H-1,4-benzodiazepin-2-one was obtained in a similar
manner to that of Preparation 59-6.
[1412] IR (Nujol, cm.sup.-1): 3400, 3310, 1720, 1680, 1610
[1413] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.8-2.4 (16H, m), 2.32
(3H, s), 2.2-2.4 (1H, br), 2.7-2.9 (1H, m), 3.88 (1H, d, J=17 Hz),
4.32 (1H, s), 5.01 (1H, d, J=17 Hz), 7.1-7.4 (3H, m)
[1414] Mass (APCI)(e/z): 356 (M'+1)
[1415] Preparation 65-1
[1416]
(3RS)-3-Benzyloxycarbonylamino-1-cyclopentylcarbonylmethyl-2,3-dihy-
dro-5,9-dimethyl-1H-1,4-benzodiazepin-2-one was obtained in a
similar manner to that of Preparation 54-1.
[1417] Mass (APCI)(e/z): 448 (M'+1)
[1418] Preparation 65-2
[1419]
(3RS)-3-Amino-1-cyclopentylcarbonylmethyl-2,3-dihydro-5,9-dimethyl--
1H-1,4-benzodiazepin-2-one was obtained in a similar manner to that
of Preparation 59-6.
[1420] Preparation 66-1
[1421]
(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylmethy-
l-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one was
obtained in a similar manner to that of Preparation 59-5.
[1422] IR (Nujol, cm.sup.-1) 3380, 1700, 1670, 1640
[1423] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.25 (3H, t, J=7.3 Hz),
1.3-1.9 (10H, m), 2.34 (3H, s), 2.8-3.0 (2H, m), 3.2-3.5 (4H, m),
3.71(1H, d, J=15.4 Hz), 5.0-5.2 (3H, m), 5.27 (1H, d, J=8.7 Hz),
6.50 (1H, d, J=8.7 Hz), 7.1-7.4 (8H, m)
[1424] Mass (APCI)(e/z): 505 (M.sup.++1)
[1425] Preparation 66-2
[1426]
(3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonyimethyl-2,3-dihydro-5-et-
hyl-9-methyl-1H-1,4-benzodiazepin-2-one was obtained in a similar
manner to that of Preparation 59-6.
[1427] IR (Nujol, cm.sup.-1)-3380, 3270, 1670, 1640
[1428] .sup.1H-NMR (CDC.sub.3, .delta.): 1.27 (3H, t, J=7.3 Hz),
1.3-2.0 (10H, br), 2.26 (2H, br), 2.34 (3H,s), 2.8-3.0 (2H, m),
3.2-3.6 (4H, m), 3.70 (1H, d, J=15.3 Hz), 4.41 (1H, s), 5.07 (1H,
d, J=15.3 Hz), 7.1-7.4 (3H, m)
[1429] Mass (APCI)(e/z):371 (M.sup.++1)
[1430] Preparation 67-1
[1431]
(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylamino-
-2,3-dihydro-5-isopropyl-9-methyl-1H-1,4-benzodiazepin-2-one was
obtained in a similar manner to that of Preparation 59-5.
[1432] IR (Nujol, cm.sup.-1): 3370, 1710, 1670, 1645
[1433] .sup.1H-NMR (CDCL .sub.3, .delta.): 1.22 (3H, d, l=7.0 Hz),
1.33 (3H, d, J=6.6 Hz), 1.3-1.9 (10H, m), 2.35 (3H, s), 3.1-3.6
(5H, m), 3.76 (1H, d, J=15.3 Hz), 4.96 (1H, d, J=15.3 Hz), 5.0-5.2
(2H, m), 5.22 (1H, d J=9 Hz), 6.48 (1H, d, J=9 Hz), 7.1-7.5 (8,
m)
[1434] Mass (APCI)(e/z): 519 (M.sup.++1)
[1435] Preparation 67-2
[1436]
(3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-is-
opropyl-9-methyl-1H-1,4-benzodiazepin-2-one was obtained in a
similar manner to that of Preparation 59-6.
[1437] IR (Nujol, cm.sup.-1): 3350, 3280, 1675, 1640
[1438] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.22 (3H, d, J=7.0 Hz),
1.34 (3H, d, J=6.6 Hz), 1.3-1.9 (10H, m), 2.23 (2H, br, s), 2.35
(3H, s), 3.1-3.6 (5H, m), 3.77 (1H, d, J=15.2 Hz), 4.36 (1H, s),
4.96 (1H, d, J=15.2 Hz), 7.1-7.4 (3H, m)
[1439] Mass (APCI)(e/z): 385 (M.sup.++1)
[1440] Preparation 68-1
[1441]
(3RS)-1-(Azacyclooctan-1-yi)carbonylmethyl-3-benzyloxycarbonylamino-
-5-cyclopropyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was
obtained in a similar manner to that of Preparation 59-5.
[1442] IR (Nujol, cm.sup.-1) 3370, 1705, 1660, 1640
[1443] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.8-1.1 (4H,m), 1.2-1.9
(10H, m), 2.0-2.2 (1H, m), 2.35 (3H, s), 3.3-3.5 (4H, m), 3.74 (1H,
d, J=15.3 Hz), 5.02 (1H,d, J=15.3 Hz), 5.0-5.2 (2H, m), 5.19 (1H,
d, J=9 Hz), 6.37 (1H, d, J=9 Hz), 7.2-7.4 (7H, m), 7.6-7.7 (1H,
m)
[1444] Mass (APCI)(e/z): 517 (M.sup.++1)
[1445] Preparation 68-2
[1446]
(3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-5-cyclopropyl-2,-
3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was obtained in a
similar manner to that of Preparation 59-6.
[1447] IR (Nujol, cm.sup.-1): 3780, 3280, 1675, 1650
[1448] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.8-1.1 (4H, m), 1.2-1.9
(10H, m), 1.9-2.2 (3H, m), 2.35 (3H, s), 3.2-3.6 (4H, m), 3.74 (1H,
d, J=15.2 Hz), 3.97 (1H, s), 5.04 (1H, d, J=15.2 Hz), 7.1-7.4 (2H,
m), 7.4-7.5 (1H, m)
[1449] Mass (APCI)(e/z): 383 (M'+1)
[1450] Preparation 69-1
[1451]
(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylamino-
-2,3-dihydro-5-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-one was
obtained in a similar manner to that of Preparation 59-5.
[1452] IR (Nujol, cm.sup.-1): 3400, 1710, 1670, 1640
[1453] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.98 (6H, d, J=6.6 Hz),
1.4-1.9 (10H, m), 2.2-2.4 (1H, m), 2.36 (3H, s), 2.5-3.0 (2H, m),
3.3-3.5 (4H, m), 3.81(1H, d, J=5.5 Hz), 4.89 (1H, d, J=15.5 Hz),
5.0-5.2 (2H, m), 5.25 (1H, d, 9 Hz), 6.50 (1H, d, J=9 Hz), 7.1-7.5
(8H, m)
[1454] Mass (APCI)(e/z): 533 (M.sup.++1)
[1455] Preparation 69-2
[1456]
(3RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-is-
obutyl-9-methyl-1H-1,4-benzodiazepin-2-one was obtained in a
similar manner to that of Preparation 59-6.
[1457] mp. 138.1-140.2.degree. C.
[1458] IR (Nujol, cm.sup.-1):3370, 3300, 1675, 1635
[1459] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.98 (6H, d, J=6.6 Hz),
1.4-1.9 (10H, m), 2.1-2.3 (3H, m), 2.36 (3H, s), 2.5-2.9 (2H, m),
3.3-3.5 (4H, m), 3.81 (1H, d, J=15.4 Hz), 4.40 (1H, s), 4.89 (1H,
d, J-15.4 Hz), 7.1-7.4 (3H, m)
[1460] Mass (APCI)(e/z): 399 (M.sup.++1)
[1461] Preparation 70-1
[1462]
(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-3-benzyloxycarbonylamino-
-5-cyclohexyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one was
obtained in a similar manner to that of Preparation 59-5.
[1463] IR (Nujol, cm.sup.-1) 3380, 1710, 1670, 1645
[1464] .sup.1H-NMR (CDCl.sub.3, 5): 1.1-2.2 (20H, m), 2.35 (3H, s),
2.7-3.0 (1H, m), 3.2-3.6 (4H, m), 3.78 (1H, d, J=15.3 Hz), 4.91
(1H, d J=15.3 Hz), 5.0-5.2 (2H, m), 5.21 (1H, d, J=8.6 Hz), 6.49
(1H, d, J=8.6 Hz), 7.1-7.5 (8H, m)
[1465] Mass (APCI)(e/z): 559 (M.sup.++1)
[1466] Preparation 70-2
[1467] (3
RS)-3-Amino-1-(azacyclooctan-1-yl)carbonylmethyl-5-cyclohexyl-2,-
3-dihydro-9-methyl-1H-1,4-bcnzodiazepin-2-one was obtained in a
similar manner to that of Preparation 59-6.
[1468] mp. 174.1-175.6.degree. C.
[1469] IR (Nujol, cm.sup.-1): 3350, 3280, 1670, 1635
[1470] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.2-2.1 (20H, m), 2.35
(3H, s), 2.7-2.9 (1H, m), 3.2-3.6 (4H, m), 3.79 (1H, d, J=15.2 Hz),
4.69 (11H, s), 4.92 (1H, d, J=15.2 Hz), 7.1-7.4 (3H, m)
[1471] Mass (APCI)(e/z): 425 (M.sup.++1)
[1472] Preparation 71
[1473]
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5,9-dimet-
hyl-2-oxo-4-oxide-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Preparation 32.
[1474] mp. 253.6-255.4.degree. C.
[1475] IR (Nujol, cm-): 3340, 1692, 1640
[1476] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-1.9 (10H, m), 2.23
(3H, s), 2.38 (3H, s), 2.41 (3H, s), 2.9-3.6 (4H, m), 4.07 (1H, d,
J=16 Hz), 4.99 (1H, d, J=16 Hz), 5.70 (1H, d, J=9.5 Hz), 6.7-6.8
(1H, m), 7.0-7.6 (7H, m), 9.26 (11H, s)
[1477] Mass (APCI)(e/z): 506 (M.sup.++1)
[1478] Preparation 72-1
[1479]
(3RS)-3-Benzyloxycarbonylamino-1-cyclooctylcarbonylmethyl-2,3-dihyd-
ro-5,9-dimethyl-1H-1,4-benzodiazepin-2-one was obtained in a
similar manner to that of Preparation 54-1.
[1480] IR (Neat, cm.sup.-1): 3400, 1730, 1690, 1670
[1481] .sup.1H-NMR (CDCl.sub.3, .delta.) 1.3-2.0 (14H, m), 2.33
(3H, s), 2.61 (3H, s), 2.4-2.6 (1H, m), 3.75 (1H, d, J=17 Hz), 5.10
(1H, d, J=17 Hz), 5.0-5.2 (2H, m), 5.24 (1H, m), 6.48 (1H, d, J=8.7
Hz), 7.1-7.5 (8H, m)
[1482] Mass (APCI)(e/z): 490 (M.sup.++1)
[1483] Preparation 72-2
[1484]
(3RS)-3-Amino-1-cyclooctylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-1-
H-1,4-benzodiazepin-2-one was obtained in a similar manner to that
of Preparation 59-6.
[1485] IR (Neat, cm) 1 3400, 3300, 1725, 1690, 1660
[1486] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.3-2.0 (14H, m), 2.16
(2H, s), 2.33 (3H, s), 2.4-2.6 (1H, m), 2.60 (3H, s), 3.74 (1H, d,
J=17 Hz), 4.39 (1H, m), 5.12 (1H, d, J=17 Hz), 7.1-7.5 (3H, m)
[1487] Mass (APCI)(e/z) 356 (M.sup.++1)
[1488] Preparation 73-1
[1489]
(3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonylmethyl-2,3-dihyd-
ro-5-isobutyl-9-methyl-1H-1,4-benzodiazepin-2-one was obtained in a
similar manner to that of Preparation 59-3.
[1490] IR (Nujol, cm.sup.-1): 3300, 1710, 1665
[1491] .sup.1H-NMR (CDCl.sub.3, .delta.):0.97 (6H, d, J=6.6 Hz),
1.1-2.0 (10H, m), 2.1-2.3 (2H, m), 2.31 (3H, s), 2.5-3.0 (2H, m),
3.90 (1H, d, J=17.3 Hz), 4.83 (1H, d, J=17.3 Hz), 5.0-5.2 (2H, m),
5.23 (1H, d, J=8.7 Hz), 6.46 (1H, d, J=8.5 Hz), 7.1-7.5 (8H, m)
[1492] Mass (APCI)(e/z): 504 (M.sup.++1)
[1493] Preparation 73-2
[1494]
(3RS)-3-Amino-1-cyclohexylcarbonylmethyl-2,3-dihydro-5-isobutyl-9-m-
ethyl-1H-1,4-benzodiazepin-2-one was obtained in a similar manner
to that of Preparation 59-6.
[1495] IR (Neat, cm.sup.-1): 3380, 3320, 1720, 1680, 1620
[1496] .sup.1H-NMR (CDCl.sub.3, .delta.):0.98 (6H, d, J=6.6 Hz),
1.1-2.0 (10H, m), 2.0-2.4 (4H, m), 2.31 (3H, s), 2.5-2.9 (2H, m),
3.90 (1H, d, J=17 Hz), 3.38 (1H, m), 4.83 (1H, d, J=17 Hz), 7.1-7.4
(3H, m)
[1497] Mass (APCI)(e/z): 370 (M.sup.++1)
[1498] Preparation 74-1
[1499]
(3RS)-1-Cyclohexylcarbonylmethyl-3-[N-t-butoxycarbonyl-(S)-phenylal-
anyl]amino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
was obtained by reacting
(3RS)-1-cyclohexylcarbonylmethyl-3-amino-5-ethyl-9-m-
ethyl-2.3-dihydro-1H-1,4-benzodiazepin-2-one with
N-t-butoxycarbonyl-(S)-p- henylalanine in a similar manner to that
of Preparation 59-5.
[1500] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.15-1.35 (9H, m), 1,37
(9H, s), 1.6-1.85 (4H, m), 1.85-2.0 (1H, m), 2.2-2.4 (1H, m), 2.34
(3H, s),2.85-3.1 (2H, m), 3.14-3.29 (1H, m), 3.75 (1H, d, J=17.2
Hz), 4.50 (1H, br, s), 4.94 (1H, br, d), 5.06 (1H, d, J=17.2 Hz),
5.39-5.46 (1H, m), 7.19-7.5 (8H, m), 7.61 (1H, br, d)
[1501] APCI-MS (m/z) =589 (M.sup.++1)
[1502] Preparation 74-2
[1503] A mixture of
(3RS)-1-cyclohexylcarbonylmethyl-3-[N-t-butoxy-carbony-
l-(S)-phenylalanyl]amino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-
-2-one (47.70 g, 81.02 mmol) and 4N-solution of hydrogen chloride
in ethyl acetate (800 ml) was stirred for 0.5 hour under cooling in
an ice-bath and stirred for 3 hours at ambient temperature. After
removal of hydrogen chloride as completely as possible by babbling
of nitrogen gas, the solution was washed with a dilute aqueous
solution of sodium bicarbonate twice and with water. After drying
over magnesium sulfate, the solvent was evaporated in vacuo to give
an oily mixture of diastereoisomers (35.51 g), which was separated
by medium pressure liquid chromatography on silica gel eluting with
a mixture of chloroform and methanol (20:1). The fractions
containing the following A-isomer and B-isomer were collected and
evaporated in vacuo to afford amorphous masses of pure A-isomer
(11.81 g) and B-isomer (14.30 g) respectively.
[1504] A-isomer:
(3R)-1-cyclohexylcarbonylmethyl-3-[(S)-phenylalanyl]amino-
-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
[1505] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.05-1.45 (5H, m), 1,28
(3H, t, J=7.4 Hz), 1.60 (2H, s), 1.6-2.0 (5H, m), 2.25-2.43 (11H,
m), 2.35 (3H, s), 2.60 (1H, dd, J=10.5 Hz, J=13.7 Hz), 2.93 (2H, q,
J=7.4 Hz), 3.34 (1H, dd, J=3.5 Hz, J=13.7 Hz), 3.66 (1H, dd, J=3.5
Hz, J=10.5 Hz), 3.75 (1H, d, J=17.1 Hz), 5.08 (1H, d, J=17.1 Hz),
5.48 (1H, d, J=8.5 Hz), 7.15-7.45 (8H, m), 8.77 (1H, d, J=8.5
Hz)
[1506] APCI-MS (m/z) =489 (M.sup.++1)
[1507] B-isomer:
(3S)-1-cyclohexylcarbonylmethyl-3-[(S)-phenylalanyl]amino-
-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
[1508] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.05-1.45 (5H, m), 1,28
(3H, t, J=7.4 Hz), 1.63 (2H, s), 1.6-2.0 (5H, m), 2.25-2.43 (1H,
m), 2.34 (3H, s), 2.70 (1H, dd, J=10.5 Hz, J=13.7 Hz), 2.94 (2H, q,
J=7.4 Hz), 3.31 (1H, dd, J=3.8 Hz, J=10.1 Hz), 3.64 (1H, dd, J=3.8
Hz, J=10.1 Hz), 3.74 (1H, d, J=17.1 Hz), 5.06 (1H, d, J=17.1 Hz),
5.46 (1H, d, J=8.5 Hz), 7.15-7.45 (8H, m), 8.73 (1H, d, J=8.5
Hz)
[1509] APCI-MS (mlz) =489 (M.sup.++1)
[1510] Preparation 74-3(1)
[1511] A mixture of
(3S)-1-cyclohexylcarbonylmethyl-3-[(S)-phenylalanyl]-a-
mino-5-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (14.30
g) and phenyl isothiocyanate (4.35 g) in methylene chloride (250
ml) was heated under stirring with vaporizing spontaneously. This
vaporizing procedure was repeated three times. The resultant
reaction mixture was evaporated in vacuo to remove methylene
chloride completely. To the oil obtained above was added
irifluoroacetic acid (200 ml) and the mixture was heated under
stirring at 50.degree. C. for 20 minutes. The mixture was
evaporated in vacuo. The resultant residue was subjected to column
chromatography on silica gel eluting with a mixture of chloroform
and methanol (20:1). The fractions containing the desired product
were combined and evaporated in vacuo to give an oily product,
which was dissolved in ethyl acetate and washed with a diluted
aqueous sodium bicarbonate. After drying over magnesium sulfate,
the organic extract was concentrated in vacuo to afford
(3S)-3-amino-1-cyclohexylcarbonylmethyl-5-
-ethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (6.30 g,
63.1%) as an amorphous mass. .sup.1H-NMR (CDCl.sub.3, .delta.):
1.05-1.4 (5H, m), 1.26 (3H, t, J=7.1 Hz), 1.55-1.95 (SH, m),
2.25-2.45 (1H, m), 2.32 (3H, s), 2.90 (2H, q, J=7.1 Hz), 2.96 (2H,
br, s), 3.75 (1H, d, J=17.1 Hz), 4.46 (1H, s), 5.07 (1H, d, J=17.1
Hz), 7.15-7.4 (3H, m)
[1512] APCI-MS (m/z) =342 (M.sup.++1)
[1513] [.alpha.].sub.2=2-6.59.degree. (C=1.41, CHCl.sub.3)
[1514] Preparation 74-3(2)
[1515]
(3R)-3-Amino-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2,3-dihydr-
o-1H-1,4-benzodiazepin-2-one was obtained in a similar manner to
that of Preparation 74-3(1).
[1516] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.05-1.4 (5H, m), 1.26
(3H, 1, J=7.1 Hz), 1.55-1.95 (5H, m), 2.25-2.45 (1H, m), 2.32 (3H,
s), 2.90 (RH, q, J=7.1 Hz), 3.47 (2H, br, s), 3.75 (1H, d, J=17.1
Hz), 4.48 (1H, s), 5.07 (1H, d, J=17.1 Hz), 7.15-7.4 (3H, m)
[1517] APCI-MS (m/z):342 (M.sup.++1)
[1518] [.alpha.].sub.D.sup.30.4=5.78.degree. (C=1.21,
CHCl.sub.3)
EXAMPLE 1(1)
[1519] To a solution of
(3RS)-3-amino-1-[3-azabicyclo[3.2.2]non-3-yl)carbo-
nylmethyl]-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one
(0.200 g) in dry methylene chloride (10 ml) was added dropwise a
solution of 3-methoxyphenyl isocyanate (0.086 g) in dry methylene
chloride (5 ml) at 5-10.degree. C. in an ice-bath. The mixture was
allowed to warm to room temperature and stirred overnight.
