SK7112000A3 - 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

Technical field

The present invention provides a pharmaceutical composition comprising a novel combination of active ingredients for the treatment of Alzheimer's type dementia, comprising 1,2,3,6-tetrahydropyridine derivatives, optionally in the form of one of its pharmaceutically acceptable salts, and a substance active in the symptomatic treatment of Alzheimer's type dementia. , in particular an acetylcholinesterase inhibitor, pharmaceutically acceptable salts and a medicament thereof for the treatment of age, optionally in the form of use for the preparation of Alzheimer's type dementia.

BACKGROUND OF THE INVENTION

Alzheimer's type dementia, hereinafter referred to as DAT (Alzheimer's type dementia), is a neurodegenerative disease characterized by clinically progressive degeneration of cognitive functions occurring in the elderly, with incidence increasing with age. In light of demographic trends, DAT is becoming an increasingly common disease.

A decrease in the level of some neurotransmitters, particularly acetylcholine, has been observed in patients suffering from DAT.

Treatment of DAT, which is currently commercially available, only involves the administration of acetylcholine esterase inhibitors, which increase its bioavailability by reducing the hydrolysis of acetylcholine. This is symptomatic treatment.

Tacrine, sold under the trademark COGNEX® and donepezil, sold under the trademark ARICEPT®, are acetylcholinesterase inhibitors for the symptomatic treatment of mild or moderate forms of DAT. Other products for symptomatic treatment are being studied. Some of them also affect the bioavailability of acetylcholine, others improve the symptomatology of patients suffering from DAT by another mechanism. While no commercially available drug has been shown to be 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-tetrahydropiridine, referred to in the literature as SR 57746, for the preparation of a medicament intended to combat neurodegenerative conditions, including age-related dementia of the Alzheimer type. The neurotrophic action of SR 57746 on the nervous system is similar to that of some endogenous neurotrophins, such as nerve growth factor (NGF).

WO 97/01536 discloses novel 4-substituted 1-phenylalkyl-1,2,3,6-tetrahydropyridines having neuroprotective and neurotrophic activity similar to some endogenous neurotrophins. Based on this activity, the compounds described in this patent application are expected to be useful in the treatment of certain diseases of the central nervous system, including Alzheimer's disease.

The activity of SR 57746 and the compounds described in WO 97/01536 in the treatment of nerve diseases such as DAT is not for the treatment of symptoms, but for the protection of neurons, to modify the course of the disease and slow down its progression.

It has been found that the combination of the above compounds, in particular in the form of one of their pharmaceutically acceptable salts, with a compound active in the symptomatic treatment of Alzheimer's type dementia, in particular an acetylcholinesterase inhibitor or one of its pharmaceutically acceptable salts, results in a complete and very effective For the treatment of DAT, the combination exhibits a rapid and complementary effect.

SUMMARY OF THE INVENTION

An object of the present invention is a pharmaceutical composition comprising as active ingredients

- a compound (a) selected from 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and a compound of formula I

where

Y is -CH- or -N-;

R ¹ is hydrogen, halogen, CF 3, C 3 -C 4 alkyl or C 1 -C 4 alkoxy;

R ² is H, halogen, OH, CF 3, alkyl having 3-4 carbon atoms or alkoxy having 1 to 4 carbon atoms;

R ³ and R ⁴ are each a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;

X is (a) an alkyl group having 3 to 6 carbon atoms; (C 3 -C 6) alkoxy; C 3 -C 7 carboxyalkyl; alkoxycarbonylalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 3 to 6 carbon atoms in the alkyl moiety; C 3 -C 7 carboxyalkoxy; or alkoxycarbonylalkoxy having from 1 to 4 carbon atoms in the first alkoxy moiety and from 3 to 6 carbon atoms in the second alkoxy moiety;

