MXPA98001838A - Derivatives of 4- (cicloalquil) piperidinas and of 4- (cicloalquilalquil) piperidinas, its preparation and its application terapeut - Google Patents

Abstract

Compounds corresponding to the general formula (i) are described wherein Ar represents (a) a phenyl group substituted with a halogen atom or (b) a group of general formula (I), wherein X represents a group of formula -CH2 -, - (CH2) 2- or - (CH2) 2- and Z represents a hydrogen halogen atom or a methyl group. Y represents a group of formula -CH2-, -CO- or -CHOH-, R1 represents a hydrogen atom or a methyl group, R2 represents a C3-C7 cycloalkyl group, and n represents the number 0, 1 2 or 3. Said compounds useful in therapeutic applications as neuroprotective and neurotrophic agents

Description

DERIVATIVES OF 4- (CICLOALQUIL) PIPERI DINAS AND OF 4- (CICLOALQU ILALQUIL) PIPERIDINAS, ITS PREPARATION AND ITS THERAPEUTIC APPLICATION The present invention relates to 4- (cycloalkyl) piperidines and 4- (cycloalkylalkyl) piperidines derivatives, to their preparation and to their therapeutic application. The compounds of the invention correspond to the general formula (I) wherein Ar represents a) a phenyl group substituted with a halogen atom or b) a group of general formula (V) (I ') in which X represents a group of formula -CH2-, - (CH2) 2- or - (CH2) 3- and Z represents a hydrogen or halogen atom or a methyl group, Y represents a group of formula -CH2-, -CO- or -CHOH-, R represents a hydrogen atom or a methyl group, R2 represents a cycloalkyl group of C3-C7l and n represents the number 0, 1, 2 or 3. The compounds of the invention can exist in the form of free bases or addition salts with acids. Moreover, when Y represents a group -CHOH-, the carbon atom of this group is asymmetric; similarly, when Ri represents a methyl group, the carbon atom that supports it is, also by itself, asymmetric. A compound according to the invention can thus, in accordance with the case, be in the form of a pure optical isomer or a mixture of such isomers. According to the invention, the compounds of general formula (I) can be prepared by processes illustrated by the schemes that follow. According to Scheme 1, a haloketone of general formula (II), in which Ar is as defined above and Hal represents a halogen atom, is first reacted with a substituted piperidine of general formula (III), in which n and R2 are as defined above, to obtain the ketone of general formula (la), which corresponds to the general formula (I) when Y represents a group -CO-.

Scheme 1 R, R, KBH, R. 1) SOCl- 2) LiAlH.

(Id If desired, this ketone can then be reduced, for example by using an alkali metal borohydride, to obtain the alcohol of general formula (Ib), which corresponds to the general formula (I) when Y represents a -CHOH group The reaction conditions for these two steps are well known to those skilled in the art, in order to obtain a compound of general formula (I) in which Y represents a group of formula -CH 2 - and Ar represents a phenyl group substituted with a halogen atom, the alcohol of general formula (Ib) can then be reduced, for example by reaction with thionyl chloride, followed by treatment of the chlorine with lithium aluminum hydride. In order to obtain a compound of general formula (I) in which Y represents a group of formula -CH 2 - and Ar represents a group of general formula (I '), and according to Scheme 2, a haloketone of general formula (II), in which Ar represents a group of general formula (I ') and Hal represents a halogen atom, is first reduced using triethylsilane and trifluoroacetic acid, according to a method described in the patent application EP-0,281, 309, in order to obtain the halo derivative of general formula (IV) , followed by the reaction of the latter with a substituted piperidine of general formula (II I), in which n and R2 are as defined above, under standard conditions, for example, in a solvent such as N, N-dimethylformamide and in the presence of a base such as sodium carbonate.

The starting compounds of the general formula (II) are commercially available or are described in the patent applications EP-0,109,317, EP-0,281,309, EP-0,351,282 and FR-2,684,379.

Scheme 2 Et3SiH / CF3CO-H Hal Ar IV) R.

R, The compound of general formula (III) in which n = 2 and R2 represents a cyclohexyl group is described in J. Org. Chem. (1957) 22 1376 and in U.S. Patents 4,005,093 and 4,028,366. The compounds of general formula (III) in which n = 1 or 3 and R2 represent a cyclohexyl group are mentioned, but not described, in U.S. Patent 4,261, 891. The other compounds of general formula (II I) are novel and form part of the invention as necessary intermediates in the process for the preparation of the compounds of general formula (I). The compounds of the general formula (III), in which n = 0, 1 or 3 and R 2 represent a cyclohexyl group, can be obtained by catalytic hydrogenation, for example in the presence of rhodium-in-carbon, of analogous derivatives in the which R2 represents a phenyl group. The other compounds of general formula (III) can be obtained either by a Wittig reaction between pyridine-4-carboxaldehyde and a phosphorous ilid obtained from a cycloalkyl halide, followed by a reduction by complete hydrolysis of the intermediate, i.e. by alkylation of 4-methylpyridine according to the method described in the 3,914,227 patent, followed by reduction of the cycloalkylalkyl pyridine intermediate by catalytic hydrogenation in the presence of platinum oxide. The following examples illustrate in detail the preparation of a few compounds according to the invention. The elemental microanalysis and the NMR and I R spectrum confirm the structures of the obtained compounds. The numbers of the compounds indicated in brackets in the titles correspond to those in Tables A and B given below.

Example 1 (Compound No. 16A). 1- (4-chlorophenyl) -2- [4- [2- (cyclohexyl) ethyl] piperid-1-yl-ethanone. eleven . 4- [2- (Cyclohexyl) ethyl] piperidine hydrochloride. 20 g (0.088 mol) of 4- (2-phenylethyl) piperidine hydrochloride, 2 g of 5% rhodium-en-carbon and 200 ml of 1 N hydrochloric acid are introduced into a Parr flask and the mixture is hydrogenated to a pressure of approximately 0.35 MPa at 50 ° C for 15 h. The catalyst was removed by filtration, the filtrate was evaporated and dried by trap with a mixture of ethanol and toluene, and 17 g of white crystalline product are obtained, said product is used without further purification in the next step. 1 .2. 1- (4-chlorophenyl) -2- [4- [2- (cyclohexyl) ethyl] piperid-1-yl] ethanone. A mixture of 8 g (0.0343 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 6.7 g (0.0343 mol) of 4- [2- (cyclohexyl) ethyl] piperidine, 30 g of potassium carbonate and 150 ml of acetonitrile was stirred at room temperature for 8 h and then allowed to stabilize overnight. The mixture was poured into water and the insoluble material was separated by filtration and dried. 10.1 g of compound were obtained. Melting point: 71 -72 ° C.

