AU703776B2

AU703776B2 - Derivatives of 4-(cycloalkyl)piperidines and of 4-(cycloalkylalkyl)piperidines, their preparation and their therapeutic application

Info

Publication number: AU703776B2
Application number: AU69344/96A
Authority: AU
Inventors: Regine Bartsch; Regis Dupont; Jonathan Frost; Pascal George; Patrick Lardenois; Wai-Tak Li; Pascale Magat; Patrick Pasau; Maria-Carmen Renones
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1995-09-08
Filing date: 1996-09-05
Publication date: 1999-04-01
Anticipated expiration: 2016-09-05
Also published as: MX9801838A; BG102282A; HUP9802938A2; KR19990044479A; CO4750660A1; ES2137015T3; CZ66598A3; DE69603613D1; GR3031513T3; NZ316981A; WO1997009309A1; BR9610408A; ATE182885T1; EP0848707A1; TR199800407T1; JPH11514975A; AU6934496A; DE69603613T2; PL325421A1; IL123557A0

Description

Derivatives of 4-(cycloalkyl)piperidines and of 4- (cycloalkylalkyl)piperidines, their preparation and their therapeutic application.

The compounds of the invention are optionally in the form of a pure optical isomer or a mixture of such isomers and correspond to the general formula (I) Ar N (CH2,).2 Ar

R!

in which Ar represents a) a phenyl group substituted with a halogen atom or a group of general formula

N

v=

H

z 9* o in which X represents a group of formula -CH 2 5

(CH

2 2 or -(CH2) 3 and Z represents a hydrogen or halogen atom or a methyl group, Y represents a group of formula -CH 2 -CO- or -CHOH-,

R

1 represents a hydrogen atom or a methyl group,

R

2 represents a C 3 cycloalkyl group, and n represents the number 0, 1, 2 or 3.

The compounds of the invention may exist 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 R, represents a methyl group, the carbon atom which bears it is, 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 isomers.

In accordance with the invention, the compounds of general formula may be prepared by processes illustrated by the schemes which follow.

According to Scheme 1, a haloketone of general formula 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 R 2 are as defined above, to obtain the ketone of general formula which corresponds to the general formula when Y represents 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 which corresponds to the general formula 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 in which Y represents a group of formula L- l 'C I Scheme 1 0 Hal Ar 1r

(II)

(III)

H~~g (CH 2

-R

(CH

,R

(Ia) KBH 4 OH 'a (C2R2

N

Ar (Ib) 1) sOC1 2 2) LiAlH 4

(CEH,)

Ar

N

(IC)

and Ar represents a phenyl group substituted 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 intermediate with lithium aluminium hydride.

In order to obtain a compound of general formula in which Y represents a group of formula and Ar represents a group of general formula and according to Scheme 2, a haloketone of general formula in which Ar represents a group of general formula 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 followed by reaction of the latter with a substituted piperidine of general formula (III), in which n and R 2 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 R 2 represents a cyclohexyl group is described in J. Org. Chem. (1957) 22 1376 and in patents US-4,005,093 and US-4,028,366. The compounds of Scheme 2

O

Ar Hl (II) Ri Et 3 SiH CF 3

CO

2

H

Hal Ar l

(IV)

R,

(CH)n

R

r N (Ic)

R,

general formula (III) in which n=l or 3 and R 2 represents a cyclohexyl group are mentioned, but not described, in patent US-4,261,891.

The other compounds of general formula (III) 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 general formula (III), in which n=0, 1 or 3 and R 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 R 2 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.

Example 1 (Compound No. 16A).

1-(4-Chlorophenyl)-2-[4-[2-(cyclohexyl)ethyl]piperid-1yl)ethanone.

1.1. 4-[2-(Cyclohexyl)ethyl]piperidine hydrochloride.

g (0.088 mol) of I I 4-(2-phenylethyl)piperidine hydrochloride, 2 g of 5 rhodium-on-charcoal and 200 ml of IN hydrochloric acid are introduced into a Parr flask and the mixture is hydrogenated at a pressure of about 0.35 MPa at 50 0

C

for 15 h.

