RU2007133718A - COMBINATION OF ORGANIC COMPOUNDS - Google Patents

Claims (36)

1. The combination, including 1) a renin inhibitor or its pharmaceutically acceptable salt, 2) a neutral endopeptidase inhibitor (NEP) or its pharmaceutically acceptable salt, or optionally at least one therapeutic agent selected from the group including a) a diuretic or its pharmaceutically acceptable salt, b) an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof. 2. The combination according to claim 1, in which the renin inhibitor is selected from the group comprising RO 66-1132, RO 66-1168 and a compound of the formula

where R ₁ means halogen, C ₁ -C ₆ halogenated, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyloxy or C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, R ₂ means halogen, C ₁ —C ₄ alkyl or C ₁ -C ₄ alkoxy, R ₃ and R ₄ independently mean branched C ₃ -C ₆ alkyl and R ₅ mean cycloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkanoyloxy (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkylamino (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ dialkylamino (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkanoylamino (C ₁ -C ₆ ) alkyl, HO (O) C (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkyl -O- (O) C (C ₁ -C ₆ ) alkyl, H ₂ N-C (O) (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkyl-HN-C (O) (C ₁ - C ₆ ) alk sludge or (C ₁ -C ₆ alkyl) ₂ N-C (O) (C ₁ -C ₆ ) alkyl, or a pharmaceutically acceptable salt thereof. 3. The combination according to claim 2, in which the renin inhibitor means a compound of formula (III), characterized by a structure

where R ₁ means 3-methoxypropyloxy, R ₂ means methoxy, and R ₃ and R ₄ mean isopropyl, or a pharmaceutically acceptable salt thereof. 4. The combination according to claim 3, in which the compound of formula (IV) is used in the form of a semi-fumarate. 5. The combination according to claim 1, in which the neutral endopeptidase inhibitor is selected from the group comprising SQ 28603, N- [N- [1 (S) -carboxyl-3-phenylpropyl] - (S) -phenylalanyl] - (S) - isoserine, N- [N - [((1S) -carboxy-2-phenyl) ethyl] - (S) -phenylalanyl] -β-alanine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, (cis-4 - [[[1- [2-carboxy-3- (2-methoxyethoxy) propyl] cyclopentyl] carbonyl] amino] cyclohexanecarboxylic acid), thiorphan, retrothiorphan, phosphoroamidone, SQ 29072, ethyl ether N - (3-carboxy-1-oxopropyl) - (4S) -para-phenylphenylmethyl) -4-amino (2R) methylbutanoic acid, (S) -cis-4- [1- [2- (5-indanyloxycarbonium l) -3- (2-methoxyethoxy) propyl] -1-cyclopentanecarboxamido] -1-cyclohexanecarboxylic acid, 3- (1- [6-endohydroxymethylbicyclo [2.2.1] heptane-2-exocarbamoyl] cyclopentyl) -2- (2-Methoxyethyl) propanoic acid, N- (1- (3- (N-tert-butoxycarbonyl- (S) -prolylamino) -2 (S) -tert-butoxycarbonylpropyl) cyclopentanecarbonyl) -O-benzyl- (S ) -serine, 4 - [[2- (mercaptomethyl) -1-oxo-3-phenylpropyl] amino] benzoic acid, 3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-R-1-carbamoyl ) cyclopentyl] -2S- (2-methoxyethoxymethyl) propanoic acid, N - ((2S) -2- (4-biphenylmethyl) -4-carboxy-5-phenoxy aleryl) glycine, N- (1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) -L-phenylalanine, (S) - (2-biphenyl-4-yl) -1- (1H-tetrazol-5-yl) ethylamino ) methylphosphonic acid, (S) -5- (N- (2- (phosphonomethylamino) -3- (4-biphenyl) propionyl) -2-aminoethyl) tetrazole, β-alanine, 3- [1,1'-biphenyl ] -4-yl-N- [diphenoxyphosphinyl) methyl] -L-alanyl, N- (2-carboxy-4-thienyl) -3-mercapto-2-benzylpropanamide, 2- (2-mercaptomethyl-3-phenylpropionamido) thiazole -4-ylcarboxylic acid, (L) - (1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) -P-alanine, N- [N - [(L) - [1 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2-pheni ethyl] -L-phenylalanyl] - (R) -alanine, N- [N - [(L) -1-carboxy-2-phenylethyl] -L-phenylalanyl] - (R) -alanine, ethyl N- [2 -acetylthiomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2-mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propanoyl ] - (S) -isoserine, N- (S) - [3-mercapto-2- (2-methylphenyl) propionyl] - (S) -2-meth6xi- (R) -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' - [dithiob c- [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, ethyl N- [1- (acetylthiomethyl) cyclopentanecarbonyl] - (S) -methionine, 3 (S) - [2- (acetylthiomethyl) -3- phenylpropionyl] amino-ε-caprolactam and N- (2-acetylthiomethyl-3- (2-methylphenyl) propionyl) methionine ethyl ester, or in each case they are pharmaceutically acceptable salable salts. 