Patent EA-004254-B1 (EA)
Title: Metalloprotease inhibitors, process for their preparation and pharmaceutical compositions containing them
Inventor: DE NANTEUIL GUILLAUME
IPC: A61P43/00
Filed: 2001-12-21
Abstract: 1. Compounds of formula (I): wherein: R1 represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)alkoxy group, X represents an oxygen atom, a sulphur atom or an NR group wherein R represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, A represents any one of the following groups: wherein Ra represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)alkoxy group, wherein Rb and Rc, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, and n is 0,1 or 2, or their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I) according to claim 1, characterised in that A represents the group: their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1, characterised in that A represents the group: their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1, characterised in that A represents the group: their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 3, characterised in that A represents the group: their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compound of formula (I) according to either claim 1 or claim 2, which is N-hydroxy-(5R)-6-{[2-(4-pyridyl)-1-benzofuran-5-yl]sulphonyl}-4,5,6,7-tetrahydro[2,3-c]-pyridine-5-carboxamide, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compound of formula (I) according to any one of claims 1, 3 or 5, which is N-hydroxy-(3S)-2,2-dimethyl-4-{[2-(4-pyridyl)-1-benzofuran-5-yl]sulphonyl}-3-thiomorpholine-carboxamide, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compound of formula (I) according to either claim 1 or claim 4, which is N-hydroxy-4-{{[2-(4-pyridyl)-1-benzofuran-5-yl]sulphonyl}methyl}tetrahydro-2''-pyran-4-carboxamide, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 9. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that, when the compounds of formula (I) are those wherein A represents any one of the groups: there is used as starting material a compound of formula (II): wherein R1 and X are as defined for formula (I) and Hal represents a halogen atom, which is reacted with any one of compounds (IIIa) and (IIIb), in racemic form or in the form of a specific isomer: wherein RB, RC and n are as defined for formula (I), to yield the compounds of formulae (IVa) and (IVb), respectively: wherein X, R1, RB, RC and n are as defined for formula (I), which are deprotected to yield the compounds of formulae (Va) and (Vb), respectively, wherein X, R1, Rb, Rc and n are as defined for formula (I), which are subjected to the action of an O-substituted hydroxylamine, to yield, after deprotection of the hydroxamate function, the compounds of formulae (I/a) and (I/b), respectively: wherein X, R1, Rb, Rc and n are as claimed for formula (I), which compounds of formulae (I/a) and (I/b): - are optionally converted to the corresponding N-oxides, - are purified, if necessary, in accordance with a conventional purification technique, - are separated, where appropriate, into their isomers in accordance with a conventional separation technique, and - converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base. 10. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that, when the compounds of formula (I) are those wherein A represents the group: the process is characterised in that there is used as starting material a compound of formula (VI): wherein R] and X are as defined for formula (I), and Hal represents a halogen atom, which is reacted with a compound of formula (VII): wherein Alk represents a linear or branched (C1-C6)alkyl group, to yield, after reaction in an acid medium, the compound of formula (VIII): wherein R1 and X are as defined for formula (I), which is reacted with an oxidation reagent, to yield the compound of formula (IX): wherein X and R1 are as defined for formula (I), which is subjected to the action of an O-substituted hydroxylamine, to yield, after deprotection of the hydroxamate function, the compound of formula (I/c), a particular case of the compounds of formula (I): wherein R1 and X are as defined for formula (I), which is optionally converted to the corresponding N-oxide, which is purified, if necessary, in accordance with a conventional purification technique, separated, where appropriate, into its isomers in accordance with a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base. 11. Pharmaceutical compositions comprising as active ingredient at least one compound according to any one of claims 1 to 8, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. 12. Pharmaceutical compositions according to claim 11 comprising at least one active ingredient according to any one of claims 1 to 8 for use as metalloprotease inhibitors.