MXPA00004600A - 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 itspharmaceutically 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 PRINCIPLES, IN PARTICULAR OF TETRAHYDROPYRIDINE INHIBITORS AND ACETILCOLINESTERASA, FOR THE TREATMENT OF SENIL DEMENTIA, SUCH AS SENIL DEMENTIA OF TYPE ALZHEIMER DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition comprising a new association of active ingredients for the treatment of senile dementia of Alzheimer's type, consisting of 1, 2,3,6-tetrahydropyridine derivatives, optionally in the form of one of its salts pharmaceutically acceptable compounds and for an active compound in the symptomatic treatment of senile dementia of Alzheimer's type, particularly 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 Alzheimer's type. Senile dementia of Alzheimer's type, hereinafter referred to as DAT (Dementia of Alzheimer's type) is a neurodegenerative disease characterized clinically by the progressive decline of cognitive functions that occurs in elderly people with an increasing incidence in relation to with the age. Taking into account the demographic trends, the DAT is going to be an increasingly widespread disease. In patients affected by DAT, a reduction in the proportions of several neurotransmitters, particularly acetylcholine, has been observed. The only treatment of DAT currently available on the market is to administer acetylcholinesterase inhibitors which, by reducing the hydrolysis of acetylcholine, increase the bioavailability of acetylcholinesterase. It is, therefore, a symptomatic treatment. Tacrine, marketed under the brand name COGNEX® and donepezil, marketed under the brand name ARICEPT®, are acetylcholinesterase inhibitors indicated for the symptomatic treatment of weak to moderate forms of DAT. Other products for the symptomatic treatment of DAT are under study. Some of them also act on the availability of acetylcholine, others improve the symptom picture of patients affected by DAT through other mechanisms. Until now, no drug available on the market is able to slow the progression of the disease. EP-458696 describes the use of 1 - (2-napht-2-i leti I) -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine, referred to in the literature as SR 57746, for the preparation of medicines designed to combat neurodegenerative conditions, among which are 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 nerve growth factor (NGF). WO 97101536 describes new 4-substituted 1-phenylalkyl-1, 2,3,6-tetrahydropyridines with a neurotrophic and neuroprotective activity similar to that of certain endogenous neurotrophins. Thanks to this activity, the compounds described in this patent application are considered useful in the treatment of various pathologies of the central nervous system, among which is Alzheimer's disease. The activity, in the treatment of nerve pathologies such as DAT, of the compound SR 57746 and of the compounds described in WO 97/01536 does not aim to treat the symptoms but, by protecting the neurons, to modify the progress of the disease and reduce your progress. It has now been found that the combination of the aforementioned compounds, optionally in the form of one of their pharmaceutically acceptable salts, with an active compound in the symptomatic treatment of senile dementia of the Alzheimer's type, particularly an acetylcholinesterase inhibitor, optionally in the form of of one of its pharmaceutically acceptable salts, allows a complete and very effective treatment of the DAT, exerting a fast and complementary effect. Thus, the present invention relates to a pharmaceutical composition containing, as active principles: a component (a) selected from 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1 , 2,3,6-tetrahydropyridine and a compound of the formula (I), wherein Y represents -CH- or -N-; R represents hydrogen, a halogen, a group CF3 (C3-C4) alkyl or (Ct-04) alkoxy; R2 represents hydrogen, a halogen, a hydroxyl, a CF3 group, (C3-C4) alkyl OICÍ-CÍ) alkoxy; R3 and R4 each represent hydrogen or uniCt-Cs) alkyl; X represents (a) a (C3-C6) alkyl; a (C3-C6) alkoxy; a (C3-C7) carboxyalkyl; a (C? -C) alkoxycarbonyl (C3-C6) alkyl; a (C3-C7) carboxyalkoxy; or a (C? -C4) alkoxycarbonyl or (C3-C6) alkoxy; (b) a radical