HK1023997B - 1-phenylalkyl-1,2,3,6-tetrahydropyridines for treating alzheimer's disease - Google Patents

Description

1-phenylalkyl-1, 2, 3, 6-tetrahydropyridines for treating alzheimer's disease

The present invention relates to novel 4-substituted 1-phenylalkyl-1, 2, 3, 6-tetrahydropyridines having neurotrophic and neuroprotective activity, to processes for their preparation and to pharmaceutical compositions containing them.

EP-0458696 discloses the use of 1- (2-naphthylethyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine for the preparation of a medicament for the treatment of cerebral and neurological diseases.

WO 93/11107 discloses piperidine and tetrahydropyridines which are capable of protecting against damage caused by hypoxic/ischemic conditions.

It has now been found that certain phenyl-or pyridyl-substituted phenylalkyl-1, 2, 3, 6-tetrahydropyridines exhibit neurotrophic effects on the nervous system similar to Nerve Growth Factor (NGF) and can restore the function of damaged cells or cells which exhibit abnormalities in physiological function.

In one aspect, the invention relates to compounds of formula (I):wherein: y is-CH-or-N-; r₁Is hydrogen, halogen or CF₃、(C₁-C₄) Alkyl or (C)₁-C₄) An alkoxy group; r₂Is methyl or ethyl; r₃And R₄Are each hydrogen or (C)₁-C₃) An alkyl group; and X is:

(a)(C₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₃-C₇) Carboxyalkyl, (C)₁-C₄) Alkoxycarbonyl (C)₁-C₆) Alkyl, (C)₃-C₇) Carboxyalkoxy or (C)₁-C₄) Alkoxycarbonyl (C)₁-C₆) An alkoxy group;

(b) one is selected from (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkoxy, (C)₃-C₇) Cycloalkylmethyl group, (C)₃-C₇) Cycloalkylamino and cyclohexenyl groups; the radical may be substituted by halogen, hydroxy, (C)₁-C₄) Alkoxy, carboxyl, (C)₁-C₄) Alkoxycarbonyl, amino or mono-or di- (C)₁-C₄) Alkyl amino substitution; or

(c) One is selected from phenyl, phenoxy, phenylamino, N- (C)₁-C₃) Groups of alkylphenylamino, benzyl, phenethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl; the phenyl group of the radical may be substituted by halogen, CF₃、(C₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, cyano, amino, mono-or di- (C)₁-C₄) Alkylamino radical, (C)₁-C₄) Acylamino, carboxyl, (C)₁-C₄) Alkoxycarbonyl, aminocarbonyl, mono-or di- (C)₁-C₄) Alkylaminocarbonyl, amino (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl or halo (C)₁-C₄) Alkyl is mono-or poly-substituted; and salts and solvates thereof, and quaternary ammonium salts thereof.

The term "(C) in the description of the present application₁-C₃) Alkyl "stands for methyl, ethyl, n-propyl and isopropyl.

Term "(C)₁-C₄) Alkyl "represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Term "(C)₁-C₆) Alkyl "represents a hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like.

The term "alkoxy" stands for a radical of formula (C)₁-C₆) Alkyl, suitably from (C)₁-C₄) Alkyl and is preferably represented by (C)₁-C₃) Alkyl-substituted hydroxyl.

If X is phenyl, the principle for the naming of biphenyl is the International Union of Pure and Applied Chemistry (IUPAC) rule, i.e., the position numbers of the two rings are as follows:and groups having this structure are named as follows:biphenyl-4-ylBiphenyl-3-ylBiphenyl-2-yl

In which X is a group (c)Of the compounds of formula (I), one group of preferred compounds is that wherein the phenyl group is substituted with 1 to 3 halogens, 1 to 3 CF₃1 to 3 (C)₁-C₄) Alkyl, 1 to 3 (C)₁-C₄) Alkoxy, 1 to 3 cyano, 1 to 3 amino, 1 to 3 mono-or di- (C)₁-C₄) Alkylamino radical, 1 to 3 (C)₁-C₄) Acylamino, 1 to 3 carboxyl groups, 1 to 3 (C)₁-C₄) Alkoxycarbonyl, 1 to 3 aminocarbonyl, 1 to 3 mono-or di- (C)₁-C₄) Alkylaminocarbonyl, 1 to 3 amino groups (C)₁-C₄) Alkyl, 1 to 3 hydroxy (C)₁-C₄) Alkyl or 1 to 3 halo (C)₁-C₄) Alkyl substituted compounds.

Another preferred group of compounds are those wherein Y is-CH-and R₁Is CF₃A compound of formula (I).

