US4680392A
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Substituted caprolactam derivatives as antihypertensives
Assignee: Merck and Co Inc
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Filing: 1986-05-19
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Granted: 1987-07-14
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Expires: 2006-05-19
Abstract
Abstract The invention in its broad aspects relates to caprolactam derivatives which are useful as angiotensin converting enxyme inhibitors and as antihypertensives.
Inventors
- 👤 Elbert E. Harris
- 👤 Arthur A. Patchett
- 👤 Eugene D. Thorsett
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 22:31
CPC Classifications
C; C07; C07K; C07K5/00; C07K5/04; C07K5/06; C07K5/06139; C07K5/02; C07K5/022; C07K5/0222; A; A61; A61K; A61K38/00
Claims Analysis
Total Claims: 32
Claim 1
Independent Claim
389 words
A compound of the formula: ##STR9## wherein R and R 4 are the same or different and are hydroxy, C 1 -C 8 alkoxy, C 2 -C 12 alkenoxy, C 6 -C 12 aryloxy, di-C 1 -c 8 -alkylamino-C 1 -C 8 -alkoxy, acylamino-C 1 -C 8 -alkoxy selected from the group: acetylaminoethoxy, nicotinoylaminoethoxy, and succinamidoethoxy; pivaloyloxyethoxy, C 6 -C 12 aryl-C 1 -C 8 alkoxy, hydroxy-C 1 -C 8 alkoxy dihydroxy-C 1 -C 8 alkoxy amino, hydroxyamino; R 1 is hydrogen, C 1 -C 12 alkyl which include branched and unsaturated alkyl groups, substituted C 1 -C 8 alkyl wherein the substituent(s) can be halo, C 1 -C 8 alkoxy, C 6 -C 12 aryloxy, amino, C 1 -C 8 alkylamino, hydroxy, di-C 1 -C 8 alkylamino, amino-C 1 -C 8 alkylthio, amino-C 1 -C 8 alkoxy, acetamido, benzamido, C 6 -C 12 arylamino, guanidino, phthalimido, mercapto, C 1 -C 8 alkylthio, C 6 -C 12 arylthio, carboxy, carboxamido or carbo-C 1 -C 8 alkoxy, C 6 -C 12 aryl-C 1 -C 8 alkyl, C 6 -C 12 aryl-C 2 -C 8 alkenyl; substituted C 6 -C 12 alkyl-C 1 -C 8 alkyl wherein the alkyl portion may be substituted by amino, hydroxy acetamido or benzamido, R 2 is hydrogen, C 1 -C 8 alkyl, unsubstituted C 3 -C 10 cycloalkyl, amino-C 1 -C 8 alkyl, C 1 -C 12 alkylamino-C 1 -C 8 alkyl, hydroxy-C 1 -C 12 alkyl, acetamido- or benzamido-C 1 -C 8 alkyl, di-C 1 -C 12 alkylamino-C 1 -C 8 alkyl including polyethyleneamino-C 3 -C 10 cycloalkyl, C 6 -C 12 aryl-C 1 -C 8 alkyl, C 6 -C 12 aryl, substituted C 6 -C 12 aryl wherein the substituent is halo, C 1 -C 12 alkyl, amino-C 1 -C 12 alkyl, or C 1 -C 12 alkoxy; R 3 is hydrogen, C 1 -C 8 alkyl, phenyl, phenyl C 1 -C 8 alkyl, hydroxyphenyl-C 1 -C 8 alkyl, hydroxy-C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, acetamido- or benzamido-C 1 -C 8 alkyl, guanidino-C 1 -C 8 alkyl, imidazolyl-C 1 -C 8 alkyl, indolyl-C 1 -C 8 alkyl, mercapto-C 1 -C 8 alkyl or C 1 -C 8 alkyl thio-C 1 -C 8 alkyl; R 5 is hydrogen or C 1 -C 8 alkyl; and, the pharmaceutically acceptable salts thereof.
