CA2231326A1 - Derivatives of 4- (cycloalkyl) piperidines and of 4- (cycloalkylalkyl) piperidines, their preparation and their therapeutic application - Google Patents

Abstract

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

Description

The present invention relates to derivatives of 4- (cycloalkyl)piperidines and of 4-(cycloalkylalkyl)piperidines, to their preparation and to their therapeutic application.
The compounds of the invention correspond to the general formula (I) ~ (CH2)n~ R (I) A ,Y ~ N
R

in which Ar represents a) a phenyl group substituted with a halogen atom or b) a group of general formula (I') ~X~

N ~ (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-, 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.
The compounds of the invention may exi~t in the form of free bases or addition salts with acids.
Moreover, when Y represents a -CHOH- group, the carbon atom of this group is asymmetric; similarly, when Rl represents a methyl group, the carbon atom which bears it i6, itself also, asymmetric. A compound according to the invention may thus, according to the case, be in the form of a pure optical isomer or a mixture of such isomer6.
In accordance with the invention, the compounds of general formula (I) may be prepared by processes illustrated by the schemes which follow.
According to Scheme l, 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 ket:one of general formula (Ia), which corresponds to the general formula (I) when Y represent~ a -CO- group.
If so desired, this ketone may then be reduced, for example 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 Scheme 1 Jl ~, Ar Rl (CH2) ~R

2 ( III ) HN

O ~ (CH.)n~R
,L~,N ~J ( a ) K~H4 .

OH ~(CH2)r~R
~ T ~ ~ ~
R;

1) SOCl2 2 ~ LiAl H A

~ ICH.),~R

-CH2- and Ar represents a phenyl group su~stituted with a halogen atom, the alcohol of general formula (Ib) may then be reduced, for example by reaction with thionyl chloride, followed by treatment of the chloro int.ermediate with lithi.um aluminium hydride.
In order to obtain a compound of general formula (I) in which Y repre~ents a group of formula -CH2- 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 patent application EP-0,281,309, in order to obtain the halo derivative of general formula (IV), followed by reaction of the latter with a substituted piperidine of general formula (III), 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 general formula (II) are commercially available or are described in patent applications EP-0,109,317, EP-0,281,309, EP-0,351,282 and FR-2,684,379.
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 p~tents US-4,005,093 and US-4,028,366. The compounds of Scheme 2 J H a l ( I I ) Et3SiH / CF3CO.H

(IV) ~ ( C H2 ) ~ R I I I I ) HN

~(C~')r~R
R. (IC) general formula (III) in which n=1 or 3 and R2 represents a cyclohexyl group are mentioned, but not described, in patent US-4,261,891.
The other compounds of general formula (III) are no~el and form part of the in~ention as necessary intermediates in the process for the preparation of the compounds of general formula (I).

The compounds of general formula (III), in which n=0, 1 or 3 and ~2 represents a cyclohexyl group, may be obtained by catalytic hydrogenation, for example in the presence of rhodium-on-charcoal, of analogous derivatives in which R2 represents a phenyl group.
The other compounds of general formula (III) may be obtained either by a Wittig reaction between pyridine-4-carboxaldehyde and a phosphorus ylid obtained from a cycloalkyl halide, followed by a reduction by complete hydrogenolysis of the intermediate, i.e. by alkylation of 4-methylpyridine according to the method described in patent US-3,914,227, followed by reduction of the intermediate cycloalkylalkyl pyridine by catalytic hydrogenation in the presence of platinum oxide.
The examples which follow illustrate in detail the preparation of a few compounds according to the invention. The elemental microanalyses and the IR
and NMR spectra confirm the structures of the compounds obtained.
The compound numbers indicated in brackets in the titles correspond to those in Tables A and B given later.
Exam~le 1 (Compound No. 16A).
1-(4-Chlorophenyl)-2-[4-[2-(cyclohexyl)ethyl]piperid-1-yl)ethanone.
1.1. 4-[2-(Cyclohexyl)ethyl]piperidine hydrochloride.
20 g (0.088 mol) of 4-(2-phenylethyl)piperidine hydrochloride, 2 g of 5 ~
rhodi~m-on-charcoal and 200 ml of lN hydrochloric acid are introduced into a Parr flask and the mixture i5 hydrogenated at a pressure of about 0.35 MPa at 50~C
for lS h.
The catalyst i8 separated out by filtration, the filtrate i8 evaporated and dried by entrainment with a mixture of ethanol and toluene, and 17 g of white crystalline product are obtained, which product is used without further purification in the following step.
1.2. 1-(4-Chlorophenyl)-2-[4-[2-(cyclohexyl)ethyl]piperid-l-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 is stirred at room temperature for 8 h and i8 then left to stand overnight.
The mixture is poured into water and the insoluble material i8 separated out by filtration and dried. 10.1 g of compound are obtained.
Melting point: 71-72~C.
Example 2 (Compound No. lA) (+)-~-(4-Chlorophenyl)-4-[2-(cyclohexyl)ethyl]piperidine-l-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 are introduced into a round-bottomed flask, the mixture is warmed in order to obtain dissolution, 5 g of potassium borohydride are added portionwise and the mixture is stirred at room temperature for 6 h.
Water i~ added, followed by 3N ~ydrochloric acid and the mixture is left to stand overnight.
The solid is collected by filtration, washed with acetone and recrystallized from 2-propanol.
4.4 g of hydrochloride are obtained.
Melting point: 245~C (decomposition).
Example 3 (Compound No. 4A).
(+)-~-(4-Chlorophenyl)-4-[(cyclohexyl)methyl]-~-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-on-charcoal are introduced into a 1 1 autoclave and hydrogenated at about 7 MPa at 80~C for 6 h.
The mixture is allowed to cool, the catalyst is separated out by filtration and the filtrate is evaporated under reduced pressure. The residue is washed with acetone and dried.
49 g of white crystalline compound are obtained, which product is used without further purification in the following step.