[1520] The reaction mixture was washed with a saturated aqueous
sodium hydrogen carbonate (10 ml) and a brine (10 ml). The organic
layer was dried over anhydrous magnesium sulfate and evaporated in
vacuo. The residue was subjected by column chromatography on silica
gel with a mixture of chloroform and methanol (10:1) as an eluent
to afford
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isop-
ropyl-2-oxo-1 H-1,4-benzodiazepin-3-yl]-N'-(3-methoxyphenyl)urea
(0.270 g).
[1521] mpg: 139-142.degree. C.
[1522] IR(KBr): 3350, 2933, 2864, 1659, 1601, 1548, 1492, 1428,
1201, 762 cm.sup.-1 .sup.1H-NMR (CDCl.sub.3, .delta.): 1.02 (3H, d,
J=7.2 Hz), 1.29 (3H, d, J=7.2 Hz), 1.55-1.80 (8H, m), 2.02-2.10
(2H, m), 3.15-3.24 (1H, m), 3.44-3.80 (4H, m), 4.42 (1H, d, J=17.2
Hz), 4.89 (1H, d, J=17.2 Hz), 5.50 (1H, d, J=8.0 Hz), 6.55 (1H, d,
J=8.4 Hz), 6.81 (JH, d, J=8.4 Hz), 6.90 (1H, d, *=8.4 Hz),
7.07-7.32 (8H, m), 7.47 (1H, t, J=7.2 Hz), 7.57 (1H, d, J=7.2
Hz)
[1523] Mass: m/e=532 (M.sup.++1)
EXAMPLE 1(2)
[1524] The following compound was prepared in a similar manner to
that of Example 1(1).
[1525]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dibydro--
5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N
'-(3-methylthiophenyl)urea
[1526] mp: 134-135.degree. C.
[1527] IR(KBr): 3350, 2931, 1659, 1541, 1451, 1201, 766
cm.sup.-1
[1528] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.99 (3H, d, J=6.8 Hz),
1.29 (3H, d, J=6.8 Hz), 1.50-1.90 (8H, m), 2.00-2.10 (2H, m), 2.41
(3H, s), 3.10-3.22 (1H, m), 3.40-3.84 (4H, m), 4.41 (1H, d, J=16.0
Hz), 4.91 (1H, d, J=16.0 Hz), 5.48 (1H, d, J=7.6 Hz), 6.85-7.31
(7H, m), 7.37 (1H, s), 7.46 (1H, t, J=7.2 Hz), 7.55 (1H, t, J=7.2
Hz)
[1529] Mass: m/e=548 (M.sup.++1)
EXAMPLE 1 (3)
[1530] The following compound was prepared in a similar manner to
that of Example 1(1).
[1531]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-phenylurea
[1532] mp: 132-135.degree. C.
[1533] IR(KBr): 3362, 2932, 1657, 1598, 1546, 1496, 1449, 1201, 756
cm.sup.-1
[1534] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.99 (3H, d, J=6.8 Hz),
1.28 (3H, d, J=6.8 Hz), 1.50-1.90 (8H, m), 1.90-2.10 (2H, m),
3.10-3.20 (1H, m), 3.13-3.75 (4H, m), 4.43 (1H, d, J=16.0 Hz), 4.76
(1H, d, J=16.0 Hz), 5.48 (1H, d, J=8.0 Hz), 6.90-7.53 (11H, m)
[1535] Mass: m/e=502 (M.sup.++1)
EXAMPLE 1(4)
[1536] The following compound was prepared in a similar manner to
that of Example 1(1).
[1537]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-cyclohexylurea
[1538] mp: 138-140.degree. C.
[1539] IR(KBr): 3373, 2930, 2861, 1658, 1546, 1451, 1201, 762
cm.sup.-1
[1540] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.98 (3H, d, J=6.8 Hz),
1.00-1.20 (6H, m), 1.28 (3H, d, J=6.8 Hz), 1.40-2.10 (14H, m),
3.10-3.20 (1H, m), -3.40-3.84 (2H, m), 4.37 (1H, d, J=16.4 Hz),
4.54 (1H, d, J=7.2 Hz), 4.86 (1H, d, J=16.4 Hz), 5.40 (1H, d, J=7.6
Hz), 6.17 (1H,d, J=7.6 Hz), 7.20-7.60 (4H, m)
[1541] Mass: m/e=508 (M' +1)
EXAMPLE 2
[1542] To a solution of
(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-amino-2,3--
dihyro-5-isporopyl-1H-1,4-benzodiazepin-2-one (0.230 g) in dry
tetrahydrofuran (20 ml) was added dropwise a solution of
3-methylphenyl isocyanatc (0.095 g) in dry tetrahydrofuran (5 ml)
at 5-10.degree. C. in an ice-bath for 10 minutes. The mixture was
allowed to warm to room temperature and stirred at ambient
temperature for 3 hours. The resultant mixture was concentrated in
vacuo and the residue was subjected by column chromatography on
silica gel with a mixture of chloroform and ethyl acetate (10:1).
The fractions containing the desired compound were combined and
evaporated in vacuo to afford N-[(3RS)-1-(2-acetylthiophen-3-
-yl)methyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3--
methylphenyl)urea (0.210 g).
[1543] mp: 219-221.degree. C. (dec.)
[1544] IR(KBr): 3324, 2968, 2926, 1661, 1649, 1559, 1491, 1415,
1381, 1247, 1165, 774, 692 cm.sup.-1
[1545] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.89 (3H, d, J=6.8 Hz),
1.29 (3H, d, J=6.8 Hz), 2.26(3H, s), 2.49(3H, s), 3.10-3.20 (1H,
m), 5.32(1H, d, J=17.2 Hz), 5.50 (1H, d, J=8.0 Hz), 5.68 (1H, d,
J=17.2 Hz), 6.80-7.55 (12H, m)
[1546] Mass: m/e=489 (M.sup.++1)
EXAMPLE 3
[1547] To a suspension of sodium hydride (0.030 g of a 65%
dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was
added gradually
N-[(3RS)-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-m-
ethylphenyl)urea (0.250 g) at 5-10.degree. C. in an ice-bath for 30
minutes. The mixture was stirred at the same temperature for 1 hour
and then at room temperature for 2 hours. To the above mixture was
added dropwise a solution of
N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (0.200 g) in dry
N,N-dimethylformamide (5 ml) for 10 minutes and stirred at ambient
temperature overnight. The reaction mixture was concentrated in
vacuo and the residue was taken up with ethyl acetate (100 ml) and
a saturated aqueous sodium hydrogen carbonate (50 ml). The organic
layer was separated, washed with a brine (50 ml), dried over
anhydrous magnesium sulfate and evaporated in vacuo to give a crude
product. The product was purified by column chromatography on
silica gel with a mixture of chloroform and ethyl acetate (10:1) as
an eluent. The fractions containing the desired compound were
combined and evaporated in vacuo to afford
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,-
3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)-
urea (0.1 60 g).
[1548] mp: 123-126.degree. C.
[1549] IR(KBr): 3364, 2929, 2862, 1660, 1616, 1554, 1451, 1201
cm.sup.-1
[1550] .sup.1H-NMR (CDCl.sub.3, .delta.) 0.99 (3H, d, J=7.2 Hz),
1.29 (3H, d, J=7.2 Hz), 1.50-1.80 (8H, m), 2.00-2.10 (2H, m), 2.28
(3H, s), 3.10-3.22 (1H, m), 3.42-3.82 (4H, m), 4.42 (1H, d, J=17.2
Hz), 4.87 (1H, d, J=17.2 Hz), 5.47 (1H, d, J=8.0 Hz), 6.72 (1H, d,
J=8.4 Hz), 6.81 (1H, d, J=7.4 Hz), 7.07-7.56 (8H, m)
[1551] Mass: m/e=516 (M.sup.++1)
EXAMPLE 4
[1552] To a solution of
(3RS)-3-amino-1-(3-azabicyclo[3.2.2]non-3-yl)carbo-
nylmethyl-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.165
g) in N,N-dimethylformamide (5 ml) was added gradually
4-nitrophenyl N-(3-acetylphenyl)carbonate (0.155 g) and then
dropwise triethylamime (0.087 g) at 5.about.10.degree. C. in an
ice-bath and the mixture was stirred at ambient temperature
overnight. The resultant mixture was concentrated in vacuo. The
residue was taken up with ethyl acetate (100 ml) and a saturated
aqueous sodium hydrogen carbonate (50 ml) and washed with a brine
(50 ml). Dryness over anhydrous magnesium sulfate and evaporation
gave a crude product. The crude product was purified by column
chromatography on silica gel with a mixture of chloroform and
methanol (50:1) as an eluent to afford
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-
-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3--
yl]-N'-(3-acetylphenyl)urea (0.190 g).
[1553] mp: 138-140.degree. C.
[1554] IR(KBr): 3363, 2933, 2865, 1682, 1661, 1550, 1488, 1217, 1
202 cm.sup.-1
[1555] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.99 (3H, d, J=7.2 Hz),
1.29 (3H, d, J=7.2 Hz), 1.56-1.80 (8H, m), 2.00-2.16 (2H, m), 2.49
(3H, s ), 3.14-3.22 (1H, m), 3.44-3.84 (4H, m), 4.49 (1H, d, J=16.0
Hz), 4.98 (1H, d, J=16.0 Hz), 5.51 (1H, d, J=7.6 Hz), 7.10-7.64
(9H, m), 7.93 (1H, s)
[1556] Mass: m/e=534 (M' +1)
EXAMPLE 5
[1557] To a solution of
(3RS)-3-amino-1-(3-azabicyclo[3.2.2]non-3-yl)carbo-
nylmethyl-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.170
g) in dry tetrahydrofuran was added gradually 4-nitrophenyl
N-[3-(tetrazol-5-yl)phenyl]carbamate (0.152 g) and then dropwise a
solution of triethylamime (0.090 g) in tetrahydrofuran (5 ml) at
room temperature. The mixture was stirred at ambient temperature
overnight. The mixture was concentrated in vacuo and the residue
was subjected by column chromatography on silica gel with a mixture
of chloroform and methanol (100:1) as an eluent to afford
N-[(3RS)-1-(3-azabicyclo[3.2.2]no-
n-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-
-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea (0.150 g).
[1558] mp: 220.degree. C. (dec.)
[1559] IR(KBr): 3347, 2933, 2866, 1655, 1584, 1452, 1273, 1204, 758
cm.sup.-1
[1560] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.91 (3H, d, J=7.2 Hz),
1.29 (3H, d, J=7.2 Hz), 1.40-1.80 (8H, m), 1.90-2.10 (2H, m),
3.20-3.30 (1H, m), 3.30-3.80 (4H, m ), 4.64 (1H, d, J=16.8 Hz),
4.93 (11H, d, J=16.8 Hz), 5.17 (1H, d, J=8.4 Hz), 7.28-7.60 (9H,
m), 7.99 (1H, s) 9.14 (1H, s)
[1561] Mass: m/e=558 (M' +1)
EXAMPLE 6(1)
[1562] To a suspension of sodium hydride (0.027 g of a 64%
dispersion in mineral oil) in N,N-dimethylformamide (3 ml) was
added gradually
N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]--
N'-(3-methylphenyl)urea (0.200 g) at ambient temperature and the
mixture was stirred for 1 hour under the same conditions. To the
mixture was added sodium iodide (0.107 g) and followed dropwise a
solution of 2-chloromethyl-3-methylpridine (0.093 g) in
N,N-dimethylformamide (2 ml) at the same temperature. The resultant
mixture was concentrated in vacuo and the residue was taken up with
ethyl acetate and water. The aqueous layer was extracted with
another ethyl acetate. The combined organic layer was dried over
sodium sulfate, filtered and concentrated in vacuo to give a crude
compound. The crude compound was recrystallized with isopropyl
ether and chloroform to give N-[(3RS)-2,3-dihydro-5-(2-methylpr-
opyl)-1-(3-methylpyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(-
3-methylphenyl)urea (0.23 g) as a colorless powder.
[1563] mp: 185-187.degree. C.
[1564] IR(KBr): 2956, 1695, 1649, 1614, 1564, 1492, 1447, 1384,
1214, 778 cm.sup.-1
[1565] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.79 (3H, d, J=8 Hz),
0.87 (3H, d, J=8 Hz), 1.82-1.88 (1H, m), 2.24 (3H, s), 2.35 (3H,
s), 2.46 (1H, dd, J=16 Hz, J=16 Hz), 2.86 (1H, dd, J=8 Hz, J=16
Hz), 5.15 (2H, q, J=18 Hz), 5.20 (1H, s), 6.73 (1H, d, J=8 Hz),
7.10-7.57 (9H, m), 7.74 (1H, d, J=8 Hz), 8.23 (1H, d, J=8 Hz), 8.87
(1H, s)
[1566] Mass: m/e=469 (Mt +1)
EXAMPLE 6(2)
[1567] The following compound was prepared in a similar manner to
that of Example 3.
[1568]
N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-1-(3-azabicyclo[3.2.2]non-3-
-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N
'-(3-methylphenyl)urea
[1569] mp: 95-100.degree. C.
[1570] IR(KBr): 2932, 1653, 1558, 1456, 1204, 774 cm.sup.-1
[1571] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.78 (3H, d, J=8 Hz),
0.88 (3H, d, J=8 Hz), 1.57-1.88 (8H, m), 2.08 (3H, br), 2.78 (3H,
s), 2.50 (1H, dd, J=16 Hz, J=16 Hz), 2.88 (1H, dd, J=8 Hz, J=16
Hz), 3.48-3.85 (4H, m), 4.20 (1H, d, J=18 Hz), 5.00 (1H, d, J=18
Hz), 5.48 (1H, d, J=8 Hz), 6.69-7.55 (10H, m)
[1572] Mass: m/e=530 (M.sup.++1)
EXAMPLE 6(3)
[1573] The following compound was prepared in a similar manner to
that of Example 3.
[1574]
N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-1-(2-methylcarbonylthiophen-
-3-yl)methyl-2-oxo-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[1575] mp: 215-218.degree. C.
[1576] IR(KBr): 3347, 2954, 1664, 1646, 1561, 1490, 1448, 1415,
1384, 1310, 1216, 1165, 772 cm.sup.-1
[1577] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.70 (3H, d, J=8 Hz),
0.80 (3H, d, J=8 Hz), 1.70-1.80 (1H, m), 2.18 (3H, s), 2.40 (3H,
s), 2.50 (1H, dd, J=16 Hz, J=16 Hz), 2.78 (1H, dd, J=8 Hz, J=16
Hz), 5.10 (1H, d, J=18 Hz), 5.16 (1H, d, J=8 Hz), 5.40 (1H, d, J=16
Hz), 6.68 (1H, d, J=8 Hz), 6.85 (1H, d, J=8 Hz), 7.03-7.13 (3H, m),
7.23-7.33 (3H, m), 7.49 (1H, t, J=8 Hz), 7.71 (1H, d, J=10 Hz),
7.78 (1H, d, J=6 Hz), 8.81 (1 H, s)
[1578] Mass: m/e=502 (M.sup.++1)
EXAMPLE 7
[1579] The following compound was prepared in a similar manner to
that of Example 4.
[1580]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-(2-methylpropyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-tetrazolyphenyl)-
urea
[1581] mp: 212-215.degree. C.
[1582] IR(KBr): 3364, 2935, 1659, 1569, 1452, 1385, 1215, 1016, 761
cm'.sup.1
[1583] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.74 (3H, d, J=8 Hz),
0.85 (3H, d, J=8 Hz), 1.03 (2H, d, J=6 Hz), 1.20-1.82 (8H, m), 2.02
(2H, br), 2.43 (1H, dd, J=16 Hz, J=16 Hz), 2.95 (1H, dd, J=8 Hz,
J=16 Hz), 3.47 (2H, d , J=18 Hz), 3.66 (1H, dd, J=8 Hz, J=16 Hz),
3.83 (1H, dd, J=8 Hz, J=16 Hz), 4.52 (1H, d, J=18 Hz), 4.95 (1H, d,
J=18 Hz), 5.18 (1H, d, J=8 Hz), 7.27-7.79 (8H, m), 8.05 (1H, s),
9.22 (1H, s) Mass: m/e=584 (M' +1)
EXAMPLE 8(1)
[1584] The following compound was prepared in a similar manner to
that of Example 6(1).
[1585]
N-[(3RS)-2,3-dihydro-5-methyl-1-(3-methylpyridin-2-yl)methyl-2-oxo--
1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[1586] mp: 225-229.degree. C.
[1587] IR(KBT): 3323, 1677, 1644, 1611, 1562, 1492, 1449, 1387,
1312, 1217, 1165, 776 cm.sup.-1
[1588] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.58 (3H, d, J=8 Hz),
2.26 (3H, s), 4.27 (1H, d, J=16 Hz), 4.60 (1H, d, J=16 Hz), 5.33
(1H, q, J=8 Hz), 6.76 (1H, s ), 6.78 (1H, d, J=8 Hz), 6.99-7.26
(13H, m ), 9.01 (1H, s)
[1589] Mass: m/e=427 (M )
EXAMPLE 8(2)
[1590] The following compound was prepared in a similar manner to
that of Example 3.
[1591]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[1592] mp: 150-153.degree. C.
[1593] IR(KBr): 3343, 2931, 1959, 1675, 1554, 1206, 1167
cm.sup.-1
[1594] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.03 (2H, d, J=6 Hz),
1.50-1.70 (8H,m), 1.98 (1H, br), 2.04 (1H, br), 2.23 (3H, s), 2.40
(3H, s), 3.48 (1H, br), 3.58-3.69 (2H, m), 4.65 (1H, d, J=16 Hz),
4.90 (1H, d, J=16 Hz), 5.10 (1H, d, J=8 Hz), 6.72 (1H, J=8 Hz),
7.07-7.18 (3H, m), 7.31-7.38 (2H, m), 7.60 (1H, t, J=8 Hz), 7.78
(1H, d, J=8 Hz), 8.90 (1H, s)
[1595] Mass: m/e=487 (M.sup.++1)
EXAMPLE 8(3)
[1596] The following compound was prepared in a similar manner to
that of Example 3.
[1597]
N-[(3RS)-1-(2-acetylthiophen-3-yl)methyl-2,3-dihydro-5-methyl-2-oxo-
-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[1598] mp: 215-219.degree. C.
[1599] IR(KBr): 3307, 1676, 1554, 1491, 1449, 1415, 1382, 1311,
1217, 1165, 770 cm.sup.-1
[1600] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.23 (3H, s), 2.44 (3H,
s), 5.18 (1H, d, J=8 Hz), 5.30 (1H, d, J=16 Hz), 5.41 (1H, d, J=16
Hz), 6.72-6.76 (2H, m), 7.08-7.37 (9H, m), 7.56 (1H, t, J=8 Hz),
7.79 (1H, d, J=8 Hz), 7.83 (1H, d, J=6 Hz), 8.91 (1H, s)
[1601] Mass: m/e=461 (M' +1)
EXAMPLE 9(1)
[1602] The following compound was prepared in a similar manner to
that of Example 6(1).
[1603]
N-[(3RS)-2,3-dihydro-5-(3-methylbutyl)-1-(3-methylpyridin-2-yl)meth-
yl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[1604] mp: 151-154.degree. C.
