Bicyclic lactams as antihypertensives

Claim 2

A compound of the formula: wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aralkyl; R 1 is hydrogen; alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups; substituted lower alkvl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, lower aralkoxy carbonyl, amino, lower alkylamino, lower dialkylamino, or acylamino; 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, lower dialkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino lower alkyl, trihaloloweralkyl, cyano, nitro, sulfonamido, aroyl, lower alkyl, halo, dihalo, and 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, aralkyl, lower alkanoyl, or aroyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, aroyl, hydroxy, halo, or dihalo; aralkyl or heteroaralkyl which include branched lower alkyl groups; substituted aralkyl or substituted heteroaralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acylamino, or hydroxyl and the aryl and heteroaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, aroyl, arylthio, amino, amino lower alkyl, lower alkanoyl amino, aroylamino, lower dialkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl, nitro, cyano, or sulfonamido; and, the pharmaceutically acceptable salts thereof.

Claim 3

A compound of Claim 1 which is a member of the group: [3R-[3α,α(S*),9aα]]-6-[(1-carboxy-3-phenylpropyl) amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid: [3R-[3α,6α(S*),9ß]]-6-[(1-carboxy-3-phenylpropyl) amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; [3R-[3α,6α(S*),9aß]]-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*),9aß]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]-azepine-3-carboxylate; Ethyl [3R-[3α,6α(S*),9aß]]-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-phenylpropyllamino]octahydro-5-oxothiazolo[3,2-a] azepine-3-carboxylate; Benzyl [3R-[3α,6α(S*),9aß]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-α]azepine-3-carboxylate; Phenyl [3R-[3a,6a(S*),9a6]]-6-[(l-carboxy-3-phenyLpropyl)amino]octahydro-5-oxothiazolo[3,2-a]-azepine-3-carboxylate; n-Butyl [3R-[3a,6a(S*),9aP]]-6-[[l-(methoxycarbonyl)-3-phenylpropyllamino]octahydro-5-oxothiazolo[3,2-al- azepine-3-carboxylate; and, Benzyl [3R-[3a,6a(S*),9a6]]-6-[[l-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]-azepine-3-carboxylate.

Claim 4

A compound having the formula: wherein R 2 is hydrogen, loweralkyl, aryl, and aralkyl.

Claim 5

A compound having the formula: wherein R 2 is hydrogen, loweralkyl, aryl, and aralkyl.

Claim 6

A compound having the formula wherein R 2 is hydrogen, loweralkyl, aryl, and aralkyl.

Claim 7

A compound having the formula wherein R 2 is hydrogen, loweralkyl, aryl, and aralkyl.

Claim 8

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the formula: wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aralkyl; R 1 is hydrogen alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups; substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, lower aralkoxy carbonyl, amino, lower alkylamino, lower dialkylamino, or acylamino; 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, lower dialkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino lower alkyl, trihalo loweralkyl, cyano, nitro, sulfonamido, aroyl, lower alkyl, halo, dihalo, and lower alkoxy, and Q is 0, S, N-R B , CONR C , NR C CO, CH=CH wherein R B is hydrogen, lower alkyl, aryl, aralkyl, lower alkanoyl, or aroyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, aroyl, hydroxy, halo, or dihalo; aralkyl or heteroaralkyl which include branched lower alkyl groups; substituted aralkyl or substituted heteroaralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acylamino, or hydroxyl and the aryl and heteroaryl groups can be substitued by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, aroyl, arylthio, amino, amino lower alkyl, lower alkanoyl amino, aroylamino, lower dialkylamino, lower alkylamino, hvdroxy, hydroxy loweralkyl, trihalo loweralkyl, nitro, cyano, or sulfonamido; and, the pharmaceutically acceptable salts thereof.

Claim 9

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the formula: wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aralkyl; R 1 is hydrogen alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups; substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, lower aralkoxy carbonyl, amino, lower alkylamino, lower dialkylamino, or acylamino; 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, lower dialkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino lower alkyl, trihalo loweralkyl, cyano, nitro, sulfonamido, aroyl, lower alkyl, halo, dihalo, and lower alkoxy, and Q is 0, S, N-R B , CONR C , NR C CO, CH=CH wherein R B is hydrogen, lower alkyl, aryl, aralkyl, lower alkanoyl, or aroyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, aroyl, hydroxy, halo, or dihalo; aralkyl or heteroaralkyl which include branched lower alkyl groups; substituted aralkyl or substituted heteroaralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acylamino, or hydroxyl and the aryl and heteroaryl groups can be substitued by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, aroyl, arylthio, amino, amino lower alkyl, lower alkanoyl amino, aroylamino, lower dialkylamino, lower alkylamino, hvdroxy, hydroxy loweralkyl, trihalo loweralkyl, nitro, cyano, or sulfonamido; and, the pharmaceutically acceptable salts thereof.