Melt:ing point: 303-305~C.
3.2. (+)-1-(4-Chlorophenyl)-2-[4-[(cyclohexyl)methyl]piperid-l-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 are stirred at room temperature for 8 h and the mixture is left to stand overnight. It is taken up with water and the insoluble material is collected by filtration, dried and used without further purification in the following step.
3.3. (+)-~-(4-Chlorophenyl)-4-[(cyclohexyl)methyl]-~-methylpiperidine-1-ethanol hydrochloride erythro lS 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 20 ml of water are introduced into a round-bottomed flask, 4 g of potassium borohydride are added portionwise and the mixture is left to stand overnight.
Water is added, followed by hydrochloric acid, some of the solvent is evaporated off and the crystals formed are filtered off, washed with water, recrystallized from 2-propanol and dried.
4.7 g of hydrochloride are obtained.
Melting point: 262-264~C.

Example 4 (Compound No. SA) (+)-~-(4-Chlorophenyl)-4-[(cyclohexyl)methyl]-~-methylpiperidine-1-ethanol hydrochloride, threo isomer.
6 g (0.0172 mol) of (+)-1-(4-chlorophenyl)-2-[4-[(cyclohexyl)methyl]piperid-l-yl]propanone, 200 ml of methanol, just enough tetrahydrofuran to obtain a solution, and then 20 ml of water are introduced into a round-bottomed flask, 4 g of potassium borohydride are adcled portionwi~e and the mixture iB stirred at room temperature for 5 h.
Water is added and the insolu~le material is separated out by filtration and purified by chromatography on a col-~mn of silica gel, eluting with a '37/3 mixture of dichloromethane and acetone.
After evaporation of the least polar fractions and recrystallization from ethanol, 2.3 g of compound are obtained.
Me:Lting point: 118-119~C.
Example 5 (Compound No. 8A) (+)-~-(4-Chlorophenyl)-4-(cyclohexyl)piperidine-1-ethanol.

5.1. 4-(Cyclohexyl)piperidine hydrochloride.
10 g (0.0645 mol) of 4-phenylpyridine, 1 g of S ~ rhodium-on-charcoal, 100 ml of lN 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 out by filtration, a few drops of concentrated hydrochloric acid are added to the filtrate, this is concentrated by evaporation and is entrained twice with ethanol. After drying, 5 11.8 g of white ~olid are obtained.
Melting point: 310-311~C.
5.2. (+)-~-(4-Chlorophenyl)-4-(cyclohexyl)piperidine-1-ethanol.
A suspen6ion 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 i8 prepared and i8 refluxed for 1 h.
The mixture i~ cooled, 4.4 g of potas~ium borohydride are added and it is stirred for 2 day~ at room temperature.
Water is added and the precipitate is collected by filtration, washed with water and dried.
2.88 g of compound are obtained.
Melting point: 135-136~C.
Example 6 (Compound No. 9A) (+)-~-(4-Chlorophenyl)-4-t3-(cyclohexyl)propyl]piperidine-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-on-charcoal ancl 200 ml of lN hydrochloric acid are introduced into a Parr flask and the mixture is hydrogenated at 0.35 MPa at 50~C for 40 h.
The catalyst is separated out by filtration, the filtrate is evaporated, the residue is taken up in a mixture of toluene and ethanol and reevaporated, 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 and the white precipitate is collected by filtration, washed with diethyl ether and dried.
15.86 g of hydrochloride are obtained.
Melting point: 229~C.
6.2. (+)-~-(4-Chlorophenyl)-4-[3-(cyclohexyl)propyl]piperidine-1-ethanol.
A suspension of 1.84 g (0.0075 mol) of 4-t3-(cyclohexyl)propyl]piperidine hydrochloride, 1.75 g (0.0075 mol) of 2-bromo-1-(4-chlorophenyl)ethanone, 1.~; g of sodium carbonate, 40 ml of ethanol and 10 ml of water is prepared and is refluxed for 1 h 30.
The mixture is cooled, 3.59 g of potassium borohydride are added and the mixture is stirred o~ernight 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 are obtained.
Meltin~ point: 85-86~C.