Claim 2
Dependent Claim
389 words
A compound of the formula: ##STR9## wherein R and R 4 are the same or different and are hydroxy, C 1 -C 8 alkoxy, C 2 -C 12 alkenoxy, C 6 -C 12 aryloxy, di-C 1 -c 8 -alkylamino-C 1 -C 8 -alkoxy, acylamino-C 1 -C 8 -alkoxy selected from the group: acetylaminoethoxy, nicotinoylaminoethoxy, and succinamidoethoxy; pivaloyloxyethoxy, C 6 -C 12 aryl-C 1 -C 8 alkoxy, hydroxy-C 1 -C 8 alkoxy dihydroxy-C 1 -C 8 alkoxy amino, hydroxyamino; R 1 is hydrogen, C 1 -C 12 alkyl which include branched and unsaturated alkyl groups, substituted C 1 -C 8 alkyl wherein the substituent(s) can be halo, C 1 -C 8 alkoxy, C 6 -C 12 aryloxy, amino, C 1 -C 8 alkylamino, hydroxy, di-C 1 -C 8 alkylamino, amino-C 1 -C 8 alkylthio, amino-C 1 -C 8 alkoxy, acetamido, benzamido, C 6 -C 12 arylamino, guanidino, phthalimido, mercapto, C 1 -C 8 alkylthio, C 6 -C 12 arylthio, carboxy, carboxamido or carbo-C 1 -C 8 alkoxy, C 6 -C 12 aryl-C 1 -C 8 alkyl, C 6 -C 12 aryl-C 2 -C 8 alkenyl; substituted C 6 -C 12 alkyl-C 1 -C 8 alkyl wherein the alkyl portion may be substituted by amino, hydroxy acetamido or benzamido, R 2 is hydrogen, C 1 -C 8 alkyl, unsubstituted C 3 -C 10 cycloalkyl, amino-C 1 -C 8 alkyl, C 1 -C 12 alkylamino-C 1 -C 8 alkyl, hydroxy-C 1 -C 12 alkyl, acetamido- or benzamido-C 1 -C 8 alkyl, di-C 1 -C 12 alkylamino-C 1 -C 8 alkyl including polyethyleneamino-C 3 -C 10 cycloalkyl, C 6 -C 12 aryl-C 1 -C 8 alkyl, C 6 -C 12 aryl, substituted C 6 -C 12 aryl wherein the substituent is halo, C 1 -C 12 alkyl, amino-C 1 -C 12 alkyl, or C 1 -C 12 alkoxy; R 3 is hydrogen, C 1 -C 8 alkyl, phenyl, phenyl C 1 -C 8 alkyl, hydroxyphenyl-C 1 -C 8 alkyl, hydroxy-C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, acetamido- or benzamido-C 1 -C 8 alkyl, guanidino-C 1 -C 8 alkyl, imidazolyl-C 1 -C 8 alkyl, indolyl-C 1 -C 8 alkyl, mercapto-C 1 -C 8 alkyl or C 1 -C 8 alkyl thio-C 1 -C 8 alkyl; R 5 is hydrogen or C 1 -C 8 alkyl; and, the pharmaceutically acceptable salts thereof.
Claim 3
Dependent Claim
205 words
A compound of the formula: ##STR10## wherein R and R 4 are the same or different and are hydroxy, C 1 -C 8 alkoxy, and C 6 -C 12 aryl-C 1 -C 8 alkoxy; R 2 is hydrogen, C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, C 6 -C 12 aryl-C 1 -C 12 alkyl, C 6 -C 12 aryl, R 5 is hydrogen; R 1 is C 1 -C 8 alkyl; substituted C 1 -C 8 alkyl wherein the substituent is amino, acetamido, benzamido, hydroxy, amino-C 1 -C 8 alkylthio, amino-C 1 -C 8 alkoxy, C 6 -C 12 arylthio, C 6 -C 12 aryloxy, or C 6 -C 12 arylamino; C 6 -C 12 aryl-C 1 -C 3 alkyl wherein the substituent(s) on the aryl group is halo, dihalo, amino, aminoC 1 -C 8 alkyl, hydroxy, C 1 -C 8 alkoxy, C 1 -C 8 alkyl, phenoxy or benzoyl; R 3 is hydrogen, C 1 -C 8 alkyl, phenyl C 1 -C 8 alkyl, hydroxy phenyl-C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, imidazolyl-C 1 -C 8 alkyl, indolyl-C 1 -C 8 alkyl, C 1 -C 8 alkyl thio-C 1 -C 8 alkyl; and, the pharmaceutically acceptable salts thereof.