Claim 10

The composition of Claim 5 which includes another antihypertensive and/or diuretic compound selected from the group 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-P{[2-(3,4-dimethoxyphenyl)ethy}- amino}-3-{4-(2-thienyl)-1H-imidazol-2-yl]phenoxy}-2-propanol, polythiazide, the pivaloyloxyethyl ester of methyldopa, indacrinone and 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, and the like, as well as admixtures and combinations thereof.

Claim 11

The composition of Claim 5 wherein said pharmaceutically effective compound is a member of the group: [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*),9aß]-6-[(1-carboxy-3-phenylpropyl) amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; [3R-[3α,6α(S*),9aß]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; [3R-[3a,6a(S*),9aa]]-6-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid; n-Butyl (3R-[3α,6α(S*),9aß]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]-azepine-3-carboxylate; Ethyl [3R-[3α,6α(S*),9aß]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a)-azepine-3-carboxylate; Ethyl [3R-[3a,6a(S * ),9aa]]-6-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a] azepine-3-carboxylate ; Benzyl [3R-[3a,6a(S*),9aß]]-6-t(1-carboxy-3-phenylpropyl)a mino]octahydro-5-oxothiazolo[3,2-alazepine-3-carboxylate; Phenyl [3R-[3α,6α(S*),9aß]]-6-[(1-carboxy-3-phenylpropyl)amino]octahydro-5-oxothiazolo[3,2-a]-azepine-3-carboxylate ; n-Butyl [3R-[3α,6α(S*),9aß]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]-azepine-3-carboxylate; and, Benzyl [3R-[3α,6α(S*)9aß]]-6-[[1-(methoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]-azepine-3-carboxylate.

Claim 12

A process for producing a compound having the formula: wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aralkyl; R l is hydrogen; alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups; substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, lower aralkoxy carbonyl, amino, lower alkylamino, lower dialkylamino, or acylamino; 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, lower dialkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino loweralkyl, trihaloloweralkyl, cyano, nitro, sulfonamido, aroyl, lower alkyl, halo, dihalo, and 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, aralkyl, lower alkanoyl, or aroyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, aroyl, hydroxy, halo, or dihalo; aralkyl or heteroaralkyl which include branched lower alkyl groups; substituted aralkyl or substituted heteroaralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acylamino, or hydroxyl and the aryl and hete oaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, aroyl, arylthio, amino, amino lower alkyl, lower alkanoylamino, aroylamino, lower dialkylamino, -lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl nitro, cyano, or sulfonamido; which process comprises:

Claim 13

A process for producing a compound having the formula: wherein: R and R 2 are independently hydrogen, loweralkyl, aryl, and aralkyl; R l is hydrogen; alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups; substituted lower alkyl wherein the substituent can be halo, hydroxy, carboxy, lower alkylthio, lower alkoxy, lower alkoxy carbonyl, lower aralkoxy carbonyl, amino, lower alkylamino, lower dialkylamino, or acylamino; 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, lower dialkylamino, lower alkylamino, hydroxy, hydroxy loweralkyl, amino loweralkyl, trihaloloweralkyl, cyano, nitro, sulfonamido, aroyl, lower alkyl, halo, dihalo, and 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, aralkyl, lower alkanoyl, or aroyl, and R C is hydrogen or lower alkyl; aryl; substituted aryl wherein the substituent is lower alkyl, amino loweralkyl, loweralkoxy, aryloxy, aroyl, hydroxy, halo, or dihalo; aralkyl or heteroaralkyl which include branched lower alkyl groups; substituted aralkyl or substituted heteroaralkyl which include branched lower alkyl groups wherein the lower alkyl groups can be substituted by amino, acylamino, or hydroxyl and the aryl and hete oaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, aroyl, arylthio, amino, amino lower alkyl, lower alkanoylamino, aroylamino, lower dialkylamino, -lower alkylamino, hydroxy, hydroxy loweralkyl, trihalo loweralkyl nitro, cyano, or sulfonamido; which process comprises:

Claim 14

synthesizing a bicyclic lactam having the formula: wherein R 2 is as defined above, and subsequently reductively alkylating said lactam with a-keto acids and esters, followed by removal of protecting groups, if any, to yield products of Formula I and, if desired, isolating the biologically more active diastereomer by chromatography or crystallization and, if further desired, preparing a pharmaceutically acceptable salt therefrom by conventional means.

Claim 15

synthesizing a bicyclic lactam having the formula: wherein R 2 is as defined above, and subsequently reductively alkylating said lactam with a-keto acids and esters, followed by removal of protecting groups, if any, to yield products of Formula I and, if desired, isolating the biologically more active diastereomer by chromatography or crystallization and, if further desired, preparing a pharmaceutically acceptable salt therefrom by conventional means.