HK1024001B - Diphenyl alkyl-tetrahydropyridines, process for their preparation, and pharmaceutical compositions containing them - Google Patents

Description

Diphenylalkyl-tetrahydropyridines, process for their preparation and pharmaceutical compositions containing them

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

EP-0458696 describes 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 neuronal disorders.

It has now been found that certain gem-diphenylalkyl-1, 2, 3, 6-tetrahydropyridine compounds substituted by phenyl or pyridyl groups are capable of producing neurotrophic effects on the nervous system, i.e. similar to the effects of Nerve Growth Factor (NGF), and of restoring the function of damaged cells or cells whose physiological effects are aberrantly manifested.

To this end, in one aspect, the present invention provides gem-diphenyl alkyl-1, 2, 3, 6-tetrahydropyridines of formula (I) and salts and solvates thereof and quaternary ammonium salts thereof:

wherein:

y is-CH-or-N-;

R₁is halogen or CF₃，(C₁-C₄) Alkyl or (C)₁-C₄) An alkoxy group;

R₂and R₃Each is hydrogen or (C)₁-C₃) An alkyl group;

n is 0 or 1; and

Ph₁and Ph₂Each independently an unsubstituted, mono-substituted or poly-substituted phenyl group.

Preferred compounds of the invention are those wherein Y is CH and R₁Is CF₃And wherein Y is N and R₁A compound of formula (I) which is Cl.

Moreover, among these compounds, those in which R is particularly preferable₂And R₃Compounds of formula (I) which are both hydrogen and n is 0 or 1.

Particularly preferred compounds are represented by formula (I'):

wherein R is₁Is' CF₃And Y' is CH, or R₁'is Cl and Y' is N, and N is 0 or 1, Ph₁And Ph₂The definition of (A) is as above.

In the formulae (I) and (I'), Ph is preferred₁And Ph₂The same, but they may also be different, which means that a chiral carbon atom is present.

Preferably Ph₁And Ph₂Each independently is phenyl; 2-, 3-or 4-position byA phenyl group monosubstituted by the group: fluorine or chlorine atom, or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyano, methoxy, methylthio, methylsulfonyl, ethoxy, ethylthio, ethylsulfonyl, (C)₁-C₃) Alkoxycarbonyl or di (C)₁-C₃) An alkylaminocarbonyl group; phenyl disubstituted in the 2, 4-, 3, 4-, 3, 5-or 2, 6-position by fluorine, chlorine atoms or by methyl, ethyl, trifluoromethyl, cyano or methoxy; or phenyl trisubstituted in the 3, 4, 5-, 2, 4, 5-or 2, 4, 6-position by chlorine, fluorine atoms or by methyl, ethyl, trifluoromethyl, cyano or methoxy.

If Ph is₁And Ph₂Otherwise, one of the two phenyl groups is preferably unsubstituted and the other is preferably monosubstituted in the 2-, 3-or 4-position, as described above.

In this specification, the term "(C)₁-C₃) Alkyl "refers to methyl, ethyl, n-propyl and isopropyl.

The term "alkoxy" refers to a group consisting of₁-C₄) Alkyl-substituted hydroxyl.

The following compounds are particularly preferred:

-1- (2, 2-diphenylethyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine;

-1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine;

-1- [2, 2- (3, 3' -bistrifluoromethyldiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine;

-1- [2, 2- (4, 4' -dimethoxydiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine;

-1- [2- (4-fluorophenyl) -2-phenylethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine;

-1- (3, 3-diphenylpropyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine;

-1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine;

and salts, solvates or quaternary ammonium salts thereof.

In another aspect, the present invention provides a process for the preparation of a compound of formula (I), a salt or solvate thereof, and a quaternary ammonium salt thereof, characterized in that:

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

wherein Y and R₁The definition of (A) is the same as that of (B),

with an acid of formula (III) or any functional derivative thereof:

wherein n, R₂，R₃，Ph₁And Ph₂The definition of (1) is as above;

(b) reducing a carbonyl intermediate of formula (IV):

and

(c) the resulting compound is isolated and optionally converted to a salt or solvate thereof or a quaternary ammonium salt thereof.