Another preferred group of compounds are those in which Y is a nitrogen atom and R is₁A chlorine atom of the compound of formula (I).

Another preferred group of compounds are those wherein X is (C)₁-C₆) Alkyl, especially ethyl, compounds of formula (I).

Particularly suitable compounds are of formula (I'):

wherein R is₁Is' CF₃And Y' is CH, or R₁'is Cl and Y' is N, R₂And X is as defined above; and salts, solvates and quaternary ammonium salts thereof.

Another preferred group of compounds is that wherein X is (C)₁-C₆) Alkyl compounds of formula (I').

Particularly advantageous compounds according to the invention are: 1- [2- (3, 4-diethylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 1- [2- (3-methyl-4-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 1- [2- (4-methyl-3-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 1- [2- (3, 4-diethylphenyl) ethyl ] -4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine and salts, solvates and quaternary ammonium salts thereof.

Another aspect of the present invention relates to a process for the preparation of compounds of formula (I) and salts or solvates thereof and quaternary ammonium salts thereof, which process is characterized in that:

(a) reacting an aryl-1, 2, 3, 6-tetrahydropyridine of formula (II):

wherein Y and R₁As defined above, with a compound of formula (III):

wherein R is₂、R₃、R₄And X has the above-mentioned meaning and L is a leaving group, for example a chlorine, bromine or iodine atom or a methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy group; and

(b) the resulting compound of formula (I) is isolated and optionally converted to one of its salts or solvates or one of its quaternary ammonium salts.

The above reaction is carried out in an organic solvent and in a range from room temperature to the reflux temperature of the solvent used.

Aliphatic alcohols having 1 to 6 carbon atoms (e.g., methanol, ethanol, isopropanol, n-butanol or n-pentanol) are preferred as the organic solvent, but other solvents such as hexane, dimethylformamide, dimethyl sulfoxide, sulfolane, acetonitrile, pyridine, etc. may also be employed.

The reaction is advantageously carried out in the presence of a basic reagent such as an alkali metal carbonate or triethylamine, especially when L is a halogen atom.

The temperature of the above reaction may vary between room temperature (about 20 ℃) and reflux temperature, with the reaction time varying. Generally, after heating at reflux for 6 to 12 hours, the reaction is complete and the final product in the form of the free base or one of its salts can be isolated by conventional techniques; the free base may optionally be converted to one of its salts by simple salt formation in an organic solvent such as an alcohol (preferably ethanol and isopropanol), an ether (e.g. 1, 2-dimethoxyethane), ethyl acetate, acetone or a hydrocarbon (e.g. hexane).

The compound of formula (I) obtained can be isolated using conventional techniques and, optionally, converted into one of its acid addition salts; furthermore, if an acid group is present, the amphoteric character of the compound will ensure the isolation of its salt either with acid or base.

For the preparation of salts of the compounds of formula (I) for use as medicaments for administration, the acid or base used must be pharmaceutically acceptable; if the salt of the compound of formula (I) is prepared for another purpose, for example to improve product purity or to improve analytical methods, any acid or base may be used.

Examples of salts with pharmaceutically acceptable acids are: those formed with inorganic acids such as hydrochloride, hydrobromide, borate, phosphate, sulfate, bisulfate, hydrogenphosphate and dihydrogenphosphate; and those formed with organic acids such as citrate, benzoate, ascorbate, methylsulfate, naphthyl-2-sulfonate, picrate, fumarate, maleate, malonate, oxalate, succinate, acetate, tartrate, methanesulfonate, toluenesulfonate, isethionate, α -ketoglutarate, α -glycerophosphate, glucose-1-phosphate and the like.

Examples of salts of compounds of formula (I) wherein the substituent X contains a carboxyl group with pharmaceutically acceptable bases are: those formed with alkali metals or alkaline earth metals, such as sodium, potassium, calcium and magnesium; and those formed with organic bases such as amines, basic amino acids (lysine, arginine, histidine), tromethamine, N-methylglucamine, and the like.

The amine starting reactants of formula (II) wherein Y is CH are known compounds or can be prepared by analogous preparation methods to those used for the preparation of known compounds.

The amine starting reactant of formula (II) wherein Y is N can be prepared by reacting the appropriate 2-halopyridine of formula (p):wherein R is₁Having the above definition and Hal being a halogen atom, with a 1, 2, 3, 6-tetrahydropyridine of formula (q):wherein P is⁰Is a protecting group (e.g., benzyl) and Z is a substituent that can be nucleophilically substituted with a pyridine halogen. Examples of such substituents are trialkylstannanes (e.g. tributyltin) or grignard reagents.