CA 0223l326 l998-03-06 Example 7 (Compound No. 12A) 1-[2-(4-Chlorophenyl)ethyl]-4-[(cyclohexyl)methyl]piperidine hydrochloride.
3.0 g (0.0089 mol) of ~-(4-chlorophenyl)-4-[(cyclohexyl~methyl~piperidine-1-ethanol suspended in 25 ml of toluene are introduced into a round-bottomed flask, the suspension is cooled in an ice bath, a solution of 3 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 off under reduced pressure, the residue is washed with toluene to remove any trace of thionyl chloride, the solvent is e~raporated off, the residue iB taken up in 60 ml of tetrahydrofuran and the suspension i8 poured dropwise into a suspension of 0.7 g of lithium aluminium hydride in 15 ml of tetrahydrofuran and, while stirring the mixture which thickens, it is gradually heated and maintained at reflux for 1 h 30.
The mixture is cooled and taken up in 40 ml of water and 30 ml of ethyl acetate, the organic phase is separated out and the solvent is evaporated off under reduced pressure.
The residue is purified by chromatography on a column of silica gel, eluting with a 95/5 mixture of dichloromethane and methanol.
The hydrochloride is prepared in propanol and, after recrystallization from 30 ml of 2-propanol, 0.,'7 g of compound is finally 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 (~)-~-(4-chlorophenyl)-4-[2-(cyclohexyl)ethyl]piperidine-1-ethanol suRpended in 25 ml of toluene are introduced into a round-bottomed flaskr the suspension is cooled in an ice bath, a solution of 3 ml of thionyl chloride in 10 ml of toluene i~ added and the mixture is Rtirred at room temperature for 5 h 30. The ~olvent i~ evaporated off under reduced pressure, the residue i6 wa~hed with toluene to remove any trace of thionyl chloride, the solvent is evaporated off, the residue i~ taken up in 60 ml of tetrahydrofuran, the suspension is poured dropwise into a suspension of 0.7 g of lithium aluminium hydride in 10 ml of tetrahydrofuran and the mixture is refluxed for 1 h 30 with stirring and then left to stand overnight.
It is taken up in 40 ml of water and 30 ml of ethyl acetate, the organic phase is separated out and the solvent is evaporated off under reduced pressure.
The residue is purified by chromatography on a column of silica gel, eluting with a 95/5 mixture of dichloromethane and methanol.
The hydrochloride is prepared by dissolving the base in ethanol and adding hydrochloric acid to pH: = 1 and, after recrystallization from 2-propanol, 0.30 g of compound is finally isolated.
Melting point: 290-291~C.
Example 9 (Compound No. 7A) (+)-~-(4-Chlorophenyl)-4-[(cyclopentyl)methyl]piperidine-l-ethanol.
9.1. 4-[(Cyclopentyl)methyl]piperidine hydrochloride (lst variant).
9.1.1. 4-[(Cyclopentyl)methyl]pyridine.
300 ml of ammonia are condensed in a 1 1 three-necked round-bottomed flask at -78~C, 100 ml of diethyl ether are added and, at -78~C, 8.28 g (0.36 mol) of sodium are added portionwise. The intenRe blue mixture i8 stirred for 15 min and 30 g (0.32 mol) of 4-methylpyridine are added dropwise. The colour 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 stirring is continued at -78~C for 2 h.
Ammonium chloride is added and the ~ Qrl; a and ether are evaporated off by means of a bath of warm water.
The residue is taken up in 200 ml of diethyl ether and 100 ml of water and is extracted three times with ether. The organic phase is washed twice with water, dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure.
10 g of crude oily product are obtained, which product is distilled under reduced pressure.

2 g of product are obtained, which product is used without further purification in the following 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 lN hydrochloric acid and 300 mg of platinum oxide are introduced into a Parr flask and the mixture is hydrogenated at 0.35 MPa at 25~C.
The cataly~t is separated off by filtration, the 601vents are evaporated off under reduced pressure, saturated aqueous sodium hydrogen carbonate 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 sulphate and filtered and the solvent i~ evaporated off under reduced pressure.
1.6 g of product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a 95/5 mixture of methanol and 25 %
aqueous ammonia.
1.6 g of purified product are obtained in free base form. The hydrochloride is prepared by dissolving the base in a O.lN solution of hydrochloric acid in 2-propanol, followed by recrystallization from a mixture of ethyl acetate and methanol.
Melting point: 275CC.

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 (temperature of the bath) under inert atmosphere for 2 h. The mixture is cooled, benzene is added with stirring and the precipitate formed 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-necked round-bottomed flask under an inert atmosphere, the temperature is cooled to -78~C, 13.75 ml of a 1.6M
solution of butyllithium in hexane are added dropwise, the mixture, which has become red, is stirred for 30 min, followed by dropwise addition of 2.359 g (0.022 mol) of pyridine-4-carboxaldehyde dissolved in 50 ml of tetrahydrofuran and the mixture i8 stirred for 1 h at -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 i5 separated out and extracted three times with ethyl acetate, the organic phase is washed twice with water and once with CA 0223l326 l998-03-06 saturated sodium chloride solution, dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure.
10 g of crude product are obtained which, after purification b~ chromatoyraphy cn a colu~n of silica gel, gives 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 lN hydrochloric acid is introduced into a Parr flask, 2.5 g of Adams catalyst (PtO2) are added and the mixture is hydrogenated at 25~C at about 0.35 MPa. The catalyst is separated out by filtration, the filtrate is concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate 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, it is dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pres~ure.
5 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting 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 O.lN solution of hydrochloric acid in 2-propanol.

