Pharmaceutical compositions comprising natriuretic peptides or neutral endopeptidase inhibitors for treating and preventing myointimal proliferation

Claim 2

A pharmaceutical composition of claim 1 wherein the natriuretic peptide, when present, is selected from the group consisting of α human AP 21, α human AP 28, α human AP 23, α human AP 24, α human AP 25, α human AP 26, α human AP 33, the corresponding atrial peptides wherein the methionine at position 12 is replaced by isoleucine, human brain natriuretic peptide and C-type natriuretic peptide.

Claim 3

A pharmaceutical composition according to claim 1 or 2 wherein the neutral endopeptidase inhibitor, when present, is selected from the group consisting of: N-[N-[(L)-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine; N-[N-[(L)-1-carboxy-2-phenylethyl]-L-phenylalanyl]-β-alanine; N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]methionine ethyl ester; N-[2-mercaptomethyl-3-(2-methylphenyl)propioyl]methionine; N-[2(S)-mercaptomethyl-3-(2-methylphenyl)propanoyl]-(S)-isoserine; N-(S)-[3-mercapto-2-(2-methylphenyl)propionyl]-(S)-2-methoxy-β-alanine; N-[1-[[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino]cyclopentylcarbonyl]-(S)-isoserine; N-[1-[[1(S)-carbonyl-3-phenylpropyl]amino]cyclopentylcarbonyl]-(S)-isoserine; 1,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)-isoserine; 1,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)-methionine; N-(3-phenyl-2-(mercaptomethyl)propionyl)-(S)-4-(methylmercapto)methionine; N-[2-acetylthiomethyl-3-phenylpropionyl]-3-aminobenzoic acid; N-[2-mercaptomethyl-3-phenylpropionyl]-3-aminobenzoic acid; N-[1-(2-carboxy-4-phenylbutyl)cyclopentanecarbonyl]-(S)-isoserine; N-[1-(acetylthiomethyl)cyclopentanecarbonyl]-(S)-methionine ethyl ester; 3(S)-[2-(acetylthiomethyl)-3-phenylpropionyl]amino-ε-caprolactam; N-(R,S)-[2-mercaptomethyl-3-(3-fluorophenyl)propionyl]glycine; N-(R,S)-[2-mercaptomethyl-3-(3-fluorophenyl)propionyl]-(S)-alanine; N-(R,S)-[2-mercaptomethyl-3-(3,4-difluorophenyl)propionyl]-(S)-alanine; N-(R,S)-[2-mercaptomethyl-3-(3,5-difluorophenyl)propionyl]-glycine; N-(R,S)-[2-mercaptomethyl-3-(3,5-difluorophenyl)propionyl]-(S)-alanine; N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxyphenyl)-propionyl]-(S)-alanine benzyl ester; N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxyphenyl)-propionyl]-(S)-alanine; SQ 28603; UK 69578; thiorphan; retro-thiorphan; phosphoramidon; SQ 29072; and MDL 100,173.

Claim 4

A pharmaceutical composition of claim 1 or 3 wherein the angiotensin converting enzyme inhibitor, when present, is selected from: spirapril, enalapril, ramipril, perindopril, indolapril, lysinopril, quinapril, pentopril, cilazapril, captopril, zofenopril, pivalopril and fosinopril.

Claim 6

A method of claim 5 wherin the natriuretic peptide, when present, is selected from the group consisting of α human AP 21, α human AP 28, α human AP 23, α human AP 24, α human AP 25, α human AP 26, α human AP 33, the corresponding atrial peptides wherein the methionine at position 12 is replaced by isoleucine, human brain natriuretic peptide and human C-type natriuretic peptide.

