Phosphonic acid derivatives and use thereof

Abstract

A phosphonic acid derivative compound represented by formula I ! or a pharmaceutically acceptable salt thereof: ##STR1## wherein R 1 , R 2 and R 3 each represent hydrocarbon groups which may be substituted, except cases in which (1) R 2 is unsubstituted methyl, ( 2 ) R 3 is an unsubstituted hydrocarbon group having 1 to 3 carbon atoms, and (3) R 1 is benzyloxycarbonylaminomethyl, R 2 is isobutyl and R 3 is isobutyl or phenylmethyl, which has endothelin-converting enzyme inhibiting activity and is useful as pharmaceutical drugs such as therapeutic agents for hypertension, cardiac or cerebral circulatory diseases and renal diseases. This is a Reissue of a Patent which was the subject of a Reexamination Certificate No. B1 5,330,978, dated Jun. 18, 1996, Request No. 90/00400, Oct. 18, 1995.

What is claimed is: 
     
       1. A compound represented by formula  I! or a pharmaceutically acceptable salt thereof: ##STR6## wherein R 1  is C 1-12  alkyl group which may be substituted by C 3-8  cycloalkyl, halogen hydroxy which may be protected, C 1-2  alkoxy, ketone or amino which may be protected, (ii) a 5 to 7 member cycloalkyl group which may be substituted by lower alkyl having 1 to 3 carbon atoms, halogen, hydroxy which may be protected, C 1-2  alkoxy, keto, or amino which may be protected or (iii) an aralkyl group which may be substituted by lower alkyl having 1 to 3 carbon atoms, C 5-6  cycloalkyl, halogen, hydroxy which may be protected, or C 1-2  alkoxy; R 2  is (i) a C 1-8  alkyl group (ii) a cyclohexylmethylene group or (iii) a benzyl group; and   R 3  is . .an indolylmethyl group or.!. a benzyl group.Iadd., except compounds in which (i) R 2  is a methyl group and (ii) R 1  is benzyloxycarbonylaminomethyl, R 2  is isobutyl and R 3  is benzyl.Iaddend..   
     
     
       2. The compound according to claim 1, in which R 1  is selected from the group which consists of an alkyl group having 1 to 12 carbon atoms; a 5-, 6- or 7-membered alicyclic alkyl group; and an alkyl group having 1 to 5 carbon atoms substituted by an aromatic hydrocarbon group having 6 to 12 carbon atoms. 
     
     
       3. The compound according to claim 2, in which said alkyl group having 1 to 12 carbon atoms is isoamyl or cyclohexylmethyl, and said alkyl group having 1 to 5 carbon atoms substituted by the aromatic hydrocarbon group is phenylethyl naphthylmethyl or naphthylethyl. . .4. The compound according to claim 1, in which said indolylmethyl group is 
     
     
        indol-3-ylmethyl..!.5. A compound represented by formula  I! or a pharmaceutically acceptable salt thereof: ##STR7## wherein R 1  is isoamyl, cyclohexylmethyl, phenethyl, naphthylmethyl or naphthylethyl R 2  is isobutyl or benzyl, and R 3  is 
     
     
        indol-3-ylmethyl. 6. The compound according to claim 5, in which said 
     
     
        compound is N-(phenethylphosphonyl)-leucyl-tryptophan. 7. The compound according to claim 5, in which said compound is 
     
     
        N-(cyclohexylmethylphosphonyl)-leucyl-tryptophan. 8. The compound according to claim 5, in which said compound is 
     
     
        N-(1-naphthylmethylphosphonyl)-leucyl-tryptophan. 9. The compound according to claim 5, in which said compound is 
     
     
        N-{2-(1-naphthyl)ethylphosphonyl}-leu-cyl-tryptophan. 10. Tne compound according to claim 5, in which said compound is 
     
     
        N-{2-(2-naphthyl)ethylphosphonyl}-leucyl-tryptophan. 11. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof claimed in claim 5 and a pharmaceutically acceptable carrier. 
     