selected from a (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical being substituted by a halogen, hydroxy, ( Ct-C4) alkoxycarboxy, (C-C4) alkoxycarbonyl, amino, mono- or di- (C 1 -C 4) alkylamino or • (c) a. a group selected from phenyl, phenoxy, phenylamino, "N-iC ^ Cs-alkyl-phenyl-amino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulphinyl or styryl, said group being mono- or polysubstituted in the phenyl group by a halogen, CF3 (C1-C4) alkyl, (C? -C) 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 halogen (C1-C4) alkyl, optionally in the form of one of its pharmaceutically acceptable salts and - one component (b) ) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when component (a) is other than 1- (2-naphth-2-ylethyl) -4 (3-trifluoromethylphenyl) -1, 2, 3,6-tetrahydropyridine or one of its pharmaceutically acceptable salts, component (b) is an acetylcholinesterase inhibiting agent. 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 the formula (I) which are mentioned above are described in WO 97/01536. "" A particularly advantageous component (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethyiphenyl) -1,2,3,6-tetrahydropyne (SR 57746), optionally in the form of one of its pharmaceutically acceptable salts. Among the pharmaceutically acceptable salts of SR 57746, the hydrochloride referred to hereafter as SR 57746A is particularly preferred. A convenient 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 the hydrochloride from 11 - ( 2-naphth-2-ylethyl) -4- (3-trifluoromethyl-enyl) -1,2,3,6-tetrahydropyridine which is then crystallized from a mixture of ethanol and water by heating and cooling to 5 ° C, to a cooling speed of 10 ° C / hour and a stirring speed of 400 turns per minute, so as to obtain a mixture of two crystalline forms in a ratio of approximately 66/34. SR 57746A is preferably used in the form of microparticles, for example in an essentially amorphous form obtained by atomization or in a microcrystalline form obtained by mechronization. Another particularly convenient component (a) is 1- [2- (4-biphenylyl) ethyl] -4 - (- trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, especially its hydrochloride salt. Other suitable compounds are those mentioned below: 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-tri-loromethyl-phenyl) -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-biphenimethyl) ethyl] -4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-biphenylyl) -2-methylpropyl] -4- (3-trifluoromethylpheni) -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-tetrahi.dropyridine; 1- [2- (4-n-butylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-n-butoxif in yl) 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-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (2-Chloro-4-biphenyl) ethyl] -4- (3-trifluoromethylphenol) -1,2,3,6-tetrahydropyridine; 1- [2- (3'-Chloro-4-biphenylyl)] - 2-methylpropyl] -4- (3-trifluoromethyl-phenyl) -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-trifluoromethylphenyl) -1,2,6,6-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-trifluoromethyl-phenyl) -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-cioropyrid-2-yl) -1,2,3,6-tetrahydropyridine; and their pharmaceutically acceptable salts. In this report, the expression "active compound in the symptomatic treatment of DAT" designates a product that is capable of improving the symptomatological picture of patients affected by DAT without intervening in the causes of the disease. Such compounds are, for example, the acetylcholinesterase inhibitors, the muscarinic agonists M, the nicotinic agonists, the N-methyl-D-aspartate (NMDA) receptor antagonists, the nootropic ones, the inhibitors of which are particularly suitable. acetylcholinesterase In 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) selected from the acetylcholinesterase inhibitors, optionally in form of one of its pharmaceutically acceptable salts. Particularly convenient acetylcholinesterase inhibitors are tacrine and donepezil. Other acetylcholinesterase inhibitors that can be used are, for example, rivastigmine (SDZ-ENA-713), galantamine, metrifonate, iaptastigmine, vetnacrine, physostigmine (Drugs, 1997, 53. (5): 752 -768- The Merck Index 12 ed.).