Claim 7

A method of claim 5 or 6 wherein the neutral endopeptidase inhibitor, when present, is selected from the group consisting of: N-[N-[(L)-[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-ß-alanine; N-[N-[(L)-1-carboxy-2-phenylethyl]-L-phenylalanyl]-ß-alanine; N-[2-acetylthiomethyl-3-(2-methylphenyl)propionyl]methionine ethyl ester; N-[2-mercaptomethyl-3-(2-methylphenyl)propioyl]methionine; N-[2(S)-mercaptomethyl-3-(2-methylphenyl)propanoyl]-(S)-isoserine; N-(S)-[3-mercapto-2-(2-methylphenyl)propionyl]-(S)-2-methoxy-β-alanine; N-[1-[[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino]cyclopentylcarbonyl]-(S)-isoserine; N-[1-[[1(S)-carbonyl-3-phenylpropyl]amino]cyclopentylcarbonyl]-(S)-isoserine; 1,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)-isoserine; 1,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)-methionine; N-(3-phenyl-2-(mercaptomethyl)-propionyl)-(S)-4-(methyl-mercapto)methionine; N-[2-acetylthiomethyl-3-phenylpropionyl]-3-aminobenzoic acid; N-[2-mercaptomethyl-3-phenylpropionyl]-3-aminobenzoic acid; N-[1-(2-carboxy-4-phenylbutyl)cyclopentanecarbonyl]-(S)-isoserine; N-[1-(acetylthiomethyl)cyclopentanecarbonyl]-(S)-methionine ethyl ester; 3(S)-[2-(acetylthiomethyl)-3-phenylpropionyl]amino-ε-caprolactam; N-(R,S)-[2-mercaptomethyl-3-(3-fluorophenyl)propionyl]glycine; N-(R,S)-[2-mercaptomethyl-3-(3-fluorophenyl)propionyl]-(S)-alanine; N-(R,S)-[2-mercaptomethyl-3-(3,4-difluorophenyl)propionyl]-(S)-alanine; N-(R,S)-[2-mercaptomethyl-3-(3,5-difluorophenyl)propionyl]-glycine; N-(R,S)-[2-mercaptomethyl-3-(3,5-difluorophenyl)propionyl]-(S)-alanine; N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxyphenyl)-propionyl]-(S)-alanine benzyl ester; N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxyphenyl)-propionyl]-(S)-alanine; SQ 28603; UK 69578; thiorphan; retro-thiorphan; phosphoramidon; SQ 29072; and MDL 100,173.

Claim 8

A method of claim 5 or 7 wherein the angiotensin converting enzyme inhibitor, when present, is selected from: spirapril, enalapril, ramipril, perindopril, indolapril, lysinopril, quinapril, pentopril, cilazapril, captopril, zofenopril, pivalopril and fosinopril.

Claim 9

A method of treating or preventing myointimal proliferation in atherosclerosis, restenosis induced by angioplasty or vascular reconstructive surgery, glomerulonephritis, glomerulosclerosis or other diseases involving vascular cell proliferation, comprising administering a composition according to claim 1 to a mammal in need of such treatment.

Claim 10

A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat or prevent myointimal proliferation in atherosclerosis, restenosis induced by angioplasty or vascular reconstructive surgery, glomerulonephritis, glomerulosclerosis or other diseases involving vascular cell proliferation in mammals which comprises in one container a pharmaceutical composition comprising a neutral endopeptidase inhibitor and in a second container a pharmaceutical composition comprising a natriuretic peptide or an angiotensin converting enzyme inhibitor.

Claim 11

The use of a natriuretic peptide, a neutral endopeptidase inhibitor, a combination of a neutral endopeptidase inhibitor and a natriuretic peptide, or a combination of a neutral endopeptidase inhibitor and an angiotensin converting enzyme inhibitor for the manufacture of a medicament for treating or preventing myointimal proliferation in atherosclerosis, restenosis induced by angioplasty or vascular reconstructive surgery, glomerulonephritis, glomerulosclerosis or other diseases involving vascular cell proliferation.

Claim 12

A process for preparing a pharmaceutical composition as claimed in claim 1 which comprises admixing a compound or combinaton of claim 1 with a pharmaceutical carrier.