Patent EA-000743-B1 (EA)
Title: Phosphonic acid derivatives with metallopeptidase inhibitory activity
Inventor: NORCINI GABRIELE
IPC: A61P9/04
Filed: 1996-11-11
Abstract: A compound of formula   wherein R is a straight or branched C1-C6 alkyl group optionally substituted with one or more fluorine atoms, an aryl or arylalkyl group with from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is a phenyl, 1-naphthyl, 2-naphthyl group or a 5 or 6 membered aromatic heterocycle with 1 or 2 heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted with one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkyl, alkoxy, alkylthio, alkylsulphonyl or alkoxycarbonyl groups with from 1 to 3 carbon atoms in the alkyl moiety, carboxy groups, aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or dialkylaminocarbonyl groups with from 1 to 3 carbon atoms in the alkyl moiety; R1 and R2, the same or different, represent a hydrogen atom or a straight or branched C1-C4 alkyl group; R3 is a straight or branched C1-C6 alkyl group or an arylalkyl group with from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is a phenyl, 1-naphthyl, 2-naphthyl group or a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted as indicated for R; R4 is a 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted with a 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur or with a phenyl group, or it is a phenyl group optionally substituted with a 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur, being the phenyl and the heterocyclic groups 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; X is a single bond or an -O-CONH- or -CONH- group; the carbon atoms marked with an asterisk are asymmetric carbon atoms; and pharmaceutically acceptable salts thereof; provided that R4 is not an imidazolyl or indolyl group. 2. A compound according to claim 1 wherein R4 represents a phenyl group substituted in position 4 with a 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur. 3. A compound according to claim 2 wherein R1 and R2 represent a hydrogen atom and R3 represents a straight or branched C1-C4 alkyl group. 4. A compound 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 phosphorylated derivative of formula   wherein R, R1 and X have the meanings reported in claim 1, W represents a halogen atom and Y represents a protective group selected among a C1-C4 alkyl, a phenyl or a phenylalkyl with from 1 to 4 carbon atoms in the alkyl moiety; and a dipeptide derivative of formula   wherein R2, R3 and R4 have the meanings reported in claim 1. 6. A pharmaceutical composition containing a therapeutically effective amount of a compound of formula I according to claim 1 in admixture with a carrier for pharmaceutical use. 7. A pharmaceutical composition according to claim 6 for the treatment of cardiovascular diseases. 8. 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. 9. A compound of formula I according to claim 1 selected between N-(N'-propyl-phosphonyl-L-leucyl)-[4-(2-furyl)-L-phenylalanine and N-(N'-propylphosphonyl-L-valyl)-[4-(2-thiazolyl)-L-phenylalanine.