OA11464A

OA11464A - Combination of active principles, in particular oftetrahydropyridins and acetylcholinesterase inhib iting agents, for treating senile dementia such asAlzheimer dementia.

Info

Publication number: OA11464A
Application number: OA1200000141A
Authority: OA
Inventors: Jean-Pierre Maffrand; Philippe Soubrie; Jean-Paul Terranova
Original assignee: Sanofi Synthelabo
Priority date: 1997-11-14
Filing date: 2000-05-12
Publication date: 2003-11-18
Also published as: IL136122A0; PL194597B1; AU743228B2; HUP0100098A2; EE200000290A; WO1999025363A1; IS5482A; HUP0100098A3; CN1285742A; JP2001523642A; SK286040B6; EE04235B1; KR20010032099A; TR200001262T2; AU1160999A; NZ504420A; SK7112000A3; CN1243540C; KR100599350B1; SA98190747B1

Abstract

The invention concerns a pharmaceutical composition containing as active principles: a constituent (a) selected between 1-(2-napht-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin and a compound (I) in which: Y represents -CH- or -N-; R1 represents hydrogen, a halogen, a hydroxyl, a CF3, a (C3-C4)alkyl or (C1-C4) alkoxyl group; R2 represents hydrogen, a halogen, a hydroxyl, a CF3, (C3-C4) alkyl or( C1-C4)alkoxyl group; R3 and R4 represent each hydrogen or a (C1-C4)alkyl; X represents (a) a (C3-C6)alkyl; a (C3-C6)alkoxyl; a (C3-C7)carboxyalkyl; a (C1-C4)alkoxycarbonyl(C3-C6-)alkyl; a (C3-C7)carboxyalkoxyl; or a (C1-C4)alkoxycarbonyl(C3-C6)alkoxyl; (b) a radical selected among a (C3-C7)cycloalkyl, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkylmethyl, (C3-C7)cycloalkylamino and cyclohexenyl, said radical capable of being substituted by a halogen, hydroxy, (C1-C4)alkoxy, carboxy, (C1-C4)alkoxycarbonyl, amino, mono- or di-(C1-C4)alkyamino or (c) a group selected among phenyl, phenoxy, phenylamino, N-(C1-C3)alkyl-phenyl-amino, phenylmethyl, phenylethyl, p henylcarbonyl, phenylthio, phenylsulphonyl, phenylsulphinyl and styryl, said group capable of being mono- or polysubstituted on the phenyl group by a 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)alk yl, hydroxy(C1-C4)alkyl, or halogeno(C1-C4)alkyl; optionally in the form of one of its pharmaceutically acceptable salts; and an constituent (b) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when constituent (a) is other than 1-(2napht-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin or one of its pharmaceutically acceptable salts, the constituent (b) is an acetylcholinesterase inhibiting agent.

Description

1 10 15 20 25 30 35 011464

The object of the présent invention is apharmaceutical composition containing a novel combinationof active ingrédients for the.treatment of senile dementiaof the Alzheimer type, constituted of 1,2,3,6-tetrahydropyridine dérivatives, optionally in the form ofone of their pharmaceutically acceptable salts and asubstance active in the symptomatic treatment of seniledementia of the Alzheimer type, in particular anacetylcholinesterase inhibitor, optionally in the form ofone of its pharmaceutically acceptable salts and its usefor the préparation of medicines designed for thetreatment of senile dementia of the Alzheimer type.

Senile dementia of the Alzheimer type designatedhereafter DAT ("dementia of the Alzheimer type") is aneurodegenerative disease characterized clinically by theprogressive degeneration of cognitive functions, occurringin elderly people with an incidence which increases withâge. In the light of démographie trends DAT will become anincreasingly widespreâd disease.