Claim 4
Dependent Claim
205 words
A compound of the formula: ##STR10## wherein R and R 4 are the same or different and are hydroxy, C 1 -C 8 alkoxy, and C 6 -C 12 aryl-C 1 -C 8 alkoxy; R 2 is hydrogen, C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, C 6 -C 12 aryl-C 1 -C 12 alkyl, C 6 -C 12 aryl, R 5 is hydrogen; R 1 is C 1 -C 8 alkyl; substituted C 1 -C 8 alkyl wherein the substituent is amino, acetamido, benzamido, hydroxy, amino-C 1 -C 8 alkylthio, amino-C 1 -C 8 alkoxy, C 6 -C 12 arylthio, C 6 -C 12 aryloxy, or C 6 -C 12 arylamino; C 6 -C 12 aryl-C 1 -C 3 alkyl wherein the substituent(s) on the aryl group is halo, dihalo, amino, aminoC 1 -C 8 alkyl, hydroxy, C 1 -C 8 alkoxy, C 1 -C 8 alkyl, phenoxy or benzoyl; R 3 is hydrogen, C 1 -C 8 alkyl, phenyl C 1 -C 8 alkyl, hydroxy phenyl-C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, imidazolyl-C 1 -C 8 alkyl, indolyl-C 1 -C 8 alkyl, C 1 -C 8 alkyl thio-C 1 -C 8 alkyl; and, the pharmaceutically acceptable salts thereof.
Claim 5
Dependent Claim
176 words
A compound of the formula ##STR11## wherein R 3 is hydrogen, C 1 -C 8 alkyl, amino-C 1 -C alkyl , indolyl-C 1 -C 8 alkyl, phenyl-C 1 -C 8 alkyl; R 1 is C 1 -C 8 alkyl; substituted C 1 -C 5 alkyl wherein the substituent is amino, acetamido, benzamido, hydroxy, amino-C 1 -C 8 alkylthio, C 6 -C 12 arylthio, C 6 -C 12 aryloxy; C 6 -C 12 aryl-C 1 -C 3 alkyl; substituted C 6 -C 12 aryl-C 1 -C 3 -alkyl wherein the alkyl groups are optionally substituted with amino, C 6 -C 12 arylamino, or hydroxy, the substituent(s) on the aryl groups is halo, amino, amino-C 1 -C 12 alkyl, hydroxy, or C 1 -C 8 alkoxy; R 5 is hydrogen; R 2 is hydrogen, C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, C 6 -C 12 aryl, and C 6 -C 12 aryl C 1 -C 12 -alkyl; R and R 4 are independently hydroxy, C 1 -C 8 alkoxy, and, the pharmaceutically acceptable salts thereof.
Claim 6
Dependent Claim
176 words
A compound of the formula ##STR11## wherein R 3 is hydrogen, C 1 -C 8 alkyl, amino-C 1 -C alkyl , indolyl-C 1 -C 8 alkyl, phenyl-C 1 -C 8 alkyl; R 1 is C 1 -C 8 alkyl; substituted C 1 -C 5 alkyl wherein the substituent is amino, acetamido, benzamido, hydroxy, amino-C 1 -C 8 alkylthio, C 6 -C 12 arylthio, C 6 -C 12 aryloxy; C 6 -C 12 aryl-C 1 -C 3 alkyl; substituted C 6 -C 12 aryl-C 1 -C 3 -alkyl wherein the alkyl groups are optionally substituted with amino, C 6 -C 12 arylamino, or hydroxy, the substituent(s) on the aryl groups is halo, amino, amino-C 1 -C 12 alkyl, hydroxy, or C 1 -C 8 alkoxy; R 5 is hydrogen; R 2 is hydrogen, C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, C 6 -C 12 aryl, and C 6 -C 12 aryl C 1 -C 12 -alkyl; R and R 4 are independently hydroxy, C 1 -C 8 alkoxy, and, the pharmaceutically acceptable salts thereof.
Claim 7
Dependent Claim
127 words
A compound of the formula: ##STR12## wherein R 3 is hydrogen or C 1 -C 8 alkyl; R 1 is C 1 -C 8 alkyl; substituted-C 1 -C 5 wherein the substituent is amino, acetamido, benzamido, C 6 -C 12 -arylthio, C 6 -C 12 aryloxy; C 6 -C 12 aryl-C 1 -C 3 alkyl substituted C 6 -C 12 aryl-C 1 -C 3 alkyl wherein the substituent(s) on the aryl group is halo, amino, aminoalkyl, hydroxy or C 1 -C 8 alkoxy; R 5 is hydrogen; R 2 is hydrogen, C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, or C 6 -C 12 aryl; R and R 4 are independently hydroxy, C 1 -C 8 alkoxy or benzyloxy; and, the pharmaceutically acceptable salts thereof.