Example 2 (Compound No. 1 A) (±) -a- (4-chlorophenyl) -4- [2- (cyclohexyl) ethyl] piperidine-1-ethanol hydrochloride. 10.1 g (0.029 mol) of 1- (4-chlorophenyl) -2- [4- [2- (cyclohexyl) ethyl] piperid-1-yl] ethanone, 300 ml of methanol and 30 ml of water were introduced into a flask The mixture was heated in order to obtain the solution, 5 g of potassium borohydride were added in portions and the mixture was stirred at room temperature for 6 h. Water was added, followed by 3N hydrochloric acid and the mixture was allowed to stabilize overnight. The solid was collected by filtration, washed with acetone and recrystallized from 2-propanol. 4.4 g of hydrochloride were obtained. Melting point: 245 ° C (decomposition).

Example 3 (Compound No. 4A). (+) - a- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] -β-methylpiperidine-1-ethanol hydrochloride, erythro isomer 3.1. 4 - [(Cyclohexyl) methyl] piperidine hydrochloride. 50 g (0.285 mol) of 4- (phenylmethyl) piperidine, 500 ml of methanol, 30 ml of concentrated hydrochloric acid and 5 g of 5% rhodium-en-carbon are introduced in a 1 l autoclave and hydrogenated to approximately 7 MPa at 80 ° C for 6 h. The mixture was allowed to cool, the catalyst was removed by filtration and the filtrate evaporated under reduced pressure. The residue is washed with acetone and dried. 49 g of white crystalline compound were obtained, said product is used without further purification in the next step. Melting point: 303-305 ° C. 3. 2. (±) -1- (4-chlorophenyl) -2- [4 - [(cyclohexyl) methyl] piperid-1-yl] propanone. A mixture of 9 g (0.0364 mol) of 2-bromo-1- (4-chlorophenyl) propanone, 6.5 g (0.0359 mol) of 4 - [(cyclohexyl) methyl] piperidine, 30 g of potassium carbonate and 150 ml of Acetonitrile is stirred at room temperature for 8 h and the mixture is allowed to stabilize overnight. It is taken with water and the insoluble material is collected by filtration, dried and used without further purification in the next step. 3. 3. (±) -a- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] -β-methylpiperidine-1-ethanol hydrochloride, erythro isomer. 6 g (0.0172 mol) of (±) -1- (4-chlorophenyl) -2- [4 - [(cyclohexyl) methyl] piperid-1-yl] propanone, 200 ml of methanol, 25 ml of acetic acid and ml of water are introduced into a round flask, 4 g of potassium borohydride are added in portions and the mixture is allowed to stabilize overnight. Water is added, followed by hydrochloric acid, some of the solvent is evaporated and the crystals formed are filtered, washed with water, and crystallized again from 2-propanol and dried. 4.7 g of hydrochloride were obtained. Melting point: 262-264 ° C.

Example 4 (Compound No. 5A) (±) -a- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] -β-methylpiperidine-1-ethanol hydrochloride, threo isomer. 6 g (0.0172 mol) of (±) -1 - (4-chlorophenyl) -2- [4 - [(cyclohexyl) methyl] piperid-1-yl] propanone, 200 ml of methanol, tetrahydrofuran sufficient to obtain a solution, and then 20 ml of water were introduced into a round flask, 4 g of potassium borohydride are added in portions and the mixture is stirred at room temperature for 5 h. Water was added and the insoluble material was separated by filtration and purified by chromatography on a column of silica gel, extracting with a 97/3 mixture of dichloromethane and acetone. After evaporation of the minimum polar fractions and recrystallization from ethanol, 2.3 g of compound were obtained. Melting point: 1 18-1 19 ° C.

Example 5 (Compound No. 8A). (±) -a- (4-chlorophenyl) -4- (cyclohexyl) piperidine-1-ethanol. 5.1. 4- (Cyclohexyl) piperidine hydrochloride. 10 g (0.0645 mol) of 4-phenylpyridine, 1 g of 5% rhodium-en-carbon, 100 ml of 1 N hydrochloric acid and 10 ml of concentrated hydrochloric acid are introduced into a Parr apparatus and the mixture is hydrogenated at 0.35. MPa at 50 ° C for 13 days (adding 0.5 g of catalyst after the first week). The catalyst is separated by filtration, a few drops of concentrated hydrochloric acid are added to the filtrate, which is concentrated by evaporation and etched twice with ethanol. After drying, 11.1 g of white solid were obtained. Melting point: 310-31 1 ° C. . 2. (±) -a- (4-chlorophenyl) -4- (cyclohexyl) piperidine-1-ethanol. A suspension of 2.03 g (0.01 mol) of 4- (cyclohexyl) piperidine hydrochloride, 2.33 g (0.01 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 2.12 g of sodium carbonate, 40 ml of ethanol and 10 ml of water was prepared and refluxed for 1 h. The mixture was cooled, 4.4 g of potassium borohydride were added and stirred for 2 days at room temperature. Water was added and the precipitate was collected by filtration, washed with water and dried. 2.88 g of compound were obtained. Melting point: 135-136 ° C.

Example 6 (Compound No. 9A) (±) -a- (4-chlorophenyl) -4- [3- (cyclohexyl) propyl] piperidin-1-ethanol. 6.1. 4- [3- (Cyclohexyl) propyl] piperidine hydrochloride. 20.3 g (0.1 mol) of 4- (3-phenylpropyl) piperidine, 2 g of 5% rhodium-en-carbon and 200 ml of 1 N hydrochloric acid are introduced into a Parr flask and the mixture is hydrogenated at 0.35 MPa a 50 ° C for 40 h. The catalyst is separated by filtration, the filtrate is evaporated, the residue is taken up in a mixture of toluene and ethanol and it is re-evaporated, the white crystalline residue is dissolved in 50 ml of hot 2-propanol containing 5% hydrochloric acid.; The solution is cooled, 50 ml of diethyl ether are added, the suspension is stirred again and the white precipitate is collected by filtration, washed with diethyl ether and dried. 15.86 g of hydrochloride were obtained.