Melting point: 275-276~C.
9.3. (+)-~-(4-Chlorophenyl)-4-[(cyclopentyl)methyl]piperidine-l-ethanol.
0.57 g (0.0024 mol) of 2-bromo-1-l4-5 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-bottomed flask and the mixture i~ heated at 80~C
(temperature of the bath) for 1 h 30.
The mixture is cooled, 1 g of potassium borohydride is added and the mixture is stirred and left to stand overnight.
26 ml of water are added, the suspension is stirred and the solid i8 separated out by filtration, washed with water and dried in the presence of phosphorus pentoxide.
0.7 g of product i6 obtained, which is purified by chromatography on a column of silica gel, eluting 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) (+)-~-(4-Chlorophenyl)-4-[(cyclohexyl)methyl]piperidine-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, 3.18 g (0.03 mol) of sodium carbonate, 160 ml of ethanol and 40 ml of water are introduced into a 500 ml round-bottomed flask and the mixture is refluxed for 2 h.
The mixture is allowed to cool to room temperature, 10 g of pota6sium borohydride are added with stirring at room temperature for 30 min and the mixture is left to stand overnight.
The mixture is poured into 320 ml of water and the yellow precipitate is separated out by filtration and dried in the presence of phosphorus pentoxide. 8.8 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a 90/10 mixture of dichloromethane and methanol. 6.36 g of compound are obtained, which product is recrystallized from ethanol.
Melting point: 122-123~C.
Example 11 (Compound No. lOA) (+)-~-(4-Chlorophenyl)-4-[(cyclohexyl)methyl]piperidine-1-ethanol.
2.8 g (0.0083 mol) of (+)-~-(4-chlorophenyl)-4-[(cyclohexyl)methyl]piperidine-1-ethanol, 2.37 g (0.01 mol) of diisopropyl (-)-tartrate and 80 ml of dichloromethane are introduced into a 500 ml round-bottomed flask under a nitrogen atmosphere and 4.95 g, i.e. 5.14 ml (0.0174 mol) of titanium tetraisopropoxide are added; the colour of the mixture changes to yellow.

The mixture is cooled to -25~C with a bath of acetone and ca~ice and 1.53 ml of a 3.3M solution of tert-butyl hydroperoxide in toluene are added, the stirring being continued at -25~C for 2 h 30.
80 ml of diethyi ether, 4 ml of water and 5 ml of 30 % sodium hydroxide are added, the mixture i8 allowed to warm to room temperature, with vigorous stirring, and is left to 6tand overnight.
The white precipitate (titanium salts) is removed by filtration and the filtrate is e~aporated.
1.67 g of white crystalline 601id are obtained, which product is purified by chromatography o~ a column of silica gel, eluting with ethyl acetate. 0.53 g of white crystals is obtained, which is recrystallized twice from ethanol in order finally to isolate 0.21 g of dextrorotatory enantiomer (ee=92.6%).
Melting point: 140-141~C [a]20 = +46.0~ (c=1; CHCl3).
Example 12 (Compound No. llA) ~ -(4-Chlorophenyl)-4-[(cyclohexyl)methyl]piperidine-1-ethanol.
The process is performed as described in the above example, using dextrorotatory diisopropyl tartrate instead of the lae~orotatory isomer. Starting with 3.36 g (0.01 mol) of racemate, 0.38 g of laevorotatory enantiomer is finally isolated (ee-90.5%).
Melting point: 140-141~C [~]20 = -46.0~ (c=l; CHCl3).

Exa~ple 13 (Compound No. 18A) (+)-~-(4-Chlor~phenyl)~4-[(cycloheptyl)methyl]piperidine-1-ethanol.
13.1. 4-[(Cycloheptyl)methyl]piperidine hydrochloride.
The process (2nd variant) described for 4-[(cyclopentyl)methyl]piperidine hydrochloride is used, starting with bromocycloheptane instead of bromocyclopentane.
Melting point: 260~C.
13.2 (+)-~-(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 is refluxed for 2 h with stirring.
The mixture is cooled and 0.8 g of potassium borohydride is added with continued stirring at room temperature overnight.
40 ml of water are added, the aqueous phase is extracted with ethyl acetate, the organic phase is washed with water and then with saturated aqueous sodium chloride solution and dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. After recrystallization from ethanol, 0.097 g of compound is finally isolated.

Melting point: 116-117~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) 3H-indol-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-bottomed flask and the mixture is refluxed for 1 h 30.
It is allowed to cool and poured into 200 ml of water and the precipitate is separated out by filtration, washed with diethyl ether and dried in the presence of phosphoru~ pentoxide.
4 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting 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 pho~phorus 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)-3~-indol-2-one, 3.47 g (0.015 mol) of 4-(2-CA 0223l326 l998-03-06 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-bottomed flask and the mixture is heated at 120~C
5 (temperature of the bath) for 1 h 30.
The mixture is cooled in 2 bath of ice and 6.61 g of potas~ium borohydride are added with stirring at room temperature overnight.
The mixture i~ poured into 200 ml of water and stirred for 10 min and the precipitate is separated out 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, which product is purified by chromatography on a column of silica gel, eluting with a 90/10 mixture of dichloromethane and methanol.
After recry~tallization and drying, 1.48 g of compound are finally i~olated.
Melting point: 210-211~C.
Example 16 (Compound No. 8B) 5-[2-[4-(2-Cyclohexylethyl)piperid-l-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-bottomed flask, the mixture is cooled with a bath of ice, 26.13 ml (0.164 mol) of triethylsilane are added dropwise and the mixture is allowed to warm to room temperature with continued stirring overnight.
The mixture i8 poured into 300 ml of ice-water with stirring for 15 min and the ~eigeprecipitate is collected by filtration, washed with water and with hexane and dried in the presence of phosphorus pentoxide.
13.75 g of compounds are obtained, which products are used without further purification in the following ~tep.
16.2 5-[2-[4-(2-Cyclohexylethyl)piperid-l-yl]ethyl]-3H-indol-2-one.
2.9 g (0.015 mol) of 5-(2-chloroethyl)-3H-indol-2-one, 3.47 g (0.015 mol) of 4-(2-cyclohexylethyl)piperidine hydrochloride, 3.17 g (0.03 mol) of sodium carbonate and 50 ml of N,N-dimethylformamide are introduced into a 500 ml round-bottomed flask and the mixture i~ heated at 120~C
(temperature of the bath) for 5 h.
150 ml of water are added with stirring for 30 min and the brown precipitate is separated out by filtration and dried in the presence of phosphorus pentoxide.
4.56 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting 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, 0.85 g of compound is finally i~olated.
S Melting point: 190-191~C.
Example 17 (Compound No. 7B) 6-[2-[4-(2-Cyclohexylethyl)piperid-1-yl]-1-oxoethyl]-3,4-dihydro-lH-quinolin-2-one.
3.35 g (0.015 mol) of 6-(chloroacetyl)-3,4-dihydro-lH-quinolin-2-one, 3.47 g (O.OlS 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-bottomed flask and the mixture is refluxed for 1 h 30.
The mixture is allowed to cool and i~ poured into 200 ml of water with stirring for 15 min and the precipitate is separated out by filtration, washed with water and dried in the presence of phosphorus pentoxide.
5.4 g of crude product are obtained, which product is purified by chromatography on a colll~n of silica gel, eluting with a 90/10 mixture of 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 are 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-lH-quinolin-2-one.
3.62 g (0.015 mol) of 6-(chloroacetyl)-8-fluoro-3,4-aihydro-lH-qu,nolin-2-one, 3.4? 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-bottomed flask and the mixture i8 refluxed for 1 h 30.
The mixture is allowed to cool and 6.5 g of potassium borohydride are added with stirring at room temperature overnight.
160 ml of water are added with ~tirring for 15 min and the beige precipitate is separated out by filtration, washed with water and with petroleum ether and dried in the presence of phosphorus pentoxide.
5 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a 90/10 mixture of dichloromethane and methanol.
After recrystallization and drying in the presence of phosphorus pentoxide, 2.7 g of compound are finally isolated.
~Ielting point: 154-155~C.
Example 19 (Compound No. 5B) 6-[2-[4-(2-Cyclohexylethyl)piperid-1-yl]ethyl]-3,4-dihydro-lH-quinolin-2-one.

