Patent EA-002527-B1 (EA)
Title: TETRAHYDROFURO[2,3-c]PYRIDINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND USE AS METALLOPROTEASE INHIBITORS
Inventor: DE NANTEUIL GUILLAUME
IPC: A61P35/00
Filed: 2000-06-30
Abstract: 1. Compounds of formula (I):   wherein: R1 represents a hydrogen or halogen atom, or a linear or branched (C1-C6)alkyl or linear or branched (C1-C6)alkoxy group, R2 represents a hydroxy, linear or branched (C1-C6)alkoxy or -NHOH group, Ar1 represents a phenylene or biphenylene group, X represents an oxygen or sulphur atom, an NR group, a -C [triple bond] [triple bond] C- group or a bond, R represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, n is an integer from 0 to 6 inclusive, Ar2 represents: - a phenyl group substituted by a heteroaryl group, - a biphenyl group substituted by a heteroaryl group, - a pyridinyl group substituted by a heteroaryl group, or - a heterocyclic group,  their isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: - "heteroaryl group" is understood to mean a mono-cyclic aromatic group- or bi-cyclic aromatic group wherein at least one cycle is aromatic containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched trihalo-(C1-C6)alkyl, linear or branched trihalo-(C1-C6)alkoxy, and hydroxy, - "heterocyclic group" is understood to mean a saturated or partially saturated, mono- or bi-cyclic non-aromatic group containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched trihalo-( C1-C6)alkyl, linear or branched trihalo-( C1-C6)alkoxy, and hydroxy. 2. Compounds of formula (I) according to claim 1, characterised in that X represents an oxygen atom or a sulphur atom. 3. Compounds of formula (I) according to either claim 1 or claim 2, characterised in that R2 represents an -NHOH group. 4. Compounds of formula (I) according to any one of claims 1, 2 and 3, characterised in that Ar1 represents a phenylene group and n is zero. 5. Compounds of formula (I) according to claim 4, characterised in that Ar2 represents a phenyl group substituted by a heteroaryl group. 6. Compounds of formula (I) according to claim 5, characterised in that Ar2 represents a phenyl group substituted by a group selected from imidazolyl, triazolyl and pyridinyl. 7. Compounds of formula (I) according to any one of claims 1 to 6, characterised in that X represents an oxygen or sulphur atom, R2 represents an -NHOH group, Ar1 represents a phenylene group, n is zero, and Ar2 represents a phenyl group substituted by a group selected from imidazolyl, triazolyl and pyridinyl. 8. Compounds of formula (I) according to any one of claims 1, 2 and 3, characterised in that Ar1 represents a biphenylene group and Ar2 represents a heterocyclic group. 9. Compound of formula (I) according to claim 1 which is 6-{4-[4-(imidazol-l-yl)phenoxy]benzenesulphonyl} -4,5,6,7-tetrahydrofuro [2,3-c]pyridine-(572)-(N-hydroxy)-carboxamide, and its addition salts with a pharmaceutically acceptable acid or base. 10. Compound of formula (I) according to claim 1 which is 6-{4'-[2-(pyrrolidin-l-yl)ethoxy]biphenyl-4-sulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-(5R)-(N-hydroxy)-carboxamide hydrochloride, and its addition salts with a pharmaceutically acceptable acid or base. 11. Compound of formula (I) according to claim 1 which is 6-{4-[4-(l,3,4-triazol-l-yl)-phenoxy]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-(5R)-(N-hydroxy)-carboxamide, and its addition salts with a pharmaceutically acceptable acid or base. 12. Compound of formula (I) according to claim 1 which is 6-{4-[4-(pyridin-4-yl)-phenoxy]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-(5R)-(N-hydroxy)-carboxamide, and its addition salts with a pharmaceutically acceptable acid or base. 13. Compound of formula (I) according to claim 1 which is 6-{4-[(4-(l,3,4-triazol-l-yl)phenylthio]benzenesulphonyl}-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-(5R)-(N-hydroxy)-carboxamide, and its addition salts with a pharmaceutically acceptable acid or base. 14. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that there is used as starting material a compound of formula (II), in racemic form or in the form of a specific isomer:   wherein R1 is as defined for formula (I), and R' represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, the amine function of which is substituted by a halogen compound of formula (III): C1SO2-Ar1-X-(CH2)n-Ar2           (III) wherein Ar1, X, n and Ar2 are as defined for formula (I), to yield: - when R' represents a hydrogen atom, a compound of formula (I/a), a particular case of the compounds of formula (I):   wherein R1, Ar1, X, N and Ar2 are as defined hereinbefore, - or, when R' represents a linear or branched (C1-C6)alkyl group (R"), a compound of formula (I/ai), a particular case of the compounds of formula (I):   wherein R1, Ar1, X, n, Ar2 and R" are as defined hereinbefore, which may be subjected to the action of an acid, to yield a compound of formula (I/a) described hereinbefore, * which compound of formula (I/a) : is subjected, if desired, to the action of an O-substituted hydroxylamine, to yield, after deprotection of the hydroxylamine function, a compound of formula (I/b),   wherein R1, Ar1, X, n and Ar2 are as defined hereinbefore, * which compounds of formulae (I/a), (I/ai) and (I/b) constitute the totality of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, are seperated, where appropriate, into their isomers according to a conventional separation technique, and are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base. 15- Pharmaceutical compositions comprising as active ingredient a compound according to any one of claims 1 to 13, in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers. 16- Pharmaceutical compositions according to claim 15 comprising as active ingredient a compound according to any one or claims 1 to 13 for use as metalloprotease inhibitors.