A réduction of the level of severalneurotransmitters, of acétylcholine in particular, hasbeen observed in patients suffering from DAT

The only treatment for DAT currently available commercially consists acetylcholinesterase inhibitors which by reducinghydrolysis of acétylcholine thus increase bioavailability. Hence it is a symptomatic treatment. of administeringthe its

Tacrine, marketed under the trade mark COGNEX , and

donepezil, sold under the trade mark ARICEPT are the acetylcholinesterase inhibitors indicated forsymptomatic treatment of mild to moderate forms of DAT.Other products for the symptomatic treatment of DAT areunder study. Some of them also act on the availability ofacétylcholine, others improve the symptomatology of patients suffering from DAT by other mechanisms.

Hitherto, no commercially available medicine has proved capable of slowing the progression of the.-disease. 2 011464 EP-458696 describes the use of l-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,designated in the literature SR 57746, for the préparationof tnedicines designed to combat neurodegenerative States,including senile dementia and Alzheimer's disease. Theneurotrophic action of SR 57746 on the nervous System issimilar to that of certain endogenous neurotrophins suchas, for example, the nerve growth factor (NGF). WO 97/01536 describes novel 4-substituted 1-phenylalkyl-1,2,3,6-tetrahydropyridines having a neuroprotective and neurotrophic activity similar to thatof certain endogenous neurotrophins. As a resuit of thisactivity, it is presumed that the compounds described inthis patent application will be useful in the treatmentof several diseases of the central nervous System,including Alzheimer's disease.

The activity of the compound SR 57746 and thecompounds described in WO 97/01536 in the treatment ofthe nervous diseases such as DAT is not designed to treatthe symptoms but, by protecting the neurones, to modifythe course of the disease and to reduce its progression.

It has now been found that the combination of theabove compounds, optionally in the form of one of theirpharmaceutically acceptable salts, with a compound activein the symptomatic treatment of senile dementia of theAlzheimer type, in particular an acetylcholinesteraseinhibitor, optionally in the form of one of itspharmaceutically acceptable salts, leads to a complété andvery efficacious treatment of DAT, the combinationexerting a rapid and complementary effect.

Thus, the object of the présent invention is apharmaceutical composition containing as activeingrédients a compound (a) selected from 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and a compound of formula (I) : 3 \W/ ch2-Ç- \\;/ '-/-γ \ -/ „ \./ ./ •1 10 15 20 25 R3 .// 4 ι ! „ ζ 011464 ,χ (I) in which Y is -CH- or -N-;

Rl 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 ,- Χ 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 beingoptionally substituted by halogen, hydroxy, (C1-C4)alkoxy, carboxy, (C1-C4) alkoxycarbonyl, amino, mono ordi-(Ci-C4) alkylamino; or (c) a group selected from phenyl, phenoxy, phenylamino, N-(C1-C3) alkylphenylamino, phenylmethyl, phenylethyl,phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinylor styryl, said phenyl group being optionally mono- orpolysubstituted by halogen, CF3, (C1-C4) alkyl, (C1-C4)alkoxy, cyano, amino, mono- or di-(C1-C4) alkylamino, (Ci-C4) acylamino, carboxy, (C1-C4) alkoxycarbonyl,aminocarbonyl, mono- or di-(Ci-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 30 4 011464 - a compound (b) active in the symptomatic treatmentof DAT, optionally in the form of one of itspharmaceutically acceptable salts provided that whencompound (a) is other than 1-(2-naphth-2-ylethyl)-4-(3- 5 trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine or oneof its pharmaceutically acceptable salts, compound (b) isan acetylcholinesterase inhibitor. 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-

1.2.3.6- tetrahydropyridine (SR 57746) was described in EP 10 101 3 81 and the compounds of formula (I) above are described in WO 97/01536. A particularly advantageous compound (a) is l-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (SR 57746), optionally in the form of 15 one of its pharmaceutically acceptable salts.

Of the pharmaceutically acceptable salts of SR 57746,the hydrochloride designated hereafter SR 57746A is aparticularly preferred sait.