Other- acetylcholinesterase inhibitors are, in addition, 5,7-dihydro-3- [2- [1- (phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [3,2-f] -1,2 -benzisoxazol-6-one also called icopezil (J. Med. Chem., 1995, 38: 2802-2808), MDL-73,745 or zifrosilone (Eur. J. Pharmacol., 1995, 276: 93-99), TAK-147 (J. Med. Chem., 1994, 37: 2292-2299).

Other inhibitors of acetylcholinesterase 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 637586, US 5,401,749, EP 742207, 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. M-receptor agonists are, for example, milamelin, besipiridin, talsacilidin, xanomellin, YM-796 and YM -954 (Eur. J. Pharmacol., 1990, 187: 479-486), 3- [N- (2-diethylamino-2-methylpropyl) -6-phenyl-5-propyl] -pyridazinamine, also called SR- 46559 (Biorg. Med. Chem. Let., 1992, 2: 833: 838), AF-102, CI-979, L-689, 660, LU 25-109, S-99 77-2 , SIB 202,026, tiopilocarpine, WAL 2014 (Pharmacol Toxicol., 1996, 78: 59-68). Suitable 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), the ABT-418 (Br. J.

Pharmacol., 1997, 120: 429-438). A suitable NMDA receptor antagonist is, for example, memantine (Arzneim, Forsch., 1991, 41: 773-780). According to a further aspect, the invention concerns the use of the compositions of the invention for the preparation of medicaments for the treatment of senile dementia of Alzheimer's type. According to another aspect, the present invention also relates to a method for the treatment of senile dementia of Alzheimer's type consisting of administering to a patient affected by this disease, an effective dose of a component (a) of those enumerated above. , optionally in the form of 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, such administrations being simultaneous, consecutive or prolonged and the effective doses of the active ingredients are presented in individual administration forms or, when the active ingredients are administered simultaneously, it will be convenient that both principles are contained in a single pharmaceutical form. The active principles of the present invention are preferably administered orally. In the pharmaceutical compositions of the present invention for oral administration, the active principles may be administered in unitary form, mixed with conventional pharmaceutical carriers, to animals or to humans for the treatment of the aforementioned conditions. Suitable unit dosage forms include, for example, possibly divisible 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 of sucrose or other suitable materials can be coated or, furthermore, given a treatment such that they have prolonged or delayed activity and continuously release a predetermined quantity of active principle. The preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the obtained mixture into soft or hard capsules. The preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably a caloric sweetener, methylparaben and propylparaben as antiseptics, a flavoring agent and an appropriate colorant. Powdered preparations or water-dispersible granules can have the active ingredient mixed with dispersing agents or wetting agents or suspending agents, such as polyvinylpyrrolidone, in addition to sweeteners or taste modifiers. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

In the pharmaceutical compositions of the present invention, the active principle can also be presented as an inclusion complex in the cyclodextrins, their ethers or esters. The amount of active principle to be administered depends, as always, on the degree of progression of the disease in addition to the age and weight of the patient. The doses of both active principles are analogous to those normally observed in the art for the isolated administration of each of these principles. The compositions of the invention therefore contain recommended doses for non-combined treatments, for example from 0.5 to 700 mg of component (a) or of one of its pharmaceutically acceptable salts and from 0.1 to 50 mg of the component (b) or one of its pharmaceutically acceptable salts or lower doses, since the combination exerts a synergistic effect. Suitable compositions are those containing, 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 are compositions containing from 0.5 to 5 mg of SR 57546 or one of its pharmaceutically acceptable salts, particularly hydrochloride and from 2 to 10 mg of donepezil or one of its pharmaceutically acceptable salts. The doses indicated in the present specification refer to the active ingredients in non-salified form. The activity of the composition of the invention has been demonstrated by using a specific model for the cholinergic septum hippocampal system, in lesions caused by the injection of vincristine. In this model, the effects of the products experienced in the amnesia induced by the injection of vincristine that induce biochemical alterations similar to the alterations present in Alzheimer's disease are evaluated. The operative modes of this model, the lesions caused by vincristine and the evaluation of social memory are described in EP 655247.

Evaluation essay of the social memory of the rat After having caused lesions by injection of vincristine, as described in EP 655247, the rats exhibit a stable and durable amnesia. The rats are divided into two groups, one of them receives solvent and the other SR 5.7746A in a dose of 5 mg / kg po, a dose that is not sufficient to allow a functional recovery in terms of memory in the rats subjected to this test ( the effective dose is 10 mg / kg as described in EP 655247). The dose of 1 mg / kg i.p. of tacrine to both groups of rats. The control group, which received a solvent and tacrine, did not show any recovery of memory, whereas the group treated with SR 57746A (sub-effective dose) and tacrine showed a significant recovery of the amnestic deficiencies. The results of this test allow to recognize a synergistic action to the association of the present invention. Thanks to the complementary and synergistic effect of the components of the association, which guarantees at the same time the protection and almost the healing of the neurons affected by the disease and the immediate improvement of the symptoms in the patient, the composition of the invention allows a treatment of the DAT in all its forms.