Claim 8
Dependent Claim
127 words
A compound of the formula: ##STR12## wherein R 3 is hydrogen or C 1 -C 8 alkyl; R 1 is C 1 -C 8 alkyl; substituted-C 1 -C 5 wherein the substituent is amino, acetamido, benzamido, C 6 -C 12 -arylthio, C 6 -C 12 aryloxy; C 6 -C 12 aryl-C 1 -C 3 alkyl substituted C 6 -C 12 aryl-C 1 -C 3 alkyl wherein the substituent(s) on the aryl group is halo, amino, aminoalkyl, hydroxy or C 1 -C 8 alkoxy; R 5 is hydrogen; R 2 is hydrogen, C 1 -C 8 alkyl, amino-C 1 -C 8 alkyl, or C 6 -C 12 aryl; R and R 4 are independently hydroxy, C 1 -C 8 alkoxy or benzyloxy; and, the pharmaceutically acceptable salts thereof.
Claim 9
Dependent Claim
8 words
A compound of claim 4 which is: 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one
Claim 10
Dependent Claim
8 words
A compound of claim 4 which is: 1-(1(S)-carboxyethyl)-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one.
Claim 11
Dependent Claim
8 words
A compound of claim 4 which is: 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one.
Claim 12
Dependent Claim
8 words
A compound of claim 4 which is: 1-(1(S)-carboxyethyl)-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one.
Claim 13
Dependent Claim
8 words
A compound of claim 4 which is: 1-benzyloxycarbonylethyl-3-[(1-carboxy-3-phenylpropyl)-amino]perhydroazepin-2-one.
Claim 14
Dependent Claim
8 words
A compound of claim 4 which is: 1(S)benzyloxycarbonylethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one.
Claim 15
Dependent Claim
8 words
A compound of claim 4 which is: 1-(1-ethoxycarbonylethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one.
Claim 16
Dependent Claim
8 words
A compound of claim 4 which is: 1-(1(S)-ethoxycarbonylethyl)-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one.
Claim 17
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one.
Claim 18
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one.
Claim 19
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]-7(R)-methylperhydroazepin-2-one.
Claim 20
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one.
Claim 21
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one.
Claim 22
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(R)-methylperhydroazepin-2-one.
Claim 23
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one.
Claim 24
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one.
Claim 25
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]-7(S)-phenylperhydroazepin-2-one.
Claim 26
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one.
Claim 27
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one.
Claim 28
Dependent Claim
8 words
A compound of claim 4 which is: 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(S)-phenylperhydroazepin-2-one.
Claim 29
Dependent Claim
107 words
A process for preparing compounds of the formula ##STR13## wherein R-R 5 are as defined in claim 1 which process comprises reductively alkylating: ##STR14## or alkylating compounds of Formula VI with α-halo compounds of the formula: ##STR15## wherein R-R 5 , are as defined above and X is a good leaving group such as Br or I, followed by removal of protecting groups, if necessary, to yield the desired product and, if desired, isolating the biologically more active isomer by chromatography, fractional crystallization, or by resolution with an appropriate, optically active acid or base and, if desired, preparing a salt of the desired product by conventional means.
Claim 30
Dependent Claim
98 words
A process for preparing compounds of the formula ##STR16## wherein R-R 5 are as defined in claim 1 which process comprises reacting ##STR17## with the alkylating agent: ##STR18## wherein R-R 5 , are as defined above and X is a good leaving group such as Br or I, to yield the desired product followed by removal of protecting groups, if necessary, and, if desired, isolating the biologically more active isomer by chromatography, fractional crystallization or by resolution with an appropriate, optically active acid or base and, if desired, preparing a salt of the desired product by conventional means.
Claim 31
Dependent Claim
104 words
A process for preparing compounds of the formula ##STR19## wherein R-R 5 are as defined in claim 4 which process comprises reacting ##STR20## or alkylating compound VI with α-halo compounds of the formula: ##STR21## wherein R-R 5 are as defined above and X is a good leaving group such as Br or I to yield the desired product followed by removal of protecting groups, if necessary, and, if further desired, isolating the biologically more active isomer by chromatography, fractional crystallization, or by resolution with an appropriate, optically active acid or base and, if desired, preparing a salt of the desired product by conventional means.
Claim 32
Dependent Claim
99 words
A process for preparing compounds of the formula ##STR22## wherein R-R 5 are as defined in claim 4 which comprises reacting ##STR23## with an alkylating agent of the formula: ##STR24## wherein R-R 5 are as defined above and X is a good leaving group such as Br or I, to yield the desired product followed by removal of protecting groups, is necessary, and, if desired, isolating the biologically more active isomer by chromatography, fractional crystallization, or by resolution with an appropriate, optically active acid or base and, if desired, preparing a salt of the desired product by conventional means.
References Cited (Backward Citations)
US3941776A
Cited
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