[1605] IR(KBr): 2955, 1644, 1612, 1555, 1492, 1384, 1308, 1206,
1165, 778, 692 cm.sup.-1
[1606] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.74 (3H, q, J=8 Hz),
0.81 (3H, d, J=8 Hz),1.17-1.50 (3H, m), 2.17 (3H, s), 2.45-2.76
(2H, m), 3.33 (3H, s), 4.92 (1H, d, J=16 Hz), 5.05 (1H, d, J=18
Hz), 5.12 (1H, d, J=16 Hz), 5.20 (1H, d, J=18 Hz), 6.67 (1H, d, J=8
Hz), 7.02-7.27 (5H, m), 7.46-7.51 (2H, m), 7.66 (1H, d, J=8 Hz),
7.71 (1H, d, J=8 Hz), 8.11 (1H, d, J=6 Hz), 8.83 (1H, d, J=16
Hz)
[1607] Mass: m/e=484 (M' +1)
EXAMPLE 9(2)
[1608] The following compound was prepared in a similar manner to
that of Example 6(3).
[1609]
N-[(3RS)-1-(2-acetylthiophen-3-yl)methyl-2,3-dihydro-5-(3-methylbut-
yl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[1610] mp: 190-195.degree. C.
[1611] IR(KBr): 3329, 2955, 1645, 1551, 1492, 1413, 1383, 1215,
1165, 774 cm.sup.-1
[1612] .sup.1H-NMR (CDCl.sub.3,(.delta.):0.80 (3H, t, J=8 Hz), 0.85
(3H, d, J=8 Hz), 1.20-1.54 (3H, m), 1.68 (2H, s), 2.27 (3H, s),
2.49 (3H, s), 2.75 (2H, d, J=lOHz), 5.34 (1H, d, J=18 Hz), 5.52
(1H, d, J=8 Hz), 5.65 (1H, d, J=18 Hz), 6.80-7.56 (10, m)
[1613] Mass: m/e=517 (M.sup.++1)
EXAMPLE 10
[1614] The following compound was prepared in a similar manner to
that of Example 3.
[1615]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-ethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[1616] mp: 115-120.degree. C.
[1617] IR(KBr): 3358, 2963, 2932, 2866, 1659, 1630, 1569, 1489,
1451, 1265, 1214, 1204, 1016 cm.sup.-1
[1618] .sup.1 H-NMR (CDCL .sub.3, .delta.): 1.14 (3H, t, J=7.2 Hz),
1.50-1.80 (8H, m), 2.00-2.10 (2H, m), 2.27 (3H, s), 2.73-2.95 (2H,
m), 3.40-3.80 (4H, m), 4.50 (1H, d, J=16.0 Hz), 4.87 (1H, d, J=16.0
Hz), 5.51 (1H, d, J=7.2 Hz), 6.66 (1H, s), 6.80-7.60 (9H, m)
EXAMPLE 11
[1619] The following compound was prepared in a similar manner to
that of Example 2.
[1620]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-butyl-2,3--
dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
[1621] mp: 121-123.degree. C.
[1622] IR(KBr): 3348, 2931, 2864, 1659, 1599, 1555, 1490, 1451,
1202, 774 cm.sup.-1
[1623] .sup.1H-NMR (CDCl.sub.3, .delta.) 0.85 (3H, t, J=7.6 Hz),
1.29 (2H, q, J=7.2 Hz), 1.40-1.80 (1OH, m), 2.00-2.10 (2H, m), 2.27
(3H, s), 2.72-2.88 (2H, m), 3.44-3.80 (4H, m), 4.39 (1H, d, J=16.4
Hz), 4.91 (1H, d, J=16.4 Hz), 5.49 (1H, d, J=7.2 Hz), 6.80-7.57
(10H, m)
[1624] Mass: m/e=530 (M.sup.++1)
EXAMPLE 12(1)
[1625] The following compound was prepared in a similar manner to
that of Example 1(1).
[1626]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclohexyl-
methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)ure-
a
[1627] mp: 164-166.degree. C.
[1628] IR(KBr): 2916, 2846, 2400, 1678, 1657, 1592, 1556, 1476,
1444, 1194 cm.sup.-1
[1629] .sup.1H-NMR (DMSO-d.sub.6,(.delta.): 0.80-1.20 (4H, m),
1.50-1.80 (1SH, m), 1.99-2.05 (2H, m), 2.23 (3H, s), 2.50-2.55 (1H,
m), 2.95-2.98 (1H, m), 3.43-3.79 (4H, m), 4.64 (1H, d, 3=17 Hz),
4.93 (1H, d, J=17 Hz), 5.20 (1H, d, J=4.0 Hz), 6.73 (1H, d, J=7.0
Hz), 7.07-7.24 (3H, m), 7.35-7.42 (3H, m), 7.65 (1H, t, J=8 Hz),
7.82 (1H, d, J=7.0 Hz), 9.04 (1H, s)
[1630] Mass: m/e=571 (M.sup.++1)
EXAMPLE 12(2)
[1631] The following compound was prepared in a similar manner to
that of Example 4.
[1632]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclohexyl-
methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)p-
henyl]urea
[1633] mp: 218-222.degree. C. (dec.)
[1634] IR(KBr): 3370, 3354, 2925, 2862, 1689, 1740, 1630, 1489,
1450, 1214, 1204 cm.sup.-1
[1635] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.80-1.2 (4H, m),
1.50-1.80 (15H, m), 1.90-2.40 (2H, m), 2.40-2.50 (1H, m), 2.80-2.90
(1H, m), 3.50-3.80 (4H, m), 4.56 (1H, d, J=17 Hz), 4.95 (1H, d,
J=17 Hz), 5.14 (1H, d, J=8.0 Hz), 7.29 (1H, d, J=8.0 Hz), 7.36-7.48
(4H, m), 7.56-7.63 (2H, m), 7.76 (1H, d, J=8.0 Hz), 8.07 (1H, s),
9.20 (1H, s)
[1636] Mass: m/e=623 (Mt
EXAMPLE 13-1
[1637]
N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-methoxyphenacyl)-9-met-
hyl-2-oxo-1H-1,4-benzodiazepin-3-yi]-N'-[3-(tetrazol-5-yl)phenyl]urea
was prepared in a similar manner to that of Example 51.
[1638] mp: 193.9-195.2.degree. C.
[1639] IR (Nujol, cm.sup.-1): 1650
[1640] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.5 (3H, br, s), 3.95
(3H, s), 4.66 (1H, d, J=18.0 Hz), 5.40 (1H, d, J=.3 Hz), 5.46 (1H,
d, J=18.0 Hz), 6.9-7.8 (15H, m ), 7.95 (1H, br, s ), 8.21 (1H, br,
s ), 9.35 (1H, br, s)
[1641] Mass (APCI): 619 (M.sup.++1)
EXAMPLE 13-2
[1642] A mixture of
N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-methoxyph-
enacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phe-
nyl]urea (200 mg) and 1N boron tribromide in methylene chloride
(3.87 ml) was stirred at 0.degree. C. under nitrogen stream for 4
hours and allowed to stand in a refrigerator overnight. Ethyl
acetate and water were added to the reaction mixture. The separated
organic layer was washed with water and brine, and then dried over
magnesium sulfate. The solvent was evaporated in vacuo to afford a
pale brown powder, which was washed with diisopropyl ether and
collected by filtration to give
N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-methyl-2--
oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyllurea
(202.0 mg) as a crystalline powder.
[1643] mp: 220.8-225.0.degree. C.
[1644] IR (Nujol, cm.sup.-1): 1640
[1645] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 4.67 (1H, d, J=18.1
Hz), 5.56 (1H, d, J=18.1 Hz), 6.7-7.9 (15H, m), 8.22 (1H, br, s),
9.37 (1H, br, s)
[1646] Mass (FAB): 605 (M.sup.++1)
EXAMPLE 13-3
[1647] A mixture of
N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyph-
enacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phe-
nyl]urea (150 mg), triethylamine (75 mg) and chlorotriphenylmethane
(69 mg) in a mixture of N,N-dimethylformamide and tetrahydrofuran
(1:3, 4 ml) was stirred overnight. Ethyl acetate and a saturated
aqueous solution of sodium bicarbonate were added to the reaction
mixture. The separated organic layer was washed with water and
brine, and then dried over sodium sulfate. The solvent was
evaporated in vacuo to afford an amorphous mass, which was
triturated in diisopropyl ether and collected by filtration to
afford
N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-me-
thyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-{3-[1-(triphenylmethyl)tetrazol-5-
-yl]phenyl}urea (186.0 mg, 88.6% yield) as a crystalline
powder.
[1648] mp: 132.1-146.0.degree. C.
[1649] IR (Nujol, cm.sup.-1): 1640
[1650] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.5 (3H, br, s), 4.81
(1H, d, J=18.4 Hz), 5.39 (1H, d, J=8.4 Hz), 5.68 (1H, d, J=18.0
Hz), 6.8-7.8 (30H, m), 8.08 (1H, br, s)
[1651] Mass (FAB): 847 (M.sup.++1)
EXAMPLE 13-4
[1652]
N-[(3RS)-1-(2-Ethoxycarbonylmethoxyphenyl)carbonylmethyl-2,3-dihydr-
o-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-{3-[1-(t-
riphenylmethyl)tetrazol-5-yl]phenyllurea was prepared in a similar
manner to that of Preparation 59-3.
[1653] IR (Neat, cm.sup.-1): 1700
[1654] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.97 (3H, t, J=7.1 Hz),
2.30 (3H, s), 3.89 (2H, q, J=7.1 Hz), 4.21 (1H, d, J=16.8 Hz), 4.68
(1H, d, J=16.8 Hz), 5.05 (2H, s), 5.20 (1H, d, J=8.6 Hz), 7.0-7.8
(30H, m), 8.50 (1H, d, J=8.5 Hz)
EXAMPLE 13-5
[1655] A mixture of
N-[(3RS)-1-(2-ethoxycabonylmethoxyphenyl)-carbonylmeth-
yl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl-
]-N'-{3-[1-(triphenylmethyl)tetrazol-5-yl]phenyl}urea (196 mg,) and
IN NaOH in 1,2-dimethoxyethane (2 ml) was stirred at room
temperature overnight. 4N-HCl in ethyl acetate (2 ml) was added to
the reaction mixture and stirred at room temperature for three
days. Ethyl acetate and water were added to the reaction mixture.
The separated organic layer was washed with water and brine
successively, and dried over magnesium sulfate. Removal of the
solvent in vacuo afforded N-[(3RS)-2,3-dihydro-5--
(2-fluorophenyl)-1-(2-carboxymethoxyphenyl)-carbonylmethyl-9-methyl-2-oxo--
1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea (66.0
mg, 47.4%).
[1656] mp 109.6-113.0.degree. C.
[1657] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 4.04 (1H, d, J=17.0
Hz), 4.64 (1H, d, J=17.0 Hz), 5.05 (2H, s), 5.18 (1H, d, J=8.6 Hz),
7.03 (1H, d, J=7.6 Hz), 7.2-7.7 (13H, m), 8.46 (1H, d, J=8.6
Hz)
[1658] Mass (FAB): 662 (M.sup.+)
EXAMPLE 14-1
[1659] A mixture of
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-
-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yI]--
N'-(3-hydroxymethylphenyl)urea (190 mg) and activated manganese
dioxide (1.5 g) in acetone (10 ml) was stirred at room temperature
for 4 hours.
[1660] The reaction mixture was filtered. The filtrate and the
washings were combined and evaporated in vacuo to afford a
colorless oil, which was triturated in diisopropyl ether and
collected by filtration to afford
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-f-
luorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-formylphenyl)-
urea (146mg, 77.1%) as a crystalline powder.
[1661] mp: 236.8-242.1.degree. C.
[1662] IR (Nujol, cm.sup.-1): 1700, 1680, 1635
[1663] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-2.2 (10H, m), 2.44
(3H, s), 2.9-3.4 (2H, m), 3.7-4.0 (2H, m), 4.13 (1H, d, J=16.1 Hz),
5.13 (1H, d, J=16.1 Hz), 5.32 (1H, d, J=8.3 Hz), 7.03 (1H, d, J=7.6
Hz), 7.1-7.4 (3H, m), 7.4-7.8 (6H, m), 8.0 (1H, br, s), 9.32 (1H,
br, s), 9.94 (1H, br, s)
[1664] Mass (APCI): 596 (Mt +1)
EXAMPLE 14-2
[1665]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-hydroxy-
iminomethylphenyl)urea was prepared in a similar manner to that of
Example 16(7)-2.
[1666] mp: 196.0-199.0.degree. C.
[1667] IR (Nujol, cm.sup.-1): 3300, 1680, 1640
[1668] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.44
(3H, s), 2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.12 (1H, d, J=16.2 Hz),
5.13 (1H, d, J=16.2 Hz), 5.31 (1H, d, J=8.4 Hz), 7.0-7.8 (12H, m),
8.05 (1H, s), 11.18 (1H, s)
[1669] Mass (APCI): 611 (M.sup.++1)
EXAMPLE 15-1
[1670]
N-[(3RS)-1-(2-aminophenacyl)-2,3-dibydro-5-(2-fluorophenyl)-9-methy-
l-2-oxo-1H-1,4-benzodiazepin-3-yI]-N
'-[3-(tetrazol-5-yl)phenyl]urea was prepared in a similar manner to
that of Example 51.
[1671] mp: 164.1-186.2.degree. C.(dec.)
[1672] IR (Nujol, cm.sup.-1): 1650
[1673] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.5 (3H, br, s), 4.69
(1H, d, J=17.4 Hz), 5.41 (1H, d, J=8.3 Hz), 5.69 (1H, d, J=17.4
Hz), 6.5-8.2 (16H, m), 9.37 (1H, br, s)
[1674] Mass (APCI): 604 (M.sup.++1)
EXAMPLE 15-2
[1675] A mixture of
N-[(3RS)-1-(2-aminophenacyl)-2,3-dihydro-5-(2-fluoroph-
enyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)pheny-
l]urea (180mg) and acetic anhydride (2 ml) in methylene chloride (2
ml) was stirred at room temperature for 6 hours. The reaction
mixture was evaporated in vacuo to afford a residue, which was
triturated in diisopropyl ether and collected by filtration to give
N-[(3RS)-1-(2-(N,N-diacetylamino)phenacyl)-2,3-dihydro-5-(2-fluorophenyl)-
-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]ure-
a (125.0 mg, 61.0% yield) as a crystalline powder.
[1676] mp: 192.0-216.6.degree. C. (dec.)
[1677] IR (Nujol, cm.sup.-1): 1670, 1645
[1678] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.91 (6H, s), 2.49 (3H,
s), 4.75 (1H, d, J=17.8 Hz), 5.44 (1H, d, J=8.3 Hz), 5.85 (1H, d,
J=17.8 Hz), 7.0-7.8 (13H, m), 8.0-8.4 (3H, m), 9.37(1H, br, s)
[1679] Mass (FAB): 688 (M.sup.++1)
EXAMPLE 16(1)
[1680]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-bromophenyl)u-
rea was prepared in a similar manner to that of Example 59.
[1681] mp: >250.degree. C.
[1682] IR (Nujol, cm.sup.-1): 1690, 1630 .sup.1H-NMR (DMSO-d.sub.6,
(5): 1.3-2.2 (10H, m), 2.44 (3H, s), 2.8-3.4 (2H, m), 3.4-4.0 (2H,
m), 4.13 (1H, d, J=16.2 Hz), 5.13 (1H, d, J=16.2 Hz), 5.30 (1H, d,
J=8.4 Hz), 7.0-7.9 (l1H, m), 9.22 (1H, br, s) Mass (APCI): 648, 646
Example 16(2)
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-f-
luorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-chlorophenyl)-
urea was prepared in a similar manner to that of Example 59.
[1683] mp: >250.degree. C.
[1684] IR (Nujol, cm'): 1680, 1630
[1685] .sup.1H-NMR (DMSO-d.sub.6, 6): 1.3-2.2 (10H, m), 2.44 (3H,
s), 2.9-3.4 (2H, m), 3.5-4.0 (2H, m), 4.13 (1H, d, J=16.2 Hz), 5.13
(1H, d, J=16.2 Hz), 5.31 (1H, d, J=8.3 Hz), 6.9-7.8 (11H, m), 9.24
(1H,
[1686] Mass (APCI): 602 (M' +1)
EXAMPLE 16(3)
[1687]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-(2-fluorop-
henyl)-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methoxy-
phenyl)urea was prepared in a similar manner to that of Example
59.
[1688] mp: 240.9-243.1-C
[1689] IR (Nujol, cm.sup.-1): 1680, 1640
[1690] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.44
(3H, s), 2.8-3.1 (1H, m), 3.1-3.3 (1H, m), 3.5-4.0 (2H, m), 3.69
(3H, s), 4.12 (1H, d, J=16.2 Hz), 5.13 (1H, d, J=16.1 Hz), 5.32
(1H, d, J=8.5 Hz), 6.50 (1H, d, J=7.8 Hz), 6.7-7.0 (1H, m), 7.0-7.8
(10H, m), 9.04 (1H, br, s)
[1691] Mass (APCI): 598 (M.sup.++1)
EXAMPLE 16(4)
[1692]
N-[(3RS)-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5--
(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-.sup.3-yl]-N'-[3-(tei-
razol-5-yl)methylphenyl]urea was prepared in a similar manner to
that of Example 51.
[1693] mp: 153.8-167.7.degree. C.
[1694] IR (Nujol, cm.sup.-1): 1650
[1695] .sup.1H-NMR (DMSO-d, .delta.)5: 1.4-2.1 (1OH, m), 2.44 (3H,
s), 2.9-4.0 (4H, m), 4.12 (1H, d, J=16.2 Hz), 4.22 (2H, br, s),
2.12 (1H, d, J=16.2 Hz), 5.30 (1H, d, J=8.4 Hz), 6.8-7.8 (12H, m),
8.0-8.2 (1H, m), 9.05 (1H, br, s)
[1696] Mass (APCI): 650 (M.sup.++1)
EXAMPLE 16(5)
[1697]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylt-
hiophenyl)urea was prepared in a similar manner to that of Example
59.
[1698] mp: 234.2-236.6.degree. C.
[1699] IR (Nujol, cm.sup.-1): 1700, 1675, 1630
[1700] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.42
(3H, s), 2.44 (3H, s), 2.9-3.4 (2H, m), 3.7-4.0 (2H, m), 4.12 (1H,
d, J=16.2 Hz), 5.13 (1H, d, J=16.2 Hz), 5.32 (1H, d, J=8.4 Hz),
6.7-6.9 (1H, m), 6.9-7.1 (2H, m ), 7.1-7.4 (4H, m ), 7.4-7.8 (4H, m
), 9.08 (1H, br, s)
[1701] Mass (APCI): 614 (M' +1)
EXAMPLE 16(6)
[1702]
N-((3RS)-1-(3-Azabicyclo[3.2.2)non-3-yl)carbonylmethyl-2,3-dihydro--
5-(2-fluorophenyl)-9-methyl-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)-
urea was prepared in a similar manner to that of Example 59.
[1703] mp: 246.2-247.2.degree. C.
[1704] IR (Nujol, cm.sup.-1): 1700, 1680, 1635
[1705] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.23
(3H, s), 2.44 (3H, s), 2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.12 (1H,
d, J=16.2 Hz), 5.12 (1H, d, J=16.2 Hz), 5.32 (1H, d, J=8.5 Hz),
6.73(1H, d, J=6.6 Hz), 7.0-7.8 (1H, m), 8.94 (1H, br, s)
[1706] Mass (APCI): 582 (M.sup.++1)
EXAMPLE 16(7)-1
[1707]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-acetylp-
henyl)urea was prepared in a similar manner to that of Example
59.
[1708] mp: >250.degree. C.
[1709] IR (Nujol, cm.sup.-1): 1700, 1680, 1640
[1710] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-2.2 (10H, m), 2.44
(3H, s), 2.53 (3H, s), 2.9-3.3 (2H, m), 3.7-4.1 (2H, m), 4.13 (1H,
d, J=16.2 Hz), 5.13 (1H, d, J=16.2 Hz), 5.33 (1H, d, J=8.4 Hz),
7.03 (1H, d, J=7.6 Hz) 7.2-7.9 (10H, m), 8.01 (1H, br, s), 9.26
(1H, br, s)
[1711] Mass (APCI): 610 (M.sup.++1)
EXAMPLE 16(7)-2
[1712] A mixture of
N-[(3RS)-1-(3-azabicyclo[3.2.23non-3-yl)carbonylmethyl-
-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]--
N'-(3-acetylphenyl)urea (217 mg) and hydroxylamine-hydrochloride
(124 mg), triethylamine (180 mg) in tetrahydrofuran (4 ml) was
stirred at room temperature overnight. Ethyl acetate and 1N aqueous
hydrochloric acid solution were added to the reaction mixture. The
separated organic layer was washed with 1N aqueous hydrochloric
acid twice, saturated aqueous sodium bicarbonate, and brine
successively and then dried over magnesium sulfate. The solvent was
evaporated in vacuo to afford
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-meth-
yl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(1-hydroxyimi-
noethyl)phenyl]urea (235.0mg) as a crystalline powder.