Melting point: 229 ° C. 6.2. (±) -a- (4-chlorophenyl) -4- [3- (cyclohexyl) propyl] piperidine-1-ethanol. A suspension of 1.84 g (0.0075 mol) of 4- [3- (cyclohexyl) propyl] piperidine hydrochloride, 1.75 g (0.0075 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 1. 6 g of sodium carbonate, 40 ml of ethanol and 10 ml of water are prepared and refluxed for 1 h 30 minutes. The mixture is cooled, 3.59 g of potassium borohydride are added and the mixture is stirred overnight at room temperature. 10 ml of water are added and the precipitate is collected by filtration, washed with water and dried in the presence of phosphorus pentoxide. 2.45 g of compound were obtained. Melting point: 85-86 ° C.

Example 7 (Compound No. 12A) 1 - [2- (4-Chlorophenyl) ethyl] -4 - [(cyclohexyl) methyl] piperidine hydrochloride. 3.0 g (0.0089 mol) of a- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] piperidin-1-ethanol suspended in 25 ml of toluene are introduced into a round flask, the suspension was cooled in an ice bath , a solution of 3 ml of thionyl chloride in 10 ml of toluene was added, and the mixture was stirred at room temperature for 5 h 30 min. The solvent evaporates under reduced pressureThe residue is washed with toluene to remove any traces of thionyl chloride, the solvent is evaporated, the residue is taken up in 60 ml of tetrahydrofuran and the suspension is emptied as drops in a suspension of 0.7 g of lithium aluminum hydride. in 1 5 ml of tetrahydrofuran and, while stirring the mixture with thickeners, gradually warm and reflux for 1 h 30. The mixture is cooled and taken up in 40 ml of water and 30 ml of ethyl acetate, the phase The organic material is separated and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, extracting with a 95/5 mixture of dichloromethane and methanol. The hydrochloride is prepared in propanol and, after recrystallization of 30 ml of 2-propanol, finally 0.77 g of compound are isolated. Melting point: 284-285 ° C.

Example 8 (Compound No. 14A) 1 - [2- (4-Chlorophenyl) ethyl] 4- [2- (cyclohexyl) ethyl] piperidine hydrochloride 3.0 g (0.0085 mol) of (±) - < x- (4-chlorophenyl) -4- [2- (cyclohexyl) ethyl [piperidin-1-ethanol suspended in 25 ml of toluene are introduced into a round flask, the suspension is cooled in an ice bath, a solution of ml of thionyl chloride in 10 ml of toluene is added and the mixture is stirred at room temperature for 5 h 30. The solvent is evaporated under reduced pressure, the residue was washed with toluene to remove any trace of thionyl chloride, evaporated the solvent, the residue was taken up in 60 ml of tetrahydrofuran, the suspension was emptied as drops in a suspension of 0.7 g of lithium aluminum hydride in 10 ml of tetrahydrofuran and the mixture was refluxed for 1 h 30 with stirring and then it was allowed to stabilize during the night.

It was taken in 40 ml of water and 30 ml of ethyl acetate, the organic phase was separated and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel, extracting with a 95/5 mixture of dichloromethane and methanol. The hydrochloride is prepared by dissolving the base in ethanol and the additional hydrochloric acid at pH = 1 and, after recrystallization from 2-propanol, finally 0.30 g of compound was isolated. Melting point: 290-291 ° C.

Example 9 (Compound No. 7A). (±) -a- (4-chlorophenyl) -4 - [(cyclopentyl) methyl] piperidin-1-ethanol. 9.1. 4 - [(Cyclopentyl) methyl] piperidine hydrochloride (1 st variant). 9.1 .1. 4 - [(cyclopentyl) methyl] pyridine. 300 ml of ammonia are condensed in a round 1-necked flask of 1 liter at -78 ° C, 100 ml of diethyl ether are added and, at -78 ° C, 8.28 g (0.36 mol) of sodium are added in the form of portions. The deep blue mixture is stirred for 15 min and 30 g (0.32 mol) of 4-methylpyridine are added in the form of drops. The color changes from blue to yellow. 47.68 g (0.32 mol) of bromocyclopentane dissolved in 100 ml of diethyl ether are then added, still at -78 ° C, and the stirring is continued at -78 ° C for 2 h. The ammonium chloride is added and the ammonia and ether are evaporated by means of a bath of lukewarm water. The residue is taken up in 200 ml of diethyl ether and 100 ml of water and extracted three times with ether. The organic phase is washed twice with water, dried over magnesium sulfate and filtered, and the solvent is evaporated under reduced pressure. 10 g of crude oily product are obtained, said product is distilled under reduced pressure. 2 g of product are obtained, said product is used without further purification in the next step. 9. 1 .2. 4 - [(Cyclopentyl) methyl] piperidine hydrochloride. A solution of 1.6 g of 4 - [(cyclopentyl) methyl] pyridine in 80 ml of a 1/1 mixture of ethanol and 1 N hydrochloric acid and 300 mg of platinum oxide are introduced into a Parr flask and the mixture hydrogenated at 0.35 MPa at 25 ° C. The catalyst is separated by filtration, the solvents are evaporated under reduced pressure, the saturated aqueous sodium bicarbonate solution is added to the residue and the mixture is extracted three times with ethyl acetate. The organic phase is washed twice with water and once with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered and the solvent is evaporated under reduced pressure. 1.6 g of product are obtained, said product is purified by chromatography on a silica gel column, extracting with a 95/5 mixture of methanol and 25% aqueous ammonia. 1.6 g of purified product are obtained in the form of free base The hydrochloride is prepared by dissolving the base in a 0.1 N solution of hydrochloric acid in 2-propanol, followed by recrystallization from a mixture of ethyl acetate and methanol. Melting point: 275 ° C. 9. 2. 4 - [(Cyclopentyl) methyl] piperidine hydrochloride (2nd variant). 9.2.1 Cyclopentyltriphenylphosphonium bromide. A mixture of 17.57 g (0.067 mol) of triphenylphosphine and 10 g (0.067 mol) of bromocyclopentane is heated at 200 ° C (bath temperature) under an inert atmosphere for 2 h. The mixture cools, benzene is added with stirring and the formed precipitate is collected by filtration and recrystallized from a mixture of ethyl acetate and methanol. 16 g of product are obtained. Melting point: 260 ° C. 9.2.2. 4 - [(cyclopentylidene) methyl] pyridine. A suspension of 8.88 g (0.022 mol) of cyclopentyltriphenylphosphonium bromide in 100 ml of tetrahydrofuran is introduced into a 250 ml two-neck round flask under an inert atmosphere, the temperature is lowered to -78 ° C, added in the form of drops 13.75 ml of a 1.6 M solution of butyllithium in hexane; the mixture, which turned red, is stirred for 30 min, followed by the addition in the form of drops of 2,359 g (0.022 mol) of pyridine-4-carboxaldehyde dissolved in 50 mil of tetrahydrofuran and the mixture is stirred for 1 ha. 78 ° C and then for 3 h at room temperature. 50 ml of water and 100 ml of ethyl acetate are added, the aqueous phase is separated and extracted three times with ethyl acetate, the organic phase is washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate and filtered, and the solvent is evaporated under reduced pressure. g of crude product are obtained, which after purification by chromatography on a column of silica gel, give 2.69 g of compound. 9.2.3. 4 - [(Cyclopentyl) methyl] piperidine hydrochloride. A solution of 4.815 g (0.030 mol) of 4- [(cyclopentylidene) methyl] pyridine in 180 ml of a 1/1 mixture of ethanol and 1 N hydrochloric acid is introduced into a Parr flask, 2.5 g of Adams catalyst (PtO2) they are added and the mixture is hydrogenated at 25 ° C to about 0.35 MPa. The catalyst is separated by filtration, the filtrate is concentrated under reduced pressure, the saturated aqueous sodium bicarbonate solution is added to the residue, the mixture is extracted three times with ethyl acetate, the organic phase is washed twice with water and once with saturated aqueous sodium chloride solution, and dried over magnesium sulfate and filtered, and the solvent is evaporated under reduced pressure. 5 g of crude product are obtained, said product is purified by chromatography on a column of silica gel, extracting with a 95/5 mixture of methanol and 25% aqueous ammonia. 4.9 g of pure base are obtained, the hydrochloride of which is formed from a 0.1 N solution of hydrochloric acid in 2-propanol. Melting point: 275-276 ° C. 9. 3 (±) -a- (4-chlorophenyl) -4 - [(cyclopentyl) methyl] piperidin-1-ethanol. 0.57 g (0.0024 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 500 mg (0.0024 mol) of 4 - [(cyclopentyl) methyl] piperidine hydrochloride, 0.52 g (0.0049 mol) of sodium carbonate, 13 ml of ethanol and 3 ml of water are introduced into a 100 ml round flask and the mixture is heated to 80 ° C (bath temperature) for 1 h 30. The mixture is cooled, 1 g of potassium borohydride is added and the mixture is stirred and allowed to stabilize overnight. 26 ml of water are added, the suspension is stirred and the solid is separated by filtration, washed with water and dried in the presence of phosphorous pentoxide. 0.7 g of product is obtained, which is purified by chromatography on a column of silica gel, extracting with a 95/5 mixture of dichloromethane and methanol. After recrystallization and drying, 0.366 g of compound is finally isolated. Melting point: 104-105 ° C.

