Aminoacid derivatives as antihypertensives

US 4,374,829 A
Filed: 02/17/1981
Issued: 02/22/1983
Est. Priority Date: 12/11/1978
Status: Expired due to Term

First Claim

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1. A compound of the formula:

##STR17## wherein R and R⁶ are the same or different and are hydroxy,lower alkoxy,lower alkenoxy,diloweralkylamino lower alkoxy,acylamino lower alkoxy,acyloxy lower alkoxy,aryloxy,arloweralkyloxysubstituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy,amino,loweralkylaminodiloweralkylamino,arloweralkylamino orhydroxyamino;

R¹ is hydrogen,alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups;

substituted lower alkyl wherein the substituent ishalohydroxylower alkoxyaryloxyaminoloweralkylaminodiloweralkylaminoacylaminoarylaminoguanidinoimidazolyl,indolyl,mercapto,loweralkylthioarylthiocarboxycarboxamidocarboloweralkoxyphenylsubstituted phenyl wherein the substituent islower alkyllower alkoxy orhalo;

arloweralkyl or heteroarloweralkyl,arloweralkenyl or heteroarloweralkenyl,substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalolower alkylhydroxylower alkoxyaminoaminomethylacylaminodiloweralkylaminoloweralkylaminocarboxylhalo loweralkylcyano orsulfonamido;

arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;

R² and R⁷ are hydrogen or lower alkyl;

R³ is hydrogenlower alkylphenyl lower alkylaminomethyl phenyl lower alkylhydroxy phenyl lower alkylhydroxy lower alkylacetylamino lower alkylacylamino lower alkylamino lower alkyldimethylamino lower alkylhalo lower alkylguanidino lower alkylimidazolyl lower alkylindolyl lower alkylmercapto lower alkyl andloweralkylthio lower alkyl;

R⁴ is hydrogen orlower alkyl;

R⁵ is hydrogenlower alkylphenylphenyl lower alkylhydroxy phenyl lower alkylhydroxy lower alkylamino lower alkylguanidino lower alkylimidazolyl lower alkylindolyl lower alkylmercapto lower alkyl orloweralkyl thio lower alkyl;

R⁴ and R⁵ 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 withhydroxylower alkoxylower alkyl ordilower alkyland 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.

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Abstract

The invention relates to new carboxyalkyl dipeptide derivatives and related compounds which are useful as antihypertensives.

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82 Claims

1. A compound of the formula:
- ##STR17## wherein R and R⁶ are the same or different and are hydroxy,lower alkoxy,lower alkenoxy,diloweralkylamino lower alkoxy,acylamino lower alkoxy,acyloxy lower alkoxy,aryloxy,arloweralkyloxysubstituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy,amino,loweralkylaminodiloweralkylamino,arloweralkylamino orhydroxyamino;
  
  R¹ is hydrogen,alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups;
  
  substituted lower alkyl wherein the substituent ishalohydroxylower alkoxyaryloxyaminoloweralkylaminodiloweralkylaminoacylaminoarylaminoguanidinoimidazolyl,indolyl,mercapto,loweralkylthioarylthiocarboxycarboxamidocarboloweralkoxyphenylsubstituted phenyl wherein the substituent islower alkyllower alkoxy orhalo;
  
  arloweralkyl or heteroarloweralkyl,arloweralkenyl or heteroarloweralkenyl,substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalolower alkylhydroxylower alkoxyaminoaminomethylacylaminodiloweralkylaminoloweralkylaminocarboxylhalo loweralkylcyano orsulfonamido;
  
  arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;
  
  R² and R⁷ are hydrogen or lower alkyl;
  
  R³ is hydrogenlower alkylphenyl lower alkylaminomethyl phenyl lower alkylhydroxy phenyl lower alkylhydroxy lower alkylacetylamino lower alkylacylamino lower alkylamino lower alkyldimethylamino lower alkylhalo lower alkylguanidino lower alkylimidazolyl lower alkylindolyl lower alkylmercapto lower alkyl andloweralkylthio lower alkyl;
  