Claims (19)

1. Pharmaceutical composition wherein comprises as active ingredients a component (a) selected from 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and a compound of the formula (I), wherein Y represents -CH- or -N-; Ri represents hydrogen, a halogen, a group CF3 (C3-C4) alkyl or (Ci-04) alkoxy; R2 represents hydrogen, a halogen, a hydroxyl, a CF3 group, (C3-C4) alkyl or (C1-C4) alkoxy; R3 and R4 each represent hydrogen or unid-Cs) alkyl; X represents (a) a (C3-C6) alkyl; a (C3-C6) alkoxy; a (C-C7) carboxyalkyl; a (C 1 -C 4) alkoxycarbonyl (C 3 -C 6) alkyl; a (C3-C7) carboxyIoxyium; or a (C 1 -C 4) alkoxycarbonyl or (C 3 -C 6) alkoxy; (b) a radical selected from a (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical being substituted by a halogen, hydroxy, ( CT-C4) alkoxycarboxy, (C? -C4) alkoxycarbonyl, amino, mono- or di- (C1-C4) alkylamino or (c) a group selected from phenyl, phenoxy, phenylamino, N-CiC-Csalkyl-phenyl- amino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulphinyl or styryl, said group being mono or polysubstituted in the phenyl group by a halogen, CF3, (C1-C) alkyl, (C? -C4) alkoxy, cyano, amino, mono- or di- (C 1 -C 4) alkylamino, (C 1 -C 4) acylamino, carboxy, (C 1 -C 4) alkoxycarbonyl, aminocarbonyl, mono- or di- (C 1 -C 4) alkylaminocarbonyl, amino (C 1 -C 4) alkyl, hydroxy (C1-C4) alkyl or halogen (C1-C4) alkyl; optionally in the form of one of its pharmaceutically acceptable salts and a component (b) active in the symptomatic treatment of the DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when the component (a) is different from the 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or one of its pharmaceutically acceptable salts, component (b) is an acetylcholinesterase inhibiting agent.

2. Composition according to claim 1, wherein it contains as active principles 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine, optionally in the form of one of its pharmaceutically acceptable salts in association with an active compound in the symptomatic treatment of senile dementia of Alzheimer's type, optionally in the form of one of its pharmaceutically acceptable salts. Composition according to claim 1, wherein it contains as active ingredients - a compound of formula (I) wherein Y represents -CH- or -N-; Ri represents hydrogen, a halogen, a group CF3 (C3-C) alkyl or (0 ^ 04) alkoxy; R2 represents hydrogen, a halogen, a hydroxyl, a CF3 group, (C3-C4) alkyl or (C? -C4) alkoxy; R3 and R4 each represent hydrogen or a (C? -C3) alkyl; X represents (a) a (C3-C6) alkyl; a (C3-C6) alkoxy; a (C3-C7) carboxyalkyl; a (C? -C4) alkoxycarbonyl (C3-C6) alkyl; a (C3-C7) carboxyalkoxy; or a (C? -C4) alkoxycarbonyl or (C3-C6) alkoxy; (b) a radical selected from a (C3-C7) cycloalkyl, (C3-C7) c-chloralkyloxy, (C3-C7) cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical being substituted by a halogen, hydroxy (CÍ-C4) alkoxycarboxy, (C? -C4) alkoxycarbonyl, amino, mono- or di- (C1-C4) alkylamino or (c) a group selected from phenyl, phenoxy, phenylamino, N-id-Csalkylamino- phenyl-amino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulphinyl or styrene, said mono- or polysubstituted group being able to be in 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 od¡- (C1-C4) alkylaminocarbonyl, amino (C1-C4) alkyl, hydroxy (C1-C) alkyl or halogen (C1-C4) alkyl; optionally in the form of one of its pharmaceutically acceptable salts and - an acetylcholinesterase inhibiting agent or a pharmaceutically acceptable salt thereof. 4. Composition according to claim 3, wherein 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, wherein the component (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-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- [2- (4-biphenylyl) -2-methylpropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-phenoxyphenii) 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-trifluoromethylphenii) -1,2,3,6-tetrahydropyridine; 1- [2- (4- (4-ethoxycarbonylpropoxy) phenyl) ethyl] -4- (3-trifluoromethylpheni) -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-trifluoromethyl-phenyl) -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-tr? Uoromethylphenyl) -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-trifluoromethyl-phenyl) -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) etl] -4- (3-trifluoromethyphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-ethoxycarbonylbutoxy-4-bi faith nyl) ethyl] -4- (3-tri fluor methyl methyl nyl) -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) etl] -4- (3-trifluoromethyphenyl) -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, wherein the active compound in the symptomatic treatment of senile dementia of the Alzheimer type is selected from acetylcholinesterase inhibitors, muscarinic agonists M ^ nicotinic agonists, NMDA receptor antagonists and nootropics. Composition according to claim 6, wherein component (b) is an acetylcholinesterase inhibiting agent. 8. Composition according to claim 7, wherein the acetylcholinesterase inhibitor is selected from tacrine and donezepil. Composition according to claim 7, wherein the acetylcholinesterase inhibitor is selected from rivastigmine, galantamine, metrifonate, eptastigmine, velnacrine, physostigmine, icozepil and zifrosilone. 10. Composition according to claim 1, wherein it contains from 0.5 to 700 mg of component (a). 11. Composition according to claim 1, wherein it contains 0.1 to 50 mg of component (b). 12. Composition according to claim 2, wherein it contains from 0.5 to 10 mg of 1- (2-naphth-2-yl-ethyl) -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyrine. 1

