Patent EA-002339-B1 (EA)
Title: Thiol derivatives with metallopeptidase (ace/nep) inhibitory activity
Inventor: PELLACINI FRANCO
IPC: C07D277/30
Filed: 1996-12-09
Abstract: 1. A compound of formula   wherein R is a mercapto group or a R4 COS group convertible in the organism to mercapto group; R1 is a straight or branched C2-C4 alkyl group or an aryl or arylalkyl group with from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is a phenyl or a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted with one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy-, alkyl-, alkylthio-, alkylsuphonyl- or alkoxycarbonyl groups with from 1 to 6 carbon atoms in the alkyl moiety, C1-C3 alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino- or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or di-alkylamino or mono- or di-alkylaminocarbonyl groups with from 1 to 6 carbon atoms in the alkyl moiety; R2 is a hydrogen atom, a straight or branched C1-C4 alkyl group or a benzyl group; R3 is a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally condensed with benzene ring, optionally substituted with a phenyl group, being the phenyl and the heterocyclic group optionally substituted with one or more substituents, the same or different, selected among halogen atoms, alkyl-, alkoxy-, alkylthio- or alkoxycarbonyl groups with from 1 to 3 carbon atoms in the alkyl moiety; R4 is a straight or branched C1-C4 alkyl group or a phenyl group; the carbon atoms marked with an asterisk are stereogenic centers; and pharmaceutically acceptable salts thereof; provided that R3 is not an imidazolyl or indolyl group. 2. A compound of formula I according to Claim 1 wherein R3 is a 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur. 3. A compound of formula I according to Claim 2 wherein R1 is a phenylalkyl group optionally substituted with one or more substituents, the same or different, selected among halogen atoms, hydroxy-, alkyl- or alkoxy groups. 4. A compound of formula I according to Claim 1 in the form of a salt with an alkali metal selected among sodium, lithium and potassium. 5. A process for the preparation of a compound of formula I according to Claim 1 comprising the reaction between a compound of formula   wherein R and R1 have the meanings reported in Claim 1; and an alanine derivative of formula   wherein R2 and R3 have the meanings reported in Claim 1. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to Claim 1 in admixture with a pharmaceutically acceptable carrier. 7. A pharmaceutical composition according to Claim 6 for the treatment of cardiovascular diseases in a mammal. 8. A method for the treatment of cardiovascular diseases in a mammal comprising the administration of a therapeutically effective amount of a compound according to Claim 1. 9. N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-(4-thiazolyl)-L-alanine methyl ester. 10. N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-(2-thienyl)-L-alanine methyl ester. 11. N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-(2-pyridyl)-L-alanine methyl ester. 12. N-(2-phenylmethyl-3-mercaptopropionyl)(4-thiazolyl)-L-alanine. 13. N-(2-phenylmethyl-3-mercaptopropionyl)(2-thienyl)-L-alanine. 14. N-(2-phenylmethyl-3-mercaptopropionyl)(2-pyridyl)-L-alanine.