WO1999025363A1 - Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia - Google Patents

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

COMBINATION OF ACTIVE INGREDIENTS, IN PARTICULAR TETRAHYDROPYRIDINES AND ACETYLCHOLINESTERASE INHIBITORS, FOR THE TREATMENT OF SENILE ALZHEIMER DEMENTIA

The subject of the present invention is a pharmaceutical composition comprising a new combination of active principles, for the treatment of senile dementia of the Alzheimer type, consisting of derivatives of 1,2,3,6-tetrahydropyridines, optionally in the form of one of their pharmaceutically acceptable salts and of a compound active in the symptomatic treatment of senile dementia of the Alzheimer type, in particular of an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts and its use for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type. Senile dementia of the Alzheimer type hereinafter called DAT (from English

"dementia of Alzheimer's type") is a neurodegenerative disease clinically characterized by the progressive decline of cognitive functions occurring in the elderly with an incidence that increases in relation to age. Given demographic trends, TAD will become an increasingly widespread disease.

In patients with DAT, a reduction in the levels of several neurotransmitters has been seen, including acetylcholine.

The only treatment for DAT currently available on the market consists of administering by acetylcholinesterase inhibitors which by reducing the hydrolysis of acetylcholine thus increase its bioavailability. It is therefore a symptomatic treatment.

Tacrine, sold under the brand COGNEX ^® , and donepezil, sold under the brand ARICEPT, are acetylcholinesterase inhibitors indicated for the symptomatic treatment of mild to moderate forms of DAT. Other products for the symptomatic treatment of TAD are being studied. Some of them also act on the availability of acetylcholine, others improve the symptomatic framework of patients affected by TAD by other mechanisms. So far, no drug available on the market has been able to slow the progression of the disease. EP-458696 describes the use of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetr.ahydropyridine, known in the literature SR 57746, for the preparation drugs to fight neurodegenerative conditions, including senile dementia and Alzheimer's disease. The neurotrophic action of SR 57746 on the nervous system is similar to that of certain endogenous neurotrophins, such as, for example, nerve growth factor (NGF).

WO 97/01536 describes new 4-substituted l-phenylalkyl-1,2,3,6-tetrahydropyridines having neurotrophic and neuroprotective activity similar to that of certain endogenous neurotrophins. Thanks to this activity, the compounds described in This patent application is said to be useful in the treatment of several pathologies of the central nervous system, including Alzheimer's disease.

The activity in the treatment of nervous pathologies such as the DAT of the compound SR57746 and of the compounds described in WO 97/01536 is not intended to treat the symptoms but, by protecting the neurons, to modify the course of the disease and to reduce the progression.

It has now been found that the combination of the above compounds, optionally in the form of one of their pharmaceutically acceptable salts with a compound active in the symptomatic treatment of senile dementia of the Alzheimer type, in particular of an inhibitor of acetylcholinesterase, optionally in the form of one of its pharmaceutically acceptable salts, allows a complete and very effective treatment of DAT, the combination exerting a rapid and complementary effect.

Thus, the subject of the present invention is a pharmaceutical composition containing as active principles a component (a) chosen from l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3 , 6-tetrahydropyridine and a compound of formula (I),

dans laquelle Y représente -CH- ou -N-;

in which Y represents -CH- or -N-;

ou (C1-C4)- dcoxyle;Ri represents hydrogen, a halogen, a CF ₃ group,

or (C1-C4) - dcoxyl;

R2 represents hydrogen, a halogen, a hydroxyl, a group CF ₃ , (C3-C4) - alkyl or (Ci-C ^ alkoxyle; R3 and R4 each represent hydrogen or a (Cι-C3) alkyl;