(b) a radical selected from the group consisting of C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 3-7 cycloalkylmethyl, C 3-7 cycloalkylamino and cyclohexenyl, said group being optionally substituted by a halogen atom, a hydroxyl group, a C 1 -C 4 alkoxy group, a carboxyl group, a C 1 -C 4 alkoxycarbonyl group, an amino group, a mono or dialkylamino group C 1 to 4 carbon atoms; or (c) a group selected from the group consisting of phenyl, phenoxy, phenylamino, N-alkylphenylamino having 1 to 3 carbon atoms in the alkyl moiety, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or phenylsulfinyl said phenyl being optionally mono- or polysubstituted with halogen, CF ₃ , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, amino, mono or dialkylamino of 1 to 4 carbon atoms in each alkyl moiety , C 1-4 acylamino, carboxyl, C 1-4 alkoxycarbonyl in each alkoxy moiety, C 1-4 aminocarbonyl, C 1-4 mono- or dialkylaminocarbonyl in each alkyl moiety ka, aminoalkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or haloalkoxy of 1 to 4 carbon atoms;

optionally in the form of one of its pharmaceutically acceptable salts and compound (b) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that if compound (a) is other than 1- (2-naphth-2) -ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or one of its pharmaceutically acceptable salts, compound (b) is an acetylcholinesterase inhibitor.

1- (2-Naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydro-pyridine (SR 57746) is described in EP 101 381 and compounds of formula (I) are described in WO 97/01536.

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

Of the pharmaceutically acceptable salts of SR 57746, a particularly preferred salt is the hydrochloride referred to hereinafter as SR 57746A.

A preferred method of preparing SR 57746A involves the reaction between 2- (2-bromomethyl) naphthalene and 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and isolating 1- (2-naphth-2-ylethyl) -4 hydrochloride - (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine which is then crystallized from ethanol / water by heating and cooling to 5 ° C at a cooling rate of 10 ° C / hour and a stirring speed of 400 rpm . In this way, a mixture of two crystal forms in a ratio of about 66/34 is obtained.

SR 57746A is preferably used in the form of microparticles, for example, in an almost amorphous form obtained by spray drying or in a microcrystalline form obtained by micronization.

Another particularly preferred compound (a) is 1- {2- (4-biphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropiridine, particularly in the form of the hydrochloride.

Other preferred compounds are as follows:

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-methyl-propyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;

1- {2- (4-phenoxyphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;

1- {2- (4-benzyloxyphenyl) 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-butoxy-phenyl) 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;

- {2- (2,3'-dichloro-4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;

1- {2- (3-chloro-4-biphenyl) 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-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;

1- {2- (3'-chloro-4-biphenylyl) -2-methylpropyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;

1- {2- (2-fluoro-4-biphenylyl) propyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;

- {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) -1,2,3,6-tetrahydropyridine;

1- {2- (3-biphenylyl) ethyl} -4- (trifluoromethyl) -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-tetrahydropyridine;

1- {2- (3,4-dipropylphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;

l- {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 pharmaceutically acceptable salts thereof.

According to the present invention, the term compound active in the symptomatic treatment of DAT is a product capable of ameliorating the symptomatology of patients suffering from DAT without affecting the causes of the disease.

Such compounds are, for example, acetylcholinesterase inhibitors, Mi muscarinic agonists, nicotine agonists, N-methyl-D-aspartate (NMDA) receptor antagonists, nootropic agents, with acetylcholinesterase inhibitors being particularly preferred.

According to a preferred embodiment, the present invention relates to a pharmaceutical composition comprising as an active ingredient compound (a), optionally in the form of one of its pharmaceutically acceptable salts, and compound (b) selected from acetylcholinesterase inhibitors, optionally in the form of one of its pharmaceutically acceptable salts.

Particularly preferred acetylcholinesterase inhibitors are tacrine and donepezil.

Other acetylcholinesterase inhibitors that 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.) .

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 as 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 acetylcholinesterase inhibitors are, for example, those described in patent applications JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 9604565, 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 627 400.