Subsequently, the 1, 2, 3, 6-tetrahydropyridine is deprotected by cleavage of the protecting group under suitable conditions.

The compounds of formula (III) may be prepared as follows:

either by reacting an appropriate benzene of formula (r):wherein R is₂And X has the abovementioned meaning, with the formula L-CH₂The acid halides of-CO-Hal, where L and Hal are as defined above, are subjected to the well-known Friedel-crafts reaction in the presence of Lewis acids; the resulting ketone of formula(s) is subsequently reduced:the reduction can be carried out by various methods disclosed in the literature to obtain R₃＝R₄A compound of formula (III) where H is;

-or by reduction of an acid of formula (V):wherein R is₂、R₃、R₄And X is as defined above, to give the corresponding alcohol and, in turn, to convert the hydroxyl group into a leaving group.

The acids of formula (v) are generally compounds which have been disclosed in the literature or can be prepared analogously.

The invention also describes the preparation examples in the experimental section.

The effect of the compounds of formula (I) on the nervous system has been demonstrated in vitro and in vivo experiments carried out according to the method described in EP-0458696, and the survival of neurons can be assessed by means of in vitro survival assays using neurons dissected from the rat embryo compartment.

In this test, the embryo compartments of 17 to 18-day-old rats were isolated under a dissecting microscope and sterilized strip alkali and subsequently dissociated in trypsin/EDTA medium. The cell suspension was placed in DME/Ham's F12 (v: v) medium (Dulbecco's modified Eagle Medium/Ham's F12 nutrient medium-R.G.ham, Proc.nat.Sci., 1965,53288), the above medium contains 5% calf serum and 5% horse serum, and is maintained at 37 ℃ for 90 minutes. This treatment method is capable of removing non-neuronal cells.

Subsequently, the neuroblasts were treated at 17X 10⁴Cells/cm²Was inoculated into a non-serum medium consisting of DME/Ham's F12 medium containing selenium (30nM) and transferrin (1.25. mu.M) in the well of a titration plate. Each well was previously treated with poly-L-lysine. The inoculated plates were placed in an incubator (37 ℃ C.; 5% CO)₂) In (1).

The test compounds were dissolved in DMSO and diluted with medium as needed.

The neuroblasts were stored in plates containing the test compound or corresponding solvent for 4 days without changing the medium.

After 4 days, the medium was replaced with tetrazolium salt (0.15mg/ml) dissolved in the medium. The cells were further left in an oven at 37 ℃ for 4 hours. Mitochondrial succinate dehydrogenase of the surviving cells reduced the tetrazolium salt to methyl * blue, which was dissolved in DMSO and the optical density was measured at 540 nm. This is achieved byOptical density values are linearly related to the number of viable cells (manthiope et al, dev. brain res., 1988,25，191-198)。

the statistical analysis using the two-tailed Dunnett t-test assesses the differences between the test and control groups containing the test compound.

The compounds of formula (I) show the same activity as the compounds described in EP-0458696 in the above test, or, alternatively, an even higher activity; certain compounds of formula (I) are twice as effective in neuronal survival as compound A described in EP-0458696.

In view of this potent neuroprotective activity and its low toxicity suitable for use as a medicament, the compounds of formula (I) and their pharmaceutically acceptable addition salts, their solvates and their quaternary ammonium salts can be used for the preparation of pharmaceutical compositions for the treatment and/or prevention of all diseases involving neuronal degeneration. In particular, the compounds of the present invention may be administered alone or in combination with other active ingredients acting on the Central Nervous System (CNS), such as acetylcholinesterase inhibitors, selective M1 cholinergic agents, NMDA antagonists and nootropic agents (e.g., pyrrolidone acetamine); in particular for the following indications: memory disorders, vascular dementia, post-encephalitis sequelae, post-stroke sequelae, post-traumatic syndromes due to cranial trauma, conditions due to cerebral hypoxia, Alzheimer's disease (Alzheimer's disease), senile dementia, subcortical dementia (such as Huntington's chorea and Parkinson's disease), dementia due to AIDS, neuropathy caused by the onset or damage of sympathetic or sensory nerves, cerebral disorders (such as cerebral edema), spinocerebellar degeneration and motor neuron degeneration (such as amyotrophic lateral sclerosis).