X represents

(a) a (C3-C,) alk le; a (C3-C6) .alkoxyl; a (C3-C7) carboxyalkyl; a (C1-C4) - alkoxycarbonyl (C3-C6) alkyl; a (C3-C7) carboxyalkoxyl; or a (Cι-C4) .alkoxycarbonyl (C3-C6) alkoxyl; (b) a radical chosen from a (C3-G7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) - cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical possibly being substituted by halogen, hydroxy, (Cι-C4) alkoxy, carboxy, (Cι-C4) alkoxycarbonyl, amino, mono- or ώ- (Cι-C4) .alkylamino; or (c) a group chosen from phenyl, phenoxy, phenylamino, N- (Cι-C ₃ ) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, said group possibly being mono- or polysubstituted on the phenyl group with a halogen, CF3, (Cj-C4) alkyl, (C [-C4) alkoxy, cyano, amino, mono- or di- (Cι-C4) alkylamino, (Cι-C4) acylamino, carboxy, ( C1-C4) alkoxyc.arbonyl, aminocarbonyl, mono- or di- (C1-C4) alkylaminocarbonyl, amino (C1-C4) alkyl, hydroxy (C1-C4) alkyl or halo (C1-C4) alkyl; optionally in the form of one of its pharmaceutically acceptable salts and - a component (b) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when the component (a) is other than 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetrahydropyridine or one of its pharmaceutically acceptable salts, the component (b ) is an acetylcholinesterase inhibitor.

1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746) has been described in EP 101 381 and the compounds of formula (I) ci above are described in WO 97/01536.

A particularly advantageous component (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746), optionally in the form one of its pharmaceutically acceptable salts.

Among the pharmaceutically acceptable salts of SR 57746, the hydrochloride hereinafter called SR 57746 A is a particularly preferred salt.

An advantageous method for the preparation of SR 57746A provides for the reaction between 2- (2-bromoethyl) naphthalene and 4- (3-trifluoromethylphenyl) - 1,2,3,6- tetrahydropyridine and the isolation of l- hydrochloride (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine which is subsequently crystallized from an ethanol / water mixture by heating and cooling to 5 ° C with a cooling rate of 10 ° C / hour and a stirring speed of 400 revolutions / minute, so as to obtain a mixture of two crystalline forms in a ratio of about 66/34.

SR 57746A is preferably used in microparticulate form, for example in an essentially amorphous form obtained by atomization or in a microcrystalline form obtained by micronization.

Another particularly advantageous component (a) is 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tet.ahydropyridine, in particular its hydrochloride salt. Other advantageous compounds are the following: 1- [2- (3'-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (2'-chloro-4-biphenylyl) ethyl] -4- (3-triπuoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-chloro-4-biρhenylyl) 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-trifluoromethylphenyl) -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-tetrahydropyridine; 1-t2- (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-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-biphenylyl) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; 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-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (2 ', 4 ^, -dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethyl-hényl) -1,2,3,6-tetrahy dropyridine; 1- [2- (2-chloro-4-biρhenylyl) ethyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3'chloro-4-biρhenylyl) -2-methylpropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; l- [2- (2-fluoro-4-biphenylyl) ρroρyl] -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetr.ahydropyridine; 1- [2- (4-methoxy-3-biphenylyl) ethyl] -4- (3-trifluoromethylphé nyl) - 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-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-ethoxycarbonylbutoxy-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3-biphenylyl) -ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydroρyridine; 1- [2- (3'chloro-4'-fluoro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahy dropyridi ne; 1- [2- (2'trifluoromethyl-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine;

1 - [2- (3, 4-diisobutylpheny 1) ethyl 1] -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.

In the present description, the expression “active compound in the symptomatic treatment of DAT” designates a product which is capable of improving the symptomatological framework of patients suffering from DAT without intervening in the causes of the disease.

Such compounds are for example acetylcholinesterase inhibitors, muscarinic agonists Mi, nicotinic agonists, receptor antagonists

N-methyl-D-aspartate (NMDA), nootropics, acetylcholinesterase inhibitors being particularly advantageous.

According to a preferred aspect, the invention relates to a pharmaceutical composition containing as active ingredient, a component (a), optionally in the form of one of its pharmaceutically acceptable salts, and a component (b) chosen from inhibitors of acetylcholinesterase, optionally in the form of one of its pharmaceutically acceptable salts.

Particularly advantageous acetylcholinesterase inhibitors are tacrine and donepezil.

Other acetylcholinesterase inhibitors which can be used are, for example, rivastigmine (SDZ-ENA-713), galanth.amine, metrifonate, eptastigmine, velnacrine, physostigmine (Drugs, 1997, 53 (5) : 752-768; The Merck

Index 12 ed.).