The reaction of step (a) may conveniently be carried out in an organic solvent at a temperature of from-10 ℃ to the reflux temperature of the reaction mixture; the reaction is preferably carried out at low temperature.

The reaction solvent used is preferably a halogenated solvent such as dichloromethane, dichloroethane, 1, 1, 1-trichloroethane, chloroform, etc., or an alcohol such as methanol or ethanol, but other organic solvents compatible with the reactants used may also be used, for example dioxane, tetrahydrofuran or hydrocarbons such as hexane.

The reaction is suitably carried out in the presence of a proton acceptor, such as an alkali metal carbonate or a tertiary amine. Suitable functional derivatives of the acids of formula (III) which may be used are the free acids [ which may be activated (for example by BOP) ], anhydrides, mixed anhydrides, activated esters or acid halides (preferably acid chlorides or acid bromides). A particularly preferred active ester is p-nitrophenyl ester, although methoxyphenyl, trityl, benzhydryl, and similar esters are also suitable.

The reduction of step (b) is conveniently carried out according to conventional techniques using a suitable reducing agent, such as an aluminium hydride or a complex hydride of lithium and aluminium, in an inert organic solvent at a temperature of from 0 ℃ to the reflux temperature of the reaction mixture.

"inert organic solvent" is understood to mean a solvent which does not interfere with the reaction. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane or 1, 2-dimethoxyethane.

Isolating the resulting compound of formula (I) using conventional techniques and optionally converting to any one of the acid addition salts; on the other hand, if acid groups are present, this amphoteric nature of the compounds enables them to be separated by salt formation with acids or with bases.

If the salt of the compound of formula (I) is to be prepared for use as a medicament for administration, the acid or base used must be pharmaceutically acceptable; however, any acid or base may be used when the prepared salt of the compound of formula (I) is used for other purposes, such as improving the purification process of the product or better performing analytical assays.

Examples of the salt with a pharmaceutically acceptable acid include salts with inorganic acids such as hydrochloride, hydrobromide, borate, phosphate, sulfate, bisulfate, hydrogenphosphate and dihydrogenphosphate, and salts with organic acids such as citrate, benzoate, ascorbate, methanesulfonate, naphthalene-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 the salt with a pharmaceutically acceptable base include salts with alkali metals or alkaline earth metals (e.g., sodium, potassium, calcium and magnesium), and salts with organic bases such as amines, basic amino acids (lysine, arginine, histidine), tromethamine, N-methylglutamine and the like.

The starting amines of formula (II) in which Y is CH are known compounds or they can be prepared in analogy to the methods used for the preparation of known compounds.

Starting amines of formula (II) wherein Y is N can be prepared by reacting an appropriate 2-halopyridine of formula (p):

wherein R is₁Are as defined above and Hal is a halogen atom,

with 1, 2, 3, 6-tetrahydropyridine of formula (q):

wherein P DEG is a protecting group such as benzyl and Z is a substituent capable of nucleophilic substitution of a halogen atom on a pyridine. Examples of such substituents include trialkylstannanes such as tributylstannane, or Grignard compounds.

The 1, 2, 3, 6-tetrahydropyridine is then deprotected by cleaving the protecting group under appropriate conditions.

Acids of formula (III) wherein n is 1 may be prepared by a Wittg reaction wherein:

a) according to the Wittig reaction (e.g. inChemical magazine of medicine(J.Med.Chem.)1996。39(11) 2197-:

wherein Ph₁And Ph₂The definition of (A) is the same as that of (B),

with a compound of formula(s):

b) thereafter catalytically reducing the intermediate of formula (t) in the presence of a catalyst such as Pd/C:

and

c) if desired to prepare compounds in which R is₂And R₃The compounds of formula (I) other than hydrogen may be alkylated in the intermediate of formula (u) in the α -position relative to the ester carbonyl group according to known methods:

and hydrolyzing the ester of formula (v):

to obtain the acid of formula (III) wherein n is 1.