[1713] mp: 199.1-207.8.degree. C.
[1714] IR (Nujol, cm.sup.-1): 1650
[1715] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.11
(3H, s), 2.44 (3H, s), 2.8-3.4 (2H, m), 3.6-4.0 (2H, m), 4.13 (1H,
d, J=16.3 Hz), 5.13 (1H, d, J=16.3 Hz), 5.33 (1H, d, J=8.4 Hz),
7.02 (1H, d, J=7.6 Hz), 7.2-7.8 (11H, m), 9.10 (1H, br, s), 11.14
(1H, br, s)
[1716] Mass (APCI): 625 (M.sup.++1)
EXAMPLE 16(8)
[1717]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-(2-fluorop-
henyl)-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetraz-
ol-5-yl)phenyllurea was prepared in a similar manner to that of
Example 51.
[1718] mp: 182.2-190.9.degree. C.
[1719] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.45
(3H, s), 2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.13 (1H, d, J=16.3 Hz),
5.14 (1H, d, J=16.3 Hz), 5.35 (1H, d, J=8.3 Hz), 6.9-7.1 (2H, m),
7.2-7.4 (3H, m), 7.4-7.8 (5H, m ), 8.0-8.2 (1H, m ), 8.20 (1H, br,
s ), 9.30 (1H, br, s)
[1720] Mass (APCI): 636 (M' +1)
EXAMPLE 16(9)-1
[1721]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonyimethyl-5-(2-fluorop-
henyl)-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-tert-bu-
toxycarbonylphenyl)urea was prepared in a similar manner to that of
Example 51.
[1722] mp: 230.4-232.2.degree. C.
[1723] IR (Nujol, cm.sup.-1): 1720, 1680
[1724] .sup.1H-NMR (DMSO-d.sub.6,&): 1.3-2.2 (10H, m), 2.44
(3H, s), 1.52 (9H, s), 2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.13 (1H,
d, J=16.2 Hz), 5.13 (1H, d, J=16.2 Hz), 5.32 (1H, d, J=8.4 Hz),
7.03 (1H, d, J=7.5 Hz), 7.2-7.8 (11H, m), 7.95 (1H, br, s), 9.52
(1H, br, s)
[1725] Mass (APCI): 668 (M.sup.++1)
EXAMPLE 16(9)-2
[1726]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-(2-fluorop-
henyl)-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-carboxy-
phenyl)urea was prepared in a similar manner to that of Example
18(3)-2.
[1727] mp: 197.1-204.2.degree. C.
[1728] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.45
(3H, s), 2.9-3.4 (2H, m), 3.8-4.0 (2H, m), 4.13 (1H, d, J=16.2 Hz),
5.13 (1H, d, J=16.2 Hz), 5.32 (1H, d, J=8.3 Hz), 7.0-7.1 (1H, m),
7.2-7.8 (10H, m), 8.05 (1H, br, s), 9.24 (1H, br, s)
EXAMPLE 17(1)
[1729]
N-[(3RS)-5-Cyclohexyl-2,3-dihydro-1,9-dimethyl-2-oxo-1H-1,4-benzodi-
azepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea was prepared in a
similar manner to that of Example 51.
[1730] mp: 198.9-200.7.degree. C.
[1731] IR (Nujol, cm.sup.-1): 1655
[1732] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.8-2.0 (IOH, m),
2.3-2.5 (3H, br, s), 2.9-3.1 (1H, m), 3.09 (3H, s), 5.12 (1H, d,
J=8.4 Hz), 7.3-7.7 (7H, m), 8.18 (1H, br, s), 9.31(1H, br, s)
[1733] Mass (APCI): 473 (M' +1)
EXAMPLE 17(2)
[1734]
N-[(3RS)-5-Cyclohexyl-2,3-dihydro-1,9-dimethyl-2-oxo-1H-1,4-benzodi-
azepin-3-yl]-N'-(3-methylphenyl)urea was prepared in a similar
manner to that of Example 59.
[1735] mp: 196.4-197.5.degree. C.
[1736] IR (Nujol, cm.sup.-1): 1685, 1640, 1610
[1737] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.8-2.0 (10H, m), 2.22
(3H, s), 2.34 (3H, s), 3.04 (1H, m), 3.07 (3H, s), 5.08 (1H, d,
3=8.3 Hz), 6.73 (1H, m), 7.0-7.6 (7H, m), 8.91 (1H, br, s)
[1738] Mass (APCI): 419 (M' +1)
EXAMPLE 18(1)
[1739]
N-[(3RS)-1-(2-Methylphenacyl)-9-methyl-5-(2-fluorophenyl)-2,3-dihyd-
ro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Example 59.
[1740] mp: 190.2-196.2.degree. C.
[1741] IR (Nujol, cm.sup.-1): 1680, 1635
[1742] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.24 (3H, s), 2.27 (3H,
s), 2.46 (3H, s), 4.70 (1H, d, J=17.5 Hz), 5.37 (1H, d, J=8.6 Hz),
5.45 (1H, d, J=17.5 Hz), 6.73 (1H, d, J=6.6 Hz), 7.0-8.0 (15H, m),
8.96 (1H, br, s)
[1743] Mass (APCI): 549 (M.sup.++1)
EXAMPLE 18(2)
[1744]
N-[(3RS)-1-(2-Methylphenacyl)-5-(2-fluorophenyl)-9-methyl-2,3-dihyd-
ro-2-oxo-1
H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea was
prepared in a similar manner to that of Example 51.
[1745] mp: 215.8-220.3.degree. C.
[1746] IR (Nujol, cm.sup.-1): 1670, 1635
[1747] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.28 (3H, s), 2.49 (3H,
s), 4.72 (1H, d, J=17.5 Hz), 5.41 (1H, d, J=8.3 Hz), 5.47 (1H, d,
J=17.5 Hz), 7.0-8.0 (15H, m), 8.21 (1H, br, s), 9.33 (1H, br,
s)
[1748] Mass (APCI) 603 (M.sup.++1)
EXAMPLE 18(3)-1
[1749]
N-[(3RS)-2,3-dihydro-5-(2-f]uorophenyl)-9-methyl-1-(2-methyl-phenac-
yl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tert-butoxycarbonyl)-phenyl]ur-
ea was prepared in a similar manner to that of Example 51.
[1750] IR (Nujol, cm.sup.-1): 1710, 1660
[1751] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.56 (9H, s), 2.31 (3H,
s), 2.45 (3 H, s), 4.38 (1H, d, J=17.2 Hz), 5.58 (1H, d, J=17.2
Hz), 5.73 (1H, d, J=8.3 Hz), 6.8-8.1 (15H, m)
[1752] Mass (APCI): 635 (M.sup.++1)
EXAMPLE 18(3)-2
[1753] A mixture of
N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2--
methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-tert-butoxycarbonyl-
phenyl)urea (170 mg) and trifluoroacetic acid (1.0 ml) in methylene
chloride (2.0 ml) was stirred at 0.degree. C. for 2 hours. The
reaction mixture was evaporated in vacuo to give a residue, which
was washed with diisopropyl ether to afford
N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-met-
hyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-carboxyphe-
nyl)urea (152.0 mg,98.0%) as a crystalline powder.
[1754] mp: 168.1-176.3.degree. C.
[1755] IR (Nujol, cm.sup.-1): 1650
[1756] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.27 (3H, s), 2.48 (3H,
s), 4.70 (1H, d, J=17.5 Hz), 5.38 (1H, d, J=8.4 Hz), 5.46 (1H, d,
J=17.5 Hz), 7.0-7.8 (14H, m), 7.8-7.9 (1H, m), 8.05 (1H, br, s),
9.24 (1H, br, s)
[1757] Mass (FAB):579 (Mt +1)
EXAMPLE 19(1)
[1758]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
9-ethyl-5-(2-fluorophenyl)-2-oxo-1H-1.4-benzodiazepin-3-yl]-N'-(3-methylph-
enyl)urea was prepared in a similar manner to that of Example
59.
[1759] mp: 162.8-168.1.degree. C.
[1760] IR (Nujol, cm.sup.-1): 1680, 1640
[1761] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.23 (3H, t, J=7.4 Hz),
1.3-2.2 (10H, br), 2.78 (2H, q, J=7.4 Hz), 2.9-3.5 (2H, m), 3.7-4.0
(2H, m), 4.03 (1H, d, J=16.2 Hz), 5.19 (1H, d, J=16.2 Hz), 5.31
(1H, d, J=8.5 Hz), 6.73(1H, d, J=6.7 Hz), 6.9-7.8 (l1H, m), 8.94
(1H, br, s)
[1762] Mass (APCI): 596 (M.sup.++1)
EXAMPLE 19(2)
[1763]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
9-ethy]-5-(2-fluorophenyl)-2-oxo-1H-1
.4-benzodiazepin-3-yl]-N'-[3-(tetraz- o]-5-y])phenyl]urea was
prepared in a similar manner to that of Example 51.
[1764] mp: 226.4-231.6.degree. C.
[1765] Mass(APCI): 650 (M.sup.++1)
[1766] IR (Nujol, cm.sup.-1): 1680, 1630
[1767] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.24 (3H, t, J=7.4 Hz),
1.3-2.2 (10H, br), 2.79 (2H, q, J=7.4 Hz), 2.9-3.4 (2H, m), 3.6-4.0
(2H, m), 4.04 (1H, d, J=16.4 Hz), 5.21 (1H, d, J=16.4 Hz), 5.34
(1H, d, J=8.3 Hz), 7.03(1H, d, J=7.6 Hz), 7.2-7.8 (11H, m), 8.20
(1H, br, s), 9.31 (1H, br, s)
EXAMPLE 20(1)
[1768]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-(2-fluorophenyl)-9-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tet-
razol-5-yl)phenyl]urea was prepared in a similar manner to that of
Example 51.
[1769] mp: 212.2-222.1.degree. C.
[1770] IR (Nujol, cm.sup.-1): 1650
[1771] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.12 (3H, d, J=6.5 Hz),
1.41 (3H, d, J=6.6 Hz), 1.3-2.2 (10H, m), 2.9-4.0 (6H, m), 5.32
(1H, d, J=17.9 Hz), 5.34 (1H, d, J=8.2 Hz), 6.9-7.1 (1H, m),
7.1-7.8 (11H, m), 8.19 (1H, br, s), 9.31 (1H, br, s)
[1772] Mass (APCI): 664 (M.sup.++1)
EXAMPLE 20(2)
[1773]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-(2-fluorophenyl)-9-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-meth-
ylphenyl)urea was prepared in a similar manner to that of Example
59.
[1774] mp: 183.3-186.8.degree. C.
[1775] IR (Nujol, cm.sup.-1): 1655
[1776] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.11 (3H, d, J=6.5 Hz),
1.40 (3H, d, J=6.7 Hz), 1.4-2.2 (10H, m), 2.8-3.4 (3H, m), 3.6-4.0
(3H, m), 5.30 (1H, d, J=14.9 Hz), 5.31 (1H, d, J=8.6 Hz), 6.74 (1H,
d, J=6.5 Hz), 6.9-7.8 (11H, m), 8.92 (1H, br, s)
[1777] Mass (APCI): 610 (M.sup.++1)
EXAMPLE 21-1
[1778]
N-[(3RS)-1-(2-Acetoxyethyl)-5-cyclohexyl-2,3-dihydro-9-methyl-2-oxo-
-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea was
prepared in a similar manner to that of Example 51.
[1779] mp: 165.2-168.4.degree. C.
[1780] IR (Nujol, cm.sup.-1): 1745, 1660
[1781] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-2.0 (1OH, m), 1.79
(3H, s), 2.34 (3H, s), 3.00 (1H, m), 3.3-3.6 (1H, m), 3.7-3.9 (2H,
m), 4.4-4.6 (1H, m), 5.06 (1H, d, J=8.3 Hz), 7.3-7.7 (7H, m), 8.16
(1H, br, s), 9.27 (1H, br, s)
[1782] Mass (APCI): 545 (M.sup.++1)
EXAMPLE 21-2
[1783]
N-[(3RS)-5-Cyclohexyl-2,3-dihydro-1-(2-hydroxyethyl)-9-methyl-2-oxo-
-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea was
prepared in a similar manner to that of Preparation 59-4.
[1784] mp: 223.5-224.2.degree. C.
[1785] IR (Nujol, cm.sup.-1): 1640
[1786] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.9-2.0 (10H, m), 2.34
(3H, s), 2.9-3.6 (4H, m), 4.2-4.4 (1H, m), 5.02 (1H, d, J=8.2 Hz),
7.3-7.7 (7H, m), 8.17 (1H, s), 9.29 (1H, br, s)
[1787] Mass (APCI): 503 (M.sup.++1)
EXAMPLE 22(1)
[1788] Potassium salt of
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylm-
ethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-
-yl]-N'-[3-(1-sulfoethyl)phenyl]urea was prepared in a similar
manner to that of Example 22(3).
[1789] mp: 247.2-255.6.degree. C.
[1790] IR (Nujol, cm.sup.-1): 1650, 1615
[1791] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-2.2 (10H, m), 1.43
(3H, d, J=7.1 Hz), 2.44 (3H, s), 2.9-3.4 (2H, m), 3.58 (1H, d,
J=6.6 Hz), 3.6-4.0 (2H, br, m), 4.11 (1H, d, J=16.2 Hz), 5.14 (1H,
d, J=16.2 Hz), 5.32 (1H, d, J=8.6 Hz), 6.8-7.0 (1H, br), 7.0-7.2
(2H, m), 7.2-7.8 (10H, m), 8.99 (1H, m)
[1792] Mass (FAB): 714 (M.sup.++1)
EXAMPLE 22(2)
[1793]
N-[(3RS)-1-(3-Azabicyclolo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydr-
o-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-hydro-
xymethylphenyl)urea was prepared in a similar manner to that of
Example 22(3).
[1794] mp: 188.2-202.2.degree. C.
[1795] IR (Nujol, cm.sup.-1): 3320, 1640
[1796] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-2.0 (10H, m), 2.26
(3H, s), 2.7-3.2 (2H, m), 3.7-3.9 (2H, m), 4.04 (1H, d, J=17.8 Hz),
4.25 (1H, d, J=5.7 Hz), 4.8-5.1 (3H, m), 5.14 (1H, d, J=8.5 Hz),
6.6-6.8 (1H, m), 6.8-6.9 (1H, m), 6.9-7.6 (10H, m), 8.82 (1H, br,
s)
[1797] Mass (APCI):598 (Me +1)
EXAMPLE 22(3)
[1798] A mixture of
(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]--
2,3-dihydro-5-(2-fluorophenyl)-3-(imidazol-1-yl)carbonylamino-9-methyl-1H--
1,4-benzodiazepin-2-one (250 mg), 3-aminophenol (55mg) and
triethylamine (93mg) in N,N-dimethylformamide (1 ml) was stirred at
100.degree. C. for 1 hour. After the reaction mixture was allowed
to cool to room temperature, ethyl acetate and 1N aqueous
hydrochloric acid were added thereto. The separated organic layer
was washed with 1N aqueous hydrochloric acid, water, saturated
aqueous sodium bicarbonate and brine successively, and then dried
over magnesium sulfate. The solvent was evaporated in vacuo to give
a colorless paste, which was washed with diisopropyl ether and
collected by filtration to afford
N-[(3RS)-1-(3-azabicyclo[3.2.2)non-3-yl)carbonylmethyl-2,3-dihydro-9-meth-
yl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-hydroxyphenyl-
)urea (184.0 mg, 68.5% yield) as a crystalline.
[1799] mp: 192.8-203.9.degree. C.
[1800] IR (Nujol, cm.sup.-1): 3300, 1650
[1801] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.44
(3H, s), 2.8-3.4 (2H, m), 3.7-4.0 (2H, m), 4.12 (1H, d, 16.2 Hz),
5.13 (1H, d, J=16.2 Hz), 5.30 (1H, d, J=8.5 Hz), 6.2-6.4 (1H, m),
6.7-7.7 (10H, m), 9.24 (11H, m)
[1802] Mass (APCI): 584 (M.sup.++1)
EXAMPLE 23(1)
[1803]
(3RS)-1-[(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyclohexyl--
2,3-dihydro-3-(indo]-2-yl)carbonylamino-9-methyl-1H-1,4-benzodiazepin-2-on-
e was prepared in a similar manner to that of Preparation 59-5.
[1804] mp: 206.2-212.2.degree. C.
[1805] IR (Nujol, cm.sup.-1): 1680, 1640
[1806] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-2.2 (10H, m), 2.40
(3H, s), 2.8-3.4 (2H, m), 2.5-4.0 (2H, m), 4.02 (1H, d, J=16.0 Hz),
5.02 (1H, d, J=16.1 Hz), 5.46 (1H, d, 8.1 Hz), 7.0-7.8 (8H, m),
9.20 (1H, d, J=8.1 Hz)
[1807] Mass (FAB): 580 (M.sup.++1)
EXAMPLE 23(2)
[1808]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclohexyl-
-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-y-
l)phenyl]urea was prepared in a similar manner to that of Example
51.
[1809] mp: 186.2-197.6.degree. C.
[1810] IR (Nujol, cm.sup.-1): 1650
[1811] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.9-2.2 (20H, m), 2.38
(4H, m), 2.8-4.0 (4H, m), 4.04 (1H, d, J=16.0 Hz), 4.98 (1H, d,
J=16.0 Hz), 5.02 (1H, d, J=8.2 Hz), 6.94 (1H, d, J=9.1 Hz), 7.3-7.8
(5H, m), 8.1-8.3 (2H, m), 9.25 (1H, br, s)
[1812] Mass (FAB): 624 (M.sup.++1)
EXAMPLE 23(3)
[1813]
N-[(3RS)-I-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclohexyl-
-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N'-(3-melhylphenyl)-
urea was obtained in a similar manner to that of Example 59.
[1814] mp: 212-214.degree. C.
[1815] IR (Nujol, cm.sup.-1): 3390, 3275, 1705, 1688, 1634
[1816] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.05-2.1 (20H, m), 2.22
(3H, s), 2.37 (3H, s), 2.90 (1H, m), 3.05-3.35 (2H, m), 3.65-3.87
(2H, m), 4.49 (2H, d, d, J=16.2 Hz, J=187 Hz), 5.08 (1H, d, J=8.4
Hz), 6.69-7.57 (8H, m), 8.85 (1H, s)
[1817] APCI-MS(e/z): 570 (M.sup.++1)
EXAMPLE 24(1)
[1818]
N-[(3RS)-5-Cyclohexyl-9-methyl-2,3-dihydro-1-(2-methylphenacyl)-2-o-
xo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea was
prepared in a similar manner to that of Example 51.
[1819] mp: 165.0-176.6.degree. C.
[1820] IR (Nujol, cm.sup.-1): 1660, 1635
[1821] .sup.1H-NMR (DMSO-d.sub.6, .delta.) 1.0-2.2 (ROH, m), 2.32
(3H, s), 2.41 (3H, s), 2.9-3.2 (1H, m), 4.58 (1H, d, 1=17.3 Hz),
5.18 (1H, d, J=8.4 Hz), 5.33 (1H, d, J=17.3 Hz), 6.9-7.0 (1H, m),
7.2-7.7 (9H, m), 7.7-7.9 (1H, m), 8.0-8.2 (2H, m), 9.22 (1H, br,
s)
[1822] Mass (FAB): 591 (M.sup.++1)
EXAMPLE 24(2)
[1823]
(3RS)-5-Cyclohexyl-2,3-dihydro-3-(indol-2-yl)carbonylamino-9-methyl-
-1-(2-methylphenacyl)-1H-1,4-benzodiazepin-2-one was prepared in a
similar manner to that of Preparation 59-5.