Example 10 (Compound No. 3A) (±) -a- (4-chlorophenyl) -4 - [(cyclohexyl) methyl [piperidin-1-ethanol. 7 g (0.03 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 5.44 g (0.03 mol) of 4 - [(cyclohexyl) methyl] piperidine, 3.1 8 g (0.03 mol) of sodium carbonate, 160 ml of ethanol and 40 ml of water are introduced into a 500 ml round flask and the mixture was refluxed for 2 h. The mixture was allowed to cool to room temperature, 10 g of potassium borohydride were added with stirring at room temperature for 30 min and the mixture was allowed to remain overnight.

The mixture was poured into 320 ml of water and the yellow precipitate was separated by filtration and dried in the presence of phosphorus pentoxide. 8.8 g of crude product were obtained, said product is purified by chromatography on a column of silica gel, extracting with a 90/10 mixture of dichloromethane and methanol. 6.36 g of compound are obtained, said product is recrystallized from ethanol. Melting point: 122-123 ° C.

Example 1 1 (Compound No. 10A) (±) -a- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] piperidine-1-ethanol. 2.8 g (0.0083 mol) of (±) -a- (4-chlorophenyl) -4- [(cyclohexyl) methyl] piperidin-1-ethanol, 2.37 g (0.01 mol) of diisopropyl (-) - tartrate and 80 ml of dichloromethane are introduced into a 500 ml round flask under a nitrogen atmosphere and 4.95 g, ie 5.14 ml (0.0174 mol) of titanium tetraisopropoxide are added; the color of the mixture changes to yellow. The mixture is cooled to -25 ° C with a bath of acetone and "cardice" and 1.53 ml of a 3.3M solution of tert-butyl hydroperoxide in toluene are added, continuing stirring at -25 ° C for 2 h 30. 80 ml of diethyl ether, 4 ml of water and 5 ml of 30% sodium hydroxide are added, the mixture is allowed to warm to room temperature, with vigorous stirring, and allowed to stabilize overnight.

The white precipitate (titanium salts) are removed by filtration and the filtrate is evaporated. 1.67 g of white crystalline solid are obtained, said product is purified by chromatography on a column of silica gel, extracting with ethyl acetate. 0.53 g of white crystals is obtained, which is crystallized twice from ethanol in order to finally isolate 0.21 g of dextrorotatory enantiomer (ee = 92.6%). Melting point 140-141 ° C [a] D20 = + 46.0 ° (c = 1; CHCl3).

Example 12 (Compound No. 1 1 A) (-) - a- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] piperidine-1-ethanol. The process was carried out as described in the previous example, using dextrorotatory diisopropyl tartrate, instead of the levorotatory isomer.

Starting with 3.36 g (0.01 mol) of racemate, 0.38 g of levorotatory enantiomer is finally isolated (ee = 90.5%). Melting point: 140-141 ° C [a] D20 = -46.0 ° (c = 1; CHCl3).

Example 13 (Compound No. 18A) (±) -a- (4-chlorophenyl) -4 - [(cycloheptyl) methyl] pi peridin-1-ethanol. 13.1. 4 - [(Cycloheptyl) methyl] piperidine hydrochloride. The process (2nd variant) described for 4- [(cyclopentyl) methyl] piperidine hydrochloride is used, starting with bromocydoheptane instead of bromocyclopentane. Melting point: 260 ° C. 13. 2 (±) -a- (4-chlorophenyl) -4 - [(cycloheptyl) methyl] piperidine-1-ethanol. A mixture of 0.4 g (0.00171 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 0.4 g (0.00171 mol) of 4 - [(cycloheptyl) methyl] piperidine hydrochloride and 0.4 g of sodium carbonate in 20 ml of ethanol and 5 ml of water was refluxed for 2 h with stirring. The mixture was cooled and 0.8 g of potassium borohydride was added with continuous stirring at room temperature overnight. 40 ml of water were added, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with water and then with a saturated aqueous sodium chloride solution and dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel, extracting with a mixture of 95/5 dichloromethane and methanol. After recrystallization from ethanol, 0.097 g of compound is finally isolated. Melting point: 1 16-117 ° C.