M 1 receptor antagonists are, for example, milameline, besipiridine, talsaclidine, xanomeline, YM-796 and YM-954 (Eur. J. Pharmacol., 1990, 187: 479-486), 3- {N- (2-diethylamino-2-methylpropyl) ) 9

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 25-109, S-99 77-2, SB 202,026, thiopilocarpine,

WAL 2014 (Pharmacol. Toxicol., 1996, 78: 59-68).

Preferred nicotine antagonists 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).

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

According to another embodiment, the present invention relates to the use of the medicament compositions for use in the preparation of the present invention for the treatment of Alzheimer's type of dementia.

According to another embodiment, the present invention also relates to another method of treating Alzheimer's type of dementia comprising administering an effective dose of compound (a), optionally in the form of one of its pharmaceutically acceptable salts, and an effective dose of compound (b), particularly an acetylcholinesterase inhibitor, optionally one of its pharmaceutically acceptable salts to a patient suffering from the disease, wherein said administration is simultaneous, sequential or alternating at intervals and the effective dosages of the active ingredients are contained in separate unit dosage forms, or when the active ingredients are administered simultaneously, both active ingredients are preferably contained in a single pharmaceutical form.

The active ingredients of the present invention are preferably administered orally.

In the pharmaceutical compositions of the present invention for oral administration, the active ingredients may be administered in unitary forms for administration, in admixture with conventional pharmaceutical vehicles, to a mammal and to a human being to be treated, for the treatment of the aforementioned diseases. Suitable unit dosage forms include, for example, suitably dividable tablets, capsules, powders, granules and solutions or oral suspensions.

When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. The tablets may be coated with sucrose or other suitable material or may be formulated to have prolonged or delayed activity and to release a predetermined amount of the active ingredient continuously.

Capsule preparations are obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules.

The syrup or elixir formulations may contain the active ingredient together with a sweetener, preferably non-caloric, methylparaben and propylparaben as an antiseptic agent, as well as flavorings and suitable colorants.

Water dispersible powders and granules may contain the active ingredient in admixture with a dispersing or wetting agent or suspending agent, such as polyvinylpyrrolidone, as well as sweetening or flavoring agents.

The active ingredient may also be formulated in the form of microcapsules, optionally with one or more excipients or excipients.

In the pharmaceutical compositions of the present invention, the active ingredient may also be in the form of an inclusion complex in cyclodextrins, ethers or esters thereof.

The amount of active ingredient to be administered depends, as usual, on the degree of disease progression as well as the age and weight of the patient. The dosages of the active ingredients are similar to those normally selected in the art for the isolated administration of each of the active ingredients.

The compositions of the present invention contain recommended dosages for the combination therapies, for example 0.5 mg to 700 mg of Compound (a) or one of their pharmaceutically acceptable salts and 0.1 to 50 mg of Compound (b) or one of their pharmaceutically acceptable salts, or even lower doses, which is due to the composition having a synergistic effect.

The compositions preferably comprise 0.5 to 5 mg of SR 57746 or one of their pharmaceutically acceptable salts and 0.1 to 50 mg of an acetylcholinesterase inhibitor or one of its pharmaceutically acceptable salts.

Preferred compositions comprise 0.5 to 5 mg of SR 57746 or one of their pharmaceutically acceptable salts, especially the hydrochloride, and 2 to 10 mg of donepezil or one of its pharmaceutically acceptable salts.

The dosages indicated according to the present description correspond to the active ingredients which are not in the form of salts.

The activity of the composition of the present invention can be demonstrated using a specific model for the septo-hippocampal cholergic system on lesions caused by vincristine injection, which induces biochemical changes that are similar to those of Alzheimer's disease.

The procedure used for this model, the lesions caused by vincristine as well as the evaluation of social memory are described in EP 655247.