6. The combination according to claim 1, in which the neutral endopeptidase inhibitor means ethyl ester of N- (3-carboxy-1-oxopropyl) - (4S) -para-phenylphenylmethyl) -4-amino (2R) -methylbutanoic acid or its pharmaceutically an acceptable salt, or N- (3-carboxy-1-oxopropyl) - (4S) -paraphenylphenylmethyl) -4-amino (2R) methylbutanoic acid or a pharmaceutically acceptable salt thereof. 7. The combination according to claim 1, in which the diuretic means hydrochlorothiazide or its pharmaceutically acceptable salt. 8. The combination according to claim 1, in which the angiotensin II receptor means valsartan or its pharmaceutically acceptable salt. 9. A pharmaceutical composition comprising 1) a renin inhibitor or its pharmaceutically acceptable salt, 2) a neutral endopeptidase inhibitor (NEP) or its pharmaceutically acceptable salt, or optionally at least one therapeutic agent selected from the group including a) a diuretic or its pharmaceutically acceptable salt, b) an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition according to claim 9, in which the renin inhibitor is selected from the group comprising RO 66-1132, RO 66-1168 and a compound of the formula

where R ₁ means halogen, C ₁ -C ₆ halogenated, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyloxy or C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, R ₂ means halogen, C ₁ —C ₄ alkyl or C ₁ -C ₄ alkoxy, R ₃ and R ₄ independently mean branched C ₃ -C ₆ alkyl and R ₅ mean cycloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkanoyloxy (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkylamino (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ dialkylamino (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkanoylamino (C ₁ -C ₆ ) alkyl, HO (O) C (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkyl -O- (O) C (C ₁ -C ₆ ) alkyl, H ₂ N-C (O) (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkyl-HN-C (O) (C ₁ - C ₆ ) alk sludge or (C ₁ -C ₆ alkyl) ₂ N-C (O) (C ₁ -C ₆ ) alkyl, or their pharmaceutically acceptable salts. 11. The pharmaceutical composition of claim 10, in which the renin inhibitor means a compound of formula (III), characterized by a structure

wherein R ₁ is 3-methoxypropyloxy, R ₂ is methoxy, and R ₃ and R _{4 are} isopropyl or a pharmaceutically acceptable salt thereof. 12. The pharmaceutical composition according to claim 11, in which the compound of formula (IV) is used in the form of a semifumarate. 13. The pharmaceutical composition according to claim 9, in which the neutral endopeptidase inhibitor is selected from the group comprising SQ 28603, N- [N- [1 (S) -carboxyl-3-phenylpropyl] - (S) -phenylalanyl] - (S) -isoserine, N- [N - [((1S) -carboxy-2-phenyl) ethyl] - (S) -phenylalanyl] -β-alanine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl ) propionyl] methionine, (cis-4 - [[[1- [2-carboxy-3- (2-methoxyethoxy) propyl] cyclopentyl] carbonyl] amino] cyclohexanecarboxylic acid), thiorphan, retrotiororphan, phosphoroamidone, SQ 29072, ethyl ether N- (3-carboxy-1-oxopropyl) - (4S) -para-phenylphenylmethyl) -4-amino (2R) methylbutanoic acid, (S) -cis-4- [1- [2- (5 ndanyloxycarbonyl) -3- (2-methoxyethoxy) propyl] -1-cyclopentanecarboxamido] -1-cyclohexanecarboxylic acid, 3- (1- [6-endohydroxymethylbicyclo [2.2.1] heptane-2-exocarbamoyl] cyclopentyl) -2- (2-Methoxyethyl) propanoic acid, N- (1- (3- (N-tert-butoxycarbonyl- (S) -prolylamino) -2 (S) -tert-butoxycarbonylpropyl) cyclopentanecarbonyl) -O-benzyl- (S ) -serine, 4 - [[2- (mercaptomethyl) -1-oxo-3-phenylpropyl] amino] benzoic acid, 3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-R-1-carbamoyl ) cyclopentyl] -2S- (2-methoxyethoxymethyl) propanoic acid, N - ((2S) -2- (4-biphenylmethyl) -4 -carboxy-5-phenoxyvaleryl) glycine, N- (1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) -L-phenylalanine, (S) - (2-biphenyl-4-yl) -1- (1H-tetrazol- 5-yl) ethylamino) methylphosphoric acid, (S) -5- (N- (2- (phosphonomethylamino) -3- (4-biphenyl) propionyl) -2-aminoethyl) tetrazole, β-alanine, 3- [1 , 1'-biphenyl] -4-yl-N- [diphenoxyphosphinyl) methyl] -L-alanyl, N- (2-carboxy-4-thienyl) -3-mercapto-2-benzylpropanamide, 2- (2-mercaptomethyl- 3-phenylpropionamido) thiazol-4-ylcarboxylic acid, (L) - (1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) -β-alanine, N- [N - [(L) - [1 - [(2,2-dimethyl-1,3-dioxolan-4-yl) metho xi] carbonyl] -2-phenylethyl] -L-phenylalanyl] - (R) -alanine, N- [N - [(L) -1-carboxy-2-phenylethyl] -L-phenylalanyl] - (R) -alanine , N- [2-acetylthiomethyl-3- (2-methylphenyl) propionyl] methionine ethyl ester, N- [2-mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2 (S) -mercaptomethyl-3 - (2-methylphenyl) propanoyl] - (S) -isoserine, N- (S) - [3-mercapto-2- (2-methylphenyl) propionyl] - (S) -2-methoxy- (R) -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, ethyl ester N- [1- (acetylthiomethyl) cyclopentanecarbonyl] - (S) -methionine, 3 (S) - [2- (Acetylthiomethyl) -3-phenylpropionyl] amino-ε-caprolactam and N- (2-acetylthiomethyl-3- (2-methylphenyl) propionyl) methionine ethyl ester, or in each case their devel- acceptable salts. 14. The pharmaceutical composition according to claim 9, in which the neutral endopeptidase inhibitor means ethyl ester of N- (3-carboxy-1-oxopropyl) - (4S) -para-phenylphenylmethyl) -4-amino (2R) -methylbutanoic acid or its a pharmaceutically acceptable salt, or N- (3-carboxy-1-oxopropyl) - (4S) -paraphenylphenylmethyl) -4-amino (2R) methylbutanoic acid or a pharmaceutically acceptable salt thereof. 15. The pharmaceutical composition according to claim 9, in which the diuretic means hydrochlorothiazide or its pharmaceutically acceptable salt. 16. The pharmaceutical composition according to claim 9, in which the angiotensin II receptor means valsartan or its pharmaceutically acceptable salt. 17. The pharmaceutical composition according to claim 9 for the prevention, retardation of the development and / or treatment of a disease or condition mediated by the activity of angiotensin II and / or neutral endopeptidase. '' 18. The pharmaceutical composition of claim 17, wherein the disease or condition mediated by angiotensin II and / or neutral endopeptidase activity is selected from the group consisting of hypertension, heart failure, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy , supraventricular and ventricular arrhythmias, atrial fibrillation, cardiofibrosis, atrial flutter, unsuccessful vascular reconstruction, plaque stabilization, myocar infarction and its consequences, atherosclerosis, angina pectoris, renal failure, renal fibrosis, polycystic kidney disease, type 2 diabetes, metabolic disorders, secondary aldosteronism, primary and secondary pulmonary hypertension, nephrotic syndrome, diabetic nephropathy, glomerulonephritis, scleroderma, scleroderma, kidney disease, renal vascular hypertension, diabetic retinopathy, end-stage kidney disease, migraine, peripheral vascular disease, Raynaud's disease, luminal gyne erplaziyu, cognitive dysfunction, glaucoma and cerebrovascular disease. 