[1824] mp: 126.7-145.2.degree. C.
[1825] IR (Nujol, cm.sup.-1): 1640
[1826] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-2.3 (10H, m), 2.32
(3H, s), 2.43 (3H, s), 3.05 (1H, m), 4.58 (1H, d, J=17.4 Hz), 5.37
(1H, d, J=17.3 Hz), 5.52 (1H, d, J=8.1 Hz), 7.0-8.1 (12H, m),
9.2-9.3 (1H, m)
[1827] Mass (APCI): 547 (M.sup.++1)
EXAMPLE 25-1
[1828] A mixture of
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethy-
l-5-acetoxymethyl-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-
-(3-methylphenyl)urea (208m-) and 15% aqueous solution of sodium
thiomethoxide in N,N-dimethylformamide was stirred at room
temperature for 8 hours. Ethyl acetate and water were added to the
reaction mixture. The separated organic layer was washed with water
and brine, and then dried over magnesium sulfate. The solvent was
evaporated in vacuo to afford a paste (214mg), which was washed
with diisopropyl ether and collected by filtration to give
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)c-
arbonylmethyl-5-hydroxymethyl-9-methyl-2,3-dihydro-2-oxo-1H-1,4-benzodiaze-
pin-3-yl]-N'-(3-methyphenyl)urea (127mg, 66.0%yield) as a
crystalline powder.
[1829] mp: 151.7-153.2.degree. C.
[1830] IR (Nujol, cm.sup.-1): 1640
[1831] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.22
(3H, s), 2.48 243 (3H, s), 2.9-3.4 (2H, m), 3.6-4.0 (2H, m), 4.01
(1H, d, J=16.3 Hz), 4.5-4.6 (2H, m), 5.11 (1H, d, J=16.3 Hz), 5.23
(1H, d, J=8.5 Hz), 6.72 (1H, d, J=6.5 Hz), 7.0-7.2 (3H, m), 7.2-7.7
(4H, m), 8.90 (1H, br, s)
[1832] Mass (APCI): 518 (M' +1)
EXAMPLE 25-2
[1833] To a mixture of
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmet-
hyl-5-hydroxymethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]--
N'-(3-methylphenyl)urea (147 mg) and diisopropylethylamine (55.1
mg) in methylene chloride (2 ml) was added dropwise a solution of
methanesulfonyl chloride (48.7 mg) in methylene chloride (1 ml)
under stirring and cooling at 0-5.degree. C. in an ice-bath. The
mixture was stirred for 1.5 hours under the same conditions. The
reaction mixture was evaporated in vacuo to afford a residue, which
was dissolved in tetrahydrofuran (2 ml) and cooled in an ice-bath.
To the solution prepared above was added 15% aqueous solution of
sodium methylmercaptide (0.5 g). The mixture was stirred under
cooling for 0.5 hour and at ambient temperature for 2 hours. The
reaction mixture was evaporated in vacuo to afford a residue, which
was dissolved in ethyl acetate and washed with water twice. The
separated organic layer was dried over magnesium sulfate and
evaporated in vacuo to afford an amorphous mass, which was
subjected to preparative thin-layer chromatography on silica gel
developing with a mixture of chloroform and methanol (10:1) to give
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-methylthiomethyl-
-9-methyl-2-oxo-2,3-dihydro-1 H-1,4-benzodiazepin-3-yl]-N
'-(3-methyphenyl)urea as an amorphous mass. This was triturated in
diisopropyl ether and collected by filtration to give a crystalline
powder (71.9mg, 41.7% yield).
[1834] mp: 172-175.5.degree. C.(dec.)
[1835] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.45-2.1 (10H, m), 2.20
(3H, s), 2.29 (3H, s), 2.38 (3H, s), 3.25-3.55 (4H, m), 3.7-3.95
(3H, m), 5.03 (1H, d, J=15.8 Hz), 5.54 (1H, d, J=8.2 Hz), 6.7-7.8
(9H, m)
[1836] APCI-MS(m/z): 548 (M.sup.++1)
EXAMPLE 26
[1837]
N-[(S)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5--
(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazcpin-3-yl]-N'-[3-(tetrazol-
-5-yl)phenyl]urea was prepared in a similar manner to that of
Example 51.
[1838] mp: 210.3-213.4.degree. C.
[1839] [.alpha.].sub.D.sup.30.4=.+-.6.6.degree. (C=0.50, EtOH)
[1840] IR (Nujol, cm.sup.-1): 1650
[1841] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-2.2 (10H, mn), 2.45
(3H, s), 2.9-3.4 (2H, m), 3.4-4.0 (2H, m), 4.14 (1H, d, J=16.2 Hz),
5.14 (1H, d, J=10.2 Hz), 5.35 (1H, d, J=8.3 Hz), 6.8-7.8 (12H, m),
8.21 (1H, br, s), 9.31 (1H, br, s)
[1842] Mass (APCI): 636 (M.sup.++1)
EXAMPLE 27
[1843]
N-[(R)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5--
(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-
-5-yl)phenyl]urea was prepared in a similar manner to that of
Example 51.
[1844] mp: 209.9-215.2.degree. C.
[1845] [.alpha.].sub.D.sup.30.4=-10.96.degree. (C=0.52, ETOH)
[1846] IR (Nujol, cm.sup.-1): 1650, 1620
[1847] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (IOH, m), 2.45
(3H, s), 2.8-4.0 (4H, m), 4.14 (1H, d, 16.3 Hz), 5.14 (1H, d, 16.3
Hz), 5.35 (1H, d, 8.3 Hz), 7.03 (1H, d, 7.5 Hz), 7.2-7.8 (11H, m),
8.21 (1H, br, s), 9.32 (1H, br, s)
[1848] Mass (APCI): 636 (M.sup.++1)
EXAMPLE 28
[1849]
N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(pyridin-2-yl)me-
thyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-
N'-[3-(tetrazol-5-yl)phenyl]urea was prepared in a similar manner
to that of Example 51.
[1850] mp: 173.9-182.0.degree. C.
[1851] IR (Nujol, cm.sup.-1): 1640
[1852] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 4.59 (1H, d, J=15.3
Hz), 5.35 (1H, d, J=8.3 Hz), 5.49 (1H, d, J=15.3 Hz), 6.9-7.8 (13H,
m), 7.95 (1H, br, s), 8.0-8.3 (2H, m), 9.33 (1H, br, s)
[1853] Mass (FAB): 562 (M.sup.++1)
EXAMPLE 29
[1854]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-9-chloro-2,3-
-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetraz-
ol-5-yl)phenyl]urea was prepared in a similar manner to that of
Example 51.
[1855] mp: 172.0-180.5.degree. C.
[1856] IR (Nujol, cm.sup.-1): 1650
[1857] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-2.2 (10H, m),
2.9-3.1 (1H, m), 3.1-3.5 (1H, m), 3.6-4.0 (2H, m), 4.41 (1H, d,
J=16.4 Hz), 5.22 (1H, d, J=16.8 Hz), 5.38 (1H, d, J=8.3 Hz), 6.93
(1H, d, J=9.2 Hz), 7.2-8.3 (1H, m), 9.30 (1H, br, s)
[1858] Mass (APCI): 657 (M.sup.++1)
EXAMPLE 30
[1859]
N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-tert-butylcarbon-
ylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea
was prepared in a similar manner to that of Example 51.
[1860] mp: 160.4-180.7.degree. C.(dec.)
[1861] IR (Nujol, cm.sup.-1): 1720, 1650
[1862] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.09 (9H, s), 2.43 (3H,
s), 4.19 (1H, d, J=17.3 Hz), 5.24 (1H, d, J=17.4 Hz), 5.32 (1H, d,
J=8.4 Hz), 7.07 (1H, d, J=7.2 Hz), 7.2-7.8 (11H, m), 8.19 (1H, br,
s), 9.27 (1H, br, s)
[1863] Mass (FAB): 569 (M.sup.++1)
EXAMPLE 31(1)
[1864] Potassium salt of
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylm-
ethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(1-s-
ulfoethyl)phenyl]urea was prepared in a similar manner to that of
Example 22(3).
[1865] mp: 246.9-249.1.degree. C.
[1866] IR (Nujol, cm.sup.-1): 1670, 1660
[1867] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 1.41
(1H, d, J=7.1 Hz), 2.37 (3H, s), 2.44 (3H, s), 3.0-3.4 (2H, m),
3.5-3.9 (3H, m), 3.96 (1H, d, J=16.5 Hz), 5.12 (1H, d, J=16.5 Hz),
5.0-5.2 (1H, m), 6.8-6.9 (1H, m), 6.9-7.6 (7H. m), 8.9-9.0 (1H,
m)
[1868] Mass (FAB): 634 (M.sup.++1)
EXAMPLE 31(2)
[1869]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-
-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(2-methylpyridin-6-yl)ure-
a was prepared in a similar manner to that of Example 22(3).
[1870] mp: 150.8-152.1.degree. C.
[1871] IR (Nujol, cm.sup.-1): 1670
[1872] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.36
(3H, s), 2.44 (3H, s), 2.42 (3H, s), 3.0-3.5 (2H, br), 3.5-3.9 (2H,
m), 3.96 (1H, d, J=16.3 Hz), 5.0-5.2 (2H, m), 6.7-7.7 (6H, m), 9.43
(1H, br, s)
[1873] Mass (APCI): 503 (M' +1)
EXAMPLE 31(3)
[1874]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-
-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(4-methylpyridin-2-yl)ure-
a was prepared in a similar manner to that of Example 22(3).
[1875] mp: 152.0-154.1.degree. C.
[1876] IR (Nujol, cm.sup.-1): 1680, 1660
[1877] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.24
(3H, s), 2.36 (3H, s), 2.44 (3H, s), 2.44 (3H, s), 2.9-3.4 (2H,
br), 3.5-3.9 (2H, m), 3.95 (1H, d, J=16.4 Hz), 5.09 (1H, d, J=16.4
Hz), 5.18 (1H, d, J=7.1 Hz), 6.8 (1H, br), 7.0-7.6 (5H, m), 8.0-8.2
(1H, m), 9.39 (1H, br, s)
[1878] Mass (APCI): 503 (M.sup.++1)
EXAMPLE 31(4)
[1879] A mixture of
(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,-
9-dimethyl-3-(imidazol-1-yl)carbonylamino-2,3-dihydro-1H-1,4-benzodiazepin-
-2-one (300mg), N,N-dimethyl-1,3-phenylenediamine dihydrochloride
(149mg) and triethylamine (2 ml) in N,N-dimethylformamide (6 ml)
was stirred at 100.degree. C. for 2 hours. After allowing to cool
to room temperature, ethyl acetate and water were added to the
reaction mixture under stirring. The separated organic layer was
washed with water and brine, and then dried over sodium sulfate.
The solvent was evaporated in vacuo to afford an amorphous powder,
which was washed with diisopropyl ether and collected by filtration
to give a pale gray powder (320 mg). To the powder dissolved in
1,4-dioxane was added 4N-hydrogen chloride in 1,4-dioxane (0.5 ml)
at ambient temperature under stirring. The resultant mixture was
evaporated in vacuo to dryness to afford a residue, which was
washed with diisopropyl ether and collected by filtration to give
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-2,3-d-
ihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(N,N-dimethylamino)phenyl]ur-
ea hydrochloride (280mg, 67.1% yield).
[1880] mp: 190.9-193.1.degree. C.
[1881] IR (Nujol, cm.sup.-1): 1690, 1630
[1882] .sup.1H-NMR (DMSO-d.sub.6, .UPSILON.): 1.3-2.2 (10H, m),
2.43 (3H, s), 2.73 (3H, s); 2.86 (3H, s), 2.7-3.4 (2H, m), 3.6-4.0
(2H, m), 4.06 (1H, d, J=16.4 Hz), 5.23 (1H, d, J=16.4 Hz), 5.61
(1H, d, J=6.2 Hz), 6.7-7.0 (1H, m), 7.2-8.0 (7H, m), 10.04(1H, br,
s)
[1883] Mass (APCI): 531(free O M.sup.++1)
EXAMPLE 32
[1884]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5,9-dimethyl-1H-1,4-benzodiazepin-2-one-4-oxide-3-yl]-N'-(3-methylephenyl)-
urea (45.3 mg) was treated with acetic anhydride (1.8 ml) at
50.degree. C. for 5 hours. After the reaction was completed, acetic
anhydride was removed under reduced pressure. The residue was
subjected to preparative thin layer chromatography on silica gel
(60F.sub.254, 0.5 mm, 20.times.20 cm; Merck) developed with a
mixture of CHCl.sub.3, AcOEt and MeOH (14:1:0.4) to give
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethy-
l-2,3-dihydro-5-acetoxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-
-(3-methylphenyl)urea as an amorphous mass (59.9 mg), which was
powdered by triturated in diisopropyl ether and collected by
filtration (26.5 mg; 59.3%).
[1885] mp: 133-134.5.degree. C.
[1886] .sup.1H-NMR(CDCl.sub.3, .delta.) 1.50-2.17 (10H, m), 2.10
(3H, s), 2.29 (3H, s), 2.38 (3H, s), 3.28-3.74 (4H, m), 4.62 (2H,
d, d, J=15.6 Hz, J=319.0 Hz), 5.17 (2H, d, d, J=9.45 Hz, J=15.7
Hz), 5.59 (1H, d, J=7.82 Hz), 6.76-7.56 (9H, m)
[1887] APCI-MS (m/z): 560.3 (M.sup.++1)
EXAMPLE 33
[1888] To a solution of
(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)-car-
bonylmethyl]-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazep-
in-2-one (285mg) in tetrahydrofuran (4 ml) was added dropwise
3-tolyl isocyanate (100 mg) under stirring at room temperature. The
mixture was stirred at room temperature for 2 hours. Removal of the
solvent in vacuo afforded a residue, which was triturated in
diisopropyl ether and collected by filtration to give a white
powder. To a solution of the powder in ethyl acetate was added
4N-hydrogen chloride in ethyl acetate (0.25 ml) under cooling. The
mixture was evaporated in vacuo to dryness. The residue was washed
with diisopropyl ether and collected by filtration to afford
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-methyl-
-9-(N, N-
dimethylamino)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(-
3-methylphenyl)urea hydrochloride (250 mg,61.5%) as a crystalline
powder.
[1889] mp: 216.5-218.7.degree. C.
[1890] IR (Nujol, cm.sup.-1): 1680, 1630
[1891] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.24
(3H, s), 2.80 (6H, br, s), 3.0-3.2 (1H, m), 3.2-3.4 (1H, m),
3.5-3.9 (2H, br, m), 4.56 (1H, d, J=16.7 Hz), 5.11 (1H, d, J=16.7
Hz), 5.67 (1H, m), 6.7-6.8 (1H, m), 7.0-7.3 (3H, m), 7.4-7.7 (3H,
m), 7.72 (1H, m), 9.56 (1H, br, s)
[1892] Mass (FAB): 531 (hydrochloride free M.sup.++1)
EXAMPLE 34
[1893]
N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-tert-butoxycarbo-
nylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]ure-
a was prepared in a similar manner to that of Example 51.
[1894] mp: 151.4-174.2.degree. C.(dec.)
[1895] IR (Nujol, cm.sup.-1): 1745, 1650
[1896] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.25 (9H, s), 2.46 (3H,
s), 4.11 (1H, d, J=16.8 Hz), 4.60 (1H, d, J=16.7 Hz), 5.34 (1H, d,
J=8.4 Hz), 6.9-7.8 (10H, m), 8.1-8.3 (2H, m), 9.32 (1H, br, s)
[1897] Mass (APCI) 585 (M.sup.++1)
EXAMPLE 35
[1898]
N-[(3RS)-1-(Adamantan-1-yl)carbonylmethyl-2,3-dihydro-5-(2-fluoroph-
enyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)pheny-
l]urea was prepared in a similar manner to that of Example 51.
[1899] mp: 195.0-218.4.degree. C.(dec.)
[1900] IR (Nujol, cm.sup.-1): 1650
[1901] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.5-2.2 (1SH, m), 2.42
(3H, br, s), 4.12 (1H, d, J=17.1 Hz), 5.23 (1H, d, J=17.5 Hz), 5.31
(1H, d, J=8.3 Hz), 6.9-7.8 (11H, m), 8.1 (1H, m), 9.28 (1H, br,
s)
[1902] Mass (FAB): 647 (M.sup.++1)
EXAMPLE 36
[1903]
N-[(3RS)-2,3-Dihydro-1,5-9-irimethyl-2-oxo-1H-1,4-benzodiazepin-3-y-
l]-N'-(3-methylphenyl)urea was prepared in a similar manner to that
of Example 59.
[1904] mp: 204.2-206.6.degree. C.
[1905] IR (Nujol, cm.sup.-1): 1685, 1645, 1610
[1906] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.22 (3H, s), 2.35 (3H,
s), 2.42 (3H, s), 3.10 (3H, s), 5.03 (1H, dd, J=1.4 Hz, J=8.5 Hz),
6.72 (1H, d, J=6.4 Hz), 7.0-7.7 (7H, m), 8.93 (1H, br, s)
[1907] Mass (APCI): 351 (M.sup.++1)
EXAMPLE 37
[1908]
N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-
-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was prepared in a
similar manner to that of Example 59.
[1909] mp: 128.4-136.2.degree. C.
[1910] IR (Nujol, cm.sup.-1): 1650
[1911] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.22 (3H, s), 2.27 (3H,
s), 2.40 (3H, s), 2.42 (3H, s), 4.55 (1H, d, J=17.1 Hz), 5.12 (1H,
d, J=8.5 Hz), 5.37 (1H, d, J=17.2 Hz), 6.7-6.8 (1H, m), 7.0-7.8
(l1H, m), 8.86 (1H, br, s)
[1912] Mass (APCI): 469 (M.sup.++1)
EXAMPLE 38
[1913]
N-[(.sup.3RS)-1-(Adamantan-1-yl)carbonylmethyl-2,3-dihydro-5,9-dime-
thyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Example 59.
[1914] mp: 182.2-184.2.degree. C.
[1915] IR (Nujol, cm.sup.-1): 1700, 1658, 1638
[1916] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.6-2.1 (15H, m), 2.22
(3H, s), 2.34 (3H, s), 3.96 (1H, d, J=17.5 Hz), 5.0-5.1 (1H, m),
5.21 (1H, d, J=17.5 Hz), 6.72 (1H, d, J=6.3 Hz), 7.1-7.7 (7H, m),
8.84 (1H, br, s)
[1917] Mass (APCI): 513 (M.sup.++1)
EXAMPLE 39
[1918]
N-[(3RS)-1-Cyclohexylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo--
1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was prepared in
a similar manner to that of Example 59.
[1919] mp: 179.2-180.9.degree. C.
[1920] IR (Nujol, cm.sup.-1): 1710, 1655, 1638
[1921] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-1.8 (10H, m),
1.8-2.0 (1H, m), 2.22 (3H, s), 2.33 (3H, s), 4.06 (1H, d, J=17.6
Hz), 5.02 (1H, d, J=17.3 Hz), 5.08 (1H, d, J=7.0 Hz), 6.72 (1H, d,
J=6.0 Hz), 7.0-7.6 (7H, m), 8.84 (1H, br, s)
[1922] Mass (APCI): 461 (M.sup.++1)
EXAMPLE 40
[1923]
N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-methylcarbonylme-
thyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea
was prepared in a similar manner to that of Example 51.
[1924] mp: 173.5-189.8.degree. C.
[1925] IR (Nujol, cm.sup.-1): 1730, 1680, 1650
[1926] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.03 (3H, s), 2.41 (3H,
s), 4.29 (1H, d, J=17.7 Hz), 4.96 (1H, d, J=17.6 Hz), 6.9-7.8 (11H,
m), 8.20 (1H, m), 9.35 (1H, br, s)
[1927] Mass (APCI): 527 (M.sup.++1)
EXAMPLE 41
[1928]
N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-tert-butylcarbonylmethyl-2-oxo--
1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was prepared in
a similar manner to that of Example 59.