Acids of formula (III) wherein n is 0 can be prepared as follows: according toAmerican society for chemistry (J.Am.Chem.Soc.)，1990， 112(18) 6690-6695 by reacting a suitable benzophenone of formula (r):

wherein Ph₁And Ph₂The definition of (A) is the same as that of (B),

reacting with trimethylsulfoxonium iodide and oxidizing the intermediate aldehyde of formula (w):

the corresponding acid is obtained.

In another process, compounds of formula (I) wherein n is 0 can also be prepared by reacting aryl-1, 2, 3, 6-tetrahydropyridines of formula (II):

wherein R is₁As defined above in relation to Y,

with an aldehyde of the formula (w) above in the presence of a reducing agent such as sodium cyanoborohydride.

The activity of the compounds of formula (I) on the nervous system was confirmed by in vitro and in vivo studies according to the method described in EP-0458696, and for the evaluation of the viability of neurons, also by in vitro survival tests using neurons isolated from dissected specimens of rat embryo compartments.

In this test, septa of 17-to 18-day-old rat embryos were excised under sterile conditions with the aid of a dissecting microscope and then dissociated in trypsin/EDTA medium. The cell suspension was placed in a culture flask containing DME/Ham's F12 (v: v) medium (Dulbecco's modified Eagle Medium/Ham's F12 medium) containing 5% calf serum and 5% horse serumNutrient mixture-r.g.ham, proc.nat.sci., 1965,53288) and held at 37 ℃ for 90 minutes. This treatment can remove non-neuronal cells.

Then at 17X 10⁴Cells/cm²Neuroblasts were seeded into serum-free medium in the wells of a titer plate consisting of DME/Ham's F12 medium containing selenium (30nM) and transferrin (1.25. mu.M). Each well was previously treated with poly-L-lysine. The inoculated plate was placed in an incubator (37 ℃ C.; 5% CO)₂)。

Test compounds were dissolved in DMSO and diluted with medium if necessary.

The neuroblasts were stored in the well plates containing the test compounds or the corresponding solvents for 4 days, during which the medium was not changed.

After 4 days, the medium was changed to tetrazolium (0.15mg/ml) in the medium. The cells were then placed in an incubator (37 ℃) for 4 hours. Mitochondrial succinate dehydrogenase in living cells reduces tetrazolium to formazan * blue, which optical density is measured at 540nm after dissolution in DMSO. There is a linear correlation between this density and the number of viable cells (manthiope et al,study of the brain Exhibition (or exhibition)(Dev.Brain Res.)，1988， 25，191-198)。

The difference between the test compound-containing group and the control group was evaluated by statistical analysis using a two-sided dunnett-test.

In said assay, it was found that the compounds of formula (I) have an activity comparable to or greater than that of the compounds described in EP-0458696, and that certain compounds of formula (I) are twice as potent as compound A described in EP-0458696 with respect to neuronal viability.

By virtue of this potent neuroprotective activity and their low toxicity acceptable as medicaments, the compounds of formula (I) and their pharmaceutically acceptable addition salts, solvates and quaternary ammonium salts can be used for the preparation of pharmaceutical compositions for the treatment and/or prevention of all diseases associated with neuronal degeneration. More particularly, the compounds of the invention, administered as such or together or in combination with other active ingredients acting on the CNS, are particularly useful in the following indications: memory disorders, vascular dementia, post-encephalitic diseases, post-stroke diseases, post-traumatic syndromes due to cranial trauma, conditions due to cerebral hypoxia, Alzheimer's disease, senile dementia, subcortical dementia such as Huntington's disease and Parkinson's disease, dementia due to AIDS, neuropathy due to pathological changes or damage to sympathetic or sensory nerves, and encephalopathies such as cerebral edema, and spinocerebellar degeneration and progressive neuronal degeneration such as amyotrophic lateral sclerosis. Wherein said other active ingredients are acetylcholinesterase inhibitors, selective M1 choline mimetics (cholinomimets), NMDA antagonists and neurotrophic agents (nonotropcs) such as piracetam.