The catalyst is separated out by filtration, the filtrate is 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- (cyclohexyl)ethyl]piperid-l-yl]ethanone.

A mixture of 8 g (0.0343 mol) of 2-bromo-l- (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 is then left to stand overnight.

The mixture is poured into water and the insoluble material is separated out by filtration and dried. 10.1 g of compound are obtained.

Melting point: 71-720C.

Example 2 (Compound No. 1A) (±)-a-(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 I- 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 is added, followed by 3N hydrochloric 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 0 C (decomposition).

Example 3 (Compound No. 4A).

(±)-a-(4-Chlorophenyl)-4-[(cyclohexyl)methyl]-fmethylpiperidine-l-ethanol hydrochloride, erythro isomer.

3.1. 4-[(Cyclohexyl)methyl]piperidine hydrochloride.

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 800C 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.

Melting point: 303-305 0

C.

3.2. (±)-l-(4-Chlorophenyl)-2-[4- [(cyclohexyl)methyl]piperid-l-yl]propanone.

A mixture of 9 g (0.0364 mol) of 2-bromo-l- (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] -3methylpiperidine-l-ethanol hydrochloride erythro isomer.

6 g (0.0172 mol) of (±)-l-(4-chlorophenyl)-2- [4-[(cyclohexyl)methyl]piperid-l-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 0

C.

II e Example 4 (Compound No. SA) (±)-a-(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 added portionwise and the mixture is stirred at room temperature for 5 h.

Water is added and the insoluble material is separated out by filtration and purified by chromatography on a column of silica gel, eluting with a 97/3 mixture of dichloromethane and acetone.

After evaporation of the least polar fractions and recrystallization from ethanol, 2.3 g of compound are obtained.

Melting point: 118-1190C.

Example 5 (Compound No. 8A) (±)-a-(4-Chlorophenyl)-4-(cyclohexyl)piperidine-lethanol.

5.1. 4-(Cyclohexyl)piperidine hydrochloride.

g (0.0645 mol) of 4-phenylpyridine, 1 g of 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 0 C for 13 days (adding g of catalyst after the first week).

i 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, 11.8 g of white solid are obtained.

Melting point: 310-311 0

C.

5.2. (±)-a-(4-Chlorophenyl)-4-(cyclohexyl)piperidine-1ethanol.

A suspension of 2.03 g (0.01 mol) of 4-(cyclohexyl)piperidine hydrochloride, 2.33 g (0.01 mol) of 2-bromo-l-(4-chlorophenyl)ethanone, 2.12 g of sodium carbonate, 40 ml of ethanol and 10 ml of water is prepared and is refluxed for 1 h.

The mixture is cooled, 4.4 g of potassium borohydride are added and it is stirred for 2 days 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 0

C.

Example 6 (Compound No. 9A) (±)-a-(4-Chlorophenyl)-4-[3- (cyclohexyl)propyl]piperidine-1-ethanol.

6.1. 4-[3-(Cyclohexyl)propyl]piperidine hydrochloride.

20.3 g (0.1 mol) of 4-(3phenylpropyl)piperidine, 2 g of 5 rhodium-on-charcoal and 200 ml of 1N hydrochloric acid are introduced into a Parr flask and the mixture is hydrogenated at

I

0.35 MPa at 50 0 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 0

C.

6.2. (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-l-(4-chlorophenyl)ethanone, 1.6 g of sodium carbonate, 40 ml of ethanol and 10 ml of water is prepared and is refluxed for 1 h The mixture is cooled, 3.59 g of potassium borohydride are added and the mixture is stirred overnight at room temperature.

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.

Melting point: o5-86 0

C.

I 13 Example 7 (Compound No. 12A) 1-[2-(4-Chlorophenyl)ethyl]-4- [(cyclohexyl)methyl]piperidine hydrochloride.

g (0.0089 mol) of u-(4-chlorophenyl)-4- [(cyclohexyl)methyl]piperidine-l-ethanol suspended in 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 evaporated off, the residue is taken up in ml of tetrahydrofuran and the suspension is 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 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, 0.77 g of compound is finally isolated.

