Substituted caprolactam derivatives as antihypertensives, process for preparing them, pharmaceutical composition containing them, and intermediates

Claim 2

A compound of the formula: wherein R and R 4 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R 1 is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched, cyclic and alkyl groups, substituted loweralkyl bereir the substituent(s) can be halo, lower alkoxy, aryloxy, amino, loweralkylamino,hydroxy, diloweralkylamino,aminoloweralkylthio, aminolower alkoxy, acylamino,arylamino, guanidino, phthalimiao,mercapto, lower. alkylthic, arylthio, carboxy,carboxamido or carboloweralsoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino aminomethyl, phenyloxy, acylamino, dilower alkylamino, loweralkylamino, carboxyl, halo loweralkyl, acyl or aroyl, and the alkyl portion may be substituted by amino, hydroxy or acylamino; R is hydrogen, lower alkyl, cyclic lower alkyl, amino, aminolower alkyl, alkylaminoloweralkyl, hydroxyalkyl, acylaminoloweralkyl, dialkylaminoloweralkyl including cyclic poly- ethyleneaminolower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; heteroaryl, heteroarlower alkyl; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R 5 is hydrogen or lower alkyl; and, the pharmaceutically acceptable salts thereof.

Claim 3

A compound of Claim 1 which is a member of the group consisting of: 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1(S)-carboxyethyl)-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1(S)-carboxyethyl)-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-benzyloxycarbonylethyl-3-[(1-carboxy-3-phenylpronyl)-amino]perhydroazepin-2-one; 1(S)-benzyloxycarbonylethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1-ethoxycarbonylethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1(S)-ethoxycarbonylethyl)-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-carboxymethyl-3- [(1-carboxy-3-ahenylpropyl) amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-ohenylpropyl. amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7(R)-methylperhydroazepin-2-one; -carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl- mino-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenvl- propyl)amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(R)-methylperhydroazepin-2-one; 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7(S)-phenylperhydroazepin-2-one; 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)-amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one; and, 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(S)-phenylperhydroazepin-2-one.

Claim 4

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensively effective amount of compound of the formula wherein R and R 4 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R is hydrogen, alkyl of from 1 to 12 carbon atoms whith include branched, cyclic and unsaturates alkyl groups, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino" aminomethyl, phenyloxy, acylamino, dilower alkylamino, loweralkylamino, carboxyl, halo loweralkyl, acyl or aroyl, and the alkyl portion may be substituted by amino, hydroxyl or acylamino; R is hydrogen, lower alkyl, cyclic lower alkyl, amino, amino lower alkyl, alkylaminoloweralkyl; hydroxyalkyl, acylaminoloweralkyl,dialkylamino lower alkyl including cyclic polyethyleneamino lower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo, alkyl, aminoalkyl or alkoxy, heteroaryl, heteroarlower alkyl; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R 5 is hydrogen or lower alkyl; and, the pharmaceutically acceptable salts thereof.

Claim 5

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensively effective amount of compound of the formula wherein R and R 4 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R is hydrogen, alkyl of from 1 to 12 carbon atoms whith include branched, cyclic and unsaturates alkyl groups, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino" aminomethyl, phenyloxy, acylamino, dilower alkylamino, loweralkylamino, carboxyl, halo loweralkyl, acyl or aroyl, and the alkyl portion may be substituted by amino, hydroxyl or acylamino; R is hydrogen, lower alkyl, cyclic lower alkyl, amino, amino lower alkyl, alkylaminoloweralkyl; hydroxyalkyl, acylaminoloweralkyl,dialkylamino lower alkyl including cyclic polyethyleneamino lower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo, alkyl, aminoalkyl or alkoxy, heteroaryl, heteroarlower alkyl; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R 5 is hydrogen or lower alkyl; and, the pharmaceutically acceptable salts thereof.