The compounds of the invention may generally be administered orally, parenterally, sublingually or transdermally. According to the method of the invention, the amount of active ingredient administered in the treatment of cerebral and neurological disorders depends on the nature and severity of the condition to be treated and on the weight of the patient. Nevertheless, preferred unit doses will generally contain from 0.25 to 700mg, suitably from 0.5 to 300mg and preferably from 1 to 150mg of the product, for example in the range 2 to 50mg, i.e. 2, 5, 10, 15, 20, 25 or 50mg of product. These unit doses are usually administered one or more times per day, for example 2, 3, 4 or 5 times per day, and preferably 1 to 3 times per day. The total dose administered in man will vary from 0.5 to 1400 mg/day, suitably from 1 to 900 mg/day (e.g. 2 to 500 mg/day) and more suitably from 2 to 200 mg/day.

In another aspect, the present invention relates to a pharmaceutical composition comprising as active ingredients a compound of formula (I) above and a compound specific for symptomatic treatment of senile dementia of the alzheimer type (DAT), or a pharmaceutically acceptable salt thereof.

The term "compound specific for use in the treatment of symptoms of dementia of the alzheimer's type (DAT)" refers to a product that is capable of improving the symptoms of DAT patients but does not have an effect on the causative agent.

Examples of such compounds are acetylcholinesterase inhibitors, M₁Muscarinic agonists, nicotinic agonists, NMDA receptor antagonists, and pyrazinamide compounds.

Preferred acetylcholinesterase inhibitors are donepezil (donepezil) and 9-aminotetrahydroacridine.

Other examples of suitable acetylcholinesterase inhibitors are rivastigmine (SDZ-ENA-713), galantamine, dipterex, elsamitrucin, wiener and physostigmine (drug, 1997,53(5) 752-768; merck index 12 th edition).

Other acetylcholinesterase inhibitors are 5, 7-dihydro-3- [2- [1- (phenylmethyl) -4-piperidinyl]Ethyl radical]-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 zifrasilone (european journal of pharmacology, 1995,27693-99) and TAK-147 (journal of medical chemistry, 1994,37，2292-2299)。

other examples of inhibitors of the enzyme acetylcholinesterase are disclosed in the patent applications: JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 96-04565, US5,455,245, WO95-21822, EP 637586, US5,401,749, EP 742207, US5,547,960, WO 96/20176, WO 96/02524, EP 677516, JP 07-188177, JP 07-133274, EP 649846, EP 648771, JP 07-048370, US5,391,553, WO 94/29272 and EP 627400.

In another aspect, the invention relates to a composition comprising a compound of formula (I) and M₁A pharmaceutical composition comprising a receptor agonist or a pharmaceutically acceptable salt thereof as an active ingredient.

Examples of M1 receptor agonists are milameline (milameline), besiflozin, tasalidine (talsaclidine), xanomeline, YM-796 and YM-954 (journal of european pharmacology, 1990,187479-propan-486), 3- [ N- (2-diethylamino-2-methylpropyl) -6-phenyl-5-propyl]Pyridazinamines (pyridazinamine) (also known as SR 46559) (biomedical and chemical literature, 1992,2833-,78，59-68)。

in another aspect, the invention relates to a pharmaceutical composition comprising as active ingredients a compound of formula (I) and a nicotinic agonist or a pharmaceutically acceptable salt thereof.

An example of a suitable nicotinic agonist is MKC-231 (biomedical and chemical literature, 1995,5(14) 1495-1500), T-588 (Ri. [ J. Pharmacology, 1993,6281-86) and ABT-418 (british journal of pharmacology, 1997,120，429-438)。

in a further aspect, the present invention relates to a pharmaceutical composition comprising as active ingredients a compound of formula (I) and an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof.

Examples of suitable NMDA receptor antagonists are memantine (arzneim. forsch., 1991,41，773-780)。

in another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) and a nootropic agent or a pharmaceutically acceptable salt thereof as active ingredients.

Nootropic agents suitable for use in the present invention are, for example, netiracetam and nebracetam (merck index, 12 th edition).

The dosage of the two combined active ingredients is generally selected from the dosages administered for each drug in monotherapy.

In another aspect, the invention relates to a method for the treatment of senile dementia of the alzheimer's type by administering to a patient suffering from this disease an effective dose of a compound of formula (I) or one of its pharmaceutically acceptable salts and an effective dose of a compound specific for the treatment of DAT symptoms or one of its pharmaceutically acceptable salts, which compounds are administered simultaneously, sequentially or in a time-dispersed manner and can contain an effective dose of the active ingredient in separate unit dosage forms; furthermore, if two active ingredients are administered simultaneously, they are suitably contained in the same pharmaceutical form.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration, the active ingredient may be administered to animals and humans for the treatment of the above-mentioned diseases in unit administration form, for example in lyophilized form, or in admixture with conventional pharmaceutical carriers. Suitable unit dosage forms include: oral forms, such as divisible tablets, gelatin capsules, powders, granules and oral solutions or suspensions; sublingual and buccal administration forms; subcutaneous, intramuscular, and intravenous administration forms; topical administration forms and rectal administration forms.