The compounds of the invention may conveniently be administered by the oral, parenteral, sublingual or transdermal routes. The amount of active ingredient administered in the treatment of cerebral and neuronal disorders using the method of the invention depends on the nature and severity of the disorder to be treated and on the weight of the patient. However, preferred unit doses will generally contain from 0.25 to 700mg, more advantageously from 0.5 to 300mg, and preferably from 1 to 150mg, for example between 2 and 50mg, i.e. 2, 5, 10, 15, 20, 25, 30, 40 or 50mg of product. These unit doses will generally be administered one or more times daily, for example 2, 3, 4 or 5 times daily, preferably 1 to 3 times daily, with the total dose per day varying between 0.5 and 1400mg, preferably 1 to 900mg, for example 2 to 500mg, more suitably 2 to 200mg, in humans.

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

The term "compound used in the symptomatic treatment of senile dementia of the alzheimer type (DAT)" means a product which does not contribute to the etiology but which is capable of modifying the symptoms of DAT patients.

Examples of such compounds include acetylcholinesterase inhibitors, M1 muscarinic receptor agonists, nicotinic receptor agonists, NMDA receptor antagonists and neurotrophic agents.

Preferred acetylcholinesterase inhibitors are donepezil and tacrine.

Examples of other acetylcholinesterase inhibitors that may be used are rivastigmine (SDZ-ENA-713), galantamine, trichlorfon, eptastastine, vinpocetine and physostigmine (R) ((R))Medicine(Drugs)，1997， 53(5) 752-768; the 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-specimen isoxazol-6-ones, also known as icoezil (R) ((R))Chemical magazine of medicine，1995， 382802-2808), MDL-73, 745 or zifrasilone(s) ((R)Eur J Pharmacology(Eur.J.Pharmacol.)，1995， 27693-99) and TAK-147(Chemical magazine of medicine，1994， 37，2292-2299)。

Examples of other acetylcholinesterase inhibitors include those described in the following patent applications: JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA96-04565, US 5,455,245, WO 95-21822, EP 637586, US 5,401,749, EP 742207, US 5,547,960, WO 96/20176, WO 96/02524, EP 677516, JP 07-188177, JP 07-133274, EP 649846, EP 648771, JP 07-048370, US 5,391,553, WO 94/29272 and EP 627400.

A further aspect of the invention relates to a pharmaceutical composition comprising as active ingredients a compound of formula (I) and M₁A receptor agonist or a pharmaceutically acceptable salt thereof.

Examples of M1 receptor agonists include milameline, besipiridine, talsaclidine, xanomeline, YM-796 and YM-954 (M1)Eur J Pharmacology，1990， 187479-propan-486), 3- [ N- (2-diethylamino-2-methylpropyl) -6-phenyl-5-propyl]Pyridazinamines [ also known as SR-46559]( Chemical general of biological organic medicine Fast(Biorg.Med.Chem.Let.)，1992， 2833-Pharmacology and toxicology(Pharmacol.Toxicol.)，1996， 78，59-68)。

Another aspect of the invention relates to pharmaceutical compositions comprising as active ingredients a compound of formula (I) and a nicotinic receptor agonist or a pharmaceutically acceptable salt thereof.

Examples of preferred nicotinic receptor agonists are MKC-231 (MKC-231: (McK-231) ((McK-231)Biological organic pharmaceutical chemistry Communication，1995， 5(14)，1495-1500)，T-588( Journal of Japanese Pharmacology(Japan J.Pharmacol.)，1993， 6281-86) and ABT-418(Journal of british pharmacology(Br.J.Pharmacol.)，1997， 120，429-438)。

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

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

yet another aspect of the present invention relates to pharmaceutical compositions comprising as active ingredients a compound of formula (I) and a neurotrophin or a pharmaceutically acceptable salt thereof.

Examples of neurotrophic agents that can be used are netiracetam and neratim (nebracetam) (Merck Index, second edition).

The dosage of the active ingredients of the two combinations selected is generally the dosage of each drug administered in the individual treatment.

