KR20010032099A - Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia - Google Patents

Abstract

The present invention is selected from 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and a compound of formula (I) Compound (a) (optionally in the form of one of its pharmaceutically acceptable salts) and

Compound (b), which is active in treating Alzheimer's type of dementia (DAT) symptoms (optionally in one of its pharmaceutically acceptable salts)

Wherein compound (b) is a compound of formula (a) wherein 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or If it is not a pharmaceutically acceptable salt thereof, it is an acetylcholinesterase inhibitor)

It relates to a pharmaceutical composition containing as an active ingredient.

<Formula I>

In the above formula,

Y is -CH- or -N-,

R ₁ is hydrogen, halogen, CF ₃ , (C ₃ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group,

R ₂ is hydrogen, halogen, hydroxyl, CF ₃ , (C ₃ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group,

R ₃ and R ₄ are each hydrogen or (C ₁ -C ₃ ) alkyl,

X is

(a) (C ₃ -C ₆ ) alkyl, (C ₃ -C ₆ ) alkoxy, (C ₃ -C ₇ ) carboxyalkyl, (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkyl, (C ₃ -C ₇ ) carboxyalkoxy, or (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkoxy,

(b) optionally substituted by halogen, hydroxy, (C ₁ -C ₄ ) alkoxy, carboxy, (C ₁ -C ₄ ) alkoxycarbonyl, amino, mono or di- (C ₁ -C ₄ ) alkylamino groups , (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyloxy, (C ₃ -C ₇ ) cycloalkylmethyl, (C ₃ -C ₇ ) cycloalkylamino and cyclohexenyl groups Or

(c) groups selected from phenyl, phenoxy, phenylamino, N- (C ₁ -C ₃ ) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl groups (The phenyl group is halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) 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 (C ₁ -C ₄ ) alkyl or halogeno (C ₁ -C ₄ ) alkyl.

Description

COMBINATION OF ACTIVE PRINCIPLES, IN PARTICULAR OF TETRAHYDROPY RIDINS AND ACETYLCHOLINESTERASE INHIBITING AGENTS, FOR TREATING SENILE DEZENAI SUMENT

In patients suffering from DAT, several neurotransmitters, especially acetylcholine levels, have been observed.

The only currently available DAT therapy is to increase the bioavailability by administering an acetylcholinesterase inhibitor to reduce the hydrolysis of acetylcholine. Therefore, this is symptomatic treatment.

Tacrine sold under the trade name COGNEX® and donepezil sold under the trade name ARICEPT® are acetylcholinesterase inhibitors known to treat mild or moderate symptoms of DAT.

Other products for DAT symptomatic therapy are under study. Some of these also affect the effectiveness of acetylcholine, while others ameliorate the symptoms of patients suffering from DAT with other mechanisms. To date, no drug has been proven to slow the development of the disease.

EP-458696 is 1- (2-naphth-2-ylethyl) -4- (3-trifluoro, designated as SR 57746 in the literature for the manufacture of a medicament designed to treat neurodegenerative diseases including senile dementia and Alzheimer's disease. Romethylphenyl) -1,2,3,6-tetrahydropyridine is described. 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 4-substituted 1-phenylalkyl-1,2,3,6-tetrahydropyridine with similar endogenous neurotropins and neuroprotection and neurotropin activity. As a result of this activity, the compounds described in this patent application are believed to be useful for treating diseases of various central nervous systems, including Alzheimer's disease.

In the treatment of neurological diseases such as DAT, the activities of the compounds described in WO 97/01536 and compound SR 57746 are not designed to treat symptoms, but are intended to modify the path of the disease to reduce its progress by protecting neurons.

The object of the present invention is to provide 1,2,3,6-tetrahydropyridine derivatives (optionally in the form of one of its pharmaceutically acceptable salts) and substances which are active in the treatment of symptoms of senile dementia of the Alzheimer type, in particular acetylcholine Preparation of a pharmaceutical composition comprising a novel combination for treating Alzheimer's type senile dementia, comprising an esterase inhibitor (optionally in the form of one of its pharmaceutically acceptable salts) and a medicament designed for treating Alzheimer's type senile dementia Its use for

Alzheimer's type senile dementia, referred to hereinafter as DAT (″ Alzheimer's type dementia ″), is a neurodegenerative disorder characterized clinically as a progressive degeneration of cognitive function. It is a disease that occurs in older people and increases with age. . In light of demographic trends, DAT will become an increasingly prevalent disease.