An advantageous method for the préparation of SR20 57746A consists of the reaction between 2-(2-bromoethyl) naphthalene and 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and the isolation of 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine hydrochloride which is then25 crystallized from an ethanol/water mixture by heating andcooling to 5°C with a rate of cooling of 10°C/hour and astirring speed of 400 revolutions/minute, so as to obtaina mixture of two crystalline forms in a ratio of about 66/34. 30 SR 57746A is preferably used in a microparticulate form, for example in an essentially amorphous formobtained by spray drying or in a microcrystalline form bymicronization.

Another particularly advantageous compound (a) is 1- 35 {2-(4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)- 1.2.3.6- tetrahydro-pyridine, in particular its hydrochloride sait.

Other advantageous compounds are the following : 5 011464 l-{2-(3'-chloro-4-biphenylyl)ethyl}-4 -(3- trif luoromethylphenyl )-1,2,3,6-tetrahydropyridine ; 1-{2-(2'-chloro-4-biphenylyl)ethyl}-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 5 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- 10 trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-cyclohexylphenyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; l-{2-(4-biphenylyl)ethyl}-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-pyridine; 15 1-{2-(4-biphenylyl)-2-methylpropyl}-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; l-{2-(4-phenoxyphenyl)ethyl}-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine; l-{2-(4-benzylphenyl)ethyl}-4-(3-trifluoromethylphenyl)- 20 1,2,3,6-tetrahydropyridine; 1-{2-(4-n-butylphenyl)ethyl}-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine; l-{2-(4-n-butoxyphenyl)ethyl}-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine; 25 l-{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-(2,31-dichloro-4-biphenylyl)ethyl}-4-(3- 30 trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3-chloro-4-biphenylyl)ethyl}-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(3',51-dichloro-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 35 l-{2-(2',41-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; 6 011464 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; 5 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 - 10 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; 15 l-(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- 20 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; 25 1-(2-(4-isobutylphenyl)propyl}-4-(6-chloropyrid-2-yl)- 1,2,3,6-tetrahydropyridine; and their pharmaceutically acceptable salts.

In the présent description, the expression "compound active in the symptomatic treatment of DAT" désignâtes a 30 product which is capable of improving the symptomatologyof patients suffering from DAT without having an effect onthe causes of the disease.

Such compounds are, for example, acetylcholinesteraseinhibitors, Mi muscarinic agonists, nicotinic agonists N- 35 methyl-D-aspartate (NMDA) receptor antagonists, nootropics, the acetylcholinesterase inhibitors being particularly advantageous. 7 011464

In accordance with a preferred feature, the invention relates to a pharmaceutical composition containing as active ingrédient a compound (a), optionally in the form of one of its pharmaceutically acceptable salts and a 5 compound (b) selected from the acetylcholinesteraseinhibitors, optionally in the form of one of itspharmaceutically acceptable salts.

Particularly advantageous acetylcholinesteraseinhibitors are tacrine and donepezil. 10 Other acetylcholinesterase inhibitors which may be used are for example rivastigmine (SDZ-ENA-713),galanthamine, metrifonate, eptastigmine, velnacrine,physostigmine (Drugs, 1997, 53 (5) : 752-768; The Merck

Index 12 ed.). 15 Other acetylcholinesterase inhibitors are 5,7- dihydro-3-{2-(1-(phenylmethyl)-4-piperidinyl)ethyl}-6H-pyrrolo (3,2-f)-1,2-benzisoxazol-6-one, also known asicopezil (J.Med. Chem., 1995, 38: 2.802-2808), MDL-73,745 or zifrosilone (Eur.J. Pharmacol., 1995, 276: 93-99), TAK- 20 147 (J. Med. Chem., 1994, 37: 2292-2299).

Other acetylcholinesterase inhibitors are for example

those which are described in the patent applications JP09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 96-04565, US 5,455,245, WO 95-21822, EP 637 586, US

25 5,401,749, EP 742 207, US 5,547,960, WO 96/20176, WO 96/02524, EP 677 516, JP 07-188177, JP 07-133274, EP 649846, EP 648 771, JP 07-048370, US 5,391,553, WO 94/29272,EP 627 400.