Example 14 (Compound No. 9B) 5- [2- [4- (2-cyclohexylethyl) piperid-1 -yl] -1-oxoethyl] -3H-indol-2-one. 3.14 g (0.015 mol) of 5- (chloroacetyl) -3W-indole-2-one, 3.47 g (0.01 5 mol) of 4- (2-cyclohexylethyl) piperidine hydrochloride, 3.17 g (0.03 mol) of sodium carbonate 80 ml of ethanol and 20 ml of water are introduced into a 500 ml round flask and the mixture was refluxed for 1 h .

The mixture was allowed to cool and was drained in 200 ml of water and the precipitate was separated by filtration, washed with diethyl ether and dried in the presence of phosphorus pentoxide. 4 g of crude product are obtained, said product is purified by chromatography on a column of silica gel, extracting with a 95/5 mixture of dichloromethane and methanol, followed by recrystallization from ethanol. After washing with diethyl ether and drying in the presence of phosphorus pentoxide, 0.96 g of compound is finally isolated. Melting point: 180-181 ° C.

Example 15 (Compound No. 4B) (±) -5- [2- [4- (2-cyclohexylethyl) piperid-1-yl] -1-hydroxyethyl] -3H-indol-2-one. 3.14 g (0.015 mol) of 5- (chloroacetyl) -3tt-indole-2-one, 3.47 g (0.015 mol) of 4- (2-cyclohexylethyl) piperidine hydrochloride, 3.18 g (0.03 mol) of sodium carbonate, 100 ml of ethanol and 20 ml of water are introduced into a 500 ml round flask and the mixture is heated to 120 ° C (bath temperature) for 1 h 30. The mixture was cooled in an ice bath and 6.61 g of potassium borohydride were added with stirring at room temperature overnight. The mixture was drained in 200 ml of water and stirred for 10 min and the precipitate was separated by filtration, washed with water and with petroleum ether and dried in the presence of phosphorus pentoxide. 4. 34 g of crude product are obtained, said product is purified by chromatography on a column of silica gel, extracting with a 90/10 mixture of dichloromethane and methanol. After recrystallization and drying, 1.48 g of compound are finally isolated. Melting point: 210-21 1 ° C.

Example 16 (Compound No. 8B) 5- [2- [4- (2-Cyclohexylethyl) piperid-1 -yl] ethyl] -3H-indol-2-one. 16.1. 5- (2-Chloroethyl) -3H-indol-2-one. 15 g (0.0715 mol) of 5- (chloroacetyl) -3H-indol-2-one suspended in 60 ml of trifluoroacetic acid are introduced into a 500 ml round flask, the mixture was cooled with an ice bath, 26.13 ml ( 0.164 mol) of triethylsilane were added in the form of drops and the mixture was allowed to warm to room temperature with continued stirring overnight. The mixture was drained in 300 ml of ice water with stirring for 15 min and the beige precipitate was collected by filtration, washed with water and with hexane and dried in the presence of phosphorus pentoxide. 13.75 g of compounds were obtained, said products are used without further purification in the next step. 16. 2. 5- [2- [4- (2-Cyclohexylethyl) piperid-1-yl] ethyl] -3H-indol-2-one. 2.9 g (0.01 5 mol) of 5- (2-chloroethyl) -3H-indol-2-one, 3.47 g (0.01 5 mol) of 4- (2-cyclohexylethyl) piperidine hydrochloride, 3.17 g (0.03 mol) ) of sodium carbonate and 50 ml of? /,? / - dimethylformamide were introduced into a 500 ml round flask and the mixture was heated to 120 ° C (bath temperature) for 5 h. 150 ml of water were added with stirring for 30 min and the brown precipitate was separated by filtration and dried in the presence of phosphorus pentoxide. 4.56 g of crude product are obtained, said product is purified by chromatography on a column of silica gel, extracting with a 90/10 mixture of dichloromethane and methanol. After recrystallization of 2-propanol, washing with diethyl ether and drying in the presence of phosphorus pentoxide, 0.85 g of compound is finally isolated. Melting point: 190-191 ° C.

Example 17 (Compound No. 7B) 6- [2- [4- (2-cyclohexylethyl) piperid-1 -yl] -1-oxoethyl] -3,4-dihydro-1 H -quinolin-2-one. 3.35 g (0.015 mol) of 6- (chloroacetyl) -3,4-dihydro-1 H-quinolin-2-one, 3. 47 g (0.015 mol) of 4- (2-cyclohexylethyl) piperidine hydrochloride, 3.17 g (0.03 mol) of sodium carbonate, 80 ml of ethanol and 20 ml of water are introduced into a 500 ml round flask and the mixture it was refluxed for 1 h 30. The mixture was allowed to cool and was emptied in 200 ml of water with stirring for 15 min and the precipitate was separated by filtration, washed with water and dried in the presence of sodium pentoxide. match. .4 g of crude product were obtained, said product is purified by chromatography on a column of silica gel, extracting with a mixture of 90/10 dichloromethane and methanol, followed by recrystallization from ethanol. After washing with diethyl ether and drying in the presence of phosphorus pentoxide, 3.82 g of compound were finally isolated. Melting point: 176-177 ° C.

Example 18 (Compound No. 3B) (±) -6- [2- [4- (2-cyclohexylethyl) piperid-1 -yl] -1-hydroxyethyl] -8-fluoro-3,4-dihydro-1H- quinolin-2-one. 3.62 g (0.015 mol) of 6- (chloroacetyl) -8-fluoro-3,4-dihydro-1 H-quinolin-2-one, 3.47 g (0.015 mol) of 4-82-cyclohexylethyl) piperidine hydrochloride, 3. 18 g (0.03 mol) of sodium carbonate, 80 ml of ethanol and 20 ml of water are introduced into a 500 ml round flask and the mixture was refluxed for 1 h 30. The mixture was allowed to cool and 6.5 g of potassium borohydride were added with stirring at room temperature overnight. 160 ml of water were added with stirring for 15 min and the beige precipitate was separated by filtration, washed with water and with petroleum ether and dried in the presence of phosphorus pentoxide. 5 g of crude product are obtained, said product is purified by chromatography on a column of silica gel, extracting with a mixture 90710 dichloromethane and methanol.

After recrystallization and drying in the presence of phosphorus pentoxide, 2.7 g of compound were finally isolated. Melting point: 154-155 ° C.