     
        2. A method for bringing about endothelin-converting enzyme inhibiting activity in a warm-blood animal, which comprises administering an effective amount of the compound or the pharmaceutically acceptable salt 
     
     
        thereof claimed in claim 5 to the warm-blood animal. 13. A compound represented by formula  I! or a pharmaceutically acceptable sat thereof: ##STR8## wherein R 1  is (i) a C 1-12  alkyl group which may be substituted by C 3-8  cycloalkyl, halogen, hydroxy which may be protected, C 1-2  alkoxy, or amino which may be protected, (ii) a 5 to 7 member cycloalkyl group which may be substituted by lower alkyl having 1 to 3 carbon atoms, halogen, hydroxy which may be protected, C 1-2  alkoxy, keto, or amino which may be protected, or (iii) a C 7-17  aralkyl group which may be substituted by lower alkyl having 1 to 3 carbon atoms, C 5-6  cycloalkyl, halogen, hydroxy which may be protected, or C 1-2  alkoxy; R 2  is (i) a C 1-8  alkyl group, (ii) a 5 to 7 member cycloalkyl group, or (iii) a benzyl group; and   R 3  is a C 1-8  alkyl group which is substituted by 3-indolyl.Iadd.,   
     
     
        except compounds in which R 2  is a methyl group.Iaddend.. 14. A compound represented by formula  I! or a pharmaceutically acceptable salt thereof: ##STR9## wherein R 1  is phenethyl, isoamyl, cyclohexylmethyl naphthylmethyl or naphthylethyl, R2 is propyl, butyl, cyclohexylmethyl or benzyl and R 3   
     
     
        is benzyl or indolylmethyl. 15. A compound represented by formula  I! or a pharmaceutically acceptable salt thereof: ##STR10## wherein R 1  is an alkyl group of 1 to 12 carbon atoms or an alkyl group having 1 to 5 carbon atoms substituted by an aromatic hydrocarbon group having 6 to 12 carbon atoms; R 2  is an alkyl group having 1 to 8 carbon atoms; an alkyl group having 1 to 8 carbon atoms substituted by a cycloalkyl group having 5 to 7 carbon atoms; or an alkyl group having 1 to 5 carbon atoms substituted by an aromatic hydrocarbon group having 6 to 12 carbon atoms; and   R 3  is alkyl having 1 to 8 carbon atoms substituted by indolyl or an aromatic hydrocarbon group having . .to.!. 6 to 12 carbon atoms.Iadd.,   
     
     
        except compounds in which R 2  is a methyl group.Iaddend.. 16. The compound of claim 15 wherein R 1  is isoamyl, cyclohexylmethyl, phenylethyl, naphthylmethyl or naphthylethyl; R 2  is isobutyl or 
     
     
        benzyl, and R 3  is indolylmethyl or benzyl. .Iadd.17.  The compound according to claim 1, in which R 2  is n-propyl, isopropyl, isobutyl, sec-butyl, cyclohexylmethyl or benzyl. .Iaddend..Iadd.18. A method for bringing about endothelin-converting enzyme inhibiting activity in a warm-blood animal, which comprises administering an effective amount of the compound or the pharmaceutically acceptable salt thereof claimed in claim 1 to the warm-blood animal. .Iaddend..Iadd.19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 or a pharmaceutically acceptable salt thereof. .Iaddend..Iadd.20. The compound according to claim 13, in which R 2  is (i) a C 3-8  alkyl group, (ii) a 5 to 7 member cycloalkyl group, or (iii) a benzyl group. .Iaddend..Iadd.21. The compound according to claim 13, in which R 2  is n-propyl, isopropyl, isobutyl, sec-butyl, cyclohexylmethyl or benzyl. .Iaddend..Iadd.22. A method for bringing about endothelin-converting enzyme inhibiting activity in a warm-blooded animal, which comprises administering an effective amount of the compound or the pharmaceutically acceptable salt thereof claimed in claim 13 to the warm-blooded animal. .Iaddend..Iadd.23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 13 or a pharmaceutically acceptable salt thereof. .Iaddend..Iadd.24. The compound according to claim 14, in which R 3  is indolylmethyl. 
     