Other acetylcholinesterase inhibitors are also 5,7-dihydro-3- [2- [l-

(phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [3, 2-f] - 1, 2-benzisoxazol-6-one called also icopezil (J. Med. Chem., 1995, 38. 2802-2808), MDL-73J45 or zifrosilone (Eur. J. Phar acol., 1995, 276: 93-99), TAK-147 (J. Med. Chem., 1994, 37: 2292-2299).

Other acetylcholinesterase inhibitors are, for example, those described in patent applications JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 96-04565, US 5,455,245, WO 95 -21822, EP 637 586, US 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 649 846, EP 648 771, JP 07-048370, US 5,391,553, WO 94/29272, EP 627400. Agonists of the Mi receptor are, for example, milamelin, besipiridine, talsaclidine, xanomelin, YM-796 and YM-954 (Eur. J. Pharmacol ., 1990, 187: 479-486), 3- [N- (2-diethylamino-2-methylpropyl) -6-phenyl-5-propyl] -pyridazinamine, also named SR-46559 (Biorg. Med. Chem. Let., 1992, 2: 833: 838), AF-102, CI-979, L-689, 660, LU 25-109, S-99 77-2, SB 202.026, thiopilocarpine, WAL 2014 (Pharmacol. Toxicol., 1996, 78: 59-68).

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

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

According to a further aspect, the present invention relates to the use of the compositions of the invention for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type.

According to a further aspect, the present invention also relates to a method of treating senile dementia of the Alzheimer type which consists in administering to a patient suffering from this disease an effective dose of component (a) above, possibly in the form one of its pharmaceutically acceptable salts and an effective dose of a component (b), in particular of an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts, said administrations being simultaneous, sequential or spread over time and the effective doses of the active principles which can be contained in separate unit administration forms or, when the active principles are administered simultaneously, the two active principles advantageously being contained in a single pharmaceutical form. The active ingredients according to the present invention are preferably administered orally.

In the pharmaceutical compositions of the present invention for oral administration, the active ingredients can be administered in unit forms administration, mixed with conventional pharmaceutical carriers, animals and humans for the treatment of the above conditions. Suitable unit dosage forms include, for example, possibly scored tablets, capsules, powders, granules and oral solutions or suspensions.

When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.

A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.

A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.

Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.

The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

In the pharmaceutical compositions according to the present invention, the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.

The amount of active ingredient to be administered depends, as always, on the degree of progression of the disease as well as on the age and weight of the patient.

The doses of the two active ingredients are analogous to those normally used in the art for the isolated administration of each of these active ingredients.

The compositions according to the invention therefore contain doses recommended for non-combined treatments, for example from 0.5 to 700 mg of component (a) or of a pharmaceutically acceptable salt thereof and 0.1 to 50 mg of component ( b) or a pharmaceutically acceptable salt thereof or lower doses, since the combination exerts a synergistic effect.

Advantageous compositions include, for example, 0.5 to 5 mg of SR 57746 or one of its pharmaceutically acceptable salts and 0.1 to 50 mg of an acetylcholinesterase inhibitor or one of its pharmaceutically acceptable salts. Preferred compositions include 0.5 to 5 mg of SR 57746 or a pharmaceutically acceptable salt thereof, especially the hydrochloride, and 2 to 10 mg of donepezil or one of its pharmaceutically acceptable salts.

The doses indicated in the present description refer to the active ingredients in non-salified form.

The activity of the composition according to the invention has been demonstrated using a specific model for the septo-hyppocampal cholinergic system, on lesions caused by the injection of vincristine. In this model, we evaluate the effects of the products tested on amnesia induced by the injection of vincristine which induces biochemical alterations similar to the alterations present in Alzheimer's disease.