DETAILED DESCRIPTION OF THE INVENTION

Evaluation of social memory test in rats

After lesion induction by vincristine injection according to EP 655247, the rats exhibit stable and durable amnesia. Rats are divided into two groups, one group receives solvent and the other group receives SR 57746A at a dose of 5 mg.kg after, a dose that is not sufficient to restore memory function in rats undergoing this treatment. test (the effective dose is 10 mg / kg as described in EP 655247). Thereafter, both groups of rats received 1 mg / kg i. p. tacrine. The control group that received solvent and tacrine showed no memory recovery, while the group treated with SR 57746A (dose lower than effective) and tacrine showed a significant recovery of memory deficit.

The test results show the synergistic action of the combination of the present invention.

This complementary and synergistic effect of the components of the combination, which at the same time ensures the protection and even treatment of the neurons affected by the disease and also immediately improves symptoms in patients, suggests that the composition of the present invention allows effective treatment of DAT in all its forms.

Claims (19)

PATENT CLAIMS FROM/ A pharmaceutical composition comprising as active ingredients - a compound (a) selected from 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and a compound of formula I wherein: Y is -CH- or -N-; R ¹ is hydrogen, halogen, CF 3, C 3 -C 4 alkyl or C 1 -C 4 alkoxy; R ² is H, halogen, OH, CF 3, alkyl having 3-4 carbon atoms or alkoxy having 1 to 4 carbon atoms; R ³ and R ⁴ are each a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; X is (a) an alkyl group having 3 to 6 carbon atoms; (C 3 -C 6) alkoxy; C 3 -C 7 carboxyalkyl; alkoxycarbonylalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 3 to 6 carbon atoms in the alkyl moiety; C 3 -C 7 carboxyalkoxy; or alkoxycarbonylalkoxy having from 1 to 4 carbon atoms in the first alkoxy moiety and from 3 to 6 carbon atoms in the second alkoxy moiety; (b) a radical selected from the group consisting of C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyloxy, C 3 -C 7 cycloalkylmethyl, C 3 -C 7 cycloalkylamino and cyclohexenyl, said group being optionally substituted by halogen, hydroxyl, C 1 -C 4 alkoxy, carboxyl, C 1 -C 4 alkoxycarbonyl, amino, C 1 -C 4 mono- or dialkylamino in each C 1 -C 4 alkyl group ; or (c) a group selected from the group consisting of phenyl, phenoxy, phenylamino, N-alkylphenylamino having 1 to 3 carbon atoms in the alkyl moiety, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or phenylsulfinyl said phenyl optionally mono- or polysubstituted with halogen, CF 3, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, amino, C 1-4 mono or dialkylamino of each C 1 -C 4 alkyl group, C 1-4 acylamino, carboxyl, C 1-4 alkoxycarbonyl in each alkoxy moiety, C 1-4 aminocarbonyl, C 1-4 mono- or dialkylaminocarbonyl in each alkyl moiety a, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl or (1-4C) haloalkyl; optionally in the form of one of its pharmaceutically acceptable salts and compound (b) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that if compound (a) is other than 1- (2-naphthyl) 2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or one of its pharmaceutically acceptable salts, compound (b) is an acetylcholinesterase inhibitor. Composition according to claim 1, characterized in that it contains 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, optionally in the form of one of the active ingredients, as active ingredients. a pharmaceutically acceptable salt thereof in combination with a compound active in the symptomatic treatment of Alzheimer's type of dementia, optionally in the form of one of its pharmaceutically acceptable salts. Composition according to claim 1, characterized in that it contains as active ingredients a compound of formula I wherein Y is -CH- or -N-; R ¹ is hydrogen, halogen, CF ₃ , C 3 -C 4 alkyl or C 1 -C 4 alkoxy; R ² is H, halogen, OH, CF _3, alkyl having 3-4 carbon atoms or alkoxy having 1 to 4 carbon atoms; R ³ and R ⁴ are each a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; X is (a) an alkyl group having 3 to 6 carbon atoms; (C 3 -C 6) alkoxy; C 3 -C 7 carboxyalkyl; alkoxycarbonylalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 3 to 6 carbon atoms in the alkyl moiety; C 3 -C 7 carboxyalkoxy; or alkoxycarbonylalkoxy having from 1 to 4 carbon atoms in the first alkoxy moiety and from 3 to 6 carbon atoms in the second alkoxy moiety; (b) a radical selected from the group consisting of C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyloxy, C 3 -C 7 cycloalkylmethyl, C 3 -C 7 cycloalkylamino