The compounds described above (optionally in the form of one of its pharmaceutically acceptable salts) and compounds which are active in the treatment of Alzheimer's type of senile dementia symptoms, in particular acetylcholinesterase inhibitors (optionally in their pharmaceutically acceptable salts) Formulations of one type) have been found to provide a quick and complementary effect, thereby making the DAT complete and very effective.

Therefore, the object of the present invention,

A compound selected from 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and a compound of formula (I) a) (optionally in the form of one of its pharmaceutically acceptable salts)

{<Formula I>

In the above formula,

Y is -CH- or -N-,

R ₁ is hydrogen, halogen, CF ₃ , (C ₃ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group,

R ₂ is hydrogen, halogen, hydroxyl, CF ₃ , (C ₃ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group,

R ₃ and R ₄ are each hydrogen or (C ₁ -C ₃ ) alkyl,

X is

(a) (C ₃ -C ₆ ) alkyl, (C ₃ -C ₆ ) alkoxy, (C ₃ -C ₇ ) carboxyalkyl, (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkyl, (C ₃ -C ₇ ) carboxyalkoxy, or (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkoxy,

(b) optionally substituted by halogen, hydroxy, (C ₁ -C ₄ ) alkoxy, carboxy, (C ₁ -C ₄ ) alkoxycarbonyl, amino, mono or di- (C ₁ -C ₄ ) alkylamino groups , (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyloxy, (C ₃ -C ₇ ) cycloalkylmethyl, (C ₃ -C ₇ ) cycloalkylamino and cyclohexenyl groups Or

(c) groups selected from phenyl, phenoxy, phenylamino, N- (C ₁ -C ₃ ) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl groups (The phenyl group is halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) 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 (C ₁ -C ₄ ) alkyl or halogeno (C ₁ -C ₄ ) alkyl optionally substituted); and

A compound (b) that is active in treating Alzheimer's type of dementia (DAT) symptoms (optionally in one of its pharmaceutically acceptable salts)

Wherein compound (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or a pharmaceutically acceptable thereof If not a possible salt, compound (b) is an acetylcholinesterase inhibitor)

It is a pharmaceutical composition containing as an active ingredient.

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

Particularly advantageous compound (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746), optionally Is a form of one of its pharmaceutically acceptable salts.

Among the pharmaceutically acceptable salts of SR 57746, particularly preferred salts are the hydrochlorides represented by SR 57746A below.

An advantageous method for preparing SR 57746A is the reaction of 2- (2-bromoethyl) naphthalene with 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and 1- (2 -Naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride is isolated, then heated and 5 ° C. at a cooling rate of 10 ° C./hour Cooled to and stirred at a speed of 400 rpm (resolution / minutes) to crystallize from the ethanol / water mixture to obtain a mixture of two crystalline forms in a ratio of about 66/34.

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

Another particularly advantageous compound (a) is 1- {2- (4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydro-pyridine, in particular its Hydrochloride.

Other advantageous compounds are as described 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-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-phenoxyphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;

1- {2- (4-benzylphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydro-pyridine;

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

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

1- {2- (4- (4-ethoxycarbonylpropoxy) phenyl) ethyl} -4- (3-trifluoro-methylphenyl) -1,2,3,6-tetrahydropyridine;

1- {2- (4-biphenylyl) ethyl} -4- (6-chloropyrid-2-yl) -1,2,3,6-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- (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-tetrahydropyridine;

1- {2- (3,4-diisopropylphenyl) 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.

As used herein, the expression ″ compounds active in treating DAT symptoms ″ refers to products that can ameliorate the symptoms of patients suffering from DAT without affecting the cause of the disease.