The operating modes of this model, lesions caused by vincristine as well as the evaluation of social memory, are described in EP 655247. Test of the evaluation of social memory in rats. After causing injury by injection of vincristine as described in EP

655247 rats have stable and lasting amnesia. The rats are divided into two groups, one group receiving solvent and the other group receiving SR 57746A at a dose of 5 mg / kg po, a dose which is not sufficient to allow functional recovery in terms of memory in rats subjected to this test (the effective dose being 10 mg / kg as described in EP 655247). The dose of 1 mg / kg i.p. tacrine is then administered to the two groups of rats. The control group, having received solvent and tacrine, shows no recovery of memory while the group having been treated with SR 57746A (sub-effective dose) and tacrine shows a significant recovery of memory deficits. The results of this test make it possible to recognize a synergistic action with the association of the present invention.

Thanks to the complementary and synergistic effect of the components of the association, ensuring at the same time the protection or even the healing of the neurons affected by the disease as well as the immediate improvement of the symptoms in the patient, the composition of the invention allows a effective treatment of DAT in all its forms.

Claims

 CLAIMS 1. Pharmaceutical composition containing as active principles a component (a) chosen from l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetrahydropyridine and a compound (I)

in which Y represents -CH- or -N-; Ri represents hydrogen, a halogen, a CF ₃ group, (C3 ~ C4) alkyl or (C1-C4) - alkoxyl; R2 represents hydrogen, halogen, hydroxyl, CF ₃ , (C3-C ₄ ) - alkyl or (C ₁ -C) alkoxyl; R3 and R4 each represent hydrogen or a (Cι-C3) alkyl; X represents (a) a (C3-C6) alkyl; a (C3-C,) alkoxyl; a (C3-C7) carboxyalkyl; a (C1-C4) - alkoxycarbonyl (C3-C6) alkyl; a (C3-C7) carboxyalkoxyl; or a (Cι-C4) alkoxycarbonyl (C3-C6) alkoxyl; (b) a radical chosen from a (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) - cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical possibly being substituted by a halogen, hydroxy, (C ₁ -C4) alkoxy, carboxy, (C ₁ -C4) alkoxycarbonyl, amino, mono- or di- (Cι-C4) alkylamino; or (c) a group chosen from phenyl, phenoxy, phenylamino, N- (Cι-C3) kyl-phenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, said group possibly being mono- or polysubstituted on the phenyl group by halogen, CF3, (Cι-C4) alkyl, (Cι-C4) alkoxy, cyano, amino, mono- or di- (Cι-C4) alkylamino, (Cι-C4) acylamino, carboxy, ( Cι-C4) alkoxycarbonyl, .aminocarbonyl, mono- or c - (Cι-C4) alkylaminocarbonyl, amino (Cι-C4) alkyl, hydroxy (Cι-C4) kyle or h £ ilo (Cι-C4) kyle; optionally in the form of one of its ph-armaceutically acceptable salts, and - a component (b) active in the highly symptomatic of DAT, optionally in the form of one of its pharmaceutically acceptable salts, with the provided that when component (a) is other than l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6-tétπιhydropyridine or one of its salts pharmaceutically acceptable, component (b) is an acetylcholinesterase inhibitor agent. 2. Composition according to claim 1 characterized in that it contains as active principles l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetrahydropyridine optionally in the form of one of its pharmaceutically acceptable salts in association with a compound active in the symptomatic treatment of senile dementia of the Alzheimer type optionally in the form of one of its pharmaceutically acceptable salts. 3. Composition according to claim 1 characterized in that it contains as active principles - a compound of formula (I)

in which Y represents -CH- or -N-; R _j represents hydrogen, a halogen, a group CF ₃ , (C3-C4) alkyl or

.alkoxyl; R2 represents hydrogen, a halogen, a hydroxyl, a group CF ₃ , (C3-C4) - alkyl or (Cι-C ₄ ) alkoxyl; R3 and R4 each represent hydrogen or a (Cι-C ₃ ) alkyl; X represents (a) a (C3-Cg) alkyl; a (C3-C, 5) alkoxyl; a (C3-C7) carboxyalkyl; a