Mi receptor antagonists are, for example, milameline, 30 besipiridine, talsaclidine, xanomeline, YM-796 and YM-954(Eur. J. Pharmacol., 1990, 187: 479-486), 3-{N-(2- diethylamino-2-methylpropyl)-6-phenyl-5-propyl}- pyridazinamine, also known as SR-46559 (Biorg. Med. Chem.Let., 1992, 2: 833-838), AF-102, CI-979, L-689,660, LU 25- 35 109, S-99 77-2, SB 202,026, thiopilocarpine, WAL 2014 (Pharmacol. Toxicol., 1996, 78.: 59-68).

Advantageous nicotine agonists are -for example MKC- 231 (Biorg.Med. Chem. Let., 1995, 5 (14): 1495-1500), T- 8 10 15 20 25 30 011464 588 (Japan J. Pharmacol., 1993, 62 : 81-86), ABT-418(Br.J.Pharmacol., 1997, 120 : 429-438).

An advantageous NMDA receptor antagonist is forexample memantine (Arzneim. Forsch., 1991, 41 : 773-780).

In accordance with another feature, the présentinvention relates to the use of the compositions of theinvention for the préparation of medicines designed forthe treatment of senile dementia of the Alzheimer type.

In accordance with another feature the présentinvention also relates to another method for the treatmentof senile dementia of the Alzheimer type which consists ofadministering to a patient suffering from this disease anefficacious dose of a compound (a) above, optionally inthe form of one of its pharmaceutically acceptable saltsand an efficacious dose of a compound (b) , in particularan acetylcholinesterase inhibitor, optionally in the formof one of its pharmaceutically acceptable salts, saidadministrations being simultaneous, sequential oralternating at intervals and the efficacious doses of theactive ingrédients being contained in separate unitforms of administration or, when the active ingrédientsare administered simultaneously, the two activeingrédients being advantageously contained in a singlepharmaceutical form.

The active ingrédients according to the présentinvention are preferably administered orally.

In the pharmaceutical compositions of the présentinvention for oral administration, the active ingrédientsmay be administered in unit forms of administration, in amixture with standard pharmaceutical vehicles, to animaisand to human beings for the treatment of the above-mentioned diseases. The appropriate unit forms ofadministration include for example optionally divisibletablets, capsules, powders, granules and solutions or oralsuspensions.

When a solid composition is prepared in the form of tablets, the principal active ingrédient,, is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, 35 9 011464 magnésium stéarate, talc, gum arabic or the like. The tablets may be coated with sucrose or other suitable materials or they may also be . treated so that they hâve a prolonged or delayed activity and that they continuously 5 release a predefined quantity of active ingrédient. A préparation of capsules is obtained by mixing the active ingrédient with a diluent and by pouring themixture obtained into soft or hard capsules. A préparation in the form of a syrup or élixir may 10 contain the active ingrédient together with a sweeteningagent, preferably calorie-free, methylparaben and propylparaben as antiseptics as well as a flavouring agentand a suitable colouring matter.

The powders and granules dispersible in water may 15 contain the active ingrédient in a mixture with dispersionagents or wetting agents, or suspension agents likepolyvinylpyrrolidone, just as with sweetening agents orflavour correctors.

The active ingrédient may also be formulated in the 20 form of microcapsules, optionally with one or morevehicles or additives.

In the pharmaceutical compositions according to theprésent invention, the active ingrédient may also be inthe form of an inclusion complex in cyclodextrins, their 25 ethers or their esters.

The quantity of active ingrédient to be administereddépends, as always, on the degree of advancement of thedisease as well as on the âge and weight of the patient.

The doses of the two active ingrédients are similar30 to those usually selected in the State of the art for theisolated administration of each of these active ingrédients.