Such compounds, eg., An acetyl cholinesterase inhibitor, M ₁ muscarinic agonists (M ₁ muscarinic agonists), nicotine agonist (nicotinic agonists), N- methyl -D- aspartate (NMDA) receptor antagonist and a pin Knut Nootropics, with acetylcholinesterase inhibitors being particularly advantageous.

According to a preferred property, the invention is selected from compound (a) (optionally in the form of one of its pharmaceutically acceptable salts) and acetylcholinesterase inhibitor (optionally in the form of one of its pharmaceutically acceptable salts) A pharmaceutical composition containing compound (b) as an active ingredient.

Particularly advantageous acetylcholinesterase inhibitors are tacrine and donepezil.

Other usable acetylcholinesterase inhibitors include, for example, rivastig-mine (SDZ-ENA-713), galanthamine, metrifonate, eptastigmine, belnakrine velnacrine, physostigmine (see Drugs, 1997, 53 (5): 752-768; The Merck Index 12 ed.).

Other acetylcholinesterase inhibitors include 5,7-dihydro-3- {2- (1- (phenylmethyl) -4-piperidinyl) ethyl} -6H-pyrrolo (3,2-f) -1,2 Benzisoxazol-6-one, which is also referred to as icopezil (see J. Med. Chem., 1995, 38: 2802-2808), MDL-73,745 or zifrosilone (documents) (Eur. J. Pharmacol., 1995, 276: 93-99), TAK-147 (see J. Med. Chem., 1994, 37: 2292-2299).

Other acetylcholinesterase inhibitors are described, for example, 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 627 400.

M ₁ receptor antagonists include, for example, milameline, besipiridine, talsaclidine, xanomeline, YM-796 and YM-954 (Eur. J. Pharmacol). , 1990, 187: 479-486), 3- {N- (2-diethylamino-2-methylpropyl) -6-phenyl-5-propyl} -pyridazinamine, and also SR-46559 (See Biog. 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 (see Pharmacol. Toxicol., 1996, 78: 59-68).

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

Advantageous NMDA receptor antagonists are, for example, memantine (Arzneim. Forsch., 1991, 41: 773-780).

According to another feature, the invention relates to the use of a composition of the invention for the manufacture of a medicament designed for the treatment of dementia of the Alzheimer type.

According to another feature, the present invention also provides an effective dosage of Compound (a) (optionally in the form of one of the pharmaceutically acceptable salts) and an effective dosage of a compound for patients suffering from Alzheimer's type of senile dementia ( b), in particular, a method for the treatment of senile dementia of the Alzheimer's type, consisting of administering an acetylcholinesterase inhibitor (optionally in the form of one of the pharmaceutically acceptable salts) simultaneously, sequentially or alternately. . Here, the active ingredients of the active dosage may be included in separate unit dosage forms, or when two active ingredients are administered simultaneously, the two active ingredients may advantageously be included in a single pharmaceutical form.

The active ingredient according to the invention is preferably administered orally.

In the pharmaceutical composition for oral administration of the present invention, the active ingredient may be administered to animals and humans in unit dosage form, in admixture with standard pharmaceutical excipients, for the treatment of the diseases described above. Suitable unit dosage forms include optionally divided tablets, capsules, powders, granules and solutions or oral suspensions and the like.

When preparing the solid composition in tablet form, the main active ingredient is mixed with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. Tablets may be coated with sucrose or other suitable material or may be treated to sustain or prolong their activity and to continuously release the active ingredient in a predetermined amount.

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

Formulations in the form of syrup or elixir may contain methylparaben and propylparaben together with the active ingredient as sweeteners, preferably calorie-free sweeteners and preservatives, as well as flavoring agents and suitable colorants.

Water-dispersible powders and granules may contain the active ingredient in admixture with a dispersing or wetting agent or with a suspending agent such as polyvinylpyrrolidone, such as a mixture of sweetening or flavor neutralizing agents.

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

In the pharmaceutical compositions according to the invention, the active ingredient may also be in the form of conjugated complexes in cyclodextrins, ethers or esters thereof.

The amount of active ingredient to be administered is administered differently according to the age, weight and extent of disease of the patient, as is common.