19.1 6-(2-Chloroethyl)-3,4-dihydro-lH-quinolin-2-one.
5.36 g (0.024 mol) c_ 6-(chloroacetyl)-3,4-dihydro-lH-quinolin-2-one and 18.5 ml of trifluoroacetic acid are introduced into a round-bcttcmed flask, the suspension is cooled in an ice-bath and 8.77 ml (0.055 mol) of triethylsilane are added dropwise with stirring at room temperature for 16 h.
The mixture is poured into 100 ml of ice-water with stirring for 15 min and the precipitate is separated out by filtration, washed with water and then with hexane and dried in the presence of phosphorus pentoxide.
5 g of compound are obtained.
Melting point: 163-164~C.
19.2 6-[2-[4-(2-Cyclohexylethyl)piperid-1-yl]ethyl]-3,4-dihydro-lH-quinolin-2-one.
3.14 g (0.015 mol) of 6-(2-chloroethyl)-3,4-dihydro-1~-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 N,N-dimethylformamide are introduced into a 500 ml round-bottomed flask and the mixture is heated at 120~C
(temperature of the bath) for 4 h 30.
150 ml of water are added, the mixture is stirred for 30 min in an ice-bath and the precipitate is separated out by filtration, washed with water and dried in the presence of phosphorus pentoxide. 4.70 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting 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 compo~nd are finally isolated.
Melting point: 192-193~C.
Example 20 (Compound No. 6B) (+)-7-[2-[4-(2-Cyclohexylethyl)piperid-1-yl]-1-hydroxyethyl]-1,3,4,5-tetrahydrobenzo[b]azepin-2-one.
3.56 g (0.015 mol) of 7-(chloroacetyl)-1,3,4,5-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-bottomed flask and the mixture is refluxed for 2 h.
It is allowed to cool and 6 g of potassium borohydride are added with stirring at room temperature overnight.
160 ml of water are added with stirring for 2 h and the precipitate is separated out by filtration, washed with water and dried in the presence of phosphorus pentoxide.
5.1 g of crude product are obtained, which product is purified by chromatography on a column of silica ael, eluting with a 90/10 mixture of dichloromethane and methanol.
After recrystallization from 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-lH-quinolin-2-one.
1.0 g (0.0041 mol) of 4-[3-(cyclohexyl)propyl]piperidine hydrochloride, 1.10 g (0.0041 mol) of 6-(bromoacetyl)-3,4-dihydro-1~-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-bottomed flask and the su6pension i6 refluxed for 2 h 30.
The mixture i~ cooled to 0~C and stirred at this temperature for 20 min, 35 ml of water are added with continued stirring at 0~C for 15 min, the light brown precipitate i6 collected by filtration and the cry6tals are washed with water and dried in the presence of phosphorus pentoxide overnight.
After recrystallization from 2-propanol, wa6hing with water, wa6hing with hexane and drying, 1.23 g of compound are obtained.
Melting point: 179~C.
Example 22 (Compound No. lOB) (+)-6-[2-[4-(3-Cyclohexylpropyl)piperid-1-yl]-1-hydroxyethyl]-3,4-dihydro-lH-quinolin-2-one.
5.5 g (0.0138 mol) of 6-[2-[4-(3-cyclohexylpropyl)piperid-1-yl]-1-oxoethyl]-3,4-dihydro-lH-quinolin-2-one, 80 ml of ethanol and 20 ml of 0.5N
hydrochloric acid are introduced into a round-bottomed flask, 6 g of potassium borohydride are added and the mixture is stirred at room temperat~re overnight.
160 ml of water are added with stirring for 30 min and the precipitate is separated out by filtration, washed with water and dried. 5.2 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a 90/10 mixture of dichloromethane and methanol.
After recrystallization from ethanol and drying, 4.24 g of compound are finally isolated.
Melting point: 151-152~C.
lS Example 23 (Compound No. 16B) 6-[2-[4-(Cyclohexyl)piperid-l-yl]ethyl]-3,4-dihydro-lH-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-lH-quinolin-2-one, 0.59 g (0.0055 mol) of sodium carbonate and 9.5 ml of N,N-dimethylformamide is prepared and the mixture is heated at 120~C (temperature of the bath) for S h 30.
The mixture is allowed to cool, 20 ml of water are added with stirring for lS min, the solid is collected by filtration and the crystals are washed witn water.