[1929] mp: 179.6-181.2.degree. C.
[1930] IR (Nujol, cm.sup.-1): 1720, 1670, 1645
[1931] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.08 (9H, s), 2.22 (3H,
s), 2.34 (3H, s), 4.01 (1H, d, J=17.4 Hz), 5.08 (1H, dd, J=1.4 Hz
and J=8.5 Hz), 5.22 (1H, d, J=17.4 Hz), 6.72 (1H, d, J=6.5 Hz),
7.0-7.7 (7H, m), 8.84 (1H, br, s)
[1932] Mass (APCI): 435 (M.sup.++1)
EXAMPLE 42
[1933]
N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-(3-nitrophenacyl-
)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea
was prepared in a similar manner to that of Example 51.
[1934] mp: 194.4-198.1.degree. C.
[1935] IR (Nujol, cm.sup.-1): 1655, 1620
[1936] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.50 (3H, s), 4.96 (1H,
d, J=17.7 Hz), 5.43 (1H, d, J=8.3 Hz), 5.84 (1H, d, *=17.8 Hz),
7.0-8.5 (1SH, m), 8.65 (1H, m), 9.33 (1H, m)
[1937] Mass (APCI): 634 (M.sup.++1)
EXAMPLE 43
[1938]
N-[(3RS)-2,3-Dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-nitrophenacyl-
)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea
was prepared in a similar manner to that of Example 51.
[1939] mp: 192.2-197.1.degree. C.
[1940] IR (Nujol, cm.sup.-1): 1650, 1620
[1941] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.45 (3H, s), 4.73 (1H,
d, J=18.1 Hz), 5.3-5.5 (2H, m), 7.0-8.2 (16H, m)
EXAMPLE 44
[1942]
N-[(3RS)-2,3-Dihydro-1-ethylcarbonylmethyl-5,9-dimethyl-2-oxo-1H-1,-
4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was prepared in a
similar manner to that of Example 59.
[1943] mp: 125.1-127.5.degree. C.
[1944] IR (Nujol, cm.sup.-1): 1720, 1640
[1945] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.87 (3H, t, J=7.2 Hz),
2.22 (3H, s), 2.33 (3H, s), 2.3-2.5 (2H, m), 4.08 (1H, d, J=17.5
Hz), 4.92 (1H, d, J=17.5 Hz), 5.10 (1H, dd, J=1.4 Hz and 8.5 Hz),
6.7-6.9 (1H, m), 7.0-7.7 (7H, m), 8.90 (1H, br, s)
[1946] Mass (APCI): 407 (M.sup.++1)
EXAMPLE 45
[1947]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-isopropyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)u-
rea was prepared in a similar manner to that of Example 59.
[1948] mp: 189.9-192.8.degree. C.
[1949] IR (Nujol, cm.sup.-1): 1650, 1610, 1700
[1950] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.11 (3H, d, J=7.0 Hz),
1.21 (3H, d, J=6.5 Hz), 1.4-2.1 (10H, m), 2.22 (3H, s), 2.37 (3H,
s), 3.0-3.4 (2H, m), 3.6-4.0 (2H, m), 4.04 (1H, d, J=16.1 Hz), 5.00
(1H, d, J=16.2 Hz), 5.09 (1H, d, J=8.4 Hz), 6.72 (1H, d, J=6.2 Hz),
7.0-7.7 (7H, m), 8.85(1H, br, s)
[1951] Mass (APCI): 530 (M.sup.++1)
EXAMPLE 46
[1952]
N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-methylcarbonylmethyl-2-oxo-1H-1-
,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was prepared in a
similar manner to that of Example 59.
[1953] mp: 126.1-127.7.degree. C.
[1954] IR (Nujol, cm.sup.-1): 1720, 1650
[1955] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.00 (3H, s), 2.22 (3H,
s), 2.33 (3H, s), 2.47 (3H, s), 4.11 (1H, d, J=17.8 Hz), 4.93 (1H,
d, J=17.6 Hz), 5.0-5.2 (1H, m), 6.7-6.8 (1H, m), 7.0-7.6 (7H, m),
8.90 (1H, br, s)
[1956] Mass (APCI): 393 (M.sup.++1)
EXAMPLE 47
[1957]
N-[(3RS)-5-Cyclohexyl-1-cyclopropylcarbonylmethyl-2,3-dihydro-9-met-
hyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea
was prepared in a similar manner to that of Example 51.
[1958] mp: 227.1-233.2.degree. C.
[1959] IR (Nujol, cm.sup.-1): 1715, 1650
[1960] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.7-2.1 (15H, m), 2.36
(3H, s), 2.8-3.0 (1H, m), 4.30 (1H, d, J=17.6 Hz), 4.96 (1H, d,
J=17.5 Hz), 5.10 (1H, d, J=8.2 Hz), 7.3-7.7 (7H, m), 8.15 (1H, br),
9.23 (1H, br, s)
[1961] Mass (APCI): 541 (M.sup.++1)
EXAMPLE 48-1
[1962]
N-[(3RS)-2,3-Dihydro-1-ethoxycarbonylmethyl-5,9-dimethyl-2-oxo-1H-1-
,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was prepared in a
similar manner to that of Example 59.
[1963] mp: 229.7-231.0.degree. C.
[1964] IR (Nujol, cm.sup.-1): 1755, 1685, 1645, 1615
[1965] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.27 (3H, t, J=7.1 Hz),
2.22 (3H, s), 2.33 (3H, s), 2.45 (3H, s), 4.02 (2H, q, J=7.1 Hz),
4.08 (1H, m), 4.68 (1H, d, J=16.8 Hz), 5.09-5.14 (1H, m), 6.72 (1H,
d, J=6.4 Hz), 7.0-7.7 (7H, m), 8.87 (1H, br, s)
[1966] Mass (APCI): 423 (M.sup.++1)
EXAMPLE 48-7
[1967] A mixture of N-[(3RS)-2,3-dihydro-1-ethoxycarbonymethyl-5,
9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
(1.3 g) and 1N aqueous sodium hydroxide (15 ml) in
1,2-dimethoxyethane (15 ml) was stirred at room temperature
overnight. 1N aqueous hydrochloric acid was added to the reaction
mixture. The mixture was evaporated to dryness to afford a residue,
which was triturated in water and collected by filtration to give
the first crop of the desired product as a white powder (417 mg,
34.3%). To the filtrate were added ethyl acetate and 0.1N aqueous
hydrochloric acid. The separated organic layer was washed with
water and brine, and then dried over magnesium sulfate. The solvent
was evaporated in vacuo to afford the second crop of
N-[(3RS)-2,3-dihydro-1-c-
arboxymethyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphe-
nyl)urea (631mg, 51.9%) as a white crystalline powder.
[1968] IR (Nujol, cm.sup.-1): 1690, 1658, 1620
[1969] Anal: C.sub.21H22N.sub.4O.sub.4.0.5H.sub.2O
[1970] calc. C: 62.52, H: 5.75, N: 13.89
[1971] found C: 62.86, H: 5.58, N: 13.84
[1972] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.22 (3H, s), 2.33 (3H,
s), 2.41 (3H, s), 3.94 (1H, d, J=17.0 Hz), 4.65 (1H, d, J=17.0 Hz),
5.10 (1H, d, J=7.2 Hz), 6.72 (1H, d, J=6.4 Hz), 7.0-7.6 (7H, m),
8.91 (1H, s)
[1973] Mass (APCI): 395 (Mt +1)
EXAMPLE 48-3(1)
[1974]
N-[(3RS)-1-[4-(Piperidino)piperidin-1-yl]carbonylmethyl-5,9-dimethy-
l-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
[1975] mp: 214.5-217.3.degree. C.
[1976] IR (Nujol, cm.sup.-1): 1660
[1977] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-1.9 (10H, m), 2.22
(3H, s), 2.35 (3H, s), 2.43 (3H, s), 2.3-2.6 (6H, m), 2.8-3.1 (1H,
m), 3.7-4.0 (2H, m), 4.1-4.3 (1H, m), 4.9-5.2 (2H, m), 6.71 (1H, d,
J=6.4 Hz), 7.0-7.7 (7H, m), 8.92 (1H, br, s)
[1978] Mass (APCI): 545 (M.sup.++1)
EXAMPLE 48-3(2)
[1979] N-[(3RS)-2,3-Dihydro-5,
9-dimethyl-1-(4-methylpiperazin-1-yl)carbon-
ylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
[1980] IR (Nujol, cm.sup.-1): 1675, 1640, 1610
[1981] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.15 (3H, s), 2.22 (3H,
s), 2.35 (3H, s), 2.43 (3H, s), 3.3-3.5 (4H, br), 3.91 (1H, d,
J=16.4 Hz), 5.04 (1H, d, J=16.1 Hz), 5.11-5.12 (1H, m), 6.71 (1H,
d, J=6.3 Hz), 7.0-7.6 (7H, m), 8.92 (1H, br, s)
[1982] Mass (APCI): 477 (M.sup.++1)
EXAMPLE 48-3(3)
[1983]
N-[(3RS)-5,9-Dimethyl-1-[(pyrrolidin-1-yl)carbonylmethyl]-2-oxo-1H--
1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was prepared in a
similar manner to that of Preparation 59-5.
[1984] IR (Nujol, cm.sup.-1): 1650
[1985] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.6-2.0 (2H, m), 2.22
(3H, s), 2.35 (3H, s), 2.43 (3H, s), 3.1-3.3 (2H, m), 3.88 (1H, d,
J=16.4 Hz), 4.86 (1H, d, J=16.4 Hz), 5.10 (1H, d, J=7.2 Hz), 6.72
(1H, d, J=6.3 Hz), 7.0-7.6 (7H, m), 8.92 (1H, s)
[1986] Mass (APCI): 448 (M.sup.++1)
EXAMPLE 48-3(4)
[1987]
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihy-
dro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
[1988] IR (Nujol, cm.sup.-1): 1650, 1610
[1989] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-1.8 (10H, m), 2.22
(3H, s), 2.36 (3H, s), 2.44 (3H, s), 2.9-3.3 (2H, m), 3.3-3.6 (2H,
m), 3.93 (1H, d, J=16.1 Hz), 4.95 (1H, d, J=16.1 Hz), 5.09 (1H, d,
J=7.1 Hz), 6.71 (1H, d, J=6.5 Hz), 7.0-7.6 (7H, m), 8.86 (1H, br,
s)
[1990] Mass (APCI): 490 (M.sup.++1)
EXAMPLE 48-3(5)
[1991]
N-{(3RS)-1-[(3RS)-3-(N,N-Diethylaminocarbonyl)piperidin-1-yl]-carbo-
nylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yI}-N'-(3--
methylphenyl)urea was prepared in a similar manner to that of
Preparation 59-5.
[1992] mp: 150.8-154.7.degree. C.
[1993] IR (Nujol, cm.sup.-1): 1655, 1610
[1994] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.9-1.3 (8H, m),
1.4-2.0 (2H, m), 2.22 (3H, s), 2.35 (3H, s), 2.43 (3H, s), 2.9-3.5
(7H, m), 3.7-4.3 (3H, m), 5.0-5.2 (2H, m), 6.71 (1H, d, J=6.2 Hz),
7.0-7.8 (7H, m), 8.90 (11H, m)
[1995] Mass (APCI): 561 (M.sup.++1)
EXAMPLE 48-3(6)
[1996]
N-[(3RS)-1-(4-Hydroxy-4-phenylpiperidin-1-yl)carbonylmethyl-5,9-dim-
ethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
[1997] mp: 163.2-164.9.degree. C.
[1998] IR (Nujol, cm.sup.-1): 1665, 1645
[1999] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-2.0 (4H, m), 2.22
(3H, s), 2.37 (3H, s), 2.45 (3H, s), 2.8-3.0 (1H, m), 3.2-3.6 (2H,
m), 3.6-4.3 (3H, m), 4.9-5.2 (2H, m), 6.71 (1H, d, 3=6.5 Hz),
7.0-7.6 (12H, m), 8.94 (1H, m)
[2000] Mass (APCI): 554 (M.sup.++1)
EXAMPLE 48-3(7)
[2001]
N-[(3RS)-2,3-dihydro-5,9-dimethyl-1-(morpholin-1-yl)-carbonylmethyl-
-1-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
[2002] mp: 219.0-220.1.degree. C.
[2003] IR (Nujol, cm.sup.-1): 1675, 1640
[2004] .sup.1H-NMR (DMSO-d .sub.6, .delta.): 2.22 (3H, s), 2.36
(3H, s), 2.43 (3H, s), 3.3-3.6 (8H, m), 3.94 (1H, d, J=16 Hz), 5.04
(1H, d, J=16 Hz), 5.10 (1H, d, J=6.9 Hz), 6.72 (1H, d, J=6.3 Hz),
7.0-7.6 (7H, m), 8.92 (1H, s)
[2005] Mass (APCI): 464 (M.sup.++1)
EXAMPLE 48-3(8)
[2006]
N-{(3RS)-2,3-Dihydro-5,9-dimethyl-1-[4-methylpiperazin-1-yl)carbony-
lmethyl]-2-oxo-1H-1,4-benzodiazepin-3-yl}-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
[2007] IR (Nujol, cm.sup.-1): 1675, 1640, 1610
[2008] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.15 (3H, s), 2.22 (3H,
s), 2.35 (3H, s), 2.43 (3H, s), 3.3-3.5 (4H, br), 3.91 (1H, d,
J=16.4 Hz), 5.04 (1H, d, J=16.1 Hz), 5.11-5.12 (1H, m), 6.71 (1H,
d, J=6.3 Hz), 7.0-7.6 (7H, m), 8.92 (1H, br, s)
[2009] Mass (APCI): 477 (M.sup.++1)
EXAMPLE 48-3(9)
[2010]
N-[(3RS)-1-(N,N-Diethylamino)carbonylmethyl-2,3-dihydro-5,9-dimethy-
l-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
[2011] IR (Nujol, cm.sup.-1): 1670, 1625
[2012] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.92 (3H, t, J=7.0 Hz),
1.13 (3H, t, J=7.0 Hz), 2.22 (3H, s), 2.36 (3H, s), 2.43 (3H, s),
3.0-3.5 (4H, m), 3.88 (1H, d, J=16.1 Hz), 4.97 (1H, d, J=16.1 Hz),
5.08 (1H, d, J=7.1 Hz), 6.71 (1H, d, J=6.5 Hz), 7.0, 7.6 (7H, m),
8.89 (1H, br, s)
[2013] Mass (APCI): 450 (M.sup.++1)
EXAMPLE 48-3(10)
[2014]
N-[(3RS)-2,3-Dihydro-1-(N-ethylamino)carbonylmethyl-5,9-dimethyl-2--
oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was prepared
in a similar manner to that of Preparation 59-5.
[2015] IR (Nujol, cm.sup.-1): 1658, 1610
[2016] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.93 (3H, 1, J=7.2 Hz),
2.22 (3H, s), 2.32 (3H, s), 2.42 (3H, s), 2.9-3.0 (2H, m), 3.76
(1H, d, J=15.8 Hz), 4.63 (1H, d, J=15.8 Hz), 5.07 (1H, d, J=8.5
Hz), 6.71 (1H, d, J=6.2 Hz), 7.0-7.3 (3H, m), 7.3-7.4 (1H, m),
7.4-7.6 (2H, m), 7.8-8.0 (1H, m), 8.91 (1H, br, s)
[2017] Mass (APCI): 422 (M.sup.++1)
EXAMPLE 48-3(11)
[2018]
N-[(3RS)-2,3-Dihydro-5,9-dimethyl-1-(N-tert-butylamino-carbonylmeth-
yl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
[2019] mp: 243.4-244.4.degree. C.
[2020] IR (Nujol, cm.sup.-1): 3310, 1645
[2021] .sup.1H-NMR (DMSO-d.sub.6, .delta.) 1.13 (9H, s), 2.22 (3H,
s), 2.32 (3H, s), 2.43 (3H, s), 3.68 (1H, d, J=15.7 Hz), 4.62 (1H,
d, J=15.7 Hz), 5.07 (1H, dd, J=1.4 Hz and 8.6 Hz), 6.72 (1H, d,
J=6.5 Hz), 7.0-7.6 (7H, m), 8.87 (1H, br, s)
[2022] Mass (APCI): 450 (M.sup.++1)
EXAMPLE 48-3(12)
[2023]
N-[(3RS)-1-(Azacycloheptan-1-yl)carbonylmethyl-2,3-dihydro-5,9-dime-
thyl-2-oxo-1H-1,4-benzodiazepin-3-yi]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
[2024] mp: 203.6-204.2.degree. C.
[2025] IR (Nujol, cm.sup.-1): 1670, 1630
[2026] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-1.9 (8H, m), 2.22
(3H, s), 2.36 (3H, s), 2.44 (3H, s), 3.0-3.2 (1H, m), 3.2-3.4 (1H,
m), 3.4-3.7 (2H, m), 3.92 (1H, d, J=16.2 Hz), 4.96 (1H, d, J=16.1
Hz), 5.09 (1H, d, J=7.4 Hz), 6.71 (1H, d, J=6.4 Hz), 7.0-7.6 (7H,
m), 8.87 (1H, br, s)
[2027] Mass (APCI): 476 (M' +1)
EXAMPLE 48-3(13)
[2028] N-[(3
RS)-1-(4-Aminocarbonylpiperidin-1-yl)carbonyImethyl-2,3-dihyd-
ro-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
[2029] mp: 196.8-198.0.degree. C.
[2030] IR (Nujol, cm.sup.-1): 1650
[2031] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.1-1.8 (4H, m), 2.22
(3H, s), 2.36 (3H, s), 2.43 (3H, s), 2.6-2.8 (1H, m), 2.8-3.2 (2H,
m), 3.7-4.2 (3H, m), 4.9-5.2 (2H, m), 6.7-6.9 (1H, br, s), 7.0-7.6
(7H, m), 8.93 (1H, br, s)
[2032] Mass (APCI): 505 (M.sup.++1)
EXAMPLE 48-3(14)
[2033]
N-[(3RS)-2,3-Dihydro-1-[4-(2-hydroxyethyl)piperazin-1-yl]carbonylme-
thyl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
[2034] mp: 221.7-224.2.degree. C.
[2035] IR (Nujol, cm.sup.-1): 1660, 1635
[2036] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.22 (3H, s), 2.35 (3H,
s), 2.43 (3H, s), 2.2-2.6 (8H, m), 3.3-3.6 (4H, m), 3.91 (1H, d,
J=16.4 Hz), 4.3-4.5 (1H, m), 5.0-5.2 (2H, m), 6.73 (1H, m), 7.0-7.6
(7H, m), 8.92 (1H, br, s)
[2037] Mass (APCI): 507 (M.sup.++1)
EXAMPLE 48-3(15)
[2038] N-[(3
RS)-2,3-Dihydro-1-(N,N-diisobutylamino)carbonylmethyl-5,9-dim-
ethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
[2039] mp: 226.9-228.1.degree. C.
[2040] IR (Nujol, cm.sup.-1): 1680, 1660
[2041] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.7-0.8 (6H, m),
0.8-1.0 (6H, m), 2.22 (3H, s), 2.36 (3H, s), 2.43 (3H, s), 2.9-3.2
(4H, m), 3.89 (1H, d, J=16.0 Hz), 4.99 (1H, d, J=16.0 Hz), 5.07
(1H, d, J=7.1 Hz), 6.71 (1H, d, J=6.3 Hz), 7.0-7.6 (7H, m), 8.85
(1H, br, s)
[2042] Mass (APCI): 506 (M.sup.++1)
EXAMPLE 48-3(16)
[2043]
N-[(3RS)-2,3-Dihydro-1-(N,N-bis-(2-hydroxyethyl)amino)-carbonylmeth-
yl-5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
[2044] mp: 160.5-161.1.degree. C.
[2045] IR (Nujol, cm.sup.-1): 1650, 3300
[2046] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.22 (31H, s), 2.34
(3H, s), 2.43 (31H, s), 2.9-3.8 (6H, m), 4.15 (1H, d, J=16.5 Hz),
4.5-4.7 (11H, m), 4.8-5.0 (1H, br), 5.0-5.2 (2H, br), 6.72 (1H, d,
J=6.3 Hz), 7.0-7.6 (7H, m), 8.92 (1H, br, s)
[2047] Mass (APCI): 482 (M.sup.++1)
EXAMPLE 49
[2048]
N-[(3RS)-5-Cyclohexyl-2,3-dihydro-1-(imidazol-4-yl)methyl-9-methyl--
2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea
was prepared in a similar manner to that of Example 51.