     
        .Iaddend..Iadd.25.  The compound according to claim 15, in which R 2  is an alkyl group having 3 to 8 carbon atoms; an alkyl group having 1 to 8 carbon atoms substituted by a cycloalkyl group having 5 to 7 carbon atoms; or an alkyl group having 1 to 5 carbon atoms substituted by an aromatic hydrocarbon group having 6 to 12 carbon atoms; and R 3  is alkyl having 1 to 8 carbon atoms substituted by indolyl. .Iaddend..Iadd.26. The compound according to claim 15, in which R 2  is n-propyl, isopropyl, isobutyl, sec-butyl, cyclohexylmethyl or benzyl. .Iaddend..Iadd.27. A method for bringing about endothelin-converting enzyme inhibiting activity in a warm-blooded animal, which comprises administering an effective amount of the compound or the pharmaceutically acceptable salt thereof claimed in claim 15 to the warm-blooded animal. .Iaddend..Iadd.28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 15 or a pharmaceutically acceptable salt thereof. .Iaddend..Iadd.29. The compound of claim 16 wherein R 3  is 
     
     
        indolylmethyl. .Iaddend..Iadd.30.  A compound represented by formula  I! or a pharmaceutically acceptable salt thereof: ##STR11##.Iaddend.wherein: R 1  is (i) a C 1-12  alkyl group which may be substituted by C 3-8  cycloalkyl, halogen, hydroxy which may be protected, C 1-2  alkoxy, ketone or amino which may be protected, (ii) a 5 to 7 member cycloalkyl group which may be substituted by lower alkyl having 1 to 3 carbon atoms, halogen, hydroxy which may be protected, C 1-2  alkoxy, keto, or amino which may be protected or (iii) an aralkyl group which may be substituted by lower alkyl having 1 to 3 carbon atoms, C 5-6  cycloalkyl, halogen, hydroxy which may be protected, or C 1-2  alkoxy;   R 2  is (i) a C 1-8  alkyl group (ii) a cyclohexylmethylene group or (iii) benzyl group and   R 3  is an indolylmethyl group, except compounds in which R 2  is a   
     
     
        methyl group. .Iadd.31.  The compound according to claim 30, in which R 1  is selected from the group which consists of an alkyl group having 1 to 12 carbon atoms; a 5-, 6- or 7-membered alicyclic alkyl group; and an alkyl group having 1 to 5 carbon atoms substituted by an aromatic 
     
     
        hydrocarbon group having 6 to 12 carbon atoms. .Iaddend..Iadd.32.  The compound according to claim 31, in which said alkyl group having 1 to 12 carbon atoms is isoamyl or cyclohexylmethyl, and said alkyl group having 1 to 5 carbon atoms substituted by the aromatic hydrocarbon group is phenylethyl, naphthylmethyl or naphthylethyl. .Iaddend..Iadd.33. The compound according to claim 30, in which said indolylmethyl group is indol-3-ylmethyl. .Iaddend..Iadd.34. The compound according to claim 30, in which R 2  is (i) a C 3-8  alkyl group, (ii) a cyclohexylmethylene group or (iii) a benzyl group; and R 3  is an indolylmethyl group. .Iaddend..Iadd.35. A method for bringing about endothelin-converting enzyme inhibiting activity in a warm-blooded animal, which comprises administering an effective amount of the compound or the pharmaceutically acceptable salt thereof claimed in claim 30 to the warm-blooded animal. .Iaddend..Iadd.36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 
     
     
        30 or a pharmaceutically acceptable salt thereof. .Iaddend..Iadd.37.  A method for bringing about endothelin-converting enzyme inhibiting activity in a warm-blooded animal, which comprises administering to the animal an effective amount of a compound represented by the formula  I! or a pharmaceutically acceptable salt thereof: ##STR12## wherein: R 1  is (i) a C 1-8  alkyl group which may be substituted by C 5-8  cycloalkyl, halogen, hydroxy which may be protected, C 1-2  alkoxy, keto or amino which may be protected, (ii) a 5 to 7 member cycloalkyl group which may be substituted by lower alkyl having 1 to 3 carbon atoms, halogen, hydroxy which may be protected C 1-2  alkoxy, keto, or amino which may be protected or (iii) an aralkyl group which may be substituted by lower alkyl having 1 to 3 carbon atoms, C 5-6  cycloalkyl, halogen, hydroxy which may be protected, or C 1-2  alkoxy; R 2  is (i) a C 1-8  alkyl group (ii) a cyclohexylmethyl group or (iii) a benzyl group; and   R 3  is an indolylmethyl group or a benzyl group; except compounds in which (i) R 2  is a methyl group and (ii) R 1  is benzyloxgycarbonylaminomethyl, R 2  is isobutyl and R 3  is benzyl. .Iaddend.