0.73 g of product is obtained, which is purified by chromatography on a column of silica gel, eluting with a 94/6 mixture of dichloromethane and methanol.
After recrystallization from 20~ 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. l9B) 6-[2-[4-[(Cyclopentyl)methyl]piperid-l-yl]ethyl]-3,4-dihydro-l~-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-lH-quinolin-2-one, 0.313 g (0.00298 mol) of sodium carbonate and 5.5 ml of N,N-dimethylformamide is prepared and the mixture is heated at 130~C
(temperature of the bath) 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, eluting with a 94/6 mixture of d chloromethane and methanol.
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 is finally isolated.
Melting point: 172-174~C.
Exam~le 25 (Compound No. 29~) 6-[2-[4-(Cycloheptyl)methyl]piperid-l-yljethyl]-3,4-dihydro-lH-quinolin-2-one.
A suspension of 0.2 g (0.000864 mol) of 4-[(cycloheptyl)methyl]piperidine hydrochloride, 3,5 ml of N,N-dimethylformamide, 0.22 g (0.000864 mol) of 6-(2-bromoethyl)-3,4-dihydro-lH-quinolin-2-one and 0.184 g (0.001728 mol) of sodium carbonate is introduced into a round-bottomed flask and the mixture is refluxed for 3 h 15.
The mixture is cooled and diluted with 8 ml of water and the precipitate is collected by filtration and dried.
0.23 g of product is obtained, which is purified by chromatography on a column of silica gel, eluting with a 96/4 mixture of dichloromethane and methanol.
0.21 g of solid is isolated, which product i8 recrystallized from 80 ml of acetone to obtain finally 0.146 g of compound.
Melting point: 154-155~C.
Tables A and B which follow illustrate the chemical structures and the physical properties of a few compounds according to the invention.

In the "R2" columns, "C5Hg" denotes a cyclopenty; group, "C6Hll" denotes a cyclohexyl group and "C7H13" denotes a cycloheptyl group.
In the "Isom." column, "(+)" denotes a racemate, "+" denotes a dextrorotatory enantiomer, denotes a laevorotatory enantiomer, "/" denotes an achiral compound, "E" denotes the erythro diastereo isomers and "T" denotes the threo diastereoisomers.
In the "salt" column, n _ n denotes a compound in the form of the base and "HCl" denotes a hydrochloride.
In the "m.p. (~C)" column, "(d)" denotes a melting point with decomposition.

Table A

~(CH2)r~R

~ ~ (I) ~1 J~ Ri No. Y Rl R2 n Isom. Salt m.p. (~C) lA CHOH H C6Hll 2 (_) HCl 245 (d) 2A CHOH CH3 C6H1l 2(+) E HCl230-244 (d) 3A CHOH H C6Hll 1~-) ~ 122-123 4A CHOH CH3 C6Hll 1(+) E HCl262-264 SA CHOH CH3 C6H~ _) T 118-119 6A CHOH CH3 C6H11 2(_) T 114-llS
7A CHOH H CsHg 1(_) - 104-105 8A CHO~ H C6H1l ~ (-) 135-136 9A CHOH H C6H11 3(+) - 85-86 10ACHOH H C6Hll 1(+) 140-141 llACHOH H C6H11 1( ) 140-141 12A CH2 H C6Hll 1 / HCl284-285 13A CH2 H C6H11 ~ / HCl300-301 14A CH2 H C6H1l 2 / HCl290-291 15A CH2 H C6H1l 3 / HCl241-242 16A CO H C6H1l 2 / 71-72 17A CO H C6H11 3 / HCl210-211 l~r.CHOH H C7Hl3 1(+~ ~ 116-117 CH~ H CsHs 1 / HCl264-285 Note: the optical rotation6 of the compounds numbered 10A and llA are, respectivelyl +46~ and -46~ (c=1;
CHCl,).