  R⁴ is hydrogen orlower alkyl;
  
  R⁵ is hydrogenlower alkylphenylphenyl lower alkylhydroxy phenyl lower alkylhydroxy lower alkylamino lower alkylguanidino lower alkylimidazolyl lower alkylindolyl lower alkylmercapto lower alkyl orloweralkyl thio lower alkyl;
  
  R⁴ and R⁵ 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 withhydroxylower alkoxylower alkyl ordilower alkyland 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.
- View Dependent Claims (2)
- - 2. Compounds of claim 1 in which the carbon bearing R¹ 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 R⁶ can each independently be hydroxy, lower alkoxy,lower alkenoxy,arloweralkyloxy,amino,diloweralkylamino lower alkoxy,acylamino lower alkoxy oracyloxy lower alkoxy,R¹ is hydrogen,alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups;
  
  substituted lower alkyl wherein the substituent ishalohydroxylower alkoxyaryloxyaminoloweralkylaminodiloweralkylaminoacylaminoarylaminoguanidinoimidazoyl,indolyl,mercapto,loweralkylthioarylthiocarboxycarboxamido orcarbolower alkoxyphenylsubstituted phenyl wherein the substituent islower alkyllower alkoxy orhalo;
  
  arloweralkyl or heteroaryloweralkyl arloweralkenyl or heteroarloweralkenyl, substituted arloweralkyl, substituted heteroarylloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl,wherein the substituent is halo or dihalolower alkylhydroxylower alkoxyaminoaminomethylacylaminodiloweralkylaminoloweralkylaminocarboxylhalo alkylcyano orsulfonamidoarloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;
  
  R² and R⁷ are hydrogen;
  
  R³ is lower alkyl, amino lower alkyl, imidazolyl, lower alkyl, halo lower alkyl;
  
  R⁴ and R⁵ 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.
- View Dependent Claims (4, 5, 6)
- - 4. Compounds of claim 3 in which the carbon bearing R¹ is of the S configuration and the other absolute configurations are those of L-amino acids.
  - 5. A compound of claim 3 wherein R⁴ and R⁵ are joined through the carbon and nitrogen atoms to which they are attached to form a ring of the formulae:
    - ##STR19## wherein Y is CH₂, S, or CH--OCH₃ and R, R¹, R², R³, R⁶ and R⁷ are as defind in claim defined
  - 6. Compounds of claim 5 in which the carbon bearing R¹ 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 R⁶ can each independently be hydroxy, lower alkoxy,lower alkenoxy,arloweralkyloxy,amino,diloweralkylamino lower alkoxy,acylamino lower alkoxy oracyloxy lower alkoxy,R¹ 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;
  
  R² and R⁷ are hydrogen;
  
  R³ is lower alkyl or amino lower alkyl;
  
  R⁴ and R⁵ 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 CH₂, S, or CH--OCH₃ 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.
- View Dependent Claims (8)
- - 8. Compounds of claim 7 in which the carbon bearing R¹ 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 R⁶ can each independently be hydroxy, lower alkoxy, aralkyloxy,R² and R⁷ are hydrogen,R³ is methyl, aminoloweralkyl,R⁴ and R⁵ are joined through the carbon and nitrogen atoms to form proline, 4-thiaproline or 4-methoxyproline, andR¹ 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.
- View Dependent Claims (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)
- - 10. Compounds of claim 9 in which the carbon bearing R¹ 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-α
    - -(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline.
  - 16. A compound of claim 9 which is N-α
    - -(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.
  - 17. A compound of claim 9 which is N-α
    - -[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline.
  - 18. A compound of claim 9 which is N-α
    - -[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline.
  - 19. A compound of claim 9 which is N-α
    - -[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline.
  - 20. A compound of claim 9 which is N-α
    - -[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L-proline.
  - 21. A compound of claim 9 which is N-α
    - -[1-carboxy-5-aminopentyl]-L-lysyl-L-proline.
  - 22. A compound of claim 9 which is N-α
    - -(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-α
  