Yet another aspect of the present invention relates to a method for the treatment of senile dementia of the alzheimer's type, which comprises administering to a patient suffering from such a disease an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which compounds may be administered simultaneously, sequentially or in dispersion over a period of time, and an effective dose of DAT or a pharmaceutically acceptable salt thereof, and the active ingredients may be contained in separate unit dosage forms; on the other hand, if the two active ingredients are administered simultaneously, they are preferably contained within a single pharmaceutical dosage form.

In the pharmaceutical compositions of the present 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 form as such (e.g. in lyophilized form) or in admixture with conventional pharmaceutical carriers. Suitable unit dosage forms include oral dosage forms such as tablets (which may be in divided form), gelatin capsules, powders, granules and solutions or suspensions for oral administration, sublingual and buccal dosage forms, subcutaneous, intramuscular or intravenous dosage forms, topical dosage forms and rectal dosage forms.

When preparing solid compositions in the form of tablets, the main active ingredient is mixed with pharmaceutically acceptable excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. These tablets may be coated with sucrose or other suitable material, or they may be treated to provide sustained or delayed release activity as well as continuous release of a predetermined amount of the active ingredient.

Formulations in the form of gelatin capsules may be prepared as follows: the active ingredient is mixed with a diluent and the resulting mixture is filled into soft or hard gelatin capsules.

Formulations in the form of syrups or elixirs may contain the active ingredient together with a sweetening agent, preferably one which is non-caloric, the preservatives methyl and propylparabens, a flavoring agent and appropriate coloring.

Water-dispersible powders or granules can contain the active compound in admixture with dispersing or wetting agents, or with suspending agents, for example polyvinylpyrrolidone, and with sweetening or flavoring agents.

Rectal administration is accomplished by means of suppositories which are prepared using binders which melt at the rectal temperature, such as cocoa butter or polyethylene glycols.

Parenteral administration is accomplished using aqueous suspensions, saline solutions or sterile injectable solutions containing pharmaceutically compatible dispersing and/or wetting agents such as propylene glycol or butylene glycol.

The active ingredient may also be formulated in microcapsules, optionally containing one or more carriers or additives.

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

The following examples illustrate the invention more clearly, but they do not limit it.

Example 1

1- (2, 2-diphenylethyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and hydrochloride thereof

1a/1- (. alpha.,. alpha. -diphenylacetyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine

To a mixture of 8g (0.035mol)4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 50ml dichloromethane and 4.96ml triethylamine at 0/+5 ℃ was added dropwise 8g α, α -diphenylacetyl chloride/50 ml dichloromethane. The reaction mixture was stirred at room temperature for 1 hour, then the solvent was distilled off under reduced pressure, and the residue was dissolved in ether and washed with 0.2M hydrochloric acid solution, water, aqueous sodium carbonate solution and water in this order. After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain 5g of the title compound.

1b/1- (2, 2-diphenylethyl) -4- (3-trifluoromethylphenyl) -1, 2, 36-tetrahydropyridine and hydrochloride thereof

To a mixture of 0.7g of lithium aluminium hydride in 10ml of diethyl ether at 25 ℃ is added dropwise a solution of 5g (0.012mol) of the product of the last step in 50ml of diethyl ether. The reaction mixture was stirred at room temperature for 1 hour, then 5ml of water was added dropwise. The phases are separated and the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 1- (2, 2-diphenylethyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine. The hydrochloride salt was prepared as a saturated solution of hydrochloric acid in ether and crystallized from 150ml of ethyl acetate. M.p. (hydrochloride salt): 207-210 ℃.

Example 2

1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and oxalate salt thereof

2 a/alpha, alpha- (4, 4' -dichlorodiphenyl) acetaldehyde

0.75g (0.025mol) of 80% sodium hydride/oil dispersion are added portionwise to 5.5g (0.025mol) of trimethylsulfoxonium iodide per 10ml of anhydrous tetrahydrofuran mixture. The reaction mixture was heated at 55 ℃ for 6 hours, then 6g (0.025mol) of 4, 4' -dichlorobenzophenone per 10ml of dry tetrahydrofuran were added. The mixture was stirred at 55 ℃ overnight, poured into water and extracted with ether. The organic phase is then dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue was dissolved in 32ml of toluene and 3ml of BF was added₃-EtO. The mixture was stirred for 2 minutes and then left for 3 minutes. Washed twice with aqueous sodium bicarbonate solution and the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give an oil which was further purified by silica gel column chromatography using 9/1 hexane/ethyl acetate mixture as eluent to give the title compound.