CA 0223l326 l998-03-06 Table B

~" (CH~)~R

y ~ '~' ~ N (I) No. X Y ~ Rl R2 n Isom. Salt m.p. (~C) lB (CH2)2 CHOH H HC6Hll 2 l+) ~ 192-193 2B (CH2)2 CHOH 8-CH3 H C6H11 2 (+) - 192-193 3B (CH2)2CHOH8-F H C6H11 2(+) ~154-155 4B C~2 CHOH H H C6H1l 2(+) -210-211 SB (CH2) 2 CH2 H H C6H11 2 / 192-193 6B (CH2) 3 CHOH H H C6Hll 2 (+) - 188-189 7B (CH2) 2 CO H H C6Hll 2 / 176-177 8B CH2 CH2 H H C6~.11 2 / 190-191 9E C~2 CO H H C6H11 2 / 180-181 10B (CH2) 2 CHOH H H C6Hll 3 (+) - 151-152 llB (CH2)2 CO H H C6Hll 1 / - 191-193 12B (CH2)2 CHOH H H C6H1l 1 (+) - 190-192 13B (CH2) 2 CH2 H H C6Hll 1 / 169-171 14B (CH2)2 CO H H C6Hll ~ / 190-192 15B (CH2) 2 CHOH H H C6H1l ~ (+) - 230-232 16B ICH2) 2 CH2 H H C6H11 ~ / 212-214 17B (CH2i 2 CO H H C6Hll 3 J 179 16B ~-H ~ H~ H H C~Hll - / 150-152 r . -~ r C S r C ! ~ 1 q 8E CC H Y C6~ / ~164-166 -1 E H CHOH H H C6H 1 1 (+) 179-181 ¦~ B C~2 ~ 2 H H C6~11 1 ;j - 160-162 CA 0223l326 l998-03-06 No. X ': Z Rl R2 r. Isom. Salt m.p. (~C) 23BCH2 CO H H C6Hll ~ / 179-181 24BCH2 CHOH H H C6Hl! ~ ~+I - 204-206 25BCH2 CO H H C6H~1 3 / 154-156 26~CH2 CH2 H H C6~il ~ ~ lE7-1s3g 27B(CH7)2CHOH H H CsHg l ~+) ~ 189-191 28BlCH2)2CO H H CsHg i / _ 162-164 29B(CH2)2CH2 H H c7Hl3 1 / 154-lSS
30BICH2)2CHOH H H C7Hl3 1 (+) - 190-192 318CH2 CH2 H H C6Hll 3 / 154-156 32BCH2 CHOH H H C6Hll 3 (+) - 164-166 33BCH2 CO H H C5Hg 1 / _ 157-lS9 34BCH2 CH2 H H CsHS 1 / 162-164 35BCH2 CHOH H H CsHg 1 (t ~ - 173-175 36BCH2 CH2 H H C7Hl3 1 ~ 156-158 The compounds of the invention formed the subject of tests which demonstrated their value as therapeutic substances.
The neurotrophic properties of the compounds of the invention were demonstrated in vivo by means of their effect6 on the regeneration of the ~ciatic nerve in rats.
These effects were evaluated after lesion by local freezing of the sciatic nerve in rat6. Lesion by freezing destroy6 the sciatic nerve fibres, which undergo a wallerian degeneration at the site of the lesion and throughout the distal trunk. This type of lesion conserves the nerve sheaths and allows nerve regeneration under reproducible conditions. The proces6 of regeneration starts from the proximal side in the hours which follow the lesion. The rate of regeneration of the sensitive fibres is measured by a pinch test 8 days after the lesion.
The animals are adult male rats of Sprague Dawley (Iffa Credo) strain weighing about 250 g. After anaesthetizing the animals with pentobarbital sodium (60 mg/kg), the skin of the thigh is disinfected with alcohol and cut at the junction of the femoral biceps.
The sciatic nerve is exposed after moving aside the Lateralis and Biceps Femoris muscles. The point of the lesion is identified by a microsuture (Ethilon~ black 10-0) on the perineurium above the trifurcation of the sciatic nerve. The lesion of the sciatic nerve is made over 1 mm by 6 cycles of freezing-thawing using a copper cryode precooled in liquid nitrogen. The wound is then closed up 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 80~, 10 min and 6 h after the lesion, then twice a day from the second to the eighth day, - treated injured animals who receive an intraperitoneal injection of a test compound, administered at doses of 0.3, 1 or 3 mg/kg in 0.1 % Tween 80~, 10 min and 6 h after the lesion, and then twice a day from the second to the eighth day.
Eight days after the operation, the animal6 are slightly anaesthetized and the 6ciatic nerve is reexposed in order to carry out the pinch test. This test con6i6ts in pinching the nerve 61ightly u6ing forceps, starting with the most distal region of the nerve and moving up 0.5 mm each time. A reflex respon6e (contraction of the muscles of the posterior region of the animal) is observed at the point where the front of the regenerated sensitive fibres is present. This point is labelled with a microsuture. The nerve is then removed and the distance between the site of the lesion and the distal microsuture is measured on millimetric graph paper under an operating microscope. After removal of the nerve, the animals are sacrificed by an overdose of pentobarbital.
It is observed that, in the treated animals, the administration of the compounds of the invention increases the distance covered by the sensitive fibres by more than 10 % relative to the controls.
The neurotrophic properties of the compounds of the invention were also studied in vivo by means of their effects on regeneration of the sciatic nerve after lesion by crushing combined with a treatment with vincristine.
Vincristine is an alkaloid from the periwinkle which is used in the treatment of certain cancers, and whose mechanism of action is well established. Vincristine binds to a cytoplasmic protein, tubulin, and disrupts its polymerization into microtubules. The latter are main elements involved in nerve regeneration after a lesion. The reason for this is that the microtu~ules ensure axonal transport of newly synthesized macromolecules which need to be conveyed to the distal part of the nerve, in order to ensure the formation and elongation of the growth cones. Thus, the administration of vincristine disrupts the rapid axonal transport and slows down, or inhibits, depending on the doses administered, the regeneration of the nerve after a lesion.

