Patent EA-004268-B1 (EA)
Title: Novel cyclobutendione compounds, process of preparation and pharmaceutical compositions, containing them
Inventor: PEGLION JEAN-LOUIS
IPC: C07D211/22
Filed: 2001-10-12
Abstract: 1. A compound selected from those of formula (I): wherein: X represents: - a monocyclic or bicyclic, saturated, partially unsaturated or aromatic heterocycle, having from 5 to 12 ring members, containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur but containing at least one nitrogen, the heterocycle being bonded to the remainder of the molecule by the nitrogen, and the heterocycle being optionally substituted, - or a group of formula -NR2R3 wherein R2 represents hydrogen or linear or branched (C1-C6)alkyl, and R3 represents optionally substituted aryl, 1,3-dihydro-2H-benzimidazolyl-2-one, or linear or branched (C1-C6)alkyl substituted by a monocyclic or bicyclic, saturated, partially unsaturated or aromatic heterocycle, having from 5 to 12 ring members, containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur but containing at least one nitrogen, the heterocycle being optionally substituted, n represents zero or 1, R1 represents hydrogen or linear or branched (C1-C6) alkyl, Ra represents a single bond or a linear or branched (C1-C6)alkylene chain, A represents a nitrogen atom or a CH group, but A represents only a CH group when Ra represents a single bond, and A represents only a nitrogen atom when n represents zero, E represents a nitrogen atom or a CRe group wherein Re represents either a hydrogen atom, or a bond to a carbon atom of W, it being understood that at least one of the groups A and E represents a nitrogen atom, Rb represents a single bond or a linear or branched (C1-C6)alkylene chain, one of the carbon atoms of which is optionally replaced by an oxygen atom or a sulphur atom, W represents an aryl or heteroaryl group, each of those groups being optionally substituted, their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid, it being understood that: - "aryl group" is understood to mean a group selected from phenyl, biphenyl, bicyclo[4.2.0]octa-1,3,5-trienyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl and indenyl, - "heteroaryl group" is understood to mean an aryl group as defined above containing from 1 to 3 identical or different hetero atoms selected from oxygen, nitrogen and sulphur, - "optionally substituted", when associated with "heterocycle", "aryl group" or "heteroaryl group", is understood to mean optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, mercapto, linear or branched (C1-C6)alkylthio, linear or branched (C1-C6)trihaloalkyl, cyano, nitro, amino, linear or branched (C1-C6)-alkylamino, dialkylamino in which each alkyl moiety has from 1 to 6 carbon atoms and is linear or branched, and methylenedioxy, - "optical isomers" are understood to mean the enantiomers and diastereoisomers. 2. The compound of claim 1, which is selected from those of formula (IA): wherein X, R1, Ra, A, E, Rb and W are as defined for formula (I), their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 3. The compound of claim 1, wherein X represents a heterocycle, as defined for formula (I), their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 4. The compound of claim 1, wherein X represents a group of formula -NR2R3, as defined for formula (I), their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 5. The compound of claim 1 or 3, wherein X represents a 1-indolinyl group optionally substituted by one or more groups as defined for formula (I), their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 6. The compound of claim 1 or 3, wherein X represents 2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl optionally substituted by one or more groups as defined for formula (I), their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 7. The compound of claim 1 or 4, wherein X represents a group of formula -NR2R3 wherein R2 represents hydrogen and R3 represents optionally substituted phenyl, their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 8. The compound of claim 1, wherein W represents heteroaryl, their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 9. The compound of claim 1 or 8, wherein W represents benzofuryl or