2b/1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and oxalate salt thereof

1.3g (0.0045mol) of the product of the above step, 1.2g (0.0053mol) of 4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine, 21ml of methanol, 0.8ml of glacial acetic acid and 0.5g of anhydrous sodium acetate were mixed at 0/+5 ℃. Thereafter, 0.76g (0.0121mol) of sodium cyanoborohydride was added to the mixture at the same temperature, and the resulting mixture was stirred at a low temperature for 1.5 hours and then at room temperature overnight. 5ml of concentrated hydrochloric acid are added dropwise and the mixture is stirredFor 10 min, the methanol is distilled off, and the residue is then dissolved in ethyl acetate/dilute NH₄In an aqueous OH solution. The phases were separated and the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give an oil which was further purified by column chromatography on silica gel using 9/1 hexane/ethyl acetate mixture as eluent to give the title compound as base. The oxalate salt was prepared using oxalic acid in isopropanol. M.p. (oxalate) 187-.

Example 3

1- [2, 2- (3, 3' -bistrifluoromethyldiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and oxalate salts thereof

3 a/alpha, alpha- (3, 3' -bistrifluoromethyldiphenyl) acetaldehyde

The title compound was prepared according to the procedure described in example 2 a/using 3, 3' -bistrifluoromethylbenzophenone.

3b/1- [2, 2- (3, 3' -bistrifluoromethyldiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and oxalate salt thereof

The title compound was prepared according to the procedure described in example 2 b/but in which the product of the previous step was used instead of α, α - (4, 4' -dichlorodiphenyl) acetaldehyde. M.p. (oxalate) 194-196 ℃.

Example 4

1- [2, 2- (4, 4' -dimethoxydiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and hydrochloride thereof

4 a/alpha, alpha- (4, 4' -dimethoxydiphenyl) acetaldehyde

The title compound was prepared according to the procedure described in example 2 a/using 4, 4' -dimethoxybenzophenone.

4b/1- [2, 2- (4, 4' -dimethoxydiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and its hydrochloride

The title compound was prepared according to the procedure described in example 2 b/but using the product of the previous step instead of α, α - (4, 4' -dichlorodiphenyl) acetaldehyde. M.p. (hydrochloride salt) 214-.

Example 5

1- [2- (4-fluorophenyl) -2-phenylethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and hydrochloride thereof

5 a/alpha-4-fluorophenyl-alpha-phenylacetaldehyde

The title compound was prepared according to the procedure described in example 2 a/using 4-fluorobenzophenone.

5b/1- [2- (4-fluorophenyl) -2-phenylethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and hydrochloride thereof

The title compound was prepared according to the procedure described in example 2 b/but using the product of the previous step instead of α, α - (4, 4' -dichlorodiphenyl) acetaldehyde. M.p. (hydrochloride salt) 206-.

Example 6

1- (3, 3-diphenylpropyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine and hydrochloride thereof

The title compound was prepared according to the method described in example 1 b/using commercially available 3, 3-diphenylpropanoic acid (Aldrich, code No. D21, 165-6) instead of 2, 2-diphenylacetic acid. M.p. (hydrochloride salt) 176-.

Example 7

1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine and hydrochloride thereof

The title compound was prepared according to example 2 b/the procedure described, but using 4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine instead of 4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine. M.p. (hydrochloride salt) 230-32 ℃.

Example 8

1- [2, 2- (4, 4' -difluorodiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

1- [2, 2- (4, 4 ' -difluorodiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine was prepared by the method described in example 2, using 4, 4 ' -difluorobenzophenone instead of 4, 4 ' -dichlorobenzophenone. The hydrochloride salt was prepared using hydrochloric acid/isopropanol solution to give the title compound. M.p.173-175 ℃.