19. A method of preventing, slowing down and / or treating a disease or condition mediated by the activity of angiotensin II and / or neutral endopeptidase, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a combination comprising 1) a renin inhibitor or its pharmaceutically acceptable salt, 2) a neutral endopeptidase inhibitor (NEP) or its pharmaceutically acceptable salt, or optionally at least one therapeutic agent selected from the group including a) a diuretic or its pharmaceutically acceptable salt, b) an angiotensin II receptor blocker (ARB) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 20. The method according to claim 19, in which the disease or condition mediated by the activity of angiotensin II and / or neutral endopeptidase is selected from the group consisting of hypertension, heart failure, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy supraventricular and ventricular arrhythmias, atrial fibrillation, cardiofibrosis, atrial flutter, unsuccessful vascular reconstruction, plaque stabilization, myocardial infarction and its consequences, atherosclerosis, angina pectoris, renal failure, renal fibrosis, polycystic kidney disease, type 2 diabetes, metabolic disorder, secondary aldosteronism, primary and secondary pulmonary hypertension, nephrotic syndrome, diabetic nephropathy, glomerulonephritis, scleroderma, glomerulomeric glomeruloma vascular hypertension, diabetic retinopathy, end-stage kidney disease, migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognition tive dysfunction, glaucoma and cerebrovascular disease. 21. The method according to claim 20, in which the renin inhibitor is selected from the group comprising RO 66-1132, RO 66-1168 and a compound of the formula

where R ₁ means halogen, C ₁ -C ₆ halogenated, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyloxy or C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, R ₂ means halogen, C ₁ —C ₄ alkyl or C ₁ -C ₄ alkoxy, R ₃ and R ₄ independently mean branched C ₃ -C ₆ alkyl and R ₅ mean cycloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkanoyloxy (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkylamino (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ dialkylamino (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkanoylamino (C ₁ -C ₆ ) alkyl, HO (O) C (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkyl -O- (O) C (C ₁ -C ₆ ) alkyl, H ₂ N-C (O) (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkyl-HN-C (O) (C ₁ - C ₆ ) alk sludge or (C ₁ -C ₆ alkyl) ₂ N-C (O) (C ₁ -C ₆ ) alkyl, or a pharmaceutically acceptable salt thereof. 22. The method according to item 21, in which the renin inhibitor means a compound of formula (III), characterized by a structure

where R ₁ means 3-methoxypropyloxy, R ₂ means methoxy and R ₃ and R ₄ mean isopropyl, or a pharmaceutically acceptable salt thereof. 23. The method according to item 22, in which the compound of formula (IV) is used in the form of a semi-fumarate. 24. The method according to claim 19, in which the neutral endopeptidase inhibitor is selected from the group comprising SQ 28603, N- [N- [1 (S) -carboxyl-3-phenylpropyl] - (S) -phenylalanyl] - (S) - isoserine, N- [N - [((1S) -carboxy-2-phenyl) ethyl] - (S) -phenylalanyl] -β-alanine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, (cis-4 - [[[1- [2-carboxy-3- (2-methoxyethoxy) propyl] cyclopentyl] carbonyl] amino] cyclohexanecarboxylic acid), thiorphan, retrothiorphan, phosphoroamidone, SQ 29072, ethyl ether N - (3-carboxy-1-oxopropyl) - (4S) -para-phenylphenylmethyl) -4-amino (2R) methylbutanoic acid, (S) -cis-4- [1- [2- (5-indanyloxycarbonyl) -3- (2-Methoxyethoxy) propyl] -1-cyclopentanecarboxamido] cyclohexanecarboxylic acid, 3- (1- [6-endohydroxymethylbicyclo [2.2.1] heptane-2-exocarbamoyl] cyclopentyl) -2- (2-methoxyethyl) propanoic acid N- (1- (3- (N-tert-butoxycarbonyl- (S) -prolylamino) -2 (S) -tert-butoxycarbonylpropyl) cyclopentanecarbonyl) -O-benzyl- (S) -serine methyl ester, 4- [ [2- (mercaptomethyl) -1-oxo-3-phenylpropyl] amino] benzoic acid, 3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-N-1-carbamoyl) cyclopentyl] -2S- ( 2-methoxyethoxymethyl) propanoic acid, N - ((2S) -2- (4-biphenylmethyl) -4-carboxy-5-phenoxyvale Ryl) glycine, N- (1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) -L-phenylalanine, (S) - (2-biphenyl-4-yl) -1- (1H-tetrazol-5-yl) ethylamino ) methylphosphonic