Claim 6

The composition of Claim 3 wherein said compound is a member of the group consisting of: 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)amino]-perhydroazepin-2-one; 1-(1(S)-carboxyethyl)-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenyl- propl)amino]perhydroazepin-2-one; 1-(1(S)-carboxyethyl)-3(S)-[(1(S)-ethoxycarbonyl]-3-phenylpropyl)amino]perhydroazepin-2-one; 1-benzyloxycarbonylethyl-3-[(1-carboxy-3-phenylpropy aminojperhydroazepin-2-one; 1 (S) -benzyloxycarbonylethyl-3 (S)-[(1(S) -carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1-ethoxycarbonylethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1(S)-ethoxycarbonylethyl)-3(S)-t(1(S)-etaoxy- carbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino methylperhydroazepin-2-one; 1-carboxymethyl-3 (S)- [(1 (S) -carboxy-3-phenylprcpyl amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phonylpic amino] -7 (R) -methylperhydroazepin-2-one -carboxymethyl-3-[(1-ethoxycarbonyl-3-pbenylpropyl p-7-methylperhydroazepin-2-one 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(R)-methylperhydroazepin-2-one; 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7(S)-phenylperhydroazepin-2-one; 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)-amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one; and, 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(S)-phenylperhydroazepin-2-one.

Claim 7

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensively effective amount of a compound of the formula: wherein R and R 4 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, lower alkoxy, aryloxy, amino, loweralkylamino, hydroxy, diloweralkylamino, aminoloweralkylthio, aminolower alkoxy, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio, arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl wherein the aryl and heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, phenyloxy, acylamino, diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl, acyl or aroyl, and the alkyl portion may be substituted by amino, hydroxy or acylamino; R 2 is hydrogen, lower alkyl, cyclic lower alkyl,amino, amino loweralkyl, alkylaminoloweralkyl, hydroxyalkyl, acylaminoloweralkyl, dialkylamino lower alkyl including cyclic polyethyleneamino lower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; heteroaryl, heteroarlower alkyl; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R 5 is hydrogen or lower alkyl; the pharmaceutically acceptable salts thereof and an antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metoprololtartate, methyclothiazide, methyldopa, methyldopate hyrochloride, minoxidil, (S)-l-{[2-(3,4-dimethoxyphenyl)ethyl] 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, rifetipine, 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, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procaine, as well as admixtures and combinations thereof.

Claim 8

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensively effective amount of a compound of the formula: wherein R and R 4 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, lower alkoxy, aryloxy, amino, loweralkylamino, hydroxy, diloweralkylamino, aminoloweralkylthio, aminolower alkoxy, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio, arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl wherein the aryl and heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, phenyloxy, acylamino, diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl, acyl or aroyl, and the alkyl portion may be substituted by amino, hydroxy or acylamino; R 2 is hydrogen, lower alkyl, cyclic lower alkyl,amino, amino loweralkyl, alkylaminoloweralkyl, hydroxyalkyl, acylaminoloweralkyl, dialkylamino lower alkyl including cyclic polyethyleneamino lower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; heteroaryl, heteroarlower alkyl; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R 5 is hydrogen or lower alkyl; the pharmaceutically acceptable salts thereof and an antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metoprololtartate, methyclothiazide, methyldopa, methyldopate hyrochloride, minoxidil, (S)-l-{[2-(3,4-dimethoxyphenyl)ethyl] 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, rifetipine, 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, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procaine, as well as admixtures and combinations thereof.

Claim 9

The pharmaceutical composition of Claim 5 wherein said compound is a member of the group consisting of: 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)amino]-perhydroazepin-2-one; 1-(1(S)-carboxyethyl)-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1(S)-carboxyethyl)-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-benzyloxycarbonylethyl-3-f(1-carboxy-3-phenylpropyl)-amino]perhydroazepin-2-one; 1(S)-benzyloxycarbonylethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1-ethoxycarbonylethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1(S)-ethoxycarbonylethyl)-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7(R)-methylperhydroazepin-2-one; l-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)-amino-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(R)-methylperhydroazepin-2-one; 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)-amino]-7(S)-phenylperhydroazepin-2-one; 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)-amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one; and, 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(S)-phenylperhydroazepin-2-one.