The compositions according to the invention thuscontain recommended doses for the uncombined treatments, 35 for example, of 0.5 mg to 700 mg of compound (a) or of oneof its pharmaceutically acceptable salts and 0.1 to 50 mgof compound (b) or of one of its pharmaceutically 10 011464 acceptable salts or even lower doses, given that thecombination exerts a synergistic effect.

Advantageous compositions contain for example 0.5 to5 mg of SR 57746 or one of its pharmaceutically acceptablesalts and 0.1 to 50 mg. of an acetylcholinesteraseinhibitor or one of its pharmaceutically acceptable salts.

Preferred compositions contain 0.5 to 5 mg of SR57746 or one of its pharmaceutically acceptable salts, inparticular the hydrochloride, and 2 to 10 mg of donepezilor one of its pharmaceutically acceptable salts.

The doses indicated in the présent prescription referto the active ingrédients not combined in sait form.

The activity of the composition according to theinvention was demonstrated by using a spécifie model forthe septo-hippocampal cholinergic System on lésions causedby the injection of vincristine which induces biochemicalalterations similar to the changes présent in Alzheimer'sdisease.

The procedures used in this model, lésions caused byvincristine as well as the évaluation of the social memoryare described in EP 655247.

Evaluation test of the social memory in the rat.

After lésions hâve provoked by injection ofvincristine as described in EP 655247 the rats exhibit astable and durable amnesia. The rats are divided into twogroups, one group receiving solvent and the other groupreceiving SR 57746A at a dose of 5 mg.kg p.o., a dosewhich is insufficient to permit functional recovery interras of memory in the rats undergoing this test (theefficacious dose being 10 mg/kg as described in EP655247) . The dose of 1 mg/kg i.p. of tacrine is thenadministered to the two groups of rats. The control groupwhich has received solvent and tacrine shows no recoveryof memory whereas the group which has been treated with SR57746A (sub-efficacious dose) and tacrine shows asignificant recovery of memory rétention déficits.

The results of this test indicate.- a synergisticaction of the combination of the présent invention. 11 011464

As a resuit of this complementary and synergisticeffect of the constituents of the combination,simultaneously guaranteeing the protection and even cureof the neurones affected by the disease as well as the5 immédiate improvement of the symptoms in the patient, thecomposition of the invention makes possible an efficacious treatment of DAT in ail its forms.

Claims

12 011464 CLAIMS

2. Composition according to Claim 1, characterized in that it contains as active ingrédients 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine, optionally in the form of one of itspharmaceutically acceptable salts in combination with a 20 compound active in the symptomatic treatment of seniledementia of the Alzheimer type, optionally in the form ofone of its pharmaceutically acceptable salts.

3. Composition according to Claim 1, characterizedin that it contains as active ingrédients 25 - a compound of formula (I) :

in which Y is -CH- or -N-; Rl is hydrogen, halogen, a CF3, (C3-C4) alkyl or (C1-C4)30 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; 14 011464 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; 10 phenylamino,phenylethyl, 15 20 (b) a radical selected from (C3-C7) cycloalkyl, (C3- C7) cycloalkyloxy, (C3-C7) cycloalkylmethyl, (C3-C7)cycloalkylamino and cyclohexenyl, said radical beingoptionally substituted by halogen, hydroxy, (C1-C4)alkoxy, carboxy, (C1-C4) alkoxycarbonyl, amino, mono or di-(Ci-C4) alkylamino; or (c) a group selected from phenyl, phenoxy, N-(Ci~C3) alkylphenylamino, phenylmethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl, said phenyl group being optionally mono- or polysubstituted by halogen, CF3, (Ci~C4) alkyl, (C1-C4) alkoxy, cyano, amino, mono- or di-(Ci-C4) alkylamino, (C1-C4) acylamino, carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, mono- or di-(Ci~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 25 30 - an acetylcholinesterase inhibitor,or a pharmaceutically acceptable sait of the latter.

4. Composition according to Claim 3, characterizedin that compound (a) is l-{2-(4-biphenylyl)ethyl}-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine or itshydrochloride sait.

