Bicyclic lactams as antihypertensives

Claim 3

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensively effective amount of a compound of the formula: ##STR82## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aryl lower alkyl; R 1 is hydrogen; alkyl, alkenyl, alkynyl and unsubstituted cycloalkyl of from 1 to 12 carbon atoms; substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, aryl lower alkoxy carbonyl, amino, lower alkylamino, diloweralkylamino, or acetylamino or benzoylamino; substituted lower alkyl having the formula R A (CH 2 ) n --Q--(CH 2 ) m wherein n is 0-2, m is 1-3, R A is aryl or heteroaryl optionally substituted by amino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino lower alkyl, trihalo loweralkyl, cyano, nitro, sulfonamido, benzoyl, 1-naphthoyl, lower alkyl, halo, dihalo, or lower alkoxy, and Q is O, S, N--R B , CONR C , NR C CO, CH═CH wherein R B is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkanoyl, benzoyl or 1-naphthoyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, benzoyl or 1-naphthoyl, hydroxy, halo, or dihalo; aryl lower alkyl or heteroaryl loweralkyl which include branched lower alkyl groups; substituted aryl loweralkyl or substituted heteroaryl loweralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acetylamino, benzoylamino, or hydroxyl and the aryl and heteroaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, benzoyl, 1-naphthoyl, arylthio, amino, amino lower alkyl, lower alkanoyl amino, benzoylamino, 1-naphthoylamino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl, nitro, cyano, or sulfonamido; or pharmaceutically acceptable salts thereof, wherein in said R, R 1 and R 2 groups, the aryl is selected from the group consisting of phenyl, naphthyl, and biphenyl; and, the heteroaryl is selected from the group consisting of indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl, and benzothienyl.

Claim 4

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensively effective amount of a compound of the formula: ##STR82## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aryl lower alkyl; R 1 is hydrogen; alkyl, alkenyl, alkynyl and unsubstituted cycloalkyl of from 1 to 12 carbon atoms; substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, aryl lower alkoxy carbonyl, amino, lower alkylamino, diloweralkylamino, or acetylamino or benzoylamino; substituted lower alkyl having the formula R A (CH 2 ) n --Q--(CH 2 ) m wherein n is 0-2, m is 1-3, R A is aryl or heteroaryl optionally substituted by amino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino lower alkyl, trihalo loweralkyl, cyano, nitro, sulfonamido, benzoyl, 1-naphthoyl, lower alkyl, halo, dihalo, or lower alkoxy, and Q is O, S, N--R B , CONR C , NR C CO, CH═CH wherein R B is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkanoyl, benzoyl or 1-naphthoyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, benzoyl or 1-naphthoyl, hydroxy, halo, or dihalo; aryl lower alkyl or heteroaryl loweralkyl which include branched lower alkyl groups; substituted aryl loweralkyl or substituted heteroaryl loweralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acetylamino, benzoylamino, or hydroxyl and the aryl and heteroaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, benzoyl, 1-naphthoyl, arylthio, amino, amino lower alkyl, lower alkanoyl amino, benzoylamino, 1-naphthoylamino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl, nitro, cyano, or sulfonamido; or pharmaceutically acceptable salts thereof, wherein in said R, R 1 and R 2 groups, the aryl is selected from the group consisting of phenyl, naphthyl, and biphenyl; and, the heteroaryl is selected from the group consisting of indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl, and benzothienyl.

Claim 5

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of the formula: ##STR83## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aryl loweralkyl; R 1 is hydrogen; alkyl, alkenyl, alkynyl and unsubstituted cycloalkyl of from 1 to 12 carbon atoms; substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, aryl lower alkoxy carbonyl, amino, lower alkylamino, diloweralkylamino, acetylamino or benzoylamino; substituted lower alkyl having the formula R A (CH 2 ) n --Q--(CH 2 ) m wherein n is 0-2, m is 1-3, R A is aryl or heteroaryl optionally substituted by amino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino lower alkyl, trihalo loweralkyl, cyano, nitro, sulfonamido, benzoyl, 1-naphthoyl, lower alkyl, halo, dihalo, or lower alkoxy, and Q is O, S, N--R B , CONR C , NR C CO, CH═CH wherein R B is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkanoyl, benzoyl or 1-naphthoyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, benzoyl, 1-naphthoyl, hydroxy, halo, or dihalo; aryl lower alkyl or heteroaryl lower alkyl which include branched lower alkyl groups; substituted aryl lower alkyl or substituted heteroaryl loweralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acetylamino, benzoylamino, or hydroxyl and the aryl and heteroaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, benzoyl, 1-naphthoyl, arylthio, amino, amino lower alkyl, lower alkanoyl amino, benzoylamino, 1-naphthoylamino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl nitro, cyano, or sulfonamido; or pharmaceutically acceptable salts thereof; and an effective amount of another antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetate and cryptenamine tannates, deserpidine, diazoxide, ethacrynic acid, furosemide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, (S)-1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-3-{[4-(2-thienyl)-1H-imidazol-2-yl]phenoxy}-2-propanol, polythiazide, the pivaloyloxyethyl ester of methyldopa, indacrinone or variable ratios of its enantiomers, nifedipine, verapamil, diltiazam, flumethiazide, bendroflumethiazide, atenolol, (+)-4-{3-{[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid, bumetanide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, quinethazone, tricrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procain, as well as admixtures and combinations thereof; wherein in said R, R 1 and R 2 groups, the aryl is selected from the group consisting of phenyl, naphthyl, and biphenyl; and, the heteroaryl is selected from the group consisting of indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl, and benzothienyl.