In the case of making the solid composition into a tablet form, the main active ingredient may be mixed with a pharmaceutically acceptable excipient such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. The tablets may be coated with sucrose or other suitable material, or they may be treated to have a long or sustained release activity to allow continuous release of a predetermined amount of the active ingredient.

Formulations in the form of gelatin capsules are prepared by mixing the active ingredient with a diluent and filling the resulting mixture into soft or hard gelatin capsules.

Formulations in the form of syrups or elixirs may contain the active ingredient in combination with a sweetening agent, preferably a non-caloric sweetening agent, methyl and propylparabens as preservatives, a flavoring agent and a suitable coloring agent.

Water-dispersible powders or granules may contain the active ingredient in admixture with dispersing or wetting agents or with suspending agents, for example polyvinylpyrrolidone, and sweetening or flavouring agents.

Rectal administration may be by means of suppositories which are prepared by mixing with binders which melt at the rectal temperature, such as coconut oil and polyethylene glycol.

Parenteral administration is suitably carried out using aqueous suspensions, saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing agents and/or wetting agents, for example propylene glycol or butylene glycol.

The active ingredient may also be formulated in microencapsulated form, optionally with one or more carriers or additives.

In the pharmaceutical composition of the present invention, the active ingredient may also be in the form of an inclusion complex within a cyclodextrin, an ether thereof, or an ester thereof.

The invention is further illustrated by the following non-limiting examples.

Example 11- [2- (3, 4-diethylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride 1 a/1-bromo-2- (3, 4-diethylphenyl) ethane

A mixture of 4.4g (0.033mol)3, 4-diethylbenzene, 50ml dichloromethane and 8.8g (0.044mol) bromoacetyl bromide was cooled to 0-5 ℃ and 5.0g (0.037mol) aluminum trichloride was added. The mixture was stirred at 0 to 5 ℃ for 1 hour, followed by standing at room temperature overnight. It is poured into a water/ice mixture and extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure. 2.9g (0.011mol) of the oil obtained are mixed with 6ml (0.079mol) of trifluoroacetic acid and 6.7ml (0.057mol) of triethylsilane, and the mixture is heated at 80 ℃ for 4 hours. Subsequently, saturated aqueous sodium bicarbonate solution was added until the pH was basic, the mixture was extracted with diethyl ether, the organic phase was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The crude oil obtained is purified by chromatography on a silica gel column using cyclohexane as eluent to give the title compound. 1b/1- [2- (3, 4-diethylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

A mixture of 2.6(0.001mol)4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 60ml of butanol, 4.1g (0.025mol) of anhydrous potassium carbonate crumble and 2.6g (0.00113mol) of the product obtained in the preceding step was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The hydrochloride salt of the oil was obtained by treatment with a saturated solution of isopropanol in hydrochloric acid to yield 1.6g of the title compound. Melting point: 220 ℃ and 222 ℃.

Example 21- [2- (3-methyl-4-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and 1- [2- (4-methyl-3-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and its oxalate salt 2 a/1-methyl-2-pentylbenzene

4.7g (0.035mol) of o-phthalaldehyde are added dropwise under a nitrogen atmosphere to a solution of 50ml (0.1mol) of 2M n-butylmagnesium chloride in THF. The mixture spontaneously warmed to 40-45 ℃. It was stirred at room temperature for 1 hour and poured into a saturated ammonium chloride solution. The mixture was extracted with diethyl ether, washed with water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The oil obtained is purified chromatographically on a silica gel column using 7/3 cyclohexane/ethyl acetate mixture as eluent. Separation has the highest R_fTo give 2.0g of an oil. The crude reaction product is dissolved in 25ml of ethanol, 1ml of concentrated sulfuric acid and 0.15g of 10%Palladium on carbon (Pd/C). The mixture was hydrogenated at room temperature for 7 hours. The catalyst was filtered off, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with an aqueous solution of sodium hydrogencarbonate and dried, and the solvent was distilled off under reduced pressure to give 1.35g of the title compound. 2 b/1-bromo-2- (3-methyl-4-pentylphenyl) ethane and 1-bromo-2- (4-methyl-3-pentylphenyl) ethane