Example 19 (Compound No. 5B) 6- [2- [4- (2-cyclohexylethyl) piperid-1-yl] ethyl] -3,4-dihydro-1 H -quinolin-2-one. 19.1. 6- (2-Chloroethyl) -3,4-dihydro-1 H-quinolin-2-one. 5.36 g (0.024 mol) of 6- (chloroacetyl) -3,4-dihydro-1 H-quinolin-2-one and 18. 5 ml of trifluoroacetic acid are introduced into a round flask, the suspension is cooled in an ice bath and 8.77 ml (0.055 mol) of triethylsilane are added in the form of droplets with stirring at room temperature for 2 h. The mixture was drained in 100 ml of ice water with stirring for 15 min and the precipitate was separated by filtration, washed with water and then with hexane and dried in the presence of phosphorus pentoxide. 5 g of compound were obtained. Melting point: 163-164 ° C. 19. 2. 6- [2- [4- (2-Cyclohexylethyl) piperid-1-yl] ethyl] -3,4-dihydro-1 H -quinolin-2-one. 3.14 g (0.015 mol) of 6- (2-chloroethyl) -3,4-dihydro-1 H-quinolin-2-one. 3. 47 g (0.015 mol) of 4- (2-cyclohexylethyl) piperidine hydrochloride, 3.18 g (0.03 mol) of sodium carbonate and 50 ml of? /,? / - dimethylformamide are introduced into a 500 ml round flask and the The mixture was heated to 120 ° C (bath temperature) for 4 h 30. 150 ml of water were added, the mixture was stirred for 30 min in an ice bath and the precipitate was separated by filtration, washed with water and dried in the presence of phosphorus pentoxide. 4.70 g of crude product are obtained, said product is purified by chromatography on a column of silica gel, extracting with a 90/10 mixture of dichloromethane and methanol. After recrystallization from 2-propanol, washing with diethyl ether and drying in the presence of phosphorus pentoxide, 2.5 g of compound are finally isolated. Melting point: 192-193 ° C.

Example 20 (Compound No. 6B) (±) -7- [2- [4- (2-cyclohexylethyl) piperid-1-yl] -1-hydroxyethyl] -1,4,4,5-tetrahydrobenzo [j] azepin -2-ona. 3.56 g (0.015 mol) of 7-8-chloroacetyl) -1,4,4,5-tetrahydrobenzo [b] azepin-2-one, 3.47 g (0.015 mol) of 4- (2-cyclohexylethyl) piperidine hydrochloride, 3.18 g (0.03 mol) of sodium carbonate, 80 ml of ethanol and 20 ml of water are introduced into a 500 ml round flask and the mixture was refluxed for 2 h. It was allowed to cool and 6 g of potassium borohydride were added with stirring at room temperature overnight. 160 ml of water were added with stirring for 2 h and the precipitate was separated by filtration, washed with water and dried in the presence of phosphorus pentoxide. . 1 g of crude product are obtained, said product is purified by chromatography on a column of silica gel, extracting with a 90/10 mixture of dichloromethane and methanol. After recrystallization of propanol and drying, 3 g of compound are finally isolated. Melting point. 188-189 ° C.

Example 21 (Compound No. 17B) 6- [2- [4- (3-cyclohexylpropyl) piperid-1 -yl] -1-oxoethyl] -3,4-dihydro-1 H -quinolin-2-one. 1.0 g (0.0041 mol) of 4- [3- (cyclohexyl) propyl] piperidine hydrochloride, 1.0 g (0.0041 mol) of 6- (bromoacetyl) -3,4-dihydro-1 H-quinolin-2 -one, 0.87 g (0.0082 mol) of sodium carbonate, 20 ml of ethanol and 5.5. ml of water are introduced into a round flask and the suspension is refluxed for 2 h 30. The mixture is cooled to 0 ° C and stirred at this temperature for 20 min, 35 ml of water are added with continuous stirring at 0 ° C. ° C for 1 5 min, the light brown precipitate was collected by filtration and the crystals were washed with water and dried in the presence of phosphorus pentoxide overnight. After recrystallization from 2-propanol, washing with water, washing with hexane and drying, 1.223 g of compound was obtained. Melting point: 179 ° C.

Example 22 (Compound No. 10B) (±) -6- [2- [4- (3-cyclohexylpropyl) piperid-1 -yl] -1-hydroxyethyl] -3,4-dihydro-1 H-quinolin-2- ona 5.5 g (0.0138 mol) of 6- [2- [4- (3-cyclohexylpropyl) piperid-1 -yl] -1-oxoethyl] -3,4-dihydro-1 H -quinolin-2-one, 80 ml of Ethanol and 20 ml of 0.5N hydrochloric acid are introduced into a round flask, 6 g of potassium borohydride are added and the mixture is stirred at room temperature overnight. 160 ml of water were added with stirring for 30 min and the precipitate was separated by filtration, washed with water and dried. 5.2 g of crude product were obtained, said product is purified by chromatography on a column of silica gel, extracting with a 90/10 mixture of dichloromethane and methanol. After recrystallization of ethanol and drying, 4.24 g of compound are finally isolated. Melting point: 151 -152 ° C.

Example 23 (Compound No. 16B) 6- [2- [4- (cyclohexyl) piperid-1-yl] ethyl] -3,4-dihydro-1 H -quinolin-2-one. A suspension of 0.565 g (0.00277 mol) of 4- (cyclohexyl) piperidine hydrochloride, 0.70 g (0.00276 mol) of 6- (2-bromoethyl) -3,4-dihydro-1 H-quinolin-2-one, 0.59 g (0.0055 mol) of sodium carbonate and 9.5 ml of ? /,? / - dimethylformamide is prepared and the mixture is heated to 120 ° C (bath temperature) for 5 h 30.

The mixture was allowed to cool, 20 ml of water are added with stirring for 15 min, the solid is collected by filtration and the crystals are washed with water. 0.73 g of product is obtained, which is purified by chromatography on a column of silica gel, extracting with a 94/6 mixture of dichloromethane and methanol. After recrystallization of 200 ml of acetone containing a little methanol, filtration, washing with water and with hexane and then drying, 0.466 g of crystals is finally isolated. Melting point: 212-214 ° C.