and cyclohexenyl, said group being optionally substituted by halogen, hydroxyl, C 1 -C 4 alkoxy, carboxyl, C 1 -C 4 alkoxycarbonyl, amino, C 1 -C 4 mono- or dialkylamino in each C 1 -C 4 alkyl group ; or (c) a group selected from the group consisting of phenyl, phenoxy, phenylamino, N-alkylphenylamino having 1 to 3 carbon atoms in the alkyl moiety, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or phenylsulfinyl said phenyl is optionally mono- or polysubstituted with halogen, CF ₃ , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, amino, mono or dialkylamino of 1 to 4 carbon atoms in each alkyl moiety , C 1-4 acylamino, carboxyl, C 1-4 alkoxycarbonyl in each alkoxy moiety, C 1-4 aminocarbonyl, C 1-4 mono- or dialkyl aminocarbonyl in each alkyl moiety C 1 -C 4 aminoalkyl, C 1 -C 4 hydroxyalkyl or C 1 -C 4 haloalkyl; optionally in the form of one of its pharmaceutically acceptable salts, and an acetylcholinesterase inhibitor, or a pharmaceutically acceptable salt thereof. The composition of claim 3, wherein compound (a) is 1- {2- (4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or its hydrochloride . The composition of claim 3, wherein compound (a) is selected from the following compounds: 1- {2- (3'-Chloro-4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (2'-Chloro-4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4'-Chloro-4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4'-Fluoro-4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (3'-Trifluoromethyl-4-biphenylyl) ethyl} -4- (3-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-methyl-propyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1-I2 (4-phenoxyphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4-benzyloxyphenyl) 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-butoxy-phenyl) 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-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (3'-Chloro-4-biphenylyl) -2-methylpropyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (2-fluoro-4-biphenylyl) propyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4-methoxy-3-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4'-Methoxy-4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4'-hydroxy-4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4'-ethoxycarbonylbutoxy-4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (3-Biphenylyl) ethyl} -4- (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-tetrahydropyridine; l- {2- (3,4-dipropylphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; l- {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 pharmaceutically acceptable salts thereof. The composition of claim 1, wherein the compound active in the symptomatic treatment of Alzheimer's type dementia is selected from acetylcholinesterase inhibitors, M muscarinic agonists, nicotine agonists, NMDA receptor antagonists, and nootropic agents. The composition of claim 6, wherein compound (b) is an acetylcholinesterase inhibitor. The composition of claim 7, wherein the acetylcholinesterase inhibitor is selected from tacrine and donepezil. The composition of claim 7, wherein the acetylcholinesterase inhibitor is selected from rivastigmine, galanthamine, metrifonate, eptastigmine, velnacrine, phystostigmine, icozepil and zifrosilone. A composition according to claim 1 comprising 0.5 to 700 mg of the compound The composition of claim 1 comprising 0.1 to 50 mg of compound m, m, m, The composition of claim 2 comprising 0.5 to 10 mg of (1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine). Composition according to Claim 2, characterized in that it contains 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine as active ingredients and donepezil or a pharmaceutically acceptable salt thereof salt. Composition according to Claim 3, characterized in that it contains 1- {2- (4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine as active ingredients and donepezil or a pharmaceutical thereof acceptable salts. Composition according to claim 2, characterized in that it contains 0.5 to 5 mg of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and 10 mg donepezil. A composition according to any one of the preceding claims for the treatment of Alzheimer's type dementia. Use of a composition according to any one of the preceding claims for the preparation of a medicament for the treatment of age dementia Alzheimer's type. Use according to claim 17, characterized in that compound (a) is selected from 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and 1 - {2- (4-Biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine. Use according to claim 17, characterized in that compound (b) is selected from tacrine and donepezil.