A mixture of 1.17g (0.0054mol) of the product of the preceding step and 0.62ml (0.0072mol) of bromoacetyl bromide is cooled to 0-5 ℃ and 0.81g (0.006mol) of aluminum trichloride is added. The mixture was stirred at 0-5 ℃ for 1 hour, and further at room temperature for 4 hours. It is poured into ice, the phases are separated, the organic phase is washed with water, dried and the solvent is distilled off under reduced pressure. The residue was dissolved in 2.9ml of trifluoroacetic acid, 3.1ml (0.0267mol) of triethylsilane were added and the mixture was heated at 80 ℃ for 5 hours. Subsequently, it was poured into an aqueous sodium bicarbonate solution and extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate to give a mixture containing the title compound. 2c/1- [2- (3-methyl-4-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and 1- [2- (4-methyl-3-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and oxalates thereof

A mixture of 0.7g (0.0031mol) of 4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 16ml of butanol, 0.9g (0.0065mol) of anhydrous potassium carbonate as a crumb and the product obtained in the preceding step (theoretical yield 0.0054mol) was heated under reflux for 6 hours. The solvent was evaporated off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The resulting oil was purified by chromatography on a silica gel column using 7/3 cyclohexane/ethyl acetate mixture as eluent. Two products with similar Rf were isolated. The product corresponding to the highest Rf is 1- [2- (3-methyl-4-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine. The oxalate salt was prepared in acetone to yield 0.12g of product. Melting point 140-. The product corresponding to the lowest Rf is the isomer 1- [2- (4-methyl-3-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine. The oxalate salt was prepared in acetone. The product was crystallized from acetone to yield 0.08g of product. Melting point 167-.

Example 31- [2- (3, 4-diethylphenyl) ethyl ] -4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine hydrochloride 3 a/(1-benzyl-1, 2, 3, 6-tetrahydropyridin-4-yl) tributylstannane

A mixture of 15.85g (0.0837mol) of 1-benzyl-4-piperidone in 140ml of anhydrous dimethoxyethane and 25g (0.0837mol) of trisiliconnitrogen (trisiladrazine) in 140ml of anhydrous dimethoxyethane was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in 420ml of anhydrous hexane, and 420ml of anhydrous tetramethylethylenediamine was added. The mixture was cooled to-78 ℃ and 156ml of n-butyllithium (0.25mol) (1.6M in hexane) were added dropwise. After 30 minutes, the temperature was raised to 0 ℃ and the reaction mixture was stirred for 15 minutes. Subsequently, 45ml (0.167mol) of tributylstannyl chloride were added. After 1 hour, the water/ice mixture was added with extreme care. After extraction with diethyl ether, the organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 70g of crude product which is purified by chromatography on a silica gel column using 95/5 cyclohexane/ethyl acetate mixture as eluent to give the title compound as an oil.¹H-NMR(CDCl₃)-d(ppm)：0.84(9H；m：CH₃)1.19-1.58(18H；m：CH₂Chains); 2.31 (2H; m); 2.53 (2H; m); 3.02 (2H; m); 3.56 (2H; s: methylene of benzyl); 5.76 (2H; m); 7.18-7.41 (5H; m: aromatic hydrogen). Satellite type spectral band³J_cis(¹H-¹¹⁷Sn) and³J_cis(¹H-¹¹⁹sn). 3 b/1-benzyl-4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine

18.5g (0.04mol) of the compound formed in the above step were dissolved in 200ml of anhydrous dimethylformamide under a nitrogen atmosphere. 11.8g (0.08mol) of 2, 6-dichloropyridine, 0.64g of Pd (II) (Ph)₃P)₂Cl₂4.38g (0.04mol) of tetramethylammonium chloride and 2.76g (0.02mol) of potassium carbonate were added to the above solution. The mixture was heated at 110 ℃ for 6 hours and then poured into 100ml of 5% sulfuric acid solution. Extracting with diethyl ether, adding ammonium hydroxideUntil the aqueous phase was basic in pH, it was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The residue was chromatographed on a silica gel column using 1/1 a cyclohexane/ethyl acetate mixture as the eluent to yield the title compound. Melting point: 100-102 ℃. 3c/4- (6-Chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

A solution of 7.0g (0.024mol) of the compound obtained in the above step in 110ml of dichloroethane was cooled to 0-5 ℃ and 5.8ml (0.054mol) of chloroethyl chloroformate was added. The mixture was stirred for 5 minutes and heated at reflux for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100ml of methanol and heated under reflux for 1 hour. The solvent was evaporated, the residue was dissolved in isopropanol and the solid was filtered off to give the title compound which was crystallized from 90% ethanol, melting point: 305 ℃ and 307 ℃. 3d/1- [2- (3, 4-diethylphenyl) ethyl ] -4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

The title compound was prepared by working as in example 1 b/procedure except substituting the product obtained in the previous step for 4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, m.p.: 234 ℃ and 236 ℃.