Example 24 (Compound No. 19B) 6- [2- [4 - [(cyclopentyl) methyl] piperid-1 -yl] ethyl] -3,4-dihydro-1 H -quinolin-2-one. A suspension of 0.30 g (0.00147 mol) of 4 - [(cyclopentyl) methyl] piperidine hydrochloride, 0.375 g (0.00147 mol) of 6- (2-bromoethyl) -3,4-dihydro-1 H-quinolin-2- ona, 0.313 g (0.00298 mol) of sodium carbonate and . 5 ml of? /,? / - dimethylformamide is prepared and the mixture is heated to 1 30 ° C (bath temperature) for 3 h. The mixture is allowed to cool, 12 ml of water is added with stirring for 15 min, the solid is collected by filtration and the crystals are washed with water and then with hexane. 0.39 g of product is obtained, which is purified by chromatography on a column of silica gel, extracting with a 94/6 mixture of dichloromethane and methanol. 1 After recrystallization from 60 ml of acetone containing a little methanol, filtration, washing with water and with hexane and then drying, 0.217 g of crystals were finally isolated. Melting point: 172-174 ° C.

Example 25 (Compound No. 29B) 6- [2- [4- (cycloheptyl) methyl] piperid-1-yl] ethyl] -3,4-dihydro-1 H -quinolin-2-one. A suspension of 0.2 g (0.00864 mol) of 4- [(cycloheptyl) methyl] piperidine hydrochloride, 3.5 ml of? /,? / - dimethylformamide, 0.22 g (0.000864) of 6- (2-bromoethyl) -3.4 -dihydro-1 H-quinolin-2-one and 0.184 g (0.001728 mol) of sodium carbonate is introduced into a round flask and the mixture was refluxed for 3 h 15. The mixture was cooled and diluted with 8 ml of water and the precipitate was collected by filtration and dried. 0.23 g of product is obtained, which is purified by chromatography on a column of silica gel, extracting with a mixture 96/4 dichloromethane and methanol. 0.21 g of solid is isolated, said product is recrystallized from 80 ml of acetone to finally obtain 0.146 g of compound. Melting point: 154- 155 ° C.

Tables A and B that follow illustrate the chemical structures and physical properties of a few compounds according to the invention.

In columns "R2", "C5H9" denotes a cyclopentyl group, "C6Hn" denotes a cyclohexyl group and "C7H13" denotes a cycloheptyl group. In the column "Isom", "(±)" denotes a racemate, "+" denotes a dextrorotatory enantiomer, "-" denotes a levorotatory enantiomer, 7"denotes an achiral compound," E "denotes the erythro diastereoisomers and" T " denotes the threo diastereoisomers In the column "salt", "-" denotes a compound in the form of the base and "HCI" denotes a hydrochloride. (° C) "," (d) "denotes a melting point with decomposition.

Table A Note: the optical rotations of the compounds numbered 10A and 11A are, respectively, + 46 ° and -46 ° (c = 1; CHCI3).

Table B The compounds of the invention formed the subject of tests, which proved their value as therapeutic substances. The neurotrophic properties of the compounds of the invention were demonstrated in vivo through their effects on the regeneration of the sciatic nerve in rats. These effects were evaluated after an injury by local freezing of the sciatic nerve in rats. Freezing injury destroys sciatic nerve fibers, which undergo "Wallerian" degeneration at the site of the lesion and through the distal trunk. This type of injury preserves the nerve covers and allows nerve regeneration under reproducible conditions. The regeneration process starts on the proximal side in the hours following the injury. The regeneration rate of the sensitive fibers is measured by a compression test 8 days after the injury. The animals are adult male rats of Sprague Dawley species (Iffa Credo) weighing approximately 250 g. After anesthetizing the animals with sodium pentobarbital (60 mg / kg), the thigh skin is disinfected with alcohol and cut at the junction of the biceps femoris. The sciatic nerve is exposed after removing the Lateralis and Biceps Femoris muscles. The point of the lesion is identified by a microsuture (black Ethilon ™ 10-0) in the perineurium on trifurcation of the sciatic nerve. Sciatic nerve injury is done over 1 mm by 6 freeze-thaw cycles using copper cryode pre-cooled in liquid nitrogen. The wound is then closed and treated with an antibiotic (Exoseptoplix®). The animals are placed in individual cages and monitored daily. After the operation, the animals are divided into several batches of 6 individuals: - injured controls, who receive an intraperitoneal injection of 0.1% Tween 80MR, 10 min and 6 h after the injury, then twice a day from the second to the eighth day. - treated injured animals, who receive an intraperitoneal injection of a test compound, administered in doses of 0.3, 1 or 3 mg / kg in 0.1% Tween 80MR, 10 min and 6 h after the injury, and then twice day from the second to the eighth day. Eight days after the operation, the animals are lightly anesthetized and the sciatic nerve is re-exposed in order to perform the compression test. This test consists of compressing the nerve slightly using forceps, starting with the most distal region of the nerve and moving 0.5 mm each time. A reflex response (contraction of the muscles of the posterior region of the animal) is observed at the point where the front of the regenerated sensitive fibers is present. This point is labeled with a microsuture. The nerve is then removed and the distance between the site of the lesion and the distal microsuture is measured in millimeter paper under a working microscope. After the nerve is removed, the animals are sacrificed by an overdose of pentobarbital.

It was observed that, in treated animals, the administration of the compounds of the invention increases the distance covered by the sensitive fibers by more than 10% in relation to the controls. The neurotrophic properties of the compounds of the invention were also studied in vivo by means of their effects on the regeneration of the sciatic nerve after squeezing injury combined with a treatment with vincristine. Vincristine is a vincapervinca alkaloid, which is used in the treatment of certain types of cancer, and whose mechanism of action is well established. Vincristine binds to a cytoplasmic protein, tubulin, and breaks its polymerization into microtubules. The latter are major elements involved in the regeneration of the nerve after an injury. The reason for this is that the microtubules ensure the axonal transport of the newly synthesized macromolecules, which need to be transported to the distal part of the nerve, in order to ensure the formation and elongation of the growth cones. In this way, the administration of vincristine breaks the rapid axonal transport and decreases, or inhibits, depending on the doses administered, the regeneration of the nerve after an injury. Experimental model: after anesthetizing with pentobarbital, on day Do, the right sciatic nerve of the rats is crushed for 1.5 minutes. The following day (Di) the animals receive a simple administration of 0.2 mg / kg of vincristine and, on day D7, the regeneration rate is evaluated by means of the compression test. The dose of 0.2 mg / kg of vincristine reduces by approximately 20%, the regeneration distance evaluated in D7 in the control animals, not treated with the test compounds. These test compounds are administered to the animals intraperitoneally, twice a day, from D0 to D6 (10 min and 6 h after the lesion, in D0, then in the morning and in the evening, with an interval of 6 days). h, from Di to D6). The most active compounds in this test increase the rate of regeneration of the wounded sciatic nerve, in animals treated with vincristine, by 12 to 14%. The compounds of the invention were also the target of an inhibition test for the binding of [3H] ifenprodil in the cerebral cortex of rats (Schoemaker et al., Eur. J. Pharmacol. (1990) 183-1670). A male Sprague-Dawley rat weighing 150 to 230 g is sacrificed and the cerebral cortex is homogenized in 20 volumes of 50 mM buffer of ice-cold Tris-HCl (pH = 7.4 at 25 ° C), by means of an Ultra-Turrax ™ machine ( Ikawerk) or Polytron ™ (Kinematica). The homogenate is washed twice by centrifugation for 10 minutes at 45,000 x g, resuspending the pellet in fresh buffer. The final pellet is taken in 20 volumes of the same shock absorber. An aliquot of 100 μl of this suspension is incubated in a final volume of 1000 μl with 0.5 nM of [3 H] ifenprodil (specific activity: 30 to 35 Ci / mmol) for 30 minutes at 37 ° C, in the absence or in the presence of the competing substance. After incubation, the membranes are recovered by filtration in Whatman GF / BMR filters pretreated with 0.05% polyethyleneimine, and then washed with 5 ml of ice-cold buffer twice.