acid, (S) -5- (N- (2- (phosphonomethylamino) -3- (4-biphenyl) propionyl) -2-aminoethyl) tetrazole, β-alanine, 3- [1,1'-biphenyl ] -4-yl-N- [diphenoxyphosphinyl) methyl] -L-alanyl, N- (2-carboxy-4-thienyl) -3-mercapto-2-benzylpropanamide, 2- (2-mercaptomethyl-3-phenylpropionamido) thiazole -4-ylcarboxylic acid, (L) - (1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) -β-alanine, N- [N - [(L) - [1 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2-phenyl yl] -L-phenylalanyl] - (R) -alanine, N- [N - [(L) -1-carboxy-2-phenylethyl] -L-phenylalanyl] - (R) -alanine, ethyl N- [2 -acetylthiomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2-mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propanoyl ] - (S) -isoserine, N- (S) - [3-mercapto-2- (2-methylphenyl) propionyl] - (S) -2-methoxy- (R) -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, ethyl N- [1- (acetylthiomethyl) cyclopentanecarbonyl] - (S) -methionine, 3 (S) - [2- (acetylthiomethyl) -3-phenylpropionyl] amino -ε-caprolactam and N- (2-acetylthiomethyl-3- (2-methylphenyl) propionyl) methionine ethyl ester, or in each case they are pharmaceutically acceptable salt e. 25. The method according to claim 19, in which the neutral endopeptidase inhibitor means ethyl ester of N- (3-carboxy-1-oxopropyl) - (4S) -para-phenylphenylmethyl) -4-amino (2R) -methylbutanoic acid or its pharmaceutically an acceptable salt, or N- (3-carboxy-1-oxopropyl) - (4S) -paraphenylphenylmethyl) -4-amino (2R) methylbutanoic acid or a pharmaceutically acceptable salt thereof. 26. The method according to claim 19, in which the diuretic means hydrochlorothiazide or its pharmaceutically acceptable salt. 27. The method according to claim 19, in which the angiotensin II receptor means valsartan or a pharmaceutically acceptable salt thereof. 28. Use of a combination comprising 1) a renin inhibitor or its pharmaceutically acceptable salt, 2) a neutral endopeptidase inhibitor (NEP) or its pharmaceutically acceptable salt, or optionally at least one therapeutic agent selected from the group including a) a diuretic or its pharmaceutically acceptable salt, b) an angiotensin II receptor blocker (ARB), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the prophylaxis, retardation and / or treatment of a disease or condition mediated by angiotensin II and / or neutral endopeptidase activity. 29. The use of claim 28, wherein the disease or condition mediated by angiotensin II and / or neutral endopeptidase activity is selected from the group consisting of hypertension, heart failure, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiomy supraventricular and ventricular arrhythmias, atrial fibrillation, cardiofibrosis, atrial flutter, unsuccessful vascular reconstruction, plaque stabilization, myocardial infarction and its consequences VIA, atherosclerosis, angina pectoris, renal failure, renal fibrosis, polycystic kidney disease, type 2 diabetes, metabolic disorder, secondary aldosteronism, primary and secondary pulmonary hypertension, nephrotic syndrome, diabetic nephropathy, glomerulonephritis, scleroderma, glomerulomas, glomerulomas, glomeruloma, and glomeruloma renal vascular hypertension, diabetic retinopathy, end-stage kidney disease, migraine, peripheral vascular disease, Raynaud’s disease, luminal hyperplasia, ognitivnuyu dysfunction, glaucoma and cerebrovascular disease 30. The application of clause 29, in which the renin inhibitor is selected from the group comprising RO 66-1132, RO 66-1168 and a compound of the formula

where R ₁ means halogen, C ₁ -C ₆ halogenated, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyloxy or C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, R ₂ means halogen, C ₁ —C ₄ alkyl or C ₁ -C ₄ alkoxy, R ₃ and R ₄ independently mean branched C ₃ -C ₆ alkyl and R ₅ mean cycloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkanoyloxy (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkylamino (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ dialkylamino (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkanoylamino (C ₁ -C ₆ ) alkyl, HO (O) C (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkyl -O- (O) C (C ₁ -C ₆ ) alkyl, H ₂ N-C (O) (C ₁ -C ₆ ) alkyl, C ₁ -C ₆ alkyl-HN-C (O) (C ₁ - C ₆ ) alk sludge or (C ₁ -C ₆ alkyl) ₂ N-C (O) (C ₁ -C ₆ ) alkyl, or a pharmaceutically acceptable salt thereof. 31. The application of clause 30, in which the renin inhibitor means a compound of formula (III), characterized by the structure

