Patent EA-003255-B1 (EA)
Title: Combination of tetrahydropyridin derivatives and acetylcholinesterase inhibiting agents for treating senile dementia such as alzheimer dementia
Inventor: MAFFRAND JEAN-PIERRE
IPC: A61P25/28
Filed: 1998-11-09
Abstract: 1. A pharmaceutical composition containing as active ingredients - a compound (a) selected from 1-(2-naphth-2-ylethyl) -4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and a compound of formula (I): in which Y is -CH- or -N-; R1 is hydrogen, halogen, a CF3, (C3-C4) alkyl or (C1-C4) alkoxy group; R2 is hydrogen, halogen, hydroxyl, CF3, (C3-C4) alkyl or (C1-C4) alkoxy group; R3 and R4 each is hydrogen or (C1-C3) alkyl; X is (a) (C3-C6) alkyl; (C3-C6) alkoxy; (C3-C7) carboxyalkyl; (C1-C4) alkoxycarbonyl (C3-C6) alkyl; (C3-C7) carboxyalkoxy; or (C1-C4) alkoxycarbonyl (C3-C6) alkoxy; (b) a radical selected from (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical being optionally substituted by halogen, hydroxy, (C1-C4) alkoxy, carboxy, (C1-C4) alkoxycarbonyl, amino, mono or di-(C1-C4) alkylamino; or (c) a group selected from phenyl, phenoxy, phenylamino, N-(C1-C3) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl, said phenyl group being optionally mono- or polysubstituted by halogen, CF3, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, amino, mono- or di-(C1-C4) alkylamino, (C1-C4) acylamino, carboxy, (C1-C4) alkoxycarbonyl, aminocarbonyl, mono- or di-(C1-C4) alkylaminocarbonyl, amino (C1-C4) alkyl, hydroxy (C1-C4) alkyl or halogeno (C1-C4) alkyl; optionally in the form of one of its pharmaceutically acceptable salts and - a compound (b) which is an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts. 2. The composition according to Claim 1, characterized in that contains 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine as a compound of the compound (a), optionally in the form of one of its pharmaceutically acceptable salts. 3. The composition according to Claim 1, characterized in that contains as the (a) compound - compound of formula (I): in which Y is -CH- or -N-; R1 is hydrogen, halogen, a CF3, (C3-C4) alkyl or (C1-C4) alkoxy group; R2 is hydrogen, halogen, hydroxyl, CF3, (C3-C4) alkyl or (C1-C4) alkoxy group; R3 and R4 each is hydrogen or (C1-C3) alkyl; X is (a) (C3-C6) alkyl; (C3-C6) alkoxy; (C3-C7) carboxyalkyl; (C1-C4) alkoxycarbonyl (C3-C6) alkyl; (C3-C7) carboxyalkoxy; or (C1-C4) alkoxycarbonyl (C3-C6) alkoxy; (b) a radical selected from (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical being optionally substituted by halogen, hydroxy, (C1-C4) alkoxy, carboxy, (C1-C4) alkoxycarbonyl, amino, mono or di-(C1-C4) alkylamino; or (c) a group selected from phenyl, phenoxy, phenylamino, N-(C1-C3) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl, said phenyl group being optionally mono- or polysubstituted by halogen, CF3, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, amino, mono- or di-(C1-C4) alkylamino, (C1-C4) acylamino, carboxy, (C1-C4) alkoxycarbonyl, aminocarbonyl, mono- or di-(C1-C4) alkylaminocarbonyl, amino (C1-C4) alkyl, hydroxy (C1-C4) alkyl or halogeno (C1-C4) alkyl; optionally in the form of one of its pharmaceutically acceptable salts and - a compound (b) which is an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts. 4. Composition according to Claim 3, characterized in that compound (a) is selected from the following compounds: 1-{2-(3'-chloro-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(2'-chloro-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4'-chloro-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4'-fluoro-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3'-trifluoromethyl-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-cyclohexylphenyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-biphenylyl)ethyl}-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-pyridine; 1-{2-(4-biphenylyl)-2-methylpropyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-phenoxyphenyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-benzylphenyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-n-butylphenyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-n-butoxyphenyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-(4-ethoxycarbonylpropoxy)phenyl)ethyl}-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-biphenylyl)ethyl}-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydro-pyridine; 1-{2-(2,3'-dichloro-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3-chloro-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3',5'-dichloro-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(2',4'-dichloro-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(2-chloro-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3'-chloro-4-biphenylyl) -2-methylpropyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(2-fluoro-4-biphenylyl)propyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-methoxy-3-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4'-methoxy-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4'-hydroxy-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4'-ethoxycarbonylbutoxy-4-biphenylyl)ethyl}-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine; 1-{2-(3'-chloro-4'-fluoro-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(2'-trifluoromethyl-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3,4-diisobutylphenyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3,4-dipropylphenyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-cyclohexylphenyl)ethyl}-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-isobutylphenyl)propyl}-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine; and their pharmaceutically acceptable salts. 6. Composition according to Claim 1, characterized in that the acetylcholinesterase inhibitor is selected from tacrine and donepezil. 7. Composition according to Claim 1, characterized in that the acetylcholinesterase inhibitor is selected from rivastigmine, galanthamine, metrifonate, eptastigmine, velnacrine, phystostigmine, icozepil and zifrosilone. 8. Composition according to Claim 1, characterized in that it contains from 0.5 to 700 mg of compound (a). 9. Composition according to Claim 1, characterized in that it contains from 0.1 to 50 mg of compound (b). 10. Composition according to Claim 2, characterized in that it contains from 0.5 to 10 mg of 1-(2-naphth-2-ylethyl)-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine. 11. Composition according to Claim 2, characterized in that it contains as active ingredients 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and donepezil or their pharmaceutically acceptable salts. 12. Composition according to Claim 3, characterized in that it contains as active ingredients 1-{2-(4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and donepezil or their pharmaceutically acceptable salts. 13. Composition according to Claim 2 containing 0.5 to 5 mg of 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 2 to 10 mg of donepezil. 14. Composition according to any one of the preceding Claims for the treatment of senile dementia of the Alzheimer type. 15. Use of the composition according to any one of the preceding Claims for the preparation of medicines designed for the treatment of senile dementia of the Alzheimer type. 16. Use according to Claim 15, characterized in that the compound (a) is selected from 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 1-{2-(4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine. 17. Use according to Claim 15, characterized in that the compound (b) is selected from tacrine and donepezil.