The non-specific ligation is determined with 10 μM of ifenprodil, the data were analyzed according to the usual methods and the concentration IC50, said concentration which inhibits the binding of [3 H]? Fenprodil by 50%, is determined. The IC50 values of the most active compounds are less than 25 nM Finally, the compounds are subjected to the global cerebral ischemia test in mice Ischemia is due to cardiac arrest induced by a rapid intravenous injection of magnesium chloride In this test , the "survival time", that is, the interval between the moment of the injection of magnesium chloride and the last observable respiratory movement, is measured for each mouse This last movement is considered to be the final indication of functioning of the central nervous system Respiratory arrest appears approximately 19 seconds after the injection of magnesium chloride Male mice (Charles River CD1) are studied in groups of 10 They are fed and provided with water ad libitum before the tests. The survival time is measured 10 minutes after the mpepeptoneal administration of the compounds of the invention. The results are given in the form of the difference between the survival time measured in a group. of 10 mice, which have received the compound and the survival time measured in a group of 10 mice, which have received the liquid from the vehicle. The proportions between the modifications in the survival time and the compound dose are recorded graphically in a semilogarithmic curve. This curve allows the calculation of the "effective dose of 3 seconds" (ED3), that is to say the dose (in mg / kg) that produces an increase of 3 seconds in the survival time in relation to the control group of the 10 mice without treating. A 3-second increase in survival time is both statistically significant and reproducible. The ED3- values of the most active compounds are less than or equal to 25 mg / kg via the intraperitoneal route. The results of the tests show that the compounds of the invention have neurotrophic properties and neuroprotective properties. They can be used for the treatment of peripheral neuropathies, such as traumatic neuropathies (cutting or squeezing of a nerve) or eschemic neuropathies, metabolic neuropathies (diabetes, uremia), medicinal, alcoholic and infectious neuropathies, genetic neuropathies, motor neuron diseases such as Spinal amyotrophies and amyotrophic lateral sclerosis. They can also be used for the treatment and prevention of brain disorders such as those following, for example, an ischemic attack, a cardiac or respiratory arrest, a thrombosis or a cerebral embolism, for the treatment of cerebral senility, dementia following heart attacks. multiple, senile dementia, for example Alzheimer's disease or Pick's disease, for the treatment of olivopontocerebellar atrophy and other neurodegenerative diseases such as Hintington's chorea, amyotrophic lateral sclerosis, for the treatment of cranial or spinal trauma, for the prevention of neuronal damage that follows convulsive attacks or that follows the presence of tumors in the nervous system, for the treatment of neurological changes due to AIDS, for the prevention and treatment of diabetic retinopathies, for optic nerve degeneration and for retinopathies associated with glaucoma. The compounds of the invention can also be combined with thrombolytic agents such as rt-PA (recombined plasminogen tissue activator, of human origin) for the treatment of cerebral infarcts of the thromboembolic type, or in combination with a compound which decreases intraocular pressure for the treatment of glaucoma, or alternatively in combination with an anticancer agent, in order to reduce the side effects (neuropathies, etc.) of the latter. To this end, they can be in any suitable pharmaceutical form for enteral or parenteral administration, in combination with suitable excipients, for example in the form of tablets, sugar-coated tablets, gelatin capsules, wafer capsules, suppositories, and suspensions or drinkable or injectable solutions, dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims (2)

4 Claims

1. The compound, optionally in the form of a pure optical isomer or a mixture of such isomers, corresponding to the general formula (I) , wherein Ar represents a) a phenyl group substituted with a halogen atom or b) a group of general formula (! ') wherein X represents a group of formula -CH2-, - (CH2) 2- or - (CH2) 3- and Z represents a hydrogen or a halogen atom or a methyl group, Y represents a group of formula -CH2- , -CO- or -CHOH-, Ri represents a hydrogen atom or a methyl group, R2 represents a C3-C7 cycloalkyl group, and n represents the number 0, 1, 2 or 3, in the form of the free base or a addition salt.

2. The process for the preparation of compound according to claim 1, characterized in that a haloketone of general formula (I I) R, wherein Ar is defined as in claim 1 and Hal represents a halogen atom, is first reacted with a substituted piperidine of general formula (III) wherein n and R2 are as defined in claim 1, to obtain the ketone of general formula (la) Which corresponds to the general formula (I) when Y represents a group -CO-, followed if desired, by the reduction of this ketone to obtain the alcohol of general formula (Ib) Which corresponds to the general formula (I) when Y represents a group -CHOH- then, if desired to obtain a compound of general formula (I) in which Y represents a group of formula -CH2- and Ar represents a group phenyl substituted with a halogen atom, the alcohol of the general formula (Ib), in which Y represents a group -CHOH- and Ar represents a phenyl group substituted with a halogen atom, is reduced by reaction with thionyl chloride, followed by treatment of the chlorine intermediate with lithium aluminum hydride, or alternatively, in order to obtain a compound of general formula (I) in which Y represents a group of formula -CH2- and Ar represents a group of general formula (I ") as defined in claim 1, a haloketone of general formula (II), in which Ar represents a group of general formula (I ') and Hal represents a halogen atom, is first reduced using tpethylsilane and acid tffluoroacetic, with e In order to obtain the halo derivative of general formula (IV) Ar '(I V) followed by reaction of the latter with a substituted pipepdine of general formula (II I), in which n and R2 are as defined in claim 1 The medicinal product, characterized in that it consists of a compound according to claim 1. The pharmaceutical composition, characterized in that it contains a compound according to claim 1, combined with an excipient.