  -(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-α
  
  -(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 R⁶ are the same or different and are hydroxy,lower alkoxy,lower alkenoxy,diloweralkylamino lower alkoxy,acylamino lower alkoxy,acyloxy lower alkoxy,aryloxy,arloweralkyloxysubstituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy,amino,loweralkylaminodiloweralkylamino,arloweralkylamino orhydroxyamino;
  
  R¹ is hydrogen,alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups;
  
  substituted lower alkyl wherein the substituent ishalohydroxylower alkoxyaryloxyaminoloweralkylaminodiloweralkylaminoacylaminoarylaminoguanidinoimidazolyl,indolyl,mercapto,loweralkylthioarylthiocarboxycarboxamidocarboloweralkoxyphenylsubstituted phenyl wherein the substituent islower alkyllower alkoxy orhalo;
  
  arloweralkyl or heteroarloweralkyl,arloweralkenyl or heteroarloweralkenyl,substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalolower alkylhydroxylower alkoxyaminoaminomethylacylaminodiloweralkylaminoloweralkylaminocarboxylhalo loweralkylcyano orsulfonamido;
  
  arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;
  
  R² and R⁷ are hydrogen or lower alkyl;
  
  R³ is hydrogenlower alkylphenyl lower alkylaminomethyl pheny lower alkylhydroxy phenyl lower alkylhydroxy lower alkylacetylamino lower alkylacylamino lower alkylamino lower alkyldimethylamino lower alkylguanidino lower alkylhalo lower alkylimidazolyl lower alkylindolyl lower alkylmercapto lower alkyl andloweralkylthio lower alkyl;
  
  R⁴ is hydrogen orlower alkyl;
  
  R⁵ is hydrogenlower alkylphenylphenyl lower alkylhydroxy phenyl lower alkylhydroxy lower alkylamino lower alkylguanidino lower alkylimidazolyl lower alkylindolyl lower alkylmercapto lower alkyl orloweralkyl thio lower alkyl;
  
  R⁴ and R⁵ 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 withhydroxylower alkoxy orlower alkyland 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 R⁶ can each independently be hydroxy, lower alkoxy,lower alkenoxy,arloweralkyloxy,amino,diloweralkylamino lower alkoxy,acylamino lower alkoxy oracyloxy lower alkoxy,R¹ 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;
  
  R² and R⁷ are hydrogen;
  
  R³ is lower alkyl or amino lower alkyl;
  
  R⁴ and R⁵ 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 CH₂, S, or CH--OCH₃ 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 R⁶ can each independently be hydroxy, lower alkoxy, aralkyloxy,R² and R⁷ are hydrogen,R³ is methyl, aminoloweralkyl,R⁴ and R⁵ are joined through the carbon and nitrogen atoms to form proline, 4-thiaproline or 4-methoxyproline, andR¹ 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.
- View Dependent Claims (35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57)
- - 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-α
    - -(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline.
  - 40. The composition of claim 34 wherein said compound is N-α
    - -(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.
  - 41. The composition of claim 34 wherein said compound is N-α
    - -[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline.
  - 42. The composition of claim 34 wherein said compound is N-α
    - -[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline.
  - 43. The composition of claim 34 wherein said compound is N-α
    - -[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline.
  - 44. The composition of claim 34 wherein said compound is N-α
    - -[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L-proline.
  - 45. The composition of claim 34 wherein said compound is N-α
    - -[1-carboxy-5-aminopentyl]-L-lysyl-L-proline.
  - 46. The composition of claim 34 wherein said compound is N-α
    - -(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-α
    - -(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-α
    - -(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-α
    - -(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 R⁶ are the same or different and are hydroxy,lower alkoxy,lower alkenoxy,diloweralkylamino lower alkoxy,acylamino lower alkoxy,acyloxy lower alkoxy,aryloxy,arloweralkyloxysubstituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy,amino,loweralkylaminodiloweralkylamino,arloweralkylamino orhydroxyamino;
  