CA 0223l326 l998-03-06 Experimental model: after anaesthetizing with pentobarbital, on day Do~ the right sciatic nerve of the rats is crushed for 1.5 min. The following day (D1) the animals receive a single administration of S 0.2 mg/kg of vincristine and, on day O7, the rate of regeneration is evaluated by means of the pinch test.
The dose of 0.2 mg/kg of vincristine reduces by about 20 % the distance of regeneration evaluated on D7 in the control animals, not treated with the test compounds. These test compounds are administered to animals intraperitoneally, twice a day, from Do to D6 (10 min and 6 h after the lesion, on Do~ then morning and evening, with a 6 h interval, from Dl to D6).
The most active compounds in this test increase the rate of regeneration of the injured sciatic nerve, in animals treated with vincristine, by 12 to 14 %.
The compounds of the invention also formed the subject of a test of inhibition of the binding of [3H]ifenprodil in rat cerebral cortex (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 ice-cold 50 mM Tris-HCl buffer (pH = 7.4 at 25~C), by means of an Ultra-TurraxTM
(Ikawerk) or Polytron~ (Kinematica) machine. The homogenate is washed twice by centrifugation for 10 minutes at 45000 x g, the pellet being resuspended in fresh buffer. The final pellet is taken up in 20 volumes of the same buffer. A 100 ~1 aliquot of this suspension is incubated in a final volume of 1000 ~1 with 0.5 nM [3H]ifenprodil (specific activity: 30 to 35 Ci/mmol) for 30 minutes at ~7~C, in the abEence or in the presence o~ competing substance. After incubation, the membranes are recovered by filtration on Whatman GF/BTM filters pretreated with 0.05 %
polyethyleneimine, and then washed with twice 5 ml of ice-cold buffer.
The non-specific binding is determined with 10 ~M ifenprodil, the data are analysed according to the usual methods and the IC50 concentration, the concentration which inhibits the binding of ~3H]ifenprodil by 50 %, i8 determined.
The IC50 values of the most active compounds are less than 25 nM.
Lastly, the compounds were subjected to the global cerebral ischaemia test in mice.
The ischaemia is due to a cardiac arrest induced by a rapid intravenous injection of magnesium chloride. In this test, the "survival time", that is to say 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 as being 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 CDl) are studied in groups of 10. They are fed and watered ad libitum before the tests. The survival time is measured 10 minutes after intraperitoneal 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 vehicle liquid. The ratios between the modifications in survival time and the dose of compound are recorded graphically on a semilogarithmic curve.
This curve allows calculation of the "3-second effective dose" (ED3~), that is to say the dose(in mg/kg) which produces a 3-second increase in the survival time relative to the control group of 10 untreated mice.
A 3-second increase in the 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 may be used for the treatment of peripheral neuropathies, such as traumatic neuropathies (section or crushing of a nerve) or ischaemic neuropathies, metabo'ic neuropathies (diabetes, uraemia), infectious, alcoholic and medicinal neuropathies, genetic neuropathies, motor neuron complaints such as spinal amyotrophies and amyotrophic lateral sclerosis.
They may also be used for the treatment and prevention of cerebral disorders such as those which follow, for example, an ischaemic attack, a cardiac or respiratory arrest, a thrombosiE or a cerebral embolism, for the treatment of cerebral senility, dementia following multiple infarcts, senile dementia, for example Alzheimer's disease or Pick's disease, for the treatment of olivopontocerebellar atrophy and other neurodegenerative diseases such as Huntington's chorea, amyotrophic lateral sclerosis, for the treatment of cranial or spinal trauma, for the prevention of neuronal injury following convulsive attacks or following the presence of tumours in the nervous system, for the treatment of neurological changes due to AIDS, for the prevention and treatment of diabetic retinopathies, for the degeneration of the optic nerve and for retinopathies associated with glaucoma.
The compounds of the invention may also be combined with thrombolytic agents such as rt-PA
(recombined plasminogen tissue activator, of human origin) for the treatment of cerebral infarcts of thromboembolic type, or in combination with a compound which lowers the 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 may be in any pharmaceutical form suited to 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 drinkable or injectable solutions or suspensions, dosed to allow a daily administration of from 1 to 1000 mg of active substance.

Claims (4)

Claims

1. Compound, optionally in the form of a pure optical isomer or a mixture of such isomers, corresponding to the general formula (I) (I) in which Ar represents a) a phenyl group substituted with a halogen atom or b) a group of general formula (I') (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-, 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, in the form of the free base or an addition salt.

2. Process for the preparation of compounds according to Claim 1, characterized in that a haloketone of general formula (II) in which Ar is as defined in Claim 1 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 in Claim 1, to obtain the ketone of general formula (Ia) which corresponds to the general formula (I) when Y
represents a -CO- group, followed, if so desired, by reduction of this ketone to obtain the alcohol of general formula (Ib) which corresponds to the general formula (I) when Y
represents a -CHOH- group, then, if it is desired to obtain a compound of general formula (I) in which Y
represents a group of formula -CH2- and Ar represents a phenyl group substituted with a halogen atom, the alcohol of general formula (Ib), in which Y represents a -CHOH- group and Ar represents a phenyl group substituted with a halogen atom, is reduced by reaction with thionyl chloride, followed by treatment of the chloro intermediate with lithium aluminium 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 triethylsilane and trifluoroacetic acid, in order to obtain the halo derivative of general formula (IV) followed by reaction of the latter with a substituted piperidine of general formula (III), in which n and R2 are as defined in Claim 1.

3. Medicinal product, characterized in that it consists of a compound according to Claim 1.

4. Pharmaceutical composition, characterized in that it contains a compound according to Claim 1, combined with an excipient.