wherein R ₁ is 3-methoxypropyloxy, R ₂ is methoxy, and R ₃ and R _{4 are} isopropyl or a pharmaceutically acceptable salt thereof. 32. The use of claim 31, wherein the compound of formula (IV) is used in the form of a semifumarate. 33. The use of claim 28, wherein the neutral endopeptidase inhibitor is selected from the group consisting of SQ 28603, N- [N- [1 (S) -carboxyl-3-phenylpropyl] - (S) -phenylalanyl] - (S) - isoserine, N- [N - [((1S) -carboxy-2-phenyl) ethyl] - (S) -phenylalanyl] -β-alanine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, (cis-4 - [[[1- [2-carboxy-3- (2-methoxyethoxy) propyl] cyclopentyl] carbonyl] amino] cyclohexanecarboxylic acid), thiorphan, retrothiorphan, phosphoroamidone, SQ 29072, ethyl ether N - (3-carboxy-1-oxopropyl) - (4S) -para-phenylphenylmethyl) -4-amino (2R) methylbutanoic acid, (S) -cis-4- [1- [2- (5-indanyloxycarbonate il) -3- (2-methoxyethoxy) propyl] -1-cyclopentanecarboxamido] cyclohexanecarboxylic acid, 3- (1- [6-endohydroxymethylbicyclo [2.2.1] heptane-2-exocarbamoyl] cyclopentyl) -2- (2 -methoxyethyl) propanoic acid, methyl N- (1- (3- (N-tert-butoxycarbonyl- (S) -prolylamino) -2 (S) -tert-butoxycarbonylpropyl) cyclopentanecarbonyl) -O-benzyl- (S) - serine, 4 - [[2- (mercaptomethyl) -1-oxo-3-phenylpropyl] amino] benzoic acid, 3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-N-1-carbamoyl) cyclopentyl ] -2S- (2-methoxyethoxymethyl) propanoic acid, N - ((2S) -2- (4-biphenylmethyl) -4-carboxy-5-phenox valeryl) glycine, N- (1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) -L-phenylalanine, (S) - (2-biphenyl-4-yl) -1- (1H-tetrazol-5-yl) ethylamino ) methylphosphonic acid, (S) -5- (N- (2- (phosphonomethylamino) -3- (4-biphenyl) propionyl) -2-aminoethyl) tetrazole, β-alanine, 3- [1,1'-biphenyl ] -4-yl-N- [diphenoxyphosphinyl) methyl] -L-alanyl, N- (2-carboxy-4-thienyl) -3-mercapto-2-benzylpropanamide, 2- (2-mercaptomethyl-3-phenylpropionamido) thiazole -4-ylcarboxylic acid, (L) - (1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) -β-alanine, N- [N - [(L) - [1 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2-fe ilethyl] -L-phenylalanyl] - (R) -alanine, N- [N - [(L) -1-carboxy-2-phenylethyl] -L-phenylalanyl] - (R) -alanine, ethyl N- [2 -acetylthiomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2-mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propanoyl ] - (S) -isoserine, N- (S) - [3-mercapto-2- (2-methylphenyl) propionyl] - (S) -2-methoxy- (R) -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' - [dithi bis- [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, ethyl N- [1- (acetylthiomethyl) cyclopentanecarbonyl] - (S) -methionine, 3 (S) - [2- (acetylthiomethyl) -3- phenylpropionyl] amino-ε-caprolactam and N- (2-acetylthiomethyl-3- (2-methylphenyl) propionyl) methionine ethyl ester, or in each case their pharmaceutically acceptable bitter salts. 34. The use of claim 28, wherein the neutral endopeptidase inhibitor is N- (3-carboxy-1-oxopropyl) - (4S) -para-phenylphenylmethyl) -4-amino (2R) methylbutanoic acid ethyl ester or a pharmaceutically acceptable ester thereof an acceptable salt, or N- (3-carboxy-1-oxopropyl) - (4S) -paraphenylphenylmethyl) -4-amino (2R) methylbutanoic acid or a pharmaceutically acceptable salt thereof. 35. The use of claim 28, wherein the diuretic means hydrochlorothiazide or a pharmaceutically acceptable salt thereof. 36. The use according to any one of p, in which the angiotensin II receptor means valsartan or its pharmaceutically acceptable salt.