Melting point: 284-285 0

C.

Example 8 (Compound No. 14A) 1-[2-(4-Chlorophenyl)ethyl]-4-[2- (cyclohexyl)ethyl]piperidine hydrochloride 3.0 g (0.0085 mol) of (±)-a-(4-chlorophenyl)- 4-[2-(cyclohexyl)ethyl]piperidine-1-ethanol suspended in 25 ml of toluene are introduced into a roundbottomed 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 evaporated off, the residue is 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 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 0

C.

Example 9 (Compound No. 7A) (±)-a-(4-Chlorophenyl)-4- [(cyclopentyl)methyl]piperidine-l-ethanol.

9.1. 4-[(Cyclopentyl)methyl]piperidine hydrochloride (1st 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 0 C, 100 ml of diethyl ether are added and, at -78 0 C, 8.28 g (0.36 mol) of sodium are added portionwise. The intense blue mixture is 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 0 C, and stirring is continued at -78 0 C for 2 h.

Ammonium chloride is added and the ammonia 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.

g of crude oily product are obtained, which product is distilled under reduced pressure.

16 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 1N 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 0

C.

The catalyst is separated off by filtration, the solvents 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 is 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 0.1N solution of hydrochloric acid in 2-propanol, followed by recrystallization from a mixture of ethyl acetate and methanol.

Melting point: 275 0

C.

17 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 0 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 0

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 0 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 min, followed by dropwise addition of 2.359 g (0.022 mol) of pyridine-4-carboxaldehyde dissolved in ml of tetrahydrofuran and the mixture is stirred for 1 h at -78 0 C and then for 3 h at room temperature.

50 ml of water and 100 nl of ethyl acetate are added, the aqueous phase is separated out 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 sulphate and filtered and the solvent is evaporated off under reduced pressure.

g of crude product are obtained which, after purification by chromatography on a column 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 IN hydrochloric acid is introduced into a Parr flask, 2.5 g of Adams catalyst (PtO 2 are added and the mixture is hydrogenated at 25 0

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 pressure.

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 0.1N solution of hydrochloric acid in 2-propanol.

Melting point: 275-276 0

C.

9.3. (±)-a-(4-Chlorophenyl)-4- [(cyclopentyl)methyl]piperidine-1-ethanol.

0.57 g (0.0024 mol) of 2-bromo-l-(4chlorophenyl)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 roundbottomed flask and the mixture is heated at 80 0

C

(temperature of the bath) for 1 h 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 is separated out by filtration, washed with water and dried in the presence of phosphorus pentoxide.

0.7 g of product is 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 0

C.

Example 10 (Compound No. 3A) (±)-a-(4-Chlorophenyl)-4- [(cyclohexyl)methyl]piperidine-1-ethanol.

7 g (0.03 mol) of 2-bromo-l-(4chlorophenyl)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 potassium 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 0

C.

Example 11 (Compound No. (4-Chlorophenyl)-4- [(cyclohexyl)methyl]piperidine-l-ethanol.

2.8 g (0.0083 mol) of (±)-a-(4-chlorophenyl)- 4-[(cyclohexyl)methyl]piperidine-l-ethanol, 2.37 g (0.01 mol) of diisopropyl (-)-tartrate and 80 ml of dichloromethane are introduced into a 500 ml roundbottomed 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.

i ~PC I~ I r I~ 21 The mixture is cooled to -25 0 C with a bath of acetone and cardice and 1.53 ml of a 3.3M solution of tertbutyl hydroperoxide in toluene are added, the stirring being continued at -25 0 C for 2 h 80 ml of diethyl ether, 4 ml of water and ml of 30 sodium hydroxide are added, the mixture is allowed to warm to room temperature, with vigorous stirring, and is left to stand overnight.

The white precipitate (titanium salts) is removed by filtration and the filtrate is evaporated.

1.67 g of white crystalline solid are obtained, which product is purified by chromatography on 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: 140-1410C 0 +46.00 CHC1 3 Example 12 (Compound No. 11A) (-)-a-(4-Chlorophenyl)-4- [(cyclohexyl)methyl]piperidine-l-ethanol.

