Patent EA-004048-B1 (EA)
Title: New benzene derivatives, preparation method and pharmaceutical compositions containing same
Inventor: BOIGEGRAIN ROBERT
IPC: C07D295/08
Filed: 2000-06-27
Abstract: 1. A compound of formula: in which: -A represents a group chosen from the following: -C [triple bond] C-, -CH=CH-; -CH2-CH2- n is equal to 1 or 2; X represents a hydrogen, chlorine or fluorine atom or a methyl or methoxy group; Y represents a hydrogen atom or a chlorine or fluorine atom; R1 represents a cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with a methyl group; a phenyl group monosubstituted or disubstituted with a fluorine or chlorine atom or with a (C1-C3)alkoxy or trifluomethyl group; a cycloheptyl, tert-butyl, dicyclopropylmethyl, bicyclo[3.2.1]octanyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl or 1- or 2-adamantyl or adamantan-2-ol group; or R1 represents a phenyl group, it being understood that, in this case, X and Y are other than hydrogen; or R1 represents cyclohexyl group, it being understood that, in this case, X and Y are other than hydrogen. R2 and R3 form together with nitrogen atom, they are connected with, 5-8-membered amino ring; morphyl group, optionally substituted in 3 and 5 positions by methyl; or 4-phenyl-1,2,3,6-tetrahydropyridyl group, optionally substituted on phenyl by halogen or trifluomethyl, (C1-C4)alkyl or (C1-C4)alkoxy group; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as the solvates and hydrates thereof. 2. A compound according to claim 1, in which: A represents a group chosen from the following: -C [triple bond] C-, -CH=CH-; -CH2-CH2-; n is equal to 1; X represents a hydrogen, chlorine or fluorine atom or a methyl group; Y represents a hydrogen atom or a chlorine; R1 represents a cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with a methyl group; a phenyl group monosubstituted or disubstituted with a fluorine or chlorine atom or with a methoxy or trifluomethyl group; tert-butyl, or 1- or 2-adamantyl group; or R1 represents a phenyl group, it being understood that, in this case, X and Y are other than hydrogen; or R1 represents cyclohexyl group, it being understood that, in this case, X and Y are other than hydrogen. R2 and R3 form together with nitrogen atom, they are connected with, 6-8-membered amino ring; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as the solvates and hydrates thereof. 3. A compound according to any of claims 1and 2 of formula: in which: A represents a group chosen from the following: -C [triple bond] C-, -CH=CH-; -CH2-CH2-; X represents a hydrogen or chlorine atom; Y represents a hydrogen atom or a chlorine atom; R1 represents a cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with a methyl group; a phenyl group monosubstituted or disubstituted with a fluorine or chlorine atom or with a methoxy group; tert-butyl, or 1- or 2-adamantyl group; or R1 represents a cyclohexyl or phenyl group, it being understood that, in this case, X and Y are other than hydrogen; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as the solvates and hydrates thereof. 4. A compound according to any of claims 1-3 in which A represents a -C [triple bond] C- group of (Z) configuration. 5. A compound according to any of claims 1-4 in which X represents a chlorine atom and Y represents a hydrogen atom. 6. A compound according to claim 5 in which R1 represents a phenyl group monosubstituted or disubstituted with a fluorine atom or a chlorine atom, or methoxy group, and the addition salts of these compounds with pharmaceutically acceptable acids, as well as the solvates and hydrates thereof. 7. Compounds: -1-[(Z)-3-(2-Chloro-3'-fluorobiphenyl-4-yl)propen-2-yl]azepane -1-[(Z)-3-(2-Chloro-3'-5'-difluorobiphenyl-4-yl)propen-2-yl]azepane ; -1-[(Z)-3-(2-Chloro-3'-methoxybiphenyl-4-yl)propen-2-yl]azepane ; according to claim 1, as well as the salts thereof with pharmaceutically acceptable acids and the solvates and hydrates thereof. 8. 1-[(Z)-3-(2-Chloro-3'-methoxybiphenyl-4-yl)propen-2-yl]azepane according to claim 1 as well as the salts thereof with pharmaceutically acceptable acids, solvates thereof and hydrates thereof. 9. A process for preparing a compound according to claim 1, in which A represents a -C [triple bond] C-, group characterized in that if n=1, a Mannich reaction is carried out between the phenylacetylene derivative of formula: in which R1, X and Y are as defined for (I), the formaldehyde and the amine (1) HNR2R3, R2 and R3 being as defined for (I). 10. A process for preparing a compound according to claim 1, in which A represents a -C [triple bond] C-, group characterized in that a Suzuki coupling is carried out between the compound of formula: in which X, Y, n, R2 and R3 are as defined for (I) and Z represents a bromine, an iodine or a trifluoromethanesulphonate (OTf) group and a boron derivative (2) of formula R1-B(OR)2 in which R represents a hydrogen atom or an alkyl or aryl group in the presence of a base and a metal catalyst; 11. A process for preparing a compound according to claim 1, in which A represents a -C [triple bond] C-, group, characterized in that, when R1 represents a cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with a methyl group; a cycloheptyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl or adamantyl group, a coupling is carried out between compound (Ia) in which Z represents an iodine or bromine atom and the ketone (3) corresponding to R1 represented by in the presence of a base, to give the intermediate compound of formula in which X, Y, n, R2 and R2 are as defined for (I); the said compound (I') then being reduced under selective conditions; 12. A process for preparing a compound according to claim 1, in which A represents a -C [triple bond] C-, group, characterized in that coupling reaction is carried out between the amine of formula: in which n, R2 and R3 are as defined for (I), and the compound of formula: in which R1, X and Y are as defined for (I) and Z represents a bromine or iodine atom or a trifluoromethylsulphonate (triflate or OTf) group. 13. A process for preparing a compound according to claim 1, in which A represents a -CH=CH-group characterized in that a hydrogenation is carried out, with nascent hydrogen or in the presence of cyclohexene, of compound (I) in which A represents an acetylene group -C [triple bond] C-, in order to prepare the ethylenic compound (I) in the form of a mixture of the Z and E isomers, or this hydrogenation is carried out in the presence of a metal catalyst on a support in order to prepare the ethylenic compound (I) in Z form, or alternatively compound (I) in which A represents an acetylene group -C [triple bond] C- is reacted with a metal hydride in order to prepare the ethylenic compound (I) in E form. 14. A process for preparing a compound according to claim 1, in which A represents a -CH2-CH2 -group characterized in that a hydrogenation of compound (I), in which A represents a -CH=CH- or -C [triple bond] C- group, is carried out. 15. A pharmaceutical composition containing, as active principle, a compound according to any one of claims 1 to 8. 16. Use of compound according to any of claims 1-8 for preparing medical product, destined for treatment of psychotic disorders. 17. Use of compound according to any of claims 1-8 for preparing medical product, destined for treatment of positive and negative symptoms of schizophrenia.