alkoxycarbonyl (C3-C6) alkyl; a (C3-C7) carboxy.alkoxyl; or a (Cι-C4) alkoxycarbonyl (C3-C6) .alkoxyl; (b) a radical chosen from a (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) - cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical possibly being substituted by halogen, hydroxy, (Cι-C4) coxy, carboxy, (Cι-C4) alkoxycarbonyl, amino, mono- or di- (Cι-C4) alkylamino; or (c) a group chosen from phenyl, phenoxy, phenylamino, N- (Cι-C3) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfmyl and styryl, said group possibly being mono- or polysubstituted on the phenyl group by halogen, CF3, (Cι-C4) alkyl, (Cι-C4) .alkoxy, cyano, amino, mono- or di- (Cι-C4) alkylamino, (Cι-C4) acylamino, carboxy, (Cj -C4) alkoxycarbonyl, aminocarbonyl, mono- or di- (Cι-C4) alkylarninocarbonyl, amino (Cj-C4) alkyl, hydroxy (Cι-C4) dkyle or h.alo (Cι-C4) .alkyl; optionally in the form of one of its pharmaceutically acceptable salts, and - an acetylcholinesterase inhibitor agent, or a pharmaceutically acceptable salt thereof. 4. Composition according to claim 3 characterized in that the component (a) is 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or its hydrochloride salt. 5. Composition according to claim 3 characterized in that component (a) is chosen from the following compounds: l- [2- (3'-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -l , 2,3,6-tetrahydropyridine; 1- [2- (2'-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethyl-phenyl) - 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-tetr.ahy dropyridine; 1- [2- (3'-trifluoromethyl-4-biphenylyl) ethyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-cyclohexylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetr ^ ydropyridine; 1 - [. 2- (4-biphenylyl) ethyl] -4- (4-fluorophenyl) -1,2,3,6-tetrahydroρyridine; 1- [2- (4-biphenylyl) -2-methylpropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetr ^ y dropyridine; 1- [2- (4-phenoxyphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetr ^ ydropyridine; 1- [2- (4-benzylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrώydropyridine; 1- [2- (4-n-butylphenyl) ethyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydroρyridine; 1- [2- (4-n-butoxyphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrώydropyridine; 1- [2- (4- (4-ethoxycMbonylpropoxy) phenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-biρhenylyl) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; 1- [2- (2,3'-dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6, - tet.ahydropyridine; 1- [2- (3-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3 ', 5'-dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (2 ^* , 4'-dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethyl-hényl) -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-biρhenylyl) -2-methylpropyl] -4- (3-trifluoromethylρhenyl) -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-trifluoromethylphé nyl) - 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-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-ethoxycarbonylbutoxy-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -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-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine; 1- [2- (2'trifluoromethyl-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3,4-diisobutylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahy dropyridine; 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-tetr ^ ydropyridine; 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 active compound in the symptomatic treatment of senile dementia of the Alzheimer type is chosen from acetylcholinesterase inhibitors, Mi muscarinic agonists, nicotinic agonists, NMDA receptor antagonists and nootropics 7. Composition according to claim 6 characterized in that component (b) is an acetylcholinesterase inhibitor agent. 8. Composition according to claim 7 characterized in that the acetylcholinesterase inhibitor is chosen between tacrine and donepezil. 9. Composition according to claim 7 characterized in that the acetylcholinesterase inhibitor is chosen from rivastigmine, galanthamine, metrifonate, eptastigmine, velnacrine, physostigmine, icoepepil and zifrosilone. 10. Composition according to claim 1 characterized in that it contains from 0.5 to 700 mg of component (a). 11 Composition according to claim 1 characterized in that it contains from 0.1 to 50 mg of component (b). 12 Composition according to claim 2 characterized in that it contains from 0.5 to 10 mg of l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6- tetrahydropyridine. 13 Composition according to claim 2 characterized in that it contains as active principles l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6- tétr∑ihydropyridine and donepezil or their ph.armaceutically acceptable salts. 14 Composition according to Claim 3, characterized in that it contains, as active principles, l- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6- tetrahydropyridine and donepezil or their ph.armaceutically acceptable salts. 15 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 hydrochloride and 2 to 10 mg of donepezil. 16 Composition according to any one of the preceding claims for the treatment of senile dementia of the Alzheimer type. 17 Use of the composition according to any one of the preceding claims for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type. 18 Use according to claim 17 characterized in that the component (a) is chosen from l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6- tet.ahydropyridine and 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetr.ahydropyridine. 19 Use according to claim 17 characterized in that the component (b) is chosen between tacrine and donepezil.