The process is performed as described in the above example, using dextrorotatory diisopropyl tartrate instead of the laevorotatory 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 0 C 0 -46.00 CHC1 3 I 22 Example 13 (Compound No. 18A) (±)-a-(4-Chlorophenyl)-4- [(cycloheptyl)methyl]piperidine-l-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 r bromocyclopentane.

Melting point: 260 0

C.

13.2 (±)-Q-(4-Chlorophenyl)-4- [(cycloheptyl)methyl]piperidine-l-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.

I

Melting point: 116-1170C.

Example 14 (Compound No. 9B) [4-(2-Cyclohexylethyl)piperid-l-yl] oxoethyl] 3H-indol-2-one.

3.14 g (0.015 mol) of 5-(chloroacetyl)-3Hindol-2-one, 3.47 g (0.015 mol) of 4-(2cyclohexylethyl)piperidine hydrochloride, 3.17 g (0.03 mol) of sodium carbonate, 80 ml of ethanol and ml of water are introduced into a 500 ml roundbottomed flask and the mixture is refluxed for 1 h 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 phosphorus 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 phosphorus pentoxide, 0.96 g of compound is finally isolated.

Melting point: 180-1810C.

Example 15 (Compound No. 4B) [2-[4-(2-Cyclohexylethyl)piperid-l-yl]-1hydroxyethyl]-3H-indol-2-one.

3.14 g (0.015 mol) of 5-(chloroacetyl)-3Hindol-2-one, 3.47 g (0.015 mol) of 4-(2-

I-LL

24 cyclohexylethyl)piperidine hydrochloride, 3.18 g (0.03 mol) of sodium carbonate, 100 ml of ethanol and ml of water are introduced into a 500 ml roundbottomed flask and the mixture is heated at 120 0

C

(temperature of the bath) for 1 h The mixture is cooled in a bath of ice and 6.61 g of potassium borohydride are added with stirring at room temperature overnight.

The mixture is 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 recrystallization and drying, 1.48 g of compound are finally isolated.

Melting point: 210-211°C.

Example 16 (Compound No. 8B) 5-[2-[4-(2-Cyclohexylethyl)piperid-1-yl]ethyl]-3Hindol-2-one.

16.1 5-(2-Chloroethyl)-3H-indol-2-one.

15 g (0.0715 mol) of 5-(chloroacetyl)-3Hindol-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 is poured into 300 ml of icewater with stirring for 15 min and the beige precipitate 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 step.

16.2 [4-(2-Cyclohexylethyl)piperid-l-yl]ethyl]-3Hindol-2-one.

2.9 g (0.015 mol) of 5-(2-chloroethyl)-3Hindol-2-one, 3.47 g (0.035 mol) of 4-(2cyclohexylethyl)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 is heated at 120 0

C

(temperature of the bath) for 5 h.

150 ml of water are added with stirring for 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.

-p After recrystllization from 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 0

C.

Example 17 (Compound No. 7B) 6-[2-[4-(2-Cyclohexylethyl)piperid-l-yl]-1-oxoethyl]- 3,4-dihydro-lH-quinolin-2-one.

3.35 g (0.015 mol) of 6-(chloroacetyl)-3,4dihydro-lH-quinolin-2-one, 3.47 g (0.015 mol) of 4-(2cyclohexylethyl)piperidine hydrochloride, 3.17 g (0.03 mol) of sodium carbonate, 80 ml of ethanol and ml of water are introduced into a 500 ml roundbottomed flask and the mixture is refluxed for 1 h The mixture is allowed to cool and is 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 column 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 0

C.

I I--I Example 18 (Compound No. 3B) (±)-6-[2-[4-(2-Cyclohexylethyl)piperid-l-yl]-1hydroxyethyl]-8-fluoro-3,4-dihydro-lH-quinolin-2-one.

3.62 g (0.015 mol) of 6-(chloroacetyl)-8fluoro-3,4-dihydro-lH-quinolin-2-one, 3.47 g (0.015 mol) of 4-(2-cyclohexylethyl)piperidine hydrochloride, 3.18 g (0.03 mol) of sodium carbonate, 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 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 stirring 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.