The dosage of the two active ingredients is similar to the dosages commonly selected in the art when independently administering each of these active ingredients.

Thus, the compositions according to the invention can be prepared in the dosages recommended for non-combination therapy, for example, between 0.5 mg and 700 mg of compound (a) or a pharmaceutically acceptable salt thereof, and compound (b) or pharmaceutically thereof Acceptable salts contain doses of 0.1 mg to 50 mg or less, the combination of which produces a synergistic effect.

Advantageous compositions contain, for example, 0.5 to 5 mg of SR 57746 or a pharmaceutically acceptable salt thereof and 0.1 to 50 mg of an acetylcholinesterase inhibitor or a pharmaceutically acceptable salt thereof.

Preferred compositions contain SR 57746 or a pharmaceutically acceptable salt thereof, especially hydrochloride, 0.5-5 mg and 2-10 mg of donepezil or a pharmaceutically acceptable salt thereof.

Dosages described in the present description are directed to active ingredients that are not formulated in salt form.

The activity of the compositions according to the invention is specific for the septo-hippocampal cholinergic system for disorders caused by the injection of vincristine, which causes biochemical modifications similar to those seen in Alzheimer's disease. Prove it using a model.

The method used in this model, the assessment of the disturbances and social memory caused by vincristine, are described in EP 655247.

〈Evaluation test of social memory in rats〉

As described in EP 655247, after injecting vincristine to cause injuries, mice remain unchanged consistently with memory loss. Rats were divided into two groups, one solvent was given and the other group received orally SR 57746A at a dose of 5 mg.kg (this amount is insufficient to functionally restore the memory of the mice undergoing this test). 10 mg / kg is the effective dose as described in EP 655247). Tacrine 1 mg / kg was then administered intraperitoneally to both groups of mice. The control group given solvent and tacrine showed no memory recovery, whereas the group treated with SR 57746A (quasi-effective dose) and tacrine showed significant recovery in memory retention disorders.

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

As a result of this complementary and synergistic effect of the components of the formulation, the composition of the present invention is in all forms by ensuring the rapid improvement of the patient's symptoms as well as the protection and even treatment of neurons affected by the disease simultaneously. To enable effective treatment of DAT.

Claims (19)

