Aminoacid derivatives as antihypertensives

A compound of the formula:

• ##STR18## wherein R and R.sup.6 can each independently be hydroxy, lower alkoxy,
• lower alkenoxy,
• arloweralkyloxy,
• amino,
• diloweralkylamino lower alkoxy,
• acylamino lower alkoxy or
• acyloxy lower alkoxy,
• R.sup.1 is hydrogen,
• alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups;
• substituted lower alkyl wherein the substituent is
• halo
• hydroxy
• lower alkoxy
• aryloxy
• amino
• loweralkylamino
• diloweralkylamino
• acylamino
• arylamino
• guanidino
• imidazoyl,
• indolyl,
• mercapto,
• loweralkylthio
• arylthio
• carboxy
• carboxamido or
• carbolower alkoxy
• phenyl
• substituted phenyl wherein the substituent is
• lower alkyl
• lower alkoxy or
• halo;
• arloweralkyl or heteroaryloweralkyl arloweralkenyl or heteroarloweralkenyl, substituted arloweralkyl, substituted heteroarylloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl,
• wherein the substituent is halo or dihalo
• lower alkyl
• hydroxy
• lower alkoxy
• amino
• aminomethyl
• acylamino
• diloweralkylamino
• loweralkylamino
• carboxyl
• halo alkyl
• cyano or
• sulfonamido
• arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;
• R.sup.2 and R.sup.7 are hydrogen;
• R.sup.3 is lower alkyl, amino lower alkyl, imidazolyl, lower alkyl, halo lower alkyl;
• R.sup.4 and R.sup.5 are joined to form an alkylene bridge of from 2 to 4 carbon atoms or an alkylene bridge of from 2 to 3 carbon atoms and one sulfur atom or an alkylene bridge of from 2 to 3 carbon atoms and one sulfur atom or an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above substituted with hydroxy, lower alkoxy or lower alkyl,
• or the pharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected from the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl, or thiazolyl.

A compound of the formula:

• ##STR20## wherein R and R.sup.6 can each independently be hydroxy, lower alkoxy,
• lower alkenoxy,
• arloweralkyloxy,
• amino,
• diloweralkylamino lower alkoxy,
• acylamino lower alkoxy or
• acyloxy lower alkoxy,
• R.sup.1 is alkyl having from 1-8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, arylthio, aryloxy or arylamino, aralkyl or heteroaralkyl wherein the alkyl portion has 1-3 carbon atoms, substituted aralkyl or heteroaralkyl wherein the alkyl groups have 1-3 carbon atoms and the substituent(s) is halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;
• R.sup.2 and R.sup.7 are hydrogen;
• R.sup.3 is lower alkyl or amino lower alkyl;
• R.sup.4 and R.sup.5 can be joined together through the carbon and nitrogen atoms to which they are attached to form a ring of the formula:
• ##STR21## wherein Y is CH.sub.2, S, or CH--OCH.sub.3 or the pharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected from the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl or thiazolyl.

A compound of the formula:

• ##STR22## wherein R and R.sup.6 can each independently be hydroxy, lower alkoxy, aralkyloxy,
• R.sup.2 and R.sup.7 are hydrogen,
• R.sup.3 is methyl, aminoloweralkyl,
• R.sup.4 and R.sup.5 are joined through the carbon and nitrogen atoms to form proline, 4-thiaproline or 4-methoxyproline, and
• R.sup.1 is alkyl having from 1-8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, arylthio or aryloxy, aralkyl or heteroaralkyl wherein the alkyl portion has 1-3 carbon atoms, substituted aralkyl or heteroaralkyl wherein the alkyl groups have 1-3 carbon atoms and the substituent(s) is halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;
• and the pharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected from the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl or thiazolyl.

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:

• ##STR23## wherein R and R.sup.6 are the same or different and are hydroxy,
• lower alkoxy,
• lower alkenoxy,
• diloweralkylamino lower alkoxy,
• acylamino lower alkoxy,
• acyloxy lower alkoxy,
• aryloxy,
• arloweralkyloxy
• substituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy,
• amino,
• loweralkylamino
• diloweralkylamino,
• arloweralkylamino or
• hydroxyamino;
• R.sup.1 is hydrogen,
• alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups;
• substituted lower alkyl wherein the substituent is
• halo
• hydroxy
• lower alkoxy
• aryloxy
• amino
• loweralkylamino
• diloweralkylamino
• acylamino
• arylamino
• guanidino
• imidazolyl,
• indolyl,
• mercapto,
• loweralkylthio
• arylthio
• carboxy
• carboxamido
• carboloweralkoxy
• phenyl
• substituted phenyl wherein the substituent is
• lower alkyl
• lower alkoxy or
• halo;
• arloweralkyl or heteroarloweralkyl,
• arloweralkenyl or heteroarloweralkenyl,
• substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalo
• lower alkyl
• hydroxy
• lower alkoxy
• amino
• aminomethyl
• acylamino
• diloweralkylamino
• loweralkylamino
• carboxyl
• halo loweralkyl
• cyano or
• sulfonamido;
• arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;
• R.sup.2 and R.sup.7 are hydrogen or lower alkyl;
• R.sup.3 is hydrogen
• lower alkyl
• phenyl lower alkyl
• aminomethyl pheny lower alkyl
• hydroxy phenyl lower alkyl
• hydroxy lower alkyl
• acetylamino lower alkyl
• acylamino lower alkyl
• amino lower alkyl
• dimethylamino lower alkyl
• guanidino lower alkyl
• halo lower alkyl
• imidazolyl lower alkyl
• indolyl lower alkyl
• mercapto lower alkyl and
• loweralkylthio lower alkyl;
• R.sup.4 is hydrogen or
• lower alkyl;
• R.sup.5 is hydrogen
• lower alkyl
• phenyl
• phenyl lower alkyl
• hydroxy phenyl lower alkyl
• hydroxy lower alkyl
• amino lower alkyl
• guanidino lower alkyl
• imidazolyl lower alkyl
• indolyl lower alkyl
• mercapto lower alkyl or
• loweralkyl thio lower alkyl;
• R.sup.4 and R.sup.5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulphur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above, substituted with
• hydroxy
• lower alkoxy or
• lower alkyl
• and the pharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected from the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl, or thiazolyl.