Examples 4 to 13

The procedure is followed as in example 2, except that the appropriate magnesium halide is used to prepare the following compounds: 1- [2- (3-Ethyl-4-methylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 41- [2- (4-ethyl-3-methylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 51- [2- (3-ethyl-4-propylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 61- [2- (4-ethyl-3-propylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 71- [2- (3-butyl-4-methylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 81- [2- (4-butyl-3-methylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 91- [2- (3-isobutyl-4-methylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 101- [2- (4-isobutyl-3-methylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 111- [2- (3-isobutyl-4-ethylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 121- [2- (4-isobutyl-3-methylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine-example 13

Example 141- [2- (6-Methylbiphenyl-3-yl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine

The title compound was prepared by the method of example 2 except that phenyllithium was used in place of n-butylmagnesium chloride.

Example 151- [2- (3, 4-dimethylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride 15 a/1-bromo-2- (3, 4-dimethylphenyl) ethane

4.5g (0.03mol) of 3, 4-dimethylacetophenone in 12ml of methanol are cooled to 0-5 ℃ and 1.5ml (0.09mol) of bromine are added dropwise. The mixture was stirred at room temperature for 24 hours, and then left at room temperature overnight. The methanol was evaporated off and the mixture was purified chromatographically on a silica gel column using 95/5 cyclohexane/ethyl acetate mixture as eluent. 5.3g (0.013mol) of the product obtained are mixed with 12.5ml (0.162mol) of trifluoroacetic acid and 18.7ml (0.011mol) of triethylsilane, and the mixture is heated at 80 ℃ for 1 hour. Saturated aqueous sodium bicarbonate was then added until the pH was basic, the mixture was extracted with diethyl ether, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give 5.2g of the title compound. 15b/1- [2- (3, 4-dimethylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

A mixture of 1.8g (0.0068mol)4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 25ml of butanol, 2.4g (0.017mol) anhydrous potassium carbonate crumble and 2g (0.0094mol) of the product of the above step was heated under reflux for 6 hours. The solvent was evaporated off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The product was purified by chromatography on a silica gel column using 7/3 cyclohexane/ethyl acetate mixture as eluent. The hydrochloride salt of the oil thus obtained was prepared by treatment with a saturated solution of isopropanol in hydrochloric acid to yield 1.1g of the title compound. Melting point: 270 ℃ and 272 ℃.

Example 161- [2- (3, 4-diethylphenyl) ethyl ] -4- (2-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride 16 a/4-hydroxy-4- (2-trifluoromethylphenyl) pyridine hydrochloride

3.25g (0.135mol) of Mg and a shovel tip I₂A solution of 30.4g (0.135mol) of 2-bromo-1-trifluoromethylbenzene in 125ml of THF was mixed and added dropwise. The mixture is stirred at room temperature for 1 hour and 10.1g (0.041mol) of benzylpiperidone are added dropwise. The mixture was stirred at room temperature for 1 hour and saturated ammonium chloride solution was added. After extraction with diethyl ether, the organic phase is dried and the solvent is evaporated off under reduced pressure. The product is purified by chromatography on a silica gel column using a cyclohexane/ethyl acetate mixture as eluent to give 6.8g of 1-benzyl-4-hydroxy-4- (2-trifluoromethylphenyl) piperidine, which is hydrogenated with 0.7g of 10% palladium on carbon in 75ml of 95% ethanol adjusted to acidic pH with hydrochloric acid and the mixture is heated at 60 ℃ for 8 hours. The catalyst is filtered off to give 2.1g of the title compound, m.p.: 247 ℃ 251 ℃.16 b/4- (2-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

2.0g (0.007mol) of the product of the above step are dissolved in 12ml of glacial acetic acid. 3ml of concentrated sulfuric acid are added dropwise and the mixture is heated at 100 ℃ for 2 hours. It is poured into ice, a concentrated solution of sodium hydroxide is added until the pH is basic, and the mixture is extracted with dichloromethane. The organic phase was dried and the solvent was evaporated under reduced pressure. The product was dissolved in 15ml of isopropanol to give 4- (2-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine. The hydrochloride salt was prepared using a hydrochloric acid solution in isopropanol to yield 0.9g of the title compound. Melting point: 213-215 ℃.16 c/1- [2- (3, 4-diethylphenyl) ethyl ] -4- (2-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

0.4g (0.0015mol) of the product of the above step in 12ml of butanol and 0.52g (0.0037mol) of anhydrous potassium carbonate were heated under reflux for 30 minutes. 0.41g (0.0017mol) of the product from example 1 a/are then added and the mixture is heated at reflux for 6 hours. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water, the organic phase was dried and the solvent was distilled off under reduced pressure. The product was purified by chromatography on a silica gel column using 8/2 cyclohexane/ethyl acetate mixture as eluent to give 1- [2- (3, 4-diethylphenyl) ethyl ] -4- (2-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine. The hydrochloride salt was obtained by treatment with hydrochloric acid solution in isopropanol to give the title compound. Melting point: 184 ℃ and 185 ℃.