Compound selected from 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and a compound of formula (I) ) (Optionally in the form of one of its pharmaceutically acceptable salts) and Compound (b), which is active in treating Alzheimer's type of dementia (DAT) symptoms (optionally in one of its pharmaceutically acceptable salts) Wherein compound (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or a pharmaceutically acceptable thereof If not a possible salt, compound (b) is an acetylcholinesterase inhibitor). Pharmaceutical composition containing as an active ingredient. <Formula I> In the above formula, Y is -CH- or -N-, R ₁ is hydrogen, halogen, CF ₃ , (C ₃ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group, R ₂ is hydrogen, halogen, hydroxyl, CF ₃ , (C ₃ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group, R ₃ and R ₄ are each hydrogen or (C ₁ -C ₃ ) alkyl, X is (a) (C ₃ -C ₆ ) alkyl, (C ₃ -C ₆ ) alkoxy, (C ₃ -C ₇ ) carboxyalkyl, (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkyl, (C ₃ -C ₇ ) carboxyalkoxy or (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkoxy, (b) optionally substituted by halogen, hydroxy, (C ₁ -C ₄ ) alkoxy, carboxy, (C ₁ -C ₄ ) alkoxycarbonyl, amino, mono or di- (C ₁ -C ₄ ) alkylamino groups , (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyloxy, (C ₃ -C ₇ ) cycloalkylmethyl, (C ₃ -C ₇ ) cycloalkylamino and cyclohexenyl groups Or (c) groups selected from phenyl, phenoxy, phenylamino, N- (C ₁ -C ₃ ) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl groups (The phenyl group is halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) 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 (C ₁ -C ₄ ) alkyl or halogeno (C ₁ -C ₄ ) alkyl. The compound of claim 1, wherein 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (optionally pharmaceutically acceptable thereof) 1) a composition which is active in the treatment of senile dementia symptoms of Alzheimer's type (optionally in one of its pharmaceutically acceptable salts) as an active ingredient. The method of claim 1, A compound of formula (I) (optionally in the form of one of its pharmaceutically acceptable salts) and Acetylcholinesterase inhibitors or pharmaceutically acceptable salts thereof Composition containing as an active ingredient. <Formula I> In the above formula, Y is -CH- or -N-, R ₁ is hydrogen, halogen, CF ₃ , (C ₃ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group, R ₂ is hydrogen, halogen, hydroxyl, CF ₃ , (C ₃ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group, R ₃ and R ₄ are each hydrogen or (C ₁ -C ₃ ) alkyl, X is (a) (C ₃ -C ₆ ) alkyl, (C ₃ -C ₆ ) alkoxy, (C ₃ -C ₇ ) carboxyalkyl, (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkyl, (C ₃ -C ₇ ) carboxyalkoxy or (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkoxy, (b) optionally substituted by halogen, hydroxy, (C ₁ -C ₄ ) alkoxy, carboxy, (C ₁ -C ₄ ) alkoxycarbonyl, amino, mono or di- (C ₁ -C ₄ ) alkylamino groups , (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyloxy, (C ₃ -C ₇ ) cycloalkylmethyl, (C ₃ -C ₇ ) cycloalkylamino and cyclohexenyl groups Or (c) groups selected from phenyl, phenoxy, phenylamino, N- (C ₁ -C ₃ ) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl groups (The phenyl group is halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) 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 (C ₁ -C ₄ ) alkyl or halogeno (C ₁ -C ₄ ) alkyl. The compound of claim 3, wherein the compound (a) is 1- {2- (4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or Hydrochloride. The composition of claim 3, wherein compound (a) is selected from the following compounds and their pharmaceutically acceptable salts: 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-phenoxyphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4-benzylphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydro-pyridine; 1- {2- (4-n-butylphenyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4-n-butoxyyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4- (4-ethoxycarbonylpropoxy) phenyl) ethyl} -4- (3-trifluoro-methylphenyl) -1,2,3,6-tetrahydropyridine; 1- {2- (4-biphenylyl) ethyl} -4- (6-chloropyrid-2-yl) -1,2,3,6-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- (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-tetrahydropyridine; 1- {2- (3,4-diisopropylphenyl) 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. The method of claim 1 wherein the compound which is active in senile dementia of the Alzheimer type treatment acetyl cholinesterase inhibitors, M ₁ muscarinic agonists (M ₁ muscarinic agonists), nicotine agonist (nicotinic agonists), NMDA receptor antagonists (NMDA a composition selected from receptor antagonists and nootropic agents. 7. The composition of claim 6, wherein compound (b) is an acetylcholinesterase inhibitor. 8. The composition of claim 7, wherein the acetylcholinesterase inhibitor is selected from tacrine and donepezil. 8. The method of claim 7, wherein the acetylcholinesterase inhibitor is rivastig-mine, galanthamine, methifoneate, metrifonate, eptastigmine, velnacrine, cysos Composition selected from physostigmine, icozepil and zifrosilone. The composition according to claim 1, which contains 0.5 to 700 mg of compound (a). The composition according to claim 1, which contains 0.1 to 50 mg of compound (b). 3. A compound according to claim 2, which contains 0.5 to 10 mg of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine. Characterized in that the composition. The compound according to claim 2, wherein 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and donepezil or pharmaceutically thereof A composition comprising an acceptable salt as an active ingredient. The method of claim 3, wherein 1- {2- (4-biphenylyl) ethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and donepezil or a pharmaceutical thereof A composition comprising a salt that is acceptable as an active ingredient. 3. 0.5-5 mg of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and donepezil 2 To 10 mg. The composition according to any one of claims 1 to 15, for treating senile dementia of the Alzheimer type. Use of a composition according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of dementia of the Alzheimer's type. 18. The compound of claim 17, wherein compound (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and 1- Use of a composition characterized in that it is selected from {2- (4-biphenylyl) ethyl} -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine. 18. Use of a composition according to claim 17 wherein compound (b) is selected from tacrine and donepezil.