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Claims for Patent: 4,374,829

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Claims for Patent: 4,374,829

Title: Aminoacid derivatives as antihypertensives
Abstract:The invention relates to new carboxyalkyl dipeptide derivatives and related compounds which are useful as antihypertensives.
Inventor(s): Harris; Elbert E. (Westfield, NJ), Patchett; Arthur A. (Westfield, NJ), Tristram; Edward W. (Watchung, NJ), Wyvratt; Matthew J. (Mountainside, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Application Number:06/235,335
Patent Claims: 1. A compound of the formula: ##STR17## 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 phenyl lower alkyl

hydroxy phenyl lower alkyl

hydroxy lower alkyl

acetylamino lower alkyl

acylamino lower alkyl

amino lower alkyl

dimethylamino lower alkyl

halo lower alkyl

guanidino 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

lower alkyl or

dilower 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.

2. Compounds of claim 1 in which the carbon bearing R.sup.1 is of the S configuration and the other absolute configurations are those of L-amino acids.

3. 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.

4. Compounds of claim 3 in which the carbon bearing R.sup.1 is of the S configuration and the other absolute configurations are those of L-amino acids.

5. A compound of claim 3 wherein R.sup.4 and R.sup.5 are joined through the carbon and nitrogen atoms to which they are attached to form a ring of the formulae: ##STR19## wherein Y is CH.sub.2, S, or CH--OCH.sub.3 and R, R.sup.1, R.sup.2, R.sup.3, R.sup.6 and R.sup.7 are as defind in claim defined

6. Compounds of claim 5 in which the carbon bearing R.sup.1 is of the S configuration and the other absolute configurations are those of L-amino acids.

7. 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.

8. Compounds of claim 7 in which the carbon bearing R.sup.1 is of the S configuration and the other absolute configurations are those of L-amino acids.

9. 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.

10. Compounds of claim 9 in which the carbon bearing R.sup.1 is of the S configuration and the other absolute configurations are those of L-amino acids.

11. A compound of claim 9 which is N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline.

12. A compound of claim 9 which is N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.

13. A compound of claim 9 which is N-(1-ethoxycarbonyl)-4-methylpentyl-L-alanyl-L-proline.

14. A compound of claim 9 which is N-(1carboxy-5-aminopentyl)-L-alanyl-L-proline.

15. A compound of claim 9 which is N-.alpha.-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline.

16. A compound of claim 9 which is N-.alpha.-(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.

17. A compound of claim 9 which is N-.alpha.-[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline.

18. A compound of claim 9 which is N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline.

19. A compound of claim 9 which is N-.alpha.-[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline.

20. A compound of claim 9 which is N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L- proline.

21. A compound of claim 9 which is N-.alpha.-[1-carboxy-5-aminopentyl]-L-lysyl-L-proline.

22. A compound of claim 9 which is N-.alpha.-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline.

23. A compound of claim 9 which is ethyl N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride.

24. A compound of claim 9 which is N-[1-(ethoxycarbonyl)-3-(4-imidazolyl)propyl]-L-alanyl-L-proline.

25. A compound of claim 9 which is N-[1-(carboxy-3-(4-imidazolyl)propyl]-L-lysyl-L-proline.

26. The compound: N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline.

27. The compound: N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.

28. The compound: N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt.

29. The compound: N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline.

30. The compound: ethyl-N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride.

31. The compound: N-.alpha.-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.

32. 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.

33. 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.

34. 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.

35. The composition of claim 34 wherein said compound is N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline.

36. The composition of claim 34 wherein said compound is N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.

37. The composition of claim 34 wherein said compound is N-(1-ethoxycarbonyl)-4-methylpentyl-L-alanyl-L-proline.

38. The composition of claim 34 wherein said compound is N-(1-carboxy-5-aminopentyl)-L-alanyl-L-proline.

39. The composition of claim 34 wherein said compound is N-.alpha.-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline.

40. The composition of claim 34 wherein said compound is N-.alpha.-(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.

41. The composition of claim 34 wherein said compound is N-.alpha.-[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline.

42. The composition of claim 34 wherein said compound is N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline.

43. The composition of claim 34 wherein said compound is N-.alpha.-[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline.

44. The composition of claim 34 wherein said compound is N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L- proline.

45. The composition of claim 34 wherein said compound is N-.alpha.-[1-carboxy-5-aminopentyl]-L-lysyl-L-proline.

46. The composition of claim 34 wherein said compound is N-.alpha.-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline.

47. The composition of claim 34 wherein said compound is ethyl N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride.

48. The composition of claim 34 wherein said compound is N-.alpha.-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline.

49. The composition of claim 34 wherein said compound is ethyl N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride.

50. The composition of claim 34 wherein said compound is N-[1-ethoxycarbonyl)-3-(4-imidazolyl)propyl]-L-alanyl-L-proline.

51. The composition of claim 34 wherein said compound is N-[1-carboxy-3-4-imidazolyl)propyl]-L-lysyl-L-proline.

52. The composition of claim 34 wherein said compound is N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline.

53. The composition of claim 34 wherein said compound is N-(1(S)-ethoxycarbonyl-3-phenyl-propyl)-L-alanyl-L-proline.

54. The composition of claim 34 wherein said compound is N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt.

55. The composition of claim 34 wherein said compound is N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline.

56. The composition of claim 34 wherein said compound is ethyl N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride.

57. The composition of claim 34 wherein said compound is N-.alpha.-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.

58. 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.

59. 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.

60. The method of claim 59 wherein said compound is N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline.

61. The method of claim 59 wherein said compound is N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.

62. The method of claim 59 wherein said compound is N-(1-ethoxycarbonyl)-4-methylpentyl-L-alanyl-L-proline.

63. The method of claim 59 wherein said compound is N-(1-carboxy-5-aminopentyl)-L-alanyl-L-proline.

64. The method of claim 59 wherein said compound is N-.alpha.-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline.

65. The method of claim 59 wherein said compound is N-.alpha.-(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.

66. The method of claim 59 wherein said compound is N-.alpha.-[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline.

67. The method of claim 59 wherein said compound is N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline.

68. The method of claim 59 wherein said compound is N-.alpha.-[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline.

69. The method of claim 59 wherein said compound is N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L- proline.

70. The method of claim 59 wherein said compound is N-.alpha.-[1-carboxy-5-aminopentyl]-L-lysyl-L-proline.

71. The method of claim 59 wherein said compound is N-.alpha.-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline.

72. The method of claim 59 wherein said compound is ethyl N-(1-ethoxy carbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride.

73. The method of claim 59 wherein said compound is N-.alpha.-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline.

74. The method of claim 59 wherein said compound is ethyl N-(1-ethoxycarbonyl-3-phenylpropyl)-1-alanyl-L-prolinate hydrochloride.

75. The method of claim 59 wherein said compound is N-[1-(ethoxycarbonyl)-3-(4-imidazolyl)propyl]-L-alanyl-L-proline.

76. The method of claim 59 wherein said compound is N-[1-carboxy-3-(4-imidazolyl)propyl]-L-lysyl-L-proline.

77. The method of claim 59 wherein said compound is N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline.

78. The method of claim 59 wherein said compound is N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.

79. The method of claim 59 wherein said compound is N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt.

80. The method of claim 59 wherein said compound is N-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline.

81. The method of claim 59 wherein said compound is ethyl N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride.

82. The method of claim 59 wherein said compound is N-.alpha.-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.
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