Antihypertensive proline derivatives

Claim 2

A compound of the formula: ##STR26## wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to ten carbon atoms which include branched, cyclic, and unsaturated alkenyl and alkynyl groups; substituted alkyl of from one to six carbon atoms and the substituent is amino, arylthio, aryloxy, hydroxy, arylamino, loweralkanoylamino, and aroylamino; aralkyl optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain from one to six carbon atoms; R 2 is hydrogen, alkyl of from one to six carbon atoms optionally substituted by amino, loweralkylamino, arylamino, loweralkanoylamino, aroylamino, or aryl groups; R 3 and R 4 may be connected together to form a proline moiety; and, a pharmaceutically acceptable salt thereof.

Claim 3

A compound of the formula: ##STR27## wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to six carbon atoms optionally substituted by amino, hydroxyl, loweralkanoylamino, aroylamino, aryloxy; aralkyl, optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain from one to six carbon atoms; R 2 is hydrogen or alkyl of from one to six carbon atoms optionally substituted by amino; R 3 and R 4 may be connected together to form a proline moiety; and, a pharmaceutically acceptable salt thereof.

Claim 4

A compound of the formula: ##STR27## wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to six carbon atoms optionally substituted by amino, hydroxyl, loweralkanoylamino, aroylamino, aryloxy; aralkyl, optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain from one to six carbon atoms; R 2 is hydrogen or alkyl of from one to six carbon atoms optionally substituted by amino; R 3 and R 4 may be connected together to form a proline moiety; and, a pharmaceutically acceptable salt thereof.

Claim 5

A compound of the formula: ##STR28## wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to six carbon atoms optionally substituted by amino, hydroxyl, loweralkanoylamino, aroylamino, aryloxy; aralkyl, optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain from one to six carbon atoms; R 2 is hydrogen or alkyl of from one to six carbon atome optionally substituted by amino, groups; R 3 and R 4 are joined through the nitrogen and carbon atoms to which they are respectively attached to form a five membered ring having the formula: ##STR29## wherein X is CH 2 , CHOH, CHOCH 3 ; 1 is one; and Ar is phenyl, 2-hydroxyphenyl, or naphthyl; or a pharmaceutically acceptable salt thereof.

Claim 6

A compound of the formula: ##STR28## wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to six carbon atoms optionally substituted by amino, hydroxyl, loweralkanoylamino, aroylamino, aryloxy; aralkyl, optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain from one to six carbon atoms; R 2 is hydrogen or alkyl of from one to six carbon atome optionally substituted by amino, groups; R 3 and R 4 are joined through the nitrogen and carbon atoms to which they are respectively attached to form a five membered ring having the formula: ##STR29## wherein X is CH 2 , CHOH, CHOCH 3 ; 1 is one; and Ar is phenyl, 2-hydroxyphenyl, or naphthyl; or a pharmaceutically acceptable salt thereof.

Claim 7

A compound of the formula: ##STR30## wherein: R is the same or different and is hydrogen or loweralkyl; R 1 is aralkyl optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain one to four carbon atoms; R 2 is hydrogen, alkyl of from one to six carbon atoms, or amino substituted alkyl of from one to six carbon atoms; R 3 and R 4 are joined through the nitrogen and carbon atoms to which they are respectively attached to form a proline ring structure; or a pharmaceutically acceptable salt thereof.

Claim 8

A compound of the formula: ##STR30## wherein: R is the same or different and is hydrogen or loweralkyl; R 1 is aralkyl optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain one to four carbon atoms; R 2 is hydrogen, alkyl of from one to six carbon atoms, or amino substituted alkyl of from one to six carbon atoms; R 3 and R 4 are joined through the nitrogen and carbon atoms to which they are respectively attached to form a proline ring structure; or a pharmaceutically acceptable salt thereof.

Claim 9

A compound of claim 4 which is: N-(2-carboxy-4-phenylbutyl)-N-ethylaminocarbonyl-L-proline.

Claim 10

A compound of claim 4 which is: N-(2-carboxy-4-phenylbutyl)-N-methylaminocarbonyl-L-proline.

Claim 11

A compound of claim 4 which is: N-[(2-ethoxycarbonyl)-4-phenylbutyl]-N-ethylaminocarbonyl-L-proline.

Claim 12

A compound of claim 4 which is: ethyl N-[(2-ethoxycarbonyl)-4-phenylbutyl]-N-ethylaminocarbonyl-L-prolinate.

Claim 13

A compound of claim 4 which is: N-(2-carboxy-4-phenylbutyl)-N-(4-aminobutyl)-aminocarbonyl-L-proline.

Claim 14

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: ##STR31## wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to ten carbon atoms which include branched, cyclic, and unsaturated alkenyl and alkynyl groups; substituted alkyl of from one to six carbon atoms and the substitutent is amino, arylthio, aryloxy, hydroxy, arylaminio, loweralkanoylamino, and aroylamino; aralkyl optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain from one to six carbon atoms; R 2 is hydrogen, alkyl of from one to six carbon atoms optionally substituted by amino, loweralkylamino, arylamino, loweralkanoylamino, aroylamino; or aryl groups; R 3 and R 4 may be connected together to form a proline moiety; and a pharmaceutically acceptable salt thereof.