  R¹ is hydrogen,alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups;
  
  substituted lower alkyl wherein the substituent ishalohydroxylower alkoxyaryloxyaminoloweralkylaminodiloweralkylaminoacylaminoarylaminoguanidinoimidazolyl,indolyl,mercapto,loweralkylthioarylthiocarboxycarboxamidocarboloweralkoxyphenylsubstituted phenyl wherein the substituent islower alkyllower alkoxy orhalo;
  
  arloweralkyl or heteroarloweralkyl,arloweralkenyl or heteroarloweralkenyl,substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalolower alkylhydroxylower alkoxyaminoaminomethylacylaminodiloweralkylaminoloweralkylaminocarboxylhalo loweralkylcyano orsulfonamido;
  
  arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;
  
  R² and R⁷ are hydrogen or lower alkyl;
  
  R³ is hydrogenlower alkylphenyl lower alkylaminomethyl pheny lower alkylhydroxy phenyl lower alkylhydroxy lower alkylacetylamino lower alkylacylamino lower alkylamino lower alkyldimethylamino lower alkylguanidino lower alkylhalo lower alkylimidazolyl lower alkylindolyl lower alkylmercapto lower alkyl andloweralkylthio lower alkyl;
  
  R⁴ is hydrogen orlower alkyl;
  
  R⁵ is hydrogenlower alkylphenylphenyl lower alkylhydroxy phenyl lower alkylhydroxy lower alkylamino lower alkylguanidino lower alkylimidazolyl lower alkylindolyl lower alkylmercapto lower alkyl orloweralkyl thio lower alkyl;
  
  R⁴ and R⁵ 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 withhydroxylower alkoxy orlower alkyland 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 R⁶ can each independently be hydroxy, lower alkoxy, aralkyloxy,R¹ 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;
  
  R² and R⁷ are hydrogen,R³ is methyl, aminoloweralkyl,R⁴ and R⁵ 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.
- View Dependent Claims (60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82)
- - 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-α
    - -(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline.
  - 65. The method of claim 59 wherein said compound is N-α
    - -(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.
  - 66. The method of claim 59 wherein said compound is N-α
    - -[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline.
  - 67. The method of claim 59 wherein said compound is N-α
    - -[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline.
  - 68. The method of claim 59 wherein said compound is N-α
    - -[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline.
  - 69. The method of claim 59 wherein said compound is N-α
    - -[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L-proline.
  - 70. The method of claim 59 wherein said compound is N-α
    - -[1-carboxy-5-aminopentyl]-L-lysyl-L-proline.
  - 71. The method of claim 59 wherein said compound is N-α
    - -(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-α
    - -(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-α
    - -(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.

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Current Assignee
Merck & Co., Inc.
Original Assignee
Merck & Co., Inc.
Inventors
Wyvratt, Matthew J., Patchett, Arthur A., Tristram, Edward W., Harris, Elbert E.
Primary Examiner(s)
Phillips, Delbert R.

Application Number

US06/235,335
Time in Patent Office

735 Days
Field of Search

260/326.2, 260/112.5 R, 424/177
US Class Current

514/15.7
CPC Class Codes

A61K 38/00   Medicinal preparations cont...

A61P 43/00   Drugs for specific purposes...

A61P 7/10   Antioedematous agents; Diur...

A61P 9/12   Antihypertensives

C07K 5/022   containing the structure -X...

C07K 5/0222   with the first amino acid b...

Y10S 530/80   Antihypertensive peptides

Aminoacid derivatives as antihypertensives

First Claim

2 Assignments

0 Petitions

Accused Products

Abstract

Citations

82 Claims

Specification

Solutions

Use Cases

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Aminoacid derivatives as antihypertensives

First Claim

2 Assignments

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

Citations

82 Claims

Specification

Subscription Required

Solutions

Use Cases

Quick Links