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:

• ##STR24## wherein R and R.sup.6 can each independently be hydroxy, lower alkoxy,
• lower alkenoxy,
• arloweralkyloxy,
• amino,
• diloweralkylamino lower alkoxy,
• acylamino lower alkoxy or
• acyloxy lower alkoxy,
• R.sup.1 is alkyl having from 1-8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, arylthio, aryloxy or arylamino, aralkyl or heteroaralkyl wherein the alkyl portion has 1-3 carbon atoms, substituted aralkyl or heteroaralkyl wherein the alkyl groups have 1-3 carbon atoms and the substituent(s) is halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;
• R.sup.2 and R.sup.7 are hydrogen;
• R.sup.3 is lower alkyl or amino lower alkyl;
• R.sup.4 and R.sup.5 can be joined together through the carbon and nitrogen atoms to which they are attached to form a ring of the formula:
• ##STR25## wherein Y is CH.sub.2, S, or CH--OCH.sub.3 or the pharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected from the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl or thiazolyl.

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:

• ##STR26## wherein R and R.sup.6 can each independently be hydroxy, lower alkoxy, aralkyloxy,
• R.sup.2 and R.sup.7 are hydrogen,
• R.sup.3 is methyl, aminoloweralkyl,
• R.sup.4 and R.sup.5 are joined through the carbon and nitrogen atoms to form proline, 4-thiaproline or 4-methoxyproline, and
• R.sup.1 is alkyl having from 1-8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, arylthio or aryloxy, aralkyl or heteroaralkyl wherein the alkyl portion has 1-3 carbon atoms, substituted aralkyl or heteroaralkyl wherein the alkyl groups have 1-3 carbon atoms and the substituent(s) is halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;
• and the pharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected from the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl or thiazolyl.

A method for treating hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of the formula:

• ##STR27## wherein R and R.sup.6 are the same or different and are hydroxy,
• lower alkoxy,
• lower alkenoxy,
• diloweralkylamino lower alkoxy,
• acylamino lower alkoxy,
• acyloxy lower alkoxy,
• aryloxy,
• arloweralkyloxy
• substituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy,
• amino,
• loweralkylamino
• diloweralkylamino,
• arloweralkylamino or
• hydroxyamino;
• R.sup.1 is hydrogen,
• alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups;
• substituted lower alkyl wherein the substituent is
• halo
• hydroxy
• lower alkoxy
• aryloxy
• amino
• loweralkylamino
• diloweralkylamino
• acylamino
• arylamino
• guanidino
• imidazolyl,
• indolyl,
• mercapto,
• loweralkylthio
• arylthio
• carboxy
• carboxamido
• carboloweralkoxy
• phenyl
• substituted phenyl wherein the substituent is
• lower alkyl
• lower alkoxy or
• halo;
• arloweralkyl or heteroarloweralkyl,
• arloweralkenyl or heteroarloweralkenyl,
• substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalo
• lower alkyl
• hydroxy
• lower alkoxy
• amino
• aminomethyl
• acylamino
• diloweralkylamino
• loweralkylamino
• carboxyl
• halo loweralkyl
• cyano or
• sulfonamido;
• arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;
• R.sup.2 and R.sup.7 are hydrogen or lower alkyl;
• R.sup.3 is hydrogen
• lower alkyl
• phenyl lower alkyl
• aminomethyl pheny lower alkyl
• hydroxy phenyl lower alkyl
• hydroxy lower alkyl
• acetylamino lower alkyl
• acylamino lower alkyl
• amino lower alkyl
• dimethylamino lower alkyl
• guanidino lower alkyl
• halo lower alkyl
• imidazolyl lower alkyl
• indolyl lower alkyl
• mercapto lower alkyl and
• loweralkylthio lower alkyl;
• R.sup.4 is hydrogen or
• lower alkyl;
• R.sup.5 is hydrogen
• lower alkyl
• phenyl
• phenyl lower alkyl
• hydroxy phenyl lower alkyl
• hydroxy lower alkyl
• amino lower alkyl
• guanidino lower alkyl
• imidazolyl lower alkyl
• indolyl lower alkyl
• mercapto lower alkyl or
• loweralkyl thio lower alkyl;
• R.sup.4 and R.sup.5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulphur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above, substituted with
• hydroxy
• lower alkoxy or
• lower alkyl
• and the pharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected from the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazolyl, or thiazolyl.

A method of treating hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of the formula:

• ##STR28## wherein R and R.sup.6 can each independently be hydroxy, lower alkoxy, aralkyloxy,
• R.sup.1 is alkyl having from 1-8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, arylthio or aryloxy, aralkyl or heteroaralkyl wherein the alkyl portion has 1-3 carbon atoms, substituted aralkyl or heteroaralkyl wherein the alkyl groups have 1-3 carbon atoms and the substituent(s) is halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;
• R.sup.2 and R.sup.7 are hydrogen,
• R.sup.3 is methyl, aminoloweralkyl,
• R.sup.4 and R.sup.5 can be joined together through the carbon and nitrogen atoms to which they are attached to form proline, 4-thiaproline or 4-methoxyproline or the pharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected from the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl or thiazolyl.