Patent EA-000991-B1 (EA)
Title: Thiol derivativeswith metallopeptidase inhibitory activity
Inventor: PELLACINI FRANCO
IPC: A61K31/505
Filed: 1996-12-17
Abstract: 1. A compound of formula   wherein R is a mercapto group or a R4COS group convertible in the organism to mercapto group; R1 is a straight or branched chain C2-C4 alkyl group or an aryl or arylalkyl group having 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 from the group, consising of nitrogen, oxygen and sulphur, optionally substituted with one or more substituents, the same or different, selected from the group consisting of halogen atoms, hydroxy groups, alkoxy, alkyl, alkylthio, alkylsulphonyl or alkoxycarbonyl groups having 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, acylainino groups, aminosulphonyl groups, mono- or dialkylamino or mono- or dialkylaminocarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety; R2 is a hydrogen atom, a straight or branched chain C1-C4alkyl or a benzyl group; R3 is a phenyl group substituted by a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, moreover the phenyl and the heterocyclic groups optionally substituted with one or more substituents, the same or different, as indicated for R1; R4 is a straight or branched chain C1-C4alkyl group or a phenyl group; the carbon atoms marked with an asterisk are stereogenic centers; and pharmaceutically acceptable salts thereof. 2. A compound of formula I according to claim 1, wherein R3 is a phenyl group substituted in position 4 with a heterocyclic group. 3. A compound of formula I according to claim 2, wherein R1 represents an arylalkyl group optionally substituted with one or more substituents, the same or different, selected from the group, consisting of halogen atoms, hydroxy, alkyl or alkoxy groups.  4. A compound of formula I according to claim 3, wherein R1 represents a phenylalkyl group optionally substituted with one or more substituents, the same or different, selected from the group, consisting of halogen atoms, hydroxy, alkyl or alkoxy groups. 5. A compound of formula I according to claim 1 in the form of a salt of an alkali metal, selected from the group, consisting of sodium, lithium and potassium. 6. 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 above reported meanings; and a phenylalanine derivative of formula   wherein R2 and R3 have the above reported meanings. 7. A pharmaceutical composition, containing a therapeutically effective amount of a compound of formula I according to claim 1 in admixture with a carrier, acceptable for pharmaceutical use. 8. A pharmaceutical composition according to claim 7 for the treatment of cardiovascular diseases. 9. A method for the treatment of cardiovascular diseases comprising the administration of a therapeutically effective amount of a compound of formula I according to claim 1. 10. A compound, selected from the group consisting of: N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(2-thiazolyl)-L-phenylalanine methyl ester; N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(2-pyridyl)-L-phenylalanine methyl ester; N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(3-pyridyl)-L-phenylalanine benzyl ester;  N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(2-furyl)-L-phenylalanine methyl ester; N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(5-pyrimidinyl)-L-phenylalanine ethyl ester; N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(2-pyrazinyl)-L-phenylalanine methyl ester; N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(2-thienyl)-L-phenylalanine methyl ester; N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(3-thienyl)-L-phenylalanine methyl ester; N-(3-phenylcarbonylthio-2-phenylmethylpropionyl)-4-(3-furyl)-L-phenylalanine methyl ester; N-[3-phenylcarbonylthio-2-(3-pyridylmethyl)propionyl]-4-(2-thiazolyl)-L-phenylalanine methyl ester; N-(3-mercapto-2-phenylmethylpropionyl)-4-(2-thiazolyl)-L-phenylalanine; N-(3-mercapto-2-phenylmethylpropionyl)-4-(2-pyridyl)-L-phenylalanine; N-(3-mercapto-2-phenylmethylpropionyl)-4-(3-pyridyl)-L-phenylalanine; N-(3-mercapto-2-phenylmethylpropionyl)-4-(2-furyl)-L-phenylalanine; N-(3-mercapto-2-phenylmethylpropionyl)-4-(5-pyrimidinyl)-L-phenylalanine; N-(3-mercapto-2-phenylmethylpropionyl)-4-(2-pyrazinyl)-L-phenylalanine; N-(3-mercapto-2-phenylmethylpropionyl)-4-(2-thienyl)-L-phenylalanine; N-(3-mercapto-2-phenylmethylpropionyl)-4-(3-thienyl)-L-phenylalanine; N-(3-mercapto-2-phenylmethylpropionyl)-4-(3-furyl)-L-phenylalanine; N-[3-mercapto-2-(3-pyridylmethyl)propionyl]-4-(2-thiazolyl)-L-phenylalanine; N-[3-acetylthio-2-(3-methoxyphenyl)methylpropionyl]-4-(2-thiazolyl)-L-phenylalanine methyl ester; N-[3-acetylthio-2-(2-fluorophenyl)methylpropionyl]-4-(2-thiazolyl)-L-phenylalanine methyl ester; N-[3-phenylcarbonylthio-2-(2-thienyl)methylpropionyl]-4-(2-thiazolyl)-L-phenylalanine methyl ester; N-[2-(2-furyl)methyl-3-phenylcarbonylthiopropionyl]-4-(2-thiazolyl)-L-phenylalanine methyl ester; N-[2-(3-methyl-5-isoxazolyl)methyl-3-phenylcarbonylthiopropionyl]-4-(2-thiazolyl)-L- phenylalanine methyl ester; N-[3-mercapto-2-(3-methoxyphenyl)methylpropionyl]-4-(2-thiazolyl)-L-phenylalanine; N-[3-mercapto-2-(3-thienyl)methylpropionyl]-4-(2-thiazolyl)-L-phenylalanine; N-[3-mercapto-2-(3-methyl-5-isoxazolyl)methylpropionyl]-4-(2-thiazolyl)-L-phenylalanine; N-[2-(2-fluorophenyl)methyl-3-mercaptopropionyl]-4-(2-thiazolyl)-L-phenylalanine; N-[2-(2-furyl)methyl-3-mercaptopropionyl]-4-(2-thiazolyl)-L-phenylalanine; and the stereoisomers (2S) or (2R) thereof.