Claim 6

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of the formula: ##STR83## wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aryl loweralkyl; R 1 is hydrogen; alkyl, alkenyl, alkynyl and unsubstituted cycloalkyl of from 1 to 12 carbon atoms; substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, aryl lower alkoxy carbonyl, amino, lower alkylamino, diloweralkylamino, acetylamino or benzoylamino; substituted lower alkyl having the formula R A (CH 2 ) n --Q--(CH 2 ) m wherein n is 0-2, m is 1-3, R A is aryl or heteroaryl optionally substituted by amino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino lower alkyl, trihalo loweralkyl, cyano, nitro, sulfonamido, benzoyl, 1-naphthoyl, lower alkyl, halo, dihalo, or lower alkoxy, and Q is O, S, N--R B , CONR C , NR C CO, CH═CH wherein R B is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkanoyl, benzoyl or 1-naphthoyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, benzoyl, 1-naphthoyl, hydroxy, halo, or dihalo; aryl lower alkyl or heteroaryl lower alkyl which include branched lower alkyl groups; substituted aryl lower alkyl or substituted heteroaryl loweralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acetylamino, benzoylamino, or hydroxyl and the aryl and heteroaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, benzoyl, 1-naphthoyl, arylthio, amino, amino lower alkyl, lower alkanoyl amino, benzoylamino, 1-naphthoylamino, diloweralkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl nitro, cyano, or sulfonamido; or pharmaceutically acceptable salts thereof; and an effective amount of another antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetate and cryptenamine tannates, deserpidine, diazoxide, ethacrynic acid, furosemide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, (S)-1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-3-{[4-(2-thienyl)-1H-imidazol-2-yl]phenoxy}-2-propanol, polythiazide, the pivaloyloxyethyl ester of methyldopa, indacrinone or variable ratios of its enantiomers, nifedipine, verapamil, diltiazam, flumethiazide, bendroflumethiazide, atenolol, (+)-4-{3-{[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid, bumetanide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, quinethazone, tricrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procain, as well as admixtures and combinations thereof; wherein in said R, R 1 and R 2 groups, the aryl is selected from the group consisting of phenyl, naphthyl, and biphenyl; and, the heteroaryl is selected from the group consisting of indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl, and benzothienyl.

Claim 7

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of the formula: ##STR84## wherein: R and R 2 are independently hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, or benzyl; and, R 1 is alkyl of 1-8 carbon atoms which include branched alkyl groups; substituted lower alkyl wherein the substituent can be amino or loweralkylthio; substituted lower alkyl having the formula R A (CH 2 ) n --Q--(CH 2 ) m -- wherein n is 0, m is 1, R A is phenyl, and Q is O or S; aryl lower alkyl wherein the aryl is phenyl or naphthyl and the alkyl group contains 1 to 3 carbon atoms, or heteroaryl lower alkyl wherein the heteroaryl group is indole, thiophene, imidazole, pyridine, quinoline or isoquinoline and the alkyl group contains 1 to 3 carbon atoms; substituted aryl lower alkyl wherein the aryl is a phenyl group, the alkyl contains 1 to 3 carbon atoms, and the phenyl substituents can be halo, hydroxy, phenoxy, lower alkoxy, amino, or aminomethyl; or pharmaceutically acceptable salts thereof; and an effective amount of another antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetate and cryptenamine tannates, deserpidine, diazoxide, ethacrynic acid, furosemide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, (S)-1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-3-{[4-(2-thienyl)-1H-imidazol-2-yl]phenoxy}-2-propanol, polythiazide, the pivaloyloxyethyl ester of methyldopa, indacrinone or variable ratios of its enantiomers, nifedipine, verapamil, diltiazam, flumethiazide, bendroflumethiazide, atenolol, (+)-4-{3-{[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid, bumetanide, prozosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, quinethazone, tricrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procain, as well as admixtures and combinations thereof.

