Substituted enantholactam derivatives as antihypertensives

Claim 2

A compound of the formula: ##STR6## wherein R and R 4 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, diloweralkylamino lower alkoxy, acetylaminoethoxy; nicotinoylaminoethoxy; succinimidoethoxy; pivaloyloxyethoxy; arloweralkoxy, amino, hydroxyamino; R 1 is hydrogen, alkyl, alkenyl, and alkynyl of from 1 to 12 carbon atoms which include straight chain and branched groups; cycloalkyl groups; substituted loweralkyl wherein the substituent(s) can be halo, hydroxy, lower alkoxy or aryloxy, amino, loweralkylamino, aminoloweralkylthio, hydroxy, aminoloweralkoxy, diloweralkylamino, acetamido; benzamido; arylamino, guanidino, phthalimido, mercapto, loweralkylthio or arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl containing one heteroatom, substituted arloweralkyl, or substituted heteroarlower alkyl containing one heteroatom, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino aminomethyl, phenyloxy, acetamido; benzamido; dilower alkylamino, loweralkylamino, carboxyl, haloloweralkyl; substituted arloweralkyl or substituted heteroarloweralkyl containing one heteroatom, wherein the alkyl portion can be substituted by amino, hydroxy, acetamido or benzamido: R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acetamido or benzamido, 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, substituted aryl, heteroaryl containing one heteroatom, aralkyl, heteroaralkyl containing one heteroatom, or substituted aryl wherein the substitutent is halo, alkyl, aminoalkyl, or alkoxy; wherein in the foregoing R-R 4 groups inclusive: the alkyl groups contain 2-12 carbon atoms; the loweralkyl groups contain 1-8 carbon atoms; the alkenyl and alkynyl grouPs contain 2-12 carbon atoms; the loweralkenyl and loweralkynyl groups contain 2-8 carbon atoms; aryl and the prefix "ar" denote unsubstituted aromatic rings of 6-12 carbon atoms; the cycloalkyl groups are unsubstituted alkyl rings of 3-10 carbon atoms; hetero denotes the heteroatoms N, O or S; heteroaryl denotes an aryl group containing a heteroatom; and, the pharmaceutically acceptable salts thereof.

Claim 3

A compound which is: 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 4

A compound which is: 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 5

A compound which is: 1-carboxymethyl-3-(S)-[(1(S)-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one.

Claim 6

A compound which is: 1-carboxymethyl-3-(S)-[(1(S)-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one.

Claim 7

A compound which is: 1-benzyloxycarbonylmethyl-3-[(1-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one.

Claim 8

A compound which is: 1-benzyloxycarbonylmethyl-3-[(1-carboxy-3-phenylpropyl) amino]perhydroazocin-2-one.

Claim 9

A compound which is: 1-benzyloxycarbonylmethyl-3-(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 10

A compound which is: 1-benzyloxycarbonylmethyl-3-(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 11

A compound which is: 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 12

A compound which is: 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 13

A compound which is: 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 14

A compound which is: 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 15

A compouond which is: 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one hydrochloride.

Claim 16

A compouond which is: 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one hydrochloride.

Claim 17

A compound which is: 1-ethoxycarbonylmethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 18

A compound which is: 1-ethoxycarbonylmethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 19

A compound which is: 1-ethoxycarbonylmethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 20

A compound which is: 1-ethoxycarbonylmethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 21

A compound which is: 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 22

A compound which is: 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one.

Claim 23

A compound which is: 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl) amino]-8-methylperhyroazocin-2-one.

Claim 24

A compound which is: 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl) amino]-8-methylperhyroazocin-2-one.

