Substituted enantholactam derivatives as antihypertensives, a process for preparing and a 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, hydroxy, dihydroxy, and acylamino substituted lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, amino, hydroxyamino; R 1 is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched and cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, hydroxy, lower alkoxy or aryloxy, amino, loweralkylamino, aminoloweralkylthio, - aminoloweralkoxy, diloweralkylamino, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio or arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl, or substituted heteroarlower alkyl, or substituted heteroarlower alkenyl, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino aminomethyl, phenyloxy, acylamino, dilower alkylamino, loweralkylamino, carboxyl, haloloweralkyl, acyl or aroyl; substituted arloweralkyl or substituted heteroarloweralkyl wherein the alkyl portion can be substituted by amino, hydroxy, or acylamino; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl 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 2 is hydrogen lower alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocycloalkyl, or substituted aryl wherein the substitutent is halo, alkyl, aminoalkyl, or alkoxy; and, the pharmaceutically acceptable salts thereof.

Claim 3

A compound of Claim 1 which is a member of the group consisting of: l-carboxymethyl-3-[(l-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one; 1-carboxymethyl-3-(S)-[(1(S)-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one; 1-benzyloxycarbonylmethyl-3-[(1-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one; 1-benzyloxycarbonylmethyl-3-(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one; 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)-amino]perhydroazocin-2-one; l-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one hydrochloride; 1-ethoxycarbonylmethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; 1-ethoxycarbonylmethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; and 1-carboxyrnethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl) amino]-8-methylperhyroazocin-2-one.

Claim 4

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensiely effective amount of an amino acid 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, hydroxy, dihydroxy and acylamino substituted lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, amino, hydroxyamino; R 1 is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched and cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, hydroxy, lower alkoxy or aryloxy, amino, loweralkylamino, aminoloweralkylthio, aminoloweralkoxy, diloweralkylamino, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio or arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, or substituted heteroarlower alkenyl, 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; substituted arloweralkyl or substituted heteroarloweralkyl wherein the alkyl portion can be substituted by amino, hydroy, or acylamino; 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 2 is hydrogen, lower alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocycloalkyl, or substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; 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 antihypertensiely effective amount of an amino acid 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, hydroxy, dihydroxy and acylamino substituted lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, amino, hydroxyamino; R 1 is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched and cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, hydroxy, lower alkoxy or aryloxy, amino, loweralkylamino, aminoloweralkylthio, aminoloweralkoxy, diloweralkylamino, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio or arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, or substituted heteroarlower alkenyl, 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; substituted arloweralkyl or substituted heteroarloweralkyl wherein the alkyl portion can be substituted by amino, hydroy, or acylamino; 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 2 is hydrogen, lower alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocycloalkyl, or substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; and, the pharmaceutically acceptable salts thereof.

Claim 6

The composition of Claim 3 wherein said compound is a member of the group: 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino] perhydroazocin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one; 1-benzyloxycarbonylmethyl-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one; 1-benzyloxycarbonylmethyl-3-(S)[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one; 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; l-carboxymethyl-3(S)-[(l(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one hydrochloride; 1-ethoxycarbonylmethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; l-ethoxycarbonylmethyl-3(S)-[(l(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; l-carboxypropyl-3-[(l-ethoxycarbonyl-3-phenylpropyl) amino]perhydroazocin-2-one; and, 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl) amino]-8-methylperhydroazocin-2-one.

Claim 7

A pharmaceutical composition useful in : the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an : antihypertensively effective amount of a compound of Claim 1; and, an antihypertensive and/or diuretic compound selected from the group consisting of atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetate and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metroprololtartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, (S)-l-[2-(3,4-dimethoxyphenyl)ethyl]amino -3- [4-(2-thienyl)-lH-imidazol-2-yl]phenoxy -2- propanol, polythiazide, the pivalogloxyethyl 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, bumethanide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, quinethazone, tricrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procaine, as well as admixtures and combinations thereof.

Claim 8

The composition of Claim 5 wherein said antihypertensively effective compound of Claim 1 is a member of the group: 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino] perhydroazocin-2-one; l-carboxymethyl-3-(S)-[(l(S)-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one; 1-benzyloxycarbonylmethyl-3-[(1-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one; 1-benzyloxycarbonylmethyl-3-(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one; 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)-amino]perhydroazocin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenyl- ; propyl)amino]perhydroazocin-2-one hydrochloride; l-ethoxycarbonylmethyl-3-[(l-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; 1-ethoxycarbonylmethyl-3(S)-[(l(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one; and, 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl) amino]-8-methylperhyroazocin-2-one.

Claim 9

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, hydroxy, dihydroxy andacylamino substituted lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, amino, hydroxyamino; R 1 is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched and cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, hydroxy, lower alkoxy or aryloxy, amino, loweralkylamino, aminoloweralkylthio, aminoloweralkoxy, diloweralkylamino, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio or arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, or substituted heteroarlower alkenyl, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, phenyloxy, acylamino, diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl, acyl or aroyl; substituted arloweralkyl or substituted heteroarloweralkyl wherein the alkyl portion can be substituted by amino, hydroxy or acylamino; 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 2 is hydrogen, lower alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocycloalkyl, or substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; which process comprises reductively alkylating a compound of the formula followed by removal of protecting groups, if necessary, to yield the desired product and, if desired, isolating the biologically more active isomer by chromatography, by fractional cyrstallization, or by resolution with an appropriate, optically active acid or base and, if further desired, preparing a salt of the desired product by conventional means.

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, hydroxy, dihydroxy andacylamino substituted lower alkoxy, acyloxy lower alkoxy, arloweralkoxy, amino, hydroxyamino; R 1 is hydrogen, alkyl of from 1 to 12 carbon atoms which include branched and cyclic and unsaturated alkyl groups, substituted loweralkyl wherein the substituent(s) can be halo, hydroxy, lower alkoxy or aryloxy, amino, loweralkylamino, aminoloweralkylthio, aminoloweralkoxy, diloweralkylamino, acylamino, arylamino, guanidino, phthalimido, mercapto, loweralkylthio or arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl, substituted arloweralkyl or substituted heteroarlower alkyl, or substituted heteroarlower alkenyl, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, phenyloxy, acylamino, diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl, acyl or aroyl; substituted arloweralkyl or substituted heteroarloweralkyl wherein the alkyl portion can be substituted by amino, hydroxy or acylamino; 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 2 is hydrogen, lower alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocycloalkyl, or substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; which process comprises reductively alkylating a compound of the formula followed by removal of protecting groups, if necessary, to yield the desired product and, if desired, isolating the biologically more active isomer by chromatography, by fractional cyrstallization, or by resolution with an appropriate, optically active acid or base and, if further desired, preparing a salt of the desired product by conventional means.

Claim 11

A compound having the formula: wherein R 3 is hydrogen or lower alkyl; R 2 is hydrogen or lower alkyl; and R 4 is hydroxy, lower alkoxy, or benzyloxy.

Claim 12

A compound having the formula: wherein R 3 is hydrogen or lower alkyl; R 2 is hydrogen or lower alkyl; and R 4 is hydroxy, lower alkoxy, or benzyloxy.

Claim 13

A compound having the formula: and the (S) isomer thereof.

Claim 14

A compound having the formula: and the (S) isomer thereof.