Claim 8

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of the formula: ##STR84## wherein: R and R 2 are independently hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, or benzyl; and, R 1 is alkyl of 1-8 carbon atoms which include branched alkyl groups; substituted lower alkyl wherein the substituent can be amino or loweralkylthio; substituted lower alkyl having the formula R A (CH 2 ) n --Q--(CH 2 ) m -- wherein n is 0, m is 1, R A is phenyl, and Q is O or S; aryl lower alkyl wherein the aryl is phenyl or naphthyl and the alkyl group contains 1 to 3 carbon atoms, or heteroaryl lower alkyl wherein the heteroaryl group is indole, thiophene, imidazole, pyridine, quinoline or isoquinoline and the alkyl group contains 1 to 3 carbon atoms; substituted aryl lower alkyl wherein the aryl is a phenyl group, the alkyl contains 1 to 3 carbon atoms, and the phenyl substituents can be halo, hydroxy, phenoxy, lower alkoxy, amino, or aminomethyl; or pharmaceutically acceptable salts thereof; and an effective amount of another antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetate and cryptenamine tannates, deserpidine, diazoxide, ethacrynic acid, furosemide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, (S)-1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-3-{[4-(2-thienyl)-1H-imidazol-2-yl]phenoxy}-2-propanol, polythiazide, the pivaloyloxyethyl ester of methyldopa, indacrinone or variable ratios of its enantiomers, nifedipine, verapamil, diltiazam, flumethiazide, bendroflumethiazide, atenolol, (+)-4-{3-{[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid, bumetanide, prozosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, quinethazone, tricrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procain, as well as admixtures and combinations thereof.

Claim 9

The composition of claim 4 wherein said antihypertensively effective compound is a member of the group consisting of: [3R-[3α,6α(S*),9aα]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; [3R -[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; [3R-[3α,6α(S*),9aα]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; n-Butyl [3R-[3α,6α(S*),9aβ]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo3,2-a]azepine-3-carboxylate; Ethyl [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate; Ethyl [3R-[3α,6α(S*),9aα]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate; Benzyl [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate; Phenyl [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate; n-Butyl [3R-[3α,6α(S*),9aβ]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate; and, Benzyl [3R-[3α,6α(S*),9aβ]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylate.

Claim 10

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 5; and, a pharmaceutically effective amount of hydrochlorothiazide.

Claim 11

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 5; and, a pharmaceutically effective amount of timolol.

Claim 12

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 5; and, a pharmaceutically effective amount of indacrinone or variable ratios of its enantiomers.

Claim 13

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 5; and, a pharmaceutically effective amount of methyldopa.

Claim 14

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 5; and, a pharmaceutically effective amount of the pivaloxyloyethyl ester of methyldopa.

Claim 15

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 5; and, a pharmaceutically effective amount of (+)-4-{3-{-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid.

Claim 16

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 5; and, a pharmaceutically effective amount of hydrochlorothiazide and timolol.

Claim 17

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 5, and, a pharmaceutically effective amount of hydrochlorothiazide and amiloride.

Claim 18

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of hydrochlorothiazide.

Claim 19

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of hydrochlorothiazide.

Claim 20

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of timolol.

Claim 21

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of timolol.

Claim 22

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*), 9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; a pharmaceutically effective amount of hydrochlorothiazide; and, a pharmacutically effective amount of indacrinone or variable ratios of its enantiomers.

Claim 23

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*), 9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; a pharmaceutically effective amount of hydrochlorothiazide; and, a pharmacutically effective amount of indacrinone or variable ratios of its enantiomers.

Claim 24

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*), 9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and a pharmaceutically effective amount of methyldopa.

Claim 25

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*), 9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and a pharmaceutically effective amount of methyldopa.

Claim 26

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of the pivaloyloxyethyl ester of methyldopa.

Claim 27

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of the pivaloyloxyethyl ester of methyldopa.

Claim 28

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*), 9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of (+)-4-{3-{-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid.

Claim 29

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*), 9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of (+)-4-{3-{-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid.

Claim 30

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-3α,6α(S*), 9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of hydrochlorothiazide and timolol.

Claim 31

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-3α,6α(S*), 9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of hydrochlorothiazide and timolol.

Claim 32

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and a pharmaceutically effective amount of hydrochlorothiazide and amiloride.

Claim 33

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and a pharmaceutically effective amount of hydrochlorothiazide and amiloride.

Claim 34

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of hydrochlorothiazide.

Claim 35

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of hydrochlorothiazide.

Claim 36

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of timolol.

Claim 37

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of timolol.

Claim 38

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*), 9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; a pharmaceutically effective amount of hydrochlorothiazide; and, a pharmacutically effective amount of indacrinone or variable ratios of its enantiomers.

Claim 39

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*), 9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; a pharmaceutically effective amount of hydrochlorothiazide; and, a pharmacutically effective amount of indacrinone or variable ratios of its enantiomers.

Claim 40

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and a pharmaceutically effective amount of methyldopa.

Claim 41

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and a pharmaceutically effective amount of methyldopa.

Claim 42

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of the pivaloyloxyethyl ester of methyldopa.

Claim 43

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of the pivaloyloxyethyl ester of methyldopa.

Claim 44

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3carboxylic acid; and, a pharmaceutically effective amount of (+)-4-{3-{-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid.

Claim 45

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3carboxylic acid; and, a pharmaceutically effective amount of (+)-4-{3-{-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid.

Claim 46

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of hydrochlorothiazide and timolol.

Claim 47

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and, a pharmaceutically effective amount of hydrochlorothiazide and timolol.

Claim 48

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and a pharmaceutically effective amount of hydrochlorothiazide and amiloride.

Claim 49

A pharmaceutical composition for the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of [3R-[3α,6α(S*),9aβ]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; and a pharmaceutically effective amount of hydrochlorothiazide and amiloride.