[2049] mp: 168.2-179.2.degree. C.
[2050] IR (Nujol, cm.sup.-1): 1650
[2051] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.9-1.9 (10H, m), 2.45
(3H, s), 2.73 (1H, br, s), 4.23 (1H, d, J=14.7 Hz), 5.03 (1H, d,
J=8.3 Hz), 5.36 (1H, d, J=14.7 Hz), 6.8-7.0 (1H, br, s), 7.2-7.6
(8H, m), 8.0-8.2 (2H, m), 9.25 (1H, br, s)
[2052] Mass (FAB): 539 (M.sup.++1)
EXAMPLE 50(1)
[2053]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-
-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-bromophenyl)urea
was prepared in a similar manner to that of Example 59.
[2054] mp: 168.1-171.1.degree. C.
[2055] IR (Nujol, cm.sup.-1 ): 1645
[2056] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.36
(3H, s), 2.45 (3H, s), 2.9-3.4 (2H, m), 3.5-3.9 (2H, m), 3.96 (1H,
d, J=16.5 Hz), 5.11 (1H, d, J=16.5 Hz), 5.09 (1H, d, J=8.6 Hz),
7.0-7.6 (7H, m), 7.75 (1H, br, s), 9.16 (1H, br, s)
[2057] Mass (APCI): 568 (M' +2), 564 (M.sup.+)
EXAMPLE 50(2)
[2058]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-
-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-chlorophenyl)urea
was prepared in a similar manner to that of Example 59.
[2059] mp: 181.2-185.1.degree. C.
[2060] IR (Nujol, cm.sup.-1 ): 1680, 1640
[2061] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (10H, m), 2.36
(3H, s), 2.44 (3H, s), 2.9-3.3 (2H, m), 3.5-3.9 (2H, m), 3.96 (1H,
d, J=16.4 Hz), 5.11 (1H, d, J=16.4 Hz), 5.0-5.2 (1H, m), 6.94 (1H,
d, J=8.5 Hz), 7.0-7.7 (7H, m), 9.17 (1H, br, s)
[2062] Mass (APCI): 522 (M.sup.++1)
EXAMPLE 50(3)
[2063]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-
-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylthiophenyl)urea
was prepared in a similar manner to that of Example 59.
[2064] mp: 237.2-238.5.degree. C.
[2065] IR (Nujol, cm.sup.-1): 1680, 1660, 1645
[2066] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.3-2.2 (1OH, m), 2.36
(3H, s), 2.40 (3H, s), 2.44 (3H, s), 2.9-3.4 (2H, m), 3.5-3.9 (2H,
m), 3.96 (1H, d, J=16.5 Hz), 5.11 (1H, d, J=16.5 Hz), 5.0-5.2 (1H,
m)
[2067] Mass (APCI): 534 (M.sup.++1)
EXAMPLE 50(4)
[2068]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5,9-dimethyl-
-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methoxyphenyl)urea
was prepared in a similar manner to that of Example 59.
[2069] mp: 169.6-170.7.degree. C.
[2070] IR (Nujol, cm'): 1700, 1675, 1640
[2071] .sup.1H-NMR (DMSO-d6,(5): 1.3-2.2 (10H, m), 2.36 (3H, s),
2.44 (3H, s), 2.9-3.3 (2H, m), 3.5-3.9 (2H, m), 3.67 (3H, s), 3.96
(1H, d, J=16.5 Hz), 5.11 (1H, d, J=16.5 Hz), 5.0-5.2 (1H, m),
6.4-6.6 (1H, m), 6.7-6.9 (1H, m), 7.0-7.6 (6H, m), 8.98 (1H, br,
s)
[2072] Mass (APCI): 518 (M.sup.++1)
EXAMPLE 50(5)
[2073]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5,9-dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Example 59.
[2074] mp: 176.9-179.1.degree. C.
[2075] IR (Nujol, cm.sup.-1): 1670, 1640
[2076] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-1.8 (8H, m),
1.9-2.1 (2H, m), 2.22 (3H, s), 2.36 (3H, s), 2.44 (3H, s), 3.0-3.4
(2H, m), 3.6-4.0 (2H, m), 3.96 (1H, d, J=16 Hz), 5.11 (1H, d, J=16
Hz), 5.0-5.1 (1H, br, m), 6.71 (1H, d, J=6.6 Hz), 7.0-7.6 (7H, m),
8.87 (1H, br, s)
[2077] Mass (APCI): 502 (M.sup.++1)
EXAMPLE 51
[2078] A mixture of
3-amino-1-(2-acetylbenzyl)-5-cyclohexyl-2,3-dihydro-9--
methyl-1H-1,4-benzodiazepin-2-one (280 mg), 4-nitrophenyl
N-13-(tetrazol-5-yl)phenyl}carbamate (249 mg) and triethylamine
(281 mg) in NN-dimethylformamide was stirred at room temperature
for 50 minutes. Ethyl acetate and 0.1 N aqueous hydrochloric acid
were added to the reaction mixture. The separated organic layer was
washed with water and brine, and then dried over magnesium sulfate.
The solvent was evaporated in vacuo to afford a residue, which was
washed with diisopropyl ether to give
N-[(3RS)-1-(2-acetylbenzyl)-5-cyclohexyl-2,3-dihydro-9-methyl-2-oxo--
1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5-yl)phenyl]urea (348mg,
84.9%) as a crystalline powder.
[2079] mp: 199.0-208.0.degree. C.
[2080] IR (Nujol, cm.sup.-1): 1635
[2081] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-2.2 (10H, m), 2.33
(3H, s), 2.41 (3H, s), 3.00 (1H, br, s), 4.57 (1H, d, J=17.4 Hz),
5.19 (1H, d, J=8.1 Hz), 5.33 (1H, d, J=17.4 Hz), 7.0-8.0 (11H, m),
9.22 (1H, br, s)
[2082] Mass (APCI): 591 (M.sup.++1)
EXAMPLE 52
[2083]
N-[(3RS)-5-(3-Azabicyclo[3.2.2]non-3-yl)methyl-2,3-dihydro-1,9-dime-
thyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Example 59.
[2084] mp: 145.6-149.2.degree. C.
[2085] IR (Nujol, cm.sup.-1): 1670, 1635, 1600
[2086] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.1-1.6 (8H, m),
1.6-1.8 (2H, m), 2.22 (3H, br, s), 2.35 (3H, s), 3.06 (3H, s),
3.06-3.10 (1H, m), 4.23 (1H, d, J=13.8 Hz), 5.12 (1H, d, J=7.9 Hz),
6.72 (1H, d, J=6.3 Hz), 7.0-7.3 (3H, m), 7.3-7.45 (2H, m), 7.45-7.6
(1H, d, J=6.9 Hz), 7.67 (1H, d, J=7.5 Hz), 8.94 (1H.s)
[2087] Mass (APCI): 474 (M.sup.++1)
EXAMPLE 53
[2088]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-methoxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphen-
yl)urea was prepared in a similar manner to that of Example 59.
[2089] mp: 178.1-182.1.degree. C.
[2090] IR (Nujol, cm.sup.-1): 1640
[2091] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-1.9 (8H, m),
1.9-2.1 (2H, m), 2.22 (3H, s), 2.38 (3H, s), 3.35 (3H, s), 3.3-4.1
(4H, m), 4.00 (1H, d, J=16.9 Hz), 4.52 (2H, m), 5.0-5.3 (2H, m),
6.74 (1H, br, s), 7.0-7.7 (7H, m), 8.88 (1H, br, s)
[2092] Mass (APCI): 532 (M.sup.++1)
EXAMPLE 54
[2093]
N-[(3RS)-5-Cyclohexyl-1-cyclohexylcarbonylmethyl-2,3-dihydro-9-meth-
yl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Example 59.
[2094] mp: 159.3-169.6.degree. C.
[2095] IR (Nujol, cm.sup.-1): 1710, 1640, 1600
[2096] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-2.1 (20H, m), 2.22
(3H, s), 2.33 (3H, s), 2.3-2.6 (1H, br, s), 2.94 (1H, br, s), 4.10
(1H, d, J=17.4 Hz), 4.89 (1H, d, J=17.4 Hz), 5.06 (1H, d, J=8.4
Hz), 6.71 (1H, d, J=5.5 Hz), 7.0-7.6 (7H, m), 8.81 (1H, br, s)
[2097] Mass (APCI): 530 (M.sup.++1)
EXAMPLE 55
[2098] N-[(3RS)-2,3-Dihydro-1,
9-dimethyl-5-(4-methylpiperazin-1-yl)-methy-
l-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Example 59.
[2099] mp: 136.2-140.1.degree. C.
[2100] IR (Nujol, cm.sup.-1): 1650, 1600
[2101] .sup.1H-NMR (DMSO-d.sub.6, .delta.):2.07 (3H, s), 2.21 (3H,
s), 2.27 (3H, s), 2.35 (3H, s), 2.0-2.6 (4H, m), 2.9-3.2 (5H, m),
4.11 (1H, d, J=11.6 Hz), 5.07 (1H, d, J=8,1 Hz), 6.7-6.9 (1H, br,
s), 7.0-7.8 (7H, m)
[2102] Mass (APCI):449 (M.sup.++1)
EXAMPLE 56
[2103]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro--
5-(N,N-dimethyaminomethyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-
-methylphenyl)urea was prepared in a similar manner to that of
Example 59.
[2104] mp: 154.0-156.9.degree. C.
[2105] IR (Nujol, cm.sup.-1): 1650, 1610
[2106] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-1.8 (8H, m),
1.9-2.1 (2H, m), 2.22 (3H, br, s), 2.25 (6H, br, s), 2.37 (3H, br,
s), 3.0-3.2 (1H, m), 3.4-3.9 (SH, m), 3.9-4.1 (1H, m), 4.9-5.1 (1H,
m), 5.13 (1H, d, J=8.0 Hz), 6.73 (1H, m), 7.0-7.2 (2H, m), 7.2-7.4
(2H, m), 7.4-7.5 (1H, m), 7.8-7.9 (1H, m), 8.88 (1H, br, s)
[2107] Mass (APCI): 545
EXAMPLE 57
[2108]
N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-cyclopropy-
l-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl-
)urea was prepared in a similar manner to that of Example 59.
[2109] mp: 172.0-174.4.degree. C.
[2110] IR (Nujol, cm.sup.-1): 1680, 1650, 1610
[2111] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.7-0.9 (2H, m),
0.9-1.3 (2H, m), 1.4-1.9 (8H, m), 1.9-2.2 (3H, m), 2.22 (3H, s),
3.38 (3H, s), 3.1-3.4 (2H, m), 3.6-3.9 (2H, m), 4.00 (1H, d, J=16
Hz), 5.04 (1H, d, J=16 Hz), 5.06 (1H, d, J=8.5 Hz), 6.71 (1H, d,
J=5.6 Hz), 7.0-7.3 (4H, m), 7.3-7.45 (1H, m), 7.45-7.6 (1H, m),
7.6-7.8 (1H, m), 8.82 (1H, br, s)
[2112] Mass (APCI): 528 (M.sup.++1)
EXAMPLE 58
[2113]
N-[(3RS)-1-(3-Azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihvdro--
5-isobutyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)ur-
ea was prepared in a similar manner to that of Example 59.
[2114] mp: 133.6-135.4.degree. C.
[2115] IR (Nujol, cm.sup.-1): 1650, 1610
[2116] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.94 (6H, d, J=6.6 Hz),
1.4-1.9 (8H, m), 1.9-2.1 (2H, m), 2.22 (3H, br, s), 3.37 (3H, br,
s), 2.1-2.2 (1H, m), 2.6-2.8 (2H, m), 3.0-3.2 (1H, m), 3.5-4.0 (3H,
m), 4.01 (1H, d, J=16 Hz), 5.00 (1H, d, J=16 Hz), 5.11 (1H, d,
J=8.6 Hz), 6.73 (1H, m), 7.0-7.6 (7H, m), 8.85 (1H, br, s)
[2117] Mass (APCI): 544 (M.sup.++1)
EXAMPLE 59
[2118] A mixture of
(3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbony-
lmethyl]-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one
(310 mg) and 3-methylphenyl isocyanate (113 mg) in tetrahydrofuran
(8 ml) was stirred at room temperature for 1 hour. The reaction
mixture was evaporated in vacuo to dryness. The residue was
triturated in diisopropyl ether and collected by filtration to
afford N-[(3RS)-1-(3-azabicyclo[3.2.- 2]non-3-yl)carbonylmethyl
2,3-dihydro-5-ethyl-9-methyl-2-oxo-1H-1,4-benzod-
iazepin-3-yl]-N'-(3-methylphenyl)urea (360mg, 86.2% yield) as a
crystalline powder.
[2119] mp: 130.1-133.0.degree. C.
[2120] IR (Nujol, cm.sup.-1): 1650, 1610
[2121] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.26 (3H, t, J=7.3 Hz),
1.4-1.9 (8H, m), 1.9-2.1 (2H, m), 2.22 (3H, s), 2.37 (3H, s),
2.7-3.0 (2H, m), 3.0-3.4 (2H, m), 3.7-3.9 (2H, m), 3.98 (1H, d,
J=16.2 Hz), 5.08 (1H, d, J=16.0 Hz), 5.14 (1H, d, J=7.7 Hz), 6.71
(1H, d, 3=6.5 Hz), 7.0-7.6 (7H, m), 8.86 (1H, br, s)
[2122] Mass (APCI): 516 (M' +1)
EXAMPLE 60(1)
[2123]
N-[(3RS)-1-(Piperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dihydro--
2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(2)
[2124]
N-[(3RS)-1-(cis-2,6-Dimethylpiperidin-1-yl)carbonylmethyl-5,9-dimet-
hyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(3)
[2125]
N-[(3RS)-1-((2RS)-2-Hydroxymethylpiperidin-1-yl)carbonylmethyl-5,9--
dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)u-
rea was prepared in a similar manner to that of Preparation
59-5.
EXAMPLE 60(4)
[2126]
N-[(3RS)-1-((3RS)-3-Carbamoylpiperidin-1-yl)carbonylmethyl-5,9-dime-
thyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(5)
[2127]
N-[(3RS)-1-((3RS)-3-Hydroxymethylpiperidin-1-yl)carbonylmethyl-5,9--
dimethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)u-
rea was prepared in a similar manner to that of Preparation
59-5.
EXAMPLE 60(6)
[2128]
N-[(3RS)-1-(4-Hydroxypiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-
-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(7)
[2129]
N-[(3RS)-1-(4-Oxopiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3-dih-
ydro-2-oxo-1 H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(8)
[2130]
N-[(3RS)-1-(4-Phenylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3--
dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(9)
[2131]
N-[(3RS)-1-(4-Benzylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3--
dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(10)
[2132]
N-[(3RS)-1-(4-Acetylpiperidin-1-yl)carbonylmethyl-5,9-dimethyl-2,3--
dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that Preparation 59-5.
EXAMPLE 60(11)
[2133]
N-[(3RS)-1-(N,N-Diisopropylamino)carbonylmethyl-5,9-dimethyl-2,3-di-
hydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(12)
[2134]
N-[(3RS)-1-(2-Hydroxyethylamino)carbonylmethyl-5,9-dimcthyl-2,3-dih-
ydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(13)
[2135]
N-[(3RS)-1-(1-Methyl-1-phcnylethylamino)carbonylmethyl-5,9-dimethyl-
-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(14)
[2136]
N-[(3RS)-1-(2-(2-Hydroxyethyl)piperidin-1-yl)carbonylmethyl-5,9-dim-
ethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(15)
[2137]
N-[(3RS)-1-(N,N-Diisobutylamino)carbonylmethyl-5,9-dimethyl-2,3-dih-
ydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(16)
[2138]
N-[(3RS)-1-(4-Phenylpiperazin-1-yl)carbonylmethyl-5,9-dimethyl-2,3--
dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(17)
[2139]
N-{3RS)-1-[4-[(Pyrrolidin-1-yl)carbonylmethyl]piperazin-1-yl]carbon-
ylmethyl-5,9-dimethyl-2,3-dihydro-2-oxo-1H-1
,4-benzodiazepin-3-yl}-N'-(3-- methylphenyl)urea was prepared in a
similar manner to that of Preparation 59-5.
EXAMPLE 60(18)
[2140]
N-{(3RS)-1-[4-(Pyridin-2-yl)piperazin-1-yl]carbonylmethyl-5,9-dimet-
hyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl}-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 60(19)
[2141]
N-{(3RS)-1-[4-(Pyrimidin-2-yl)piperazin-1-yl]carbonylmethyl-5,9-dim-
ethyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl}-N'-(3-methylphenyl)urea
was prepared in a similar manner to that of Preparation 59-5.
EXAMPLE 61
[2142]
N-[(3RS)-1-Cyclohexylcarbonylmethyl-2,3-dihydro-5-ethyl-9-methyl-2--
oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was obtained
in a similar manner to that of Example 59.
[2143] mp: 161.2-164.0.degree. C.
[2144] IR (Nujol, cm.sup.-1): 3350, 1730, 1680, 1650
[2145] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.0-1.4 (8H, m),
1.5-2.0 (5H, m), 2.22 (3H, s), 2.35 (3H, s), 2.2-2.5 (1H, m),
2.8-3.1 (2H, m), 4.11 (1H, d, J=17.6 Hz), 5.04 (1H, d, J=17.6 Hz),
5.21 (1H, d, J=7.4 Hz), 6.72 (1H, d, J=6.6 Hz), 7.0-7.7 (7H, m),
8.99 (1H, s)
[2146] Mass (APCI)(e/z): 475 (M.sup.++1)
EXAMPLE 62
[2147]
N-[(3RS)-1-Cyclohexylcarbonyimethyl-2,3-dihydro-5-isopropyl-9-methy-
l-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
obtained in a similar manner to that of Example 59.
[2148] mp: 142.4-146.1.degree. C.
[2149] IR (Nujol, cm.sup.-1): 3320, 1730, 1680, 1650
[2150] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.09 (3H, d, J=7.7 Hz),
1.22 (3H, d, J=6.5 Hz), 1.0-1.4 (5H, m), 1.5-1.8 (4H, m), 1.8-2.0
(1H, m), 2.22 (3H, s), 2.34 (3H, s), 2.3-2.5 (1H, m), 3.2-3.5 (1H,
m), 4.11 (1H, d, J=17.4 Hz), 4.94 (1H, d, J=17.4 Hz), 5.08 (1H, d,
J=7.8 Hz), 6.6-6.8 (1H, m), 7.0-7.6 (7H, m), 8.84 (1H, s)
[2151] Mass (APCI)(e/z) 489 (M.sup.++1)
EXAMPLE 63
[2152]
N-[(3RS)-1-Cycloheptylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-
-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was obtained in
a similar manner to that of Example 59.
[2153] mp: 171.3-174.6.degree. C.
[2154] IR (Nujol, cm.sup.-1): 3360, 1720, 1660, 1640
[2155] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-2.0 (2H, m), 2.22
(3H, s), 2.33 (3H, s), 2.4-2.7 (1H, m), 4.09 (1H, d, J=18 Hz), 5.00
(1H, d, J=18 Hz), 5.06 (1H, d, J=8.3 Hz), 6.7-6.8 (1H, m), 7.0-7.7
(7H, m), 8.86 (1H, s)
[2156] Mass (APCI)(e/z): 475 (M.sup.++1)
EXAMPLE 64
[2157]
N-[(3RS)-1-Cyclohexylcarbonylmethyl-5-cyclopropyl-2,3-dihydro-9-met-
hyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
obtained in a similar manner to that of Example 59.
[2158] mp: 143.6-144.2.degree. C.