indolyl, their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 10. The compound of claim 1, wherein -Rb-W together represents aryloxyalkyl in which the alkyl moiety has from 1 to 5 carbon atoms and is linear or branched and the aryl moiety is optionally substituted, their optical isomers, their hydrates, their solvates and addition salts thereof with pharmaceutically acceptable acid. 11. The compound of claim 1, selected from: 3-anilino-4-({2-[4-(phenoxymethyl)-1-piperidinyl]ethyl}amino)-3-cyclobutene-1,2-dione and its methanesulphonate, 3-(4-chloroanilino)-4-({2-[4-(phenoxymethyl)-1-piperidinyl]ethyl}amino)-3-cyclo-butene-1,2-dione and its methanesulphonate, 3-(2,3-dihydro-1H-indol-1-yl)-4-({2-[4-(phenoxymethyl)-1-piperidinyl]ethyl}amino)-3-cyclobutene-1,2-dione and its methanesulphonate, 3-({1-[2-(1-benzofuran-3-yl)ethyl]-4-piperidinyl}amino)-4-(4-fluoroanilino)-3-cyclo-butene-1,2-dione and its methanesulphonate, 4-{[2-({1-[2-(1-benzofuran-3-yl)ethyl]-4-piperidinyl}amino)-3,4-dioxo-1-cyclobuten-1-yl]amino}benzonitrile and its methanesulphonate, 3-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-4-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-3-cyclobutene-1,2-dione and its methanesulphonate 3-(5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-4-({2-[4-(phenoxymethyl)-1-piperidinyl]ethyl}amino)-3-cyclobutene-1,2-dione and its dihydrochloride, 3-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-4-(5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-3-cyclobutene-1,2-dione and its dihydrochloride 3-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-4-(4,5,6-trimethoxy-2,3-dihydro-1H-indol-1-yl)-3-cyclobutene-1,2-dione and its methanesulphonate, 3-(6-chloro-2,3-dihydro-1H-indol-1-yl)-4-[(2-{4-[2-(4-fluorophenoxy)-ethyl]-1-piperidinyl}ethyl)amino]-3-cyclobutene-1,2-dione and its methanesulphonate, 3-(2,3-dihydro-1H-indol-1-yl)-4-[({1-[2-(1H-indol-3-yl)ethyl]-3-piperidinyl}methyl)amino]-3-cyclobutene-1,2-dione and its hydrochloride, 3-(5,6-dimethoxy-2,3-dihydro-1H-indol-1-yl)-4-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-3-cyclobutene-1,2-dione and its methanesulphonate, 3-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-4-(6-methoxy-2,3-dihydro-1H-indol-1-yl)-3-cyclobutene-1,2-dione and its methanesulphonate, and 3-(4,5-dimethoxy-2,3-dihydro-1H-indol-1-yl)-4-[(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidinyl}ethyl)amino]-3-cyclobutene-1,2-dione and its methanesulphonate. 12. Process for the preparation of compounds of formula(I) according to claim 1, characterized in that there is used as starting material a compound of formula (II): wherein G represents a linear or branched (C1-C4)alkyl group, which compound of formula (II) is reacted with an amine of formula (III): X-H (III), wherein X is as defined for formula (I), to yield a compound of formula (IV): wherein X and G are as defined hereinbefore, which compound of formula (IV) is treated with a compound of formula (V): wherein n, R1, Ra, Rb, A, E and W are as defined for formula (I), to yield compounds of formula (I) as defined: which compounds of formula (I) are purified, if necessary, according to a conventional purification technique, may, if desired, be separated into their different isomers according to a conventional separation technique, and are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid. 13. A pharmaceutical composition comprising as active principle at least one compound of formula (I) as claimed in any of claims 1-11, together with one or more inert, non-toxic pharmaceutically acceptable excipients or vehicles. 14. A pharmaceutical composition comprising at least one active principle, as claimed in any of claims 1-11, useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known. 15. A pharmaceutical composition comprising at least one active principle, as claimed in any of claims 1-11, useful in preventing the development and extension of atherosclerotic lesions, and atherosclerotic lesions, associated with them, and in the prevention of vascular complications after vascular bypass, vascular dilatation, vascular repermeabilisation, in the treatment of myocardial or peripheral ischaemia, cardiac insufficiency, pulmonary arterial hypertension, and heart transplantation.