Claim 25

A process for preparing compounds of the formula ##STR7## wherein R and R 4 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acetylaminoethoxy, nicotinoylaminoethoxy, succinimidoethoxy, and pivaloyloxyethoxy, arloweralkoxy, amino, hydroxyamino; R 1 is hydrogen, alkyl, alkenyl, and alkynyl of from 1 to 12 carbon atoms which include straight chain and branched groups; cycloalkyl groups; substituted loweralkyl Wherein the substituent(s) can be halo, hydroxy, lower alkoxy or aryloxy, amino, loweralkylamino, aminoloweralkylthio, hydroxy. aminoloweralkoxy. diloweralkylamino, acetamido, benzamido, arylamino, guanidino, phthalimido, mercapto, loweralkylthio or arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl containing one heteroatom or heteroarlower alkenyl containing one heteroatom, substituted arloweralkyl or substituted heteroarlower alkyl containing one heteroatom, or substituted heteroarlower alkenyl containing one heteroatom, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, phenyloxy, acetamido, benzamido, diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl; substituted arloweralkyl or substituted heteroarloweralkyl containing one heteroatom wherein the alkyl portion can be substituted by amino, hydroxy, acetamido, benzamido; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acetamido or benzamido, 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, hydroxyalky, aryl, heteroaryl containing one heteroatom, aralkyl, heteroaralkyl containing one heteroatom, or substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; wherein in the foregoing R-R 4 groups inclusive: the alkyl groups contain 2-12 carbon atoms: the loweralkyl groups contain 1-8 carbon atoms; the alkenyl and alkynyl groups contain 2-12 carbon atoms; the loweralkenyl and loweralkynyl groups contain 2-8 carbon atoms; aryl and the prefix "ar" denote unsubstituted aromatic rings of 6-12 carbon atoms: the cycloalkyl groups are unsubstituted alkyl rings of 3-10 carbon atoms; hetero denotes the heteroatoms N, O or S; heteroaryl denotes an aryl group containing a heteroatom; which process comprises reductively alkylating a compound of the formula ##STR8## wherein R, R 1 , R 2 and R 3 are as defined above, 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 crystallization, 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 26

A process for preparing compounds of the formula ##STR7## wherein R and R 4 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, aryloxy, diloweralkylamino lower alkoxy, acetylaminoethoxy, nicotinoylaminoethoxy, succinimidoethoxy, and pivaloyloxyethoxy, arloweralkoxy, amino, hydroxyamino; R 1 is hydrogen, alkyl, alkenyl, and alkynyl of from 1 to 12 carbon atoms which include straight chain and branched groups; cycloalkyl groups; substituted loweralkyl Wherein the substituent(s) can be halo, hydroxy, lower alkoxy or aryloxy, amino, loweralkylamino, aminoloweralkylthio, hydroxy. aminoloweralkoxy. diloweralkylamino, acetamido, benzamido, arylamino, guanidino, phthalimido, mercapto, loweralkylthio or arylthio, carboxy, carboxamido or carboloweralkoxy, arloweralkyl, arloweralkenyl, heteroarlower alkyl containing one heteroatom or heteroarlower alkenyl containing one heteroatom, substituted arloweralkyl or substituted heteroarlower alkyl containing one heteroatom, or substituted heteroarlower alkenyl containing one heteroatom, wherein the aryl or heteroaryl substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, phenyloxy, acetamido, benzamido, diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl; substituted arloweralkyl or substituted heteroarloweralkyl containing one heteroatom wherein the alkyl portion can be substituted by amino, hydroxy, acetamido, benzamido; R 3 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, acetamido or benzamido, 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, hydroxyalky, aryl, heteroaryl containing one heteroatom, aralkyl, heteroaralkyl containing one heteroatom, or substituted aryl wherein the substituent is halo, alkyl, aminoalkyl, or alkoxy; wherein in the foregoing R-R 4 groups inclusive: the alkyl groups contain 2-12 carbon atoms: the loweralkyl groups contain 1-8 carbon atoms; the alkenyl and alkynyl groups contain 2-12 carbon atoms; the loweralkenyl and loweralkynyl groups contain 2-8 carbon atoms; aryl and the prefix "ar" denote unsubstituted aromatic rings of 6-12 carbon atoms: the cycloalkyl groups are unsubstituted alkyl rings of 3-10 carbon atoms; hetero denotes the heteroatoms N, O or S; heteroaryl denotes an aryl group containing a heteroatom; which process comprises reductively alkylating a compound of the formula ##STR8## wherein R, R 1 , R 2 and R 3 are as defined above, 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 crystallization, 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.