Claim 10

A process for preparing compounds of the formula wherein R and R 4 are the same or different and are hydroxy- lower alkoxy, lower alkenoxy, aryloxy diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, lower alkoxy, aryloxy, amino, loweralkylamino, hydroxy, diloweralkylamino, aminoloweralkylthio, aminolower alkoxy, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio, arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino aminomethyl, phenyloxy, acylamino, dilower alkylamino, loweralkylamino, carboxyl, halo loweralkyl, acyl or aroyl, and the alkyl portion may be substituted by amino, hydroxyl or acylamino; R 2 is hydrogen, lower alkyl, cyclic loweralkyl, amino, amino lower alkyl, alkylaminoloweralkyl, hydroxyalkyl, acylaminoloweralkyl, dialkylamino lower alkyl including cyclic polyethyleneamino lower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo; alkyl, aminoalkyl, or alkoxy; heteroaryl, heteroarlower alkyl; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R 5 is hydrogen or lower alkyl, which process comprises reductively alkylating: or alkylating compounds of Formula VI with a-halo compounds of the formula: or reacting with the alkylating agent: wherein R , R 1 , R 2 , R 3 , R 4 and R 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 11

A process for preparing compounds of the formula wherein R and R 4 are the same or different and are hydroxy- lower alkoxy, lower alkenoxy, aryloxy diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, lower alkoxy, aryloxy, amino, loweralkylamino, hydroxy, diloweralkylamino, aminoloweralkylthio, aminolower alkoxy, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio, arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino aminomethyl, phenyloxy, acylamino, dilower alkylamino, loweralkylamino, carboxyl, halo loweralkyl, acyl or aroyl, and the alkyl portion may be substituted by amino, hydroxyl or acylamino; R 2 is hydrogen, lower alkyl, cyclic loweralkyl, amino, amino lower alkyl, alkylaminoloweralkyl, hydroxyalkyl, acylaminoloweralkyl, dialkylamino lower alkyl including cyclic polyethyleneamino lower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo; alkyl, aminoalkyl, or alkoxy; heteroaryl, heteroarlower alkyl; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R 5 is hydrogen or lower alkyl, which process comprises reductively alkylating: or alkylating compounds of Formula VI with a-halo compounds of the formula: or reacting with the alkylating agent: wherein R , R 1 , R 2 , R 3 , R 4 and R 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 12

The compound: wherein R 4 is hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R 2 is hydrogen, lower alkyl, cyclic lower alkyl, aminolower alkyl, alkylaminoloweralkyl, hydroxyalkyl, acylaminoloweralkly, dialkylaminoloweralkyl including cyclic poly- ethyleneaminolower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; heteroaryl, heteroarlower alkyl; R is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R is hydrogen or lower alkyl; and, the pharmaceutically acceptable salts thereof.

Claim 13

The compound: wherein R 4 is hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, hydroxy lower alkoxy dihydroxy lower alkoxy amino, hydroxyamino; R 2 is hydrogen, lower alkyl, cyclic lower alkyl, aminolower alkyl, alkylaminoloweralkyl, hydroxyalkyl, acylaminoloweralkly, dialkylaminoloweralkyl including cyclic poly- ethyleneaminolower alkyl, arlower alkyl, aryl, substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; heteroaryl, heteroarlower alkyl; R is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkyl thio lower alkyl; R is hydrogen or lower alkyl; and, the pharmaceutically acceptable salts thereof.

Claim 14

9 . The compound: and the lower alkyl and benzyl esters thereof.

Claim 15

9 . The compound: and the lower alkyl and benzyl esters thereof.

Claim 16

The compound: and the lower alkyl and benzyl esters thereof.

Claim 17

The compound: and the lower alkyl and benzyl esters thereof.

Claim 18

The compound: and the lower alkyl and benzyl esters thereof.

Claim 19

The compound: and the lower alkyl and benzyl esters thereof.