Claim 15

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: ##STR31## wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to ten carbon atoms which include branched, cyclic, and unsaturated alkenyl and alkynyl groups; substituted alkyl of from one to six carbon atoms and the substitutent is amino, arylthio, aryloxy, hydroxy, arylaminio, loweralkanoylamino, and aroylamino; aralkyl optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain from one to six carbon atoms; R 2 is hydrogen, alkyl of from one to six carbon atoms optionally substituted by amino, loweralkylamino, arylamino, loweralkanoylamino, aroylamino; or aryl groups; R 3 and R 4 may be connected together to form a proline moiety; and a pharmaceutically acceptable salt thereof.

Claim 16

The composition of claim 10 wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to six carbon atoms optionally substituted by amino, hydroxyl, loweralkanoylamino, aroylamino, aryloxy; aralkyl, optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain from one to six carbon atoms; R 2 is hydrogen or alkyl of from one to six carbon atoms optionally substituted by amino, R 3 and R 4 may be connected together to form a proline moiety.

Claim 17

The composition of claim 11 wherein: R 3 and R 4 are joined through the nitrogen and carbon atoms to which they are respectively attached to form a five membered ring having the formula: ##STR32## wherein X is CH 2 , CHOH, CHOCH 3 ; 1 is one; and, Ar is phenyl, 2-hydroxyphenyl, or naphthyl.

Claim 18

The composition of claim 10 wherein: R is the same or different and is hydrogen or loweralkyl; R 1 is aralkyl optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain one to four carbon atoms; R 2 is hydrogen, alkyl of from one to six carbon atoms, or amino substituted alkyl of from one to six carbon atoms; and, R 3 and R 4 are joined through the nitrogen and carbon atoms to which they are respectively attached to form a proline ring structure.

Claim 19

The composition of claim 13 wherein said compounds is: N-(2-carboxy-4-phenylbutyl)-N-ethylaminocarbonyl-L-proline.

Claim 20

The composition of claim 13 wherein said compounds is: N-(2-carboxy-4-phenylbutyl)-N-methylamino-carbonyl-L-proline.

Claim 21

The composition of claim 13 wherein said compound is: N-[(2-ethoxycarbonyl)-4-phenylbutyl]-N-ethylamino-carbonyl-L-proline.

Claim 22

The composition of claim 13 wherein said compound is: ethyl N-[(2-ethoxycarbonyl)-4-phenylbutyl]-N-ethylaminocarbonyl-L-prolinate.

Claim 23

The composition of claim 13 wherein said compound is: N-(2-carboxy-4-phenylbutyl)-N-(4-aminobutyl)-aminocarbonyl-L-proline.

Claim 26

The method of claim 19 wherein: R is the same or different and is hydrogen, loweralkyl, aralkyl; R 1 is alkyl of from one to six carbon atoms optionally substituted by amino, hydroxyl, loweralkanoylamino, aroylamino, aryloxy, aralkyl, optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl group contain from one to six carbon atoms; R 2 is hydrogen or alkyl of from one to six carbon atoms optionally substituted by amino, or heteroaryl groups; R 3 and R 4 may be connected together to form a proline moiety.

Claim 27

The method of claim 20 wherein: R 3 and R 4 are joined through the nitrogen and carbon atoms to which they are respectively attached to form five membered ring having the formula: ##STR34## wherein X is CH 2 , CHOH, CHOCH 3 ; 1 is one; and, Ar is phenyl, 2-hydroxyphenyl, or naphthyl.

Claim 28

The method of claim 19 wherein: R is the same or different and is hydrogen or loweralkyl; R 1 is aralkyl optionally substituted by halo, loweralkyl, hydroxy, alkoxy, and amino groups wherein the alkyl groups contain one to four carbon atoms; R 2 is hydrogen, alkyl of from one to six carbon atoms, or amino substituted alkyl of from one to six carbon atoms; and, R 3 and R 4 are joined through the nitrogen and carbon atoms to which they are respectively attached to form a proline ring structure.

Claim 29

The method of claim 22 wherein said compound is: N-(2-carboxy-4-phenylbutyl)-N-ethylaminocarbonyl-L-proline.

Claim 30

The method of claim 22 wherein said compound is: N-(2-carboxy-4-phenylbutyl)-N-methylaminocarbonyl-L-proline.

Claim 31

The method of claim 22 wherein said compound is: N-[(2-ethoxycarbonyl)-4-phenylbutyl]-N-ethylaminocarbonyl-L-proline.

Claim 32

The method of claim 22 wherein said compound is: ethyl N-[(2-ethoxycarbonyl)-4-phenylbutyl]-N-ethylaminocarbonyl-L-prolinate.

Claim 33

The method of claim 22 wherein said compound is: N-(2-carboxy-4-phenylbutyl)-N-(4-aminobutyl)aminocarbonyl-L-proline.