Claims (10)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:wherein: y is-CH-or-N-; r₁Is hydrogen, halogen or CF₃、C₁-C₄Alkyl or C₁-C₄An alkoxy group; r₂Is methyl or ethyl; r₃And R₄Are each hydrogen or C₁-C₃An alkyl group; and X is:

(a)C₁-C₆alkyl radical, C₁-C₆Alkoxy radical, C₃-C₇Carboxyalkyl, C₁-C₄Alkoxycarbonyl radical C₁-C₆Alkyl radical, C₃-C₇Carboxyalkoxy or C₁-C₄Alkoxycarbonyl radical C₁-C₆An alkoxy group;

(b) one is selected from C₃-C₇Cycloalkyl radical, C₃-C₇Cycloalkoxy, C₃-C₇Cycloalkyl methyl, C₃-C₇Cycloalkylamino and cyclohexenyl groups; the radicals being optionally substituted by halogen, hydroxy, C₁-C₄Alkoxy, carboxyl, C₁-C₄Alkoxycarbonyl, amino or mono-or di-C₁-C₄Alkyl amino substitution; or

C) One is selected from phenyl, phenoxy, phenylamino, N-C₁-C₃Groups of alkylphenylamino, benzyl, phenethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl; the phenyl group of the radical may be substituted by halogen, CF₃、C₁-C₄Alkyl radical, C₁-C₄Alkoxy, cyano, amino, mono-or di-C₁-C₄Alkylamino radical, C₁-C₄Acylamino, carboxyl, C₁-C₄Alkoxycarbonyl, aminocarbonyl, mono-or di-C₁-C₄Alkylaminocarbonyl, amino C₁-C₄Alkyl, hydroxy C₁-C₄Alkyl or halo C₁-C₄Alkyl is mono-or polysubstituted.

2. The compound of claim 1, wherein Y is-CH-and R₁Is CF₃-。

3. The compound of claim 1, wherein Y is a nitrogen atom and R is₁Is a chlorine atom.

4. The compound of any one of claims 1 to 3, wherein X is C₁-C₆An alkyl group.

5. The compound of claim 1, wherein X is a group C), the phenyl group in the group C) being substituted with 1 to 3 halogens, 1 to 3 CF₃1 to 3C₁-C₄Alkyl, 1 to 3C₁-C₄Alkoxy, 1 to 3 cyano, 1 to 3 amino, 1 to 3 mono-or di-C₁-C₄Alkylamino radical, 1 to 3C₁-C₄Acylamino, 1 to 3 carboxyl, 1 to 3C₁-C₄Alkoxycarbonyl, 1 to 3 aminocarbonyl, 1 to 3 mono-or di-C₁-C₄Alkylaminocarbonyl, 1 to 3 amino C₁-C₄Alkyl, 1 to 3 hydroxy C₁-C₄Alkyl or 1 to 3 halogeno-C₁-C₄Alkyl substitution.

6. The compound of formula (Γ) of claim 1, or a pharmaceutically acceptable salt thereof:wherein: r₁Is' CF₃And Y' is CH, or R₁'is Cl and Y' is N, R₂And X is as defined for compounds of formula (I) in claim 1.

7. The compound of claim 6, wherein X is C₁-C₆An alkyl group.

8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: 1- [2- (3, 4-diethylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 1- [2- (3-methyl-4-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 1- [2- (4-methyl-3-pentylphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 1- [2- (3, 4-diethylphenyl) ethyl ] -4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine.

9. A process for preparing compound (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that:

(a) an aryl-1, 2, 3, 6-tetrahydropyridine represented by the formula (II):

wherein Y and R₁As defined for compound (I) in claim 1, with a compound of formula (III):

wherein R is₂、R₃、R₄And X is as defined for compound (I) in claim 1 and L is a leaving group; and

(b) the resulting compound of formula (I) is isolated and optionally converted to one of its pharmaceutically acceptable salts.

10. A pharmaceutical composition characterized by: the composition contains a compound according to any one of claims 1 to 8 as an active ingredient.