Example 9

1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (2-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

9 a/4-hydroxy-4- (2-trifluoromethylphenyl) piperidine hydrochloride

3.25g (0.135mol) of Mg are mixed with a full spatula I2, a solution of 30.4g (0.135mol) of 2-bromo-1-trifluoromethylbenzene in 125ml of THF is added dropwise, the mixture is stirred at room temperature for 1 hour and then 10.1g (0.041mol) of benzylpiperidone are added dropwise. The mixture was stirred at room temperature for 1 hour, and a saturated solution of ammonium chloride was added. After extraction with diethyl ether, the organic phase is dried and the solvent is distilled off under reduced pressure. The product obtained 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 in turn hydrogenated with the aid of 0.7g of 10% Pd/C in 75ml of 95% ethanol (hydrochloric acid has been added to adjust to the acidic pH) and the mixture is heated at 60 ℃ for 8 hours. The catalyst was filtered off to give 2.1g of the title compound. M.p.247-251 ℃.

9b/4- (2-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

2.0g (0.007mol) of the product of the previous 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. They were then poured onto ice, concentrated sodium hydroxide solution was added to make the pH alkaline, and the mixture was extracted with dichloromethane. The organic phase was dried and the solvent was removed 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/isopropanol solution to give 0.9g of the title compound. M.p.213-215 ℃.

9c/1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (2-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

0.5g (0.0022mol) of the base form obtained in the preceding step are mixed at 0/+5 ℃ with 9ml of methanol, 0.33ml of glacial acetic acid and 0.2g of anhydrous sodium acetate. Then, 0.5g (0.0019mol) of α, α - (4, 4' -dichlorodiphenyl) acetaldehyde (prepared according to example 2 a/b.) and 0.33g of sodium cyanoborohydride were added to the resulting mixture in this order at the same temperature, and the resulting mixture was stirred at low temperature for 1.5 hours and then at room temperature overnight. 2.1ml of concentrated hydrochloric acid are added dropwise, the mixture is stirred for 15 minutes, the methanol is then distilled off and the residue is dissolved in ethyl acetate and NH₄A mixture of dilute aqueous OH solutions. The organic phase was dried, a saturated hydrochloric acid/isopropanol solution was added, and the solvent was distilled off to obtain 0.48g of the title compound, which was further crystallized from ethyl acetate. M.p.229-230 ℃.

Claims (5)

1. A compound of formula (I) or a salt thereof with a pharmaceutically acceptable acid or base:

wherein:

R₂and R₃Each is hydrogen;

n is 0 or 1;

Ph₁and Ph₂Each independently being a fluorine or chlorine atom, trifluoromethyl or C₁-C₄Alkoxy radical selectionAn optionally substituted phenyl group;

or Y is-CH-and R₁Is 2-or 3-trifluoromethyl;

or Y is N and R₁Is 6-halogen.

2. A compound according to claim 1, wherein Ph₁And Ph₂The same is true.

3. A compound according to claim 1 selected from 1- (2, 2-diphenylethyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine; 1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine; 1- [2, 2- (3, 3' -bistrifluoromethyldiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine; 1- [2, 2- (4, 4' -dimethoxydiphenyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine; 1- [2- (4-fluorophenyl) -2-phenylethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine; 1- (3, 3-diphenylpropyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine; 1- [2, 2- (4, 4' -dichlorodiphenyl) ethyl ] -4- (6-chloropyridin-2-yl) -1, 2, 3, 6-tetrahydropyridine; and salts thereof with pharmaceutically acceptable acids or bases.

4. A process for the preparation of a compound of formula (I), a salt or solvate thereof, and a quaternary ammonium salt thereof, according to claim 1, characterized in that:

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

wherein Y and R₁The compound (I) as defined in claim 1,

with an acid of formula (III) or any functional derivative thereof:

wherein n, R₂，R₃，Ph₁And Ph₂Is as defined in claim 1;

(b) reducing a carbonyl intermediate of formula (IV):

and

(c) the resulting compound of formula (I) is isolated and optionally converted to a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 3.