[2159] IR (Nujol, cm.sup.-1): 3370, 1720, 1680, 1650
[2160] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.8-1.4 (9H, m),
1.5-2.0 (5H, m), 2.1-2.5 (2H, m), 2.22 (3H, s), 2.34 (3H, s),
2.8-3.0 (1H, m), 4.09 (1H, d, J=17 Hz), 4.94 (1H, d, J=17 Hz), 5.06
(1H, d, J=8.3 Hz), 6.7-6.8 (1H, m), 7.0-7.8 (7H, m), 8.8-9.0 (1H,
m)
[2161] Mass (APCI)(e/z): 487 (M' +1)
EXAMPLE 65
[2162]
N-[(3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo-
-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was obtained in
a similar manner to that of Example 59.
[2163] mp: 150.1-155.5.degree. C.
[2164] IR (Nujol, cm.sup.-1): 3280, 1720, 1670, 1645
[2165] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.4-1.9 (8H, m), 2.22
(3H, s), 2.33 (3H, s), 2.47 (3H, s), 2.8-3.0 (1H, m), 4.10 (1H, d,
J=17.5 Hz), 4.97 (1H, d, J=17.5 Hz), 5.08 (1H, m), 6.7-6.8 (1H, m),
7.0-7.7 (7H, m), 8.86 (1H, s)
[2166] Mass (APCI)(e/z): 447 (M' +1)
EXAMPLE 66
[2167]
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-ethyl-9-
-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Example 59.
[2168] mp: 189.0-189.5.degree. C.
[2169] IR (Nujol, cm.sup.-1): 3350, 1690, 1630
[2170] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.23 (3H, t, J=7.3 Hz),
1.3-1.9 (10H, m), 2.22 (3H, s), 2.36 (3H, s), 2.7-2.95 (2H, m),
2.95-3.35 (2H, m), 3.35-3.60 (2H, m),3.15 (1H, d, J=16.0 Hz), 4.94
(1H, d, J=16.0 Hz), 5.13 (1H, d, J=8.5 Hz), 6.71 (1H, d, J=6.4 Hz),
7.0-7.6 (6H, m), 8.83 (1H, s)
[2171] Mass (APCI)(e/z): 504 (M' +1)
EXAMPLE 67
[2172]
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-isoprop-
yl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Example 59.
[2173] mp: 131.7-132.8.degree. C.
[2174] IR (Nujol, cm.sup.-1): 3320, 1685, 1645, 1605
[2175] .sup.1H-NMR (DMSO-d, .delta.): 1.12 (3H, d, J=7.0 Hz), 1.21
(3H, d, J=6.5 Hz), 1.3-1.9 (10H, m), 2.22 (3H, s), 2.37 (3H, s),
3.0-3.6 (5H, m), 3.98 (1H, d, J=16.0 Hz), 4.87 (1H, d, J=16.0 Hz),
5.09 (1H, d, J=8.5 Hz), 6.72 (1H, d, J=6.2 Hz), 7.0-7.6 (7H, m),
8.82 (1H, s)
[2176] Mass (APCI)(e/z): 518 (M.sup.++1)
EXAMPLE 68
[2177]
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-5-cyclopropyl-2,3-dih-
ydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Example 59.
[2178] mp: 177.7-179.2.degree. C.
[2179] IR (Nujol, cm.sup.-1): 3300, 1660, 1630, 1605
[2180] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.7-1.3 (4H, m),
1.3-1.9 (10H, m), 2.0-2.2 (1H, m), 2.22 (3H, s), 2.37 (3H, s),
3.0-3.6 (4H, m), 3.96 (1H, d, J=16.0 Hz), 4.90 (1H, d, J=16.0 Hz),
5.05 (1H, d, J=8.5 Hz), 6.7-6.9 (1H, m), 7.0-7.8 (7H, m), 8.79 (1H,
s)
[2181] Mass (APCI)(e/z): 516 (M.sup.++1)
EXAMPLE 69
[2182]
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-isobuty-
l-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Example 59.
[2183] mp: 131.6-133.4.degree. C.
[2184] IR (Nujol, cm.sup.-1): 3370, 3320, 1700, 1635, 1605
[2185] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.94 (6H, d, J=6.4 Hz),
1.3-1.9 (10H, m), 2.1-2.3 (1H, m), 2.22 (3H, s), 2.37 (3H, s), 2.68
(2H, d, J=6.7 Hz), 3.0-3.6 (4H, m), 3.97 (1H, d, J=16.1 Hz), 4.88
(1H, d, J=16.1 Hz), 5.12 (1H, d, J=8.5 Hz), 6.72 (1H, d, J=6.3 Hz),
7.0-7.6 (7H, m), 8.84 (1H, s)
[2186] Mass (APCI)(e/z): 532 (M.sup.++1)
EXAMPLE 70
[2187]
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-5-cyclohexyl-2,3-dihy-
dro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Example 59.
[2188] mp: 153.6-155.3.degree. C.
[2189] IR (Nujol, cm.sup.-1): 3360, 3330, 1695, 1650, 1630
[2190] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.1-2.1 (20H, m), 2.22
(3H, s), 3.37 (3H, s), 2.8-3.0 (1H, m), 3.0-3.6 (4H, m), 3.98 (1H,
d, J=16.0 Hz), 4.84 (1H, d, J=16.0 Hz), 5.08 (1H, d, J=8.3 Hz),
6.7-6.8 (1H, m), 7.0-7.6 (7H, m), 8.83 (1H, s)
[2191] Mass (APCI)(e/z): 558 (M.sup.++1)
EXAMPLE 71-1
[2192]
N-[(3RS)-5-Aceloxymethyl-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-d-
ihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Example 32.
[2193] mp: 112.2-114.2.degree. C.
[2194] IR (Nujol, cm.sup.-1): 3330, 1735, 1680, 1640
[2195] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-1.8 (10H, m), 2.06
(3H, s), 2.22 (3H, s), 2.30 (3H, s), 2.9-3.6 (4H, m), 3.97 (1H, d,
J=16 Hz), 4.8-5.0 (2H, m), 5.18 (1H, d, J=8.4 Hz), 5.35 (1H, d,
J=16 Hz), 6.7-6.8 (1H, m ), 7.0-7.2 (3H, m ), 7.2-7.4 (2H, m ),
7.4-7.7 (2H, m ), 8.87 (1H, s)
[2196] Mass (APCI)(e/z): 506 (M.sup.++1)
EXAMPLE 71-2
[2197]
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-hydroxy-
methyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Preparation 14.
[2198] mp: 214.5-216.0.degree. C.
[2199] IR (Nujol, cm.sup.-1): 3380, 3280, 1690, 1615
[2200] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-1.9 (10H, m), 2.22
(3H, s), 2.38 (3H, s), 2.9-3.2 (1H, m), 3.2-3.4 (3H, m), 3.99 (1H,
d, 1=16 Hz), 4.56 (1H, s), 4.57 (2H, s), 4.97 (1H, d, J=16 Hz),
5.22 (1H, d, J=8.5 Hz), 6.72 (1H, d, 1=6.6 Hz), 7.0-7.7 (7H, m),
8.89 (1H, s)
[2201] Mass (APCI)(e/z): 506 (M.sup.++1)
EXAMPLE 71-3(1)
[2202] To a solution of
N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3--
dihydro-5-hydroxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-me-
thylphenyl)urea (300 mg) and diisopropylethylamine (115 mg) in
methylene chloride (4 ml) was added methanesuifonyl chloride (102
mg) under stirring and cooling in an ice-bath. The mixture was
stirred under the same conditions for 4 hours. A mixture of 50%
aqueous dimethylamine (2 ml) and tetrahydrofuran (2 ml) was added
to the reaction mixture obtained above and the resultant mixture
was stirred under cooling in an ice-bath for 3.5 hours. Ethyl
acetate and water were added to the reaction mixture. The separated
organic layer was washed with water and brine, and dried over
sodium sulfate. The solvent was evaporated in vacuo to afford a
residue, which was triturated in diisopropyl cther and collected by
filtration to give
N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihy-
dro-5-(N,N-dimethylamino)methyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]--
N'-(3-methylphenyl)urea as crystalline powder (209mg, 66.2%
yield).
[2203] mp: 147.9-149.1.degree. C.
[2204] IR (Nujol, cm.sup.-1): 3450, 1670, 1650, 1610
[2205] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-1.9 (10H, m), 2.22
(3H, s), 2.25 (6H, s), 2.37 (3H,s), 3.0-3.6 (4H, m), 3.52 (2H, s),
3.97 (1H, d, J=16 Hz), 4.86 (1H, d, J=16 Hz), 5.13 (1H, d, J=8.4
Hz), 6.7-6.8 (1H, m), 7.0-7.5 (6H, m), 7.7-7.9 (1H, m), 8.87 (1H,
s)
[2206] Mass (APCI)(e/z): 533 (M' +1)
EXAMPLE 71-3(2)
[2207] A mixture of
N-[(3RS)-I-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihy-
dro-5-hydroxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methyl-
phenyl)urea (1.50 mg) and manganese dioxide (15.0 g) in acetone (40
ml) was stirred at ambient temperature for 5 hours. The undissolved
substances were removed by filtration. The filtrate was evaporated
in vacuo to afford a residue, which was triturated in diisopropyl
ether and collected by filtration to give
N-[(3RS)-1-(azacyclooctan-1-yl)carbonylme-
thyl-2,3-dihydro-5-formyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3--
methylphenyl)urea as crystalline powder (1.20 g, 80.2% yield).
[2208] mp: 137.9-141.0.degree. C.
[2209] IR (Nujol, cm.sup.-1 ): 3350, 1710, 1680, 1640
[2210] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-1.9 (10H, m), 2.23
(3H, s), 2.39 (3H, s), 2.8-3.6 (4H, br), 3.98 (1H, d, J=16 Hz),
4.94 (1H, d, J=16 Hz), 5.47 (1H, d, J=8.3 Hz), 6.7-6.8 (1H, m),
7.0-7.7 (7H, m), 8.97 (1H, s), 9.64 (1H, s)
[2211] Mass (APCI)(e/z): 504 (Mt +1)
EXAMPLE 72
[2212]
N-[(3RS)-1-Cyclooctylcarbonylmethyl-2,3-dihydro-5,9-dimethyl-2-oxo--
1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was obtained in
a similar manner to that of Example 59.
[2213] mp: 162.9-164.4.degree. C.
[2214] IR (Nujol, cm.sup.-1 ): 3350, 1720, 1680, 1640, 1605
[2215] .sup.1H-NMR (DMSO-d.sub.6, .delta.) 1.3-2.0 (14H, m), 2.22
(3H, s), 2.33 (3H, s), 2.47 (3H, s), 2.5-2.7 (1H, m), 4.09 (1H, d,
J=l8 Hz), 5.00 (1H, d, J=18 Hz), 5.07 (1H, d, J=9.4 Hz), 6.7-6.8
(1H, m), 7.0-7.6 (7H, m), 8.85 (1H, s)
[2216] Mass (APCI)(e/z): 489 (M.sup.++1)
EXAMPLE 73
[2217]
N-[(3RS)-1-Cyclohexylcarbonylmethyl-2,3-dihydro-5-isobutyl-9-methyl-
-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was
obtained in a similar manner to that of Example 59.
[2218] mp: 152.3-154.8.degree. C.
[2219] IR (Nujol, cm.sup.-1): 3410, 3250, 1730, 1680, 1650
[2220] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.94 (6H, d, J=6.6 Hz),
1.1-1.4 (5H, m), 1.5-2.0 (5H, m), 2.0-2.2 (1H, m), 2.22 (3H, s),
2.32 (3H, s), 3.3-3.6 (1H, m), 3.6-3.8 (2H, m), 4.72 (1H, d, J=17.6
Hz), 4.89 (1H, d, J=17.6 Hz), 5.09 (1H, d, J=8.5 Hz), 6.7-6.8 (1H,
m), 7.0-7.6 (7H, m), 8.83 (1H, s)
[2221] Mass (APCI)(e/z): 503 (M' +1)
EXAMPLE 74
[2222]
N-{(3RS)-2,3-dihydro-5,9-dimethyl-1-[N-methyl-N-(2-pyridyl)aminolca-
rbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl}-N'-(3-methylphenyl)urea
was obtained in a similar manner to that of Example 59.
[2223] mp: 222.3-224.2.degree. C.
[2224] IR (Nujol, cm.sup.-1): 3280, 1680, 1670, 1650
[2225] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.21 (3H, s), 2.25 (3H,
s), 3.23 (3H, s), 2.47 (3H, s), 4.13 (1H, d, J=17 Hz), 4.91 (1H, d,
3=17 Hz), 5.09 (1H, d, J=7.9 Hz), 6.6-6.8 (1H, br), 7.0-7.7 (9H,
m), 7.8-8.0 (1H, m), 8.4-8.6 (1H, m), 8.91 (1H, s)
[2226] Mass (APCI)(e/z): 485 (M.sup.++1)
EXAMPLE 75(1)-1
[2227] To a suspension of sodium hydride (31 mg, 60% in mineral
oil) in tetrahydrofuran was added ethyl diethylphosphonoacetate
(195 mg) under stirring and cooling in an ice-bath. After stirring
for 15 minutes, a solution of
N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-f-
ormyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea
(300 mg) in tetrahydrofuran (5 ml) was added to the reaction
mixture under the same conditions. The mixture was stirred at
ambient temperature for 4 hours. To a reaction mixture was added
0.1N aqueous hydrochloric acid (20 ml) and the resultant mixture
was extracted with ethyl acetate. The separated organic layer was
washed with water and brine, and dried over magnesium sulfate. The
solvent was evaporated in vacuo to afford a residue, which was
subjected to column chromatography on silica gel eluting with a
mixture of toluene and ethyl acetate (3:1) to give
N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-((EZ)-2-(etho-
xycarbonyl)ethenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin
-3-yl]-N'-(3-methylphenyl)urea (266mg, 77.8% yield) as crystalline
powder.
[2228] mp: 175.2-177.7.degree. C.
[2229] IR (Nujol, cm.sup.-1): 3260, 1730, 1700, 1665, 1620
[2230] .sup.1H-NMR (DMSO-d.sub.56, .delta.): 1.21 (3H, t, J=7.1
Hz), 1.2-1.8 (10H, m), 2.27 (3H, s), 2.34 (3H, s), 3.0-3.6 (4H, m),
4.10 (2H, q, J=7.1 Hz), 3.9-4.1 (1H, m), 4.86 (1H, d, J=16 Hz),
5.3-5.5 (1H, m), 6.8-6.9 (1H, m), 7.0-7.4 (9H, m), 9.54 (1H, s),
10.22 (1H, s)
[2231] Mass (APCI)(e/z): 574 (M.sup.++1)
EXAMPLE 75(1)-2
[2232] A mixture of
N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-5-((EZ)--
2-(ethoxycarbonyl)ethenyl)-2,.sup.3-dihydro-9-methyl-2-oxo-1H-1,4-benzodia-
zepin-3-yl]-N'-(3-methylphenyl)urea (230 mg) and 1N sodium
hydroxide (1.6 ml) in, 1,2-dimethoxyethane (6.0 ml) was stirred at
ambient temperature overnight. Ethyl acetate and water were added
to the reaction mixture. The separated aqueous layer was made
acidic with 1N aqueous hydrochloric acid and extracted with ethyl
acetate. The extract was dried over magnesium sulfate and
evaporated in vacuo to afford a residue, which was triturated in
diisopropyl ether and collected by filtration to give
N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-((EZ)-2-carbo-
xylethenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)u-
rea (80mg. 36.6% yield) as crystalline powder.
[2233] mp: 129.3-134.1.degree. C.
[2234] IR (Nujol, cm.sup.-1): 3200, 1710, 1660, 1630
[2235] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-1.8 (10H, m), 2.34
(3H, s), 2.26 (3H, s), 3.0-3.6 (4H, m), 4.05 (1H, d, J=17 Hz), 4.86
(1H, d, J=17 Hz), 5.4-5.6 (1H, m), 6.8-6.9 (1H, m), 7.0-7.4 (9H,
m), 10.26 (1H, s)
[2236] Mass (APCI)(e/z): 546 (M.sup.++1)
EXAMPLE 75(2)
[2237] A mixture of
N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihy-
dro-5-formyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)-
urea (300 mg), hydroxylamine hydrochloride (41 mg) and sodium
acetate (51 mg) in acetic acid (1.5 ml) was stirred at ambient
temperature for 2.5 hours. Acetic anhydride (0.4 ml) was added to
the reaction mixture, and the resultant mixture was stirred at
90.degree. C. for 11.5 hours. After the reaction mixture was
allowed to cool to ambient temperature, ethyl acetate and aqueous
sodium hydrogen carbonate were added into the mixture successively
under stirring. The separated organic layer was washed with aqueous
sodium hydrogen carbonate and brine, and dried over magnesium
sulfate. The solvent was evaporated in vacuo to afford a residue,
which was subjected to column chromatography on silica gel eluting
with a mixture of toluene and ethyl acetate (4:1) to give
N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-5-cyano-2,3-dihydro-9-methy-
l-2-oxo-1H-1,4-benzodiagepin-3-yl]-N'-(3-methylphenyl)urea as
crystalline powder (80 mg).
[2238] mp: 213.4-216.7.degree. C.
[2239] IR (Nujol, cm.sup.-1): 3300, 2210, 1690, 1656
[2240] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.2-1.9 (IOH, m), 2.25
(3H, s), 2.38 (3H, s), 2.9-3.8 (4H, m), 4.22 (1H, d, J=16 Hz), 5.06
(1H, d, J=16 Hz), 5.37 (1H, d, J=8.1 Hz), 6.7-6.9 (1H, m), 7.0-7.8
(9H, m), 9.4-9.7 (1H, m)
[2241] Mass (APCJ)(e/z): 501 (M.sup.++1)
EXAMPLE 76(1)
[2242] To a solution of
(3S)-3-amino-1-cyclohexylcarbonylmethyl-5-ethyl-9--
methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (6.30 g) in
tetrahydrofuran (100 ml) was added m-tolyl isocyanate (2.62 g)
under stirring at ambient temperature. The mixture was stirred for
3 hours further under the same conditions. After removal of the
solvent in vacuo, the residue was dissolved in ethyl acetate and
washed with a diluted hydrochloric acid, a diluted aqueous sodium
bicarbonate and water successively. The organic extract was dried
over magnesium sulfate and evaporated in vacuo to afford an oil
(9.36 g), which was subjected to column chromatography on silica
gel eluting with a mixture of methylene chloride and methanol
(50:1). The fractions containing the desired product were combined
and evaporated in vacuo to give
N-[(3S)-1-cyclohexylcarbonylmethyl-5-ethyl-9--
methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)ure-
a (6.34 g, 72.4%) as an amorphous mass.
[2243] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.05-1.4 (5H, m), 1.26
(3H, t, J=7.4 Hz), 1.55-1.9 (5H, m), 2.02 (1H, br, s), 2.2-2.35
(1H, m), 2.29 (3H, s), 2.33 (3H, s), 2.92 (2H, q, J=7.4 Hz), 3.77
(1H, d, J=17.2 Hz), 5.06 (1H, d, J=17.2 Hz),5.48(1H, d, J=8.3 Hz),
6.7-7.4 (8H, m) APCI-MS(m/z): 475 (M.sup.++1)
[2244] [.alpha.].sub.D.sup.30=-53.36.degree. (C=1.16,
CHCl.sub.3)
EXAMPLE 76(2)
[2245]
N-1(3R)-1-cyclohexylcarbonylmethyl-5-ethyl-9-methyl-2-oxo-2,3-dihyd-
ro-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea was obtained
in a similar manner to that of Example 76(1).
[2246] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.05-1.4 (5H, m), 1.26
(3H, t, J=7.4 Hz), 1.55-1.9 (5H, m), 1.95-2.35 (2H, m), 2.29 (3H,
s), 2.32 (3H, s), 2.92 (2H, q, J=7.4 Hz), 3.77 (1H, d, J=17.2 Hz),
5.06 (1H, d, J=17.2 Hz), 5.48 (1H, d, J=8.3 Hz), 6.7-7.4 (8H,
m)
[2247] APCI-MS(m/z): 475 (M.sup.++1)
[2248] [.alpha.].sub.D.sup.30=-50.92.degree. (C=1.08,
CHCl.sub.3)
* * * * *