5. Composition according to Claim 3, characterizedin that compound (a) is selected from the followingcompounds : 1-{2-(3'-chloro-4-biphenylyl)ethyl}-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 35 15 011464 1-{2-(21-chloro-4-biphenylyl)ethyl}-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-(2- (4'-chloro-4-biphenylyl)ethyl}-4-(3- trifluoromethylphenyl)-l,2,3,6-tetrahydropyridine; 5 1-{2-(4'-fluoro-4-biphenylyl)ethyl}-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;l-{2- (3 '-trifluoromethyl-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 1- {2 - (4-cycl.ohexylphenyl) ethyl} - 4- (3- 10 trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; l-{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; 15 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; l-{2-(4-n-butylphenyl)ethyl}-4-(3-trifluoromethylphenyl)- 20 1,2,3,6 -1etrahydropyridine; l-{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; 25 l-{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;l-{2-(3-chloro-4-biphenylyl)ethyl}-4-(3- 30 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-(21,4'-dichloro-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 35 l-(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; 16 011464 l-{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; 5 l-{2-(41-methoxy-4-biphenylyl)ethyl}-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(41-hydroxy-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4'-ethoxycarbonylbutoxy-4-biphenylyl)ethyl}-4-(3- 10 trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine; l-{2-(3-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine; l-{2-(3'-chloro-4'-fluoro-4-biphenylyl)ethyl}-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine; 15 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- 20 trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-{2-(4-cyclohexylphenyl)ethyl}-4-(6-chloropyrid-2-yl)- 1,2,3,6-tetrahydropyridine; l-{2-(4-isobutylphenyl)propyl}-4-(6-chloropyrid-2-yl)- 1,2,3,6-tetrahydropyridine; 25 and their pharmaceutically acceptable salts.

6. Composition according to Claim 1 characterized inthat the compound active in the symptomatic treatment ofsenile dementia of the Alzheimer type is selected fromacetylcholinesterase inhibitors, Μχ muscarinic agonists, 30 nicotinic agonists, NMDA receptor antagoniste andnootropic agents.

7. Composition according to Claim 6, characterizedin that compound (b) is an acetylcholinesterase inhibitor.

8. Composition according to Claim 7, characterized 35 in that the acetylcholinesterase inhibitor is selected from tacrine and donepezil.

9. Composition according to Claim- 7, characterized in that the acetylcholinesterase inhibitor is selected 17 011464 from rivastigmine, galanthamine, metrifonate, eptastigmine, velnacrine, phystostigmine, icozepil andzifrosilone.

10. Composition according to Claim 1, characterized 5 in that it contains from 0.5 to 700 mg of compound (a).

11. Composition according to Claim 1, characterizedin that it contains from 0.1 to 50 mg of compound (b).

12. Composition according to Claim 2, characterizedin that it . contains from 0.5 to 10 mg of 1-(2-naphth-2- 10 ylethyl)-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine.

13. Composition according to Claim 2, characterizedin that it contains as active ingrédients 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6- 15 tetrahydropyridine and donepezil or their pharmaceuticallyacceptable salts.

14. Composition according to Claim 3, characterizedin that it contains as active ingrédients l-{2-(4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)-1,2,3,6- 20 tetrahydropyridine and donepezil or their pharmaceuticallyacceptable salts.

15. Composition according to Claim 2 containing 0.5 to 5 mg of 1-(2-naphth-2-yle.thyl)-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 2 to 25 10 mg of donepezil.

16. Composition according to any. one of theprecéding Claims for the treatment of senile dementia ofthe Alzheimer type.

17. Use of the composition according to any one of30 the preceding Claims for the préparation of medicines designed for the treatment of senile dementia of theAlzheimer type.

18. Use according to Claim 17, characterized in thatthe compound (a) is selected from 1-(2-naphth-2-ylethyl)- 35 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 1-{2-(4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine. 18 011464

19. Use according to Claim 17, characterized in thatthe compound (b) is selected from tacrine and donepezil.