3. Composition according to claim 2, wherein it contains as active principles 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyrine and donezepil or its compounds. pharmaceutically acceptable salts. Composition according to claim 3, wherein it contains as active principles 1 - [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyrine and donezepil or its pharmaceutically acceptable salts. 15. Composition according to claim 2, wherein, it comprises 0.5 to 5 mg of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1, 2,3,6 hydrochloride. -tetrahydropyrine and from 2 to 10 mg of donepezil. 16. Composition according to any of the preceding claims wherein it is used for the treatment of senile dementia of Alzheimer's type. 17. Use of the composition according to any of the preceding claims wherein it is used for the preparation of drugs for the treatment of senile dementia of Alzheimer's type. 18. Use according to claim 17, wherein the component (a) is selected from the 1- (2-naphth-2-ylethyl) -4- (3-trifluoror-ethylphenyl) -1,2,3,6-tetrahydropyrin and 1 - [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyrine. 19. Use according to claim 17, wherein component (b) is selected from tacrine and donezepil. SUMMARY The invention relates to a pharmaceutical composition containing as active principles: a component (a) selected from 1- (2-naphth-2-yl) -4- (3-trifluoromethylphenyl) -1, 2,3,6 -tetrahydropyridine and a compound of the formula (I), wherein Y represents -CH- or -N-; Ri represents hydrogen, a halogen, a group CF3 (C3-C4) alkyl or (C1-C) alkoxy; R2 represents hydrogen, a halogen, a hydroxyl, a CF3 group, (C3-C4) alkyl or (C1-C4) alkoxy; R3 and R4 each represent hydrogen or a (d-C3) alkyl; X represents (a) a (C3-C6) alkyl; a (C3-C6) alkoxy; a (C3-C7) carboxyalkyl; a (C 1 -C 4) alkoxycarbonyl (C 3 -C 6) alkyi; a (C3-C7) carboxyalkoxy; or a (C 1 -C 4) alkoxycarbonyl or (C 3 -C 6) alkoxy; (b) a radical selected from a (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical being substituted by a halogen, hydroxy, ( d-C4) alkoxycarboxy, (C 1 -C 4) alkoxycarbonyl, amino, mono or di- (C 1 -C) alkylamino or (c) a group selected from phenyl, phenoxy, phenylamino, N- (d-C 3) alkyl- phenyl-amino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulphinyl or styryl, said mono- or polysubstituted group being in the phenyl group by a halogen, CF3, (d-C4) alkyl, (C1-C4) alkoxy , cyano, amino, mono- or di- (C-C4) alkylamino, (d-C4) acylamino, carboxy, (C1-C) alkoxycarbonyl, aminocarbonyl, mono- or di- (C-C4) alkylaminocarbonyl, amino (d-C4) ) alkyl, hydroxy (C1-C) alkyi or halogen (C1-C4) alkyl; optionally in the form of one of its pharmaceutically acceptable salts and a component (b) active in the symptomatic treatment of the DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when the component (a) is different from the 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or one of its pharmaceutically acceptable salts, the component (b) is an acetylcholinesterase inhibiting agent.