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.

Melting point: 154-155 0

C.

Example 19 (Compound No. 6-[2-[4-(2-Cyclohexylethyl)piperid-l-yl]ethyl]-3,4dihydro-lH-quinolin-2-one.

_I I ~a 19.1 6-(2-Chloroethyl)-3,4-dihydro-1H-quinolin-2-one.

5.36 g (0.024 mol) of 6-(chloroacetyl)-3,4dihydro-lH-quinolin-2-one and 18.5 ml of trifluoroacetic acid are introduced into a roundbottomed 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 icewater 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.

g of compound are obtained.

Melting point: 163-164 0

C.

19.2 (2-Cyclohexylethyl)piperid-l-yl]ethyl]- 3,4-dihydro-1H-quinolin-2-one.

3.14 g (0.015 mol) of 6-(2-chloroethyl)-3,4dihydro-1H-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 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 111 -r I~" 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 compound are finally isolated.

Melting point: 192-193 0

C.

Example 20 (Compound No. 6B) (±)-7-[2-[4-(2-Cyclohexylethyl)piperid-1-yl]-lhydroxyethyl]-1,3,4,5-tetrahydrobenzo[blazepin-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, 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 gel, 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 0

C.

Example 21 (Compound No. 17B) 6-[2-[4-(3-Cyclohexylpropyl)piperid-l-yl]-1-oxoethyl]- 3,4-dihydro-1H-quinolin-2-one.

g (0.0041 mol) of 4-[3- (cyclohexyl)propyl]piperidine hydrochloride, 1.10 g (0.0041 mol) of 6-(bromoacetyl)-3,4-dihydro-1Hquinolin-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 suspension is refluxed for 2 h The mixture is 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 is collected by filtration and the crystals are 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, 1.23 g of compound are obtained.

Melting point: 179 0

C.

Example 22 (Compound No. (±)-6-[2-[4-(3-Cyclohexylpropyl)piperid-l-yl]-1hydroxyethyl]-3,4-dihydro-lH-quinolin-2-one.

g (0.0138 mol) of cyclohexylpropyl)piperid-l-yl]-1-oxoethyl]-3,4-dihydro- 1H-quinolin-2-one, 80 ml of ethanol and 20 ml of hydrochloric acid are introduced into a round-bottomed flask, 6 g of potassium borohydride are added and the mixture is stirred at room temperature overnight.

160 ml of water are added with stirring for 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 0

C.

Example 23 (Compound No. 16B) 6-[2-[4-(Cyclohexyl)piperid-1-yl]ethyl]-3,4-dihydro-lHquinolin-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-lHquinolin-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 0 C (temperature of the bath) for 5 h The mixture is 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.

.I,

N 32 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 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 0

C.

Example 24 (Compound No. 19B) 6-[2-[4-[(Cyclopentyl)methyl]piperid-1-yl]ethyl]-3,4dihydro-lH-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-lHquinolin-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 0

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 dichloromethane and methanol.

After recrystallization from 60 ml of acetone 33 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 0

C.

Example 25 (Compound No. 29B) 6-[2-[4-(Cycloheptyl)methyl]piperid-l-yl]ethyl]-3,4dihydro-1H-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-1H-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 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 is recrystallized from 80 ml of acetone to obtain finally 0.146 g of compound.

Melting point: 154-155 0

C.

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

L

In the "R 2 columns, "C 5

H

g denotes a cyclopentyl group, "C 6 HI" denotes a cyclohexyl group and "C 7 HI3" denotes a cycloheptyl group.

In the "Isom." column, denotes a racemate, denotes a dextrorotatory enantiomer, denotes a laevorotatory enantiomer, denotes an achiral compound, denotes the erythro diastereo isomers and denotes the threo diastereoisomers.

In the "salt" column, denotes a compound in the form of the base and "HC1" denotes a hydrochloride.

In the column, denotes a melting point with decomposition.

I

Table A (CH 2 SYNa cCr.1R No. Y R, R 2 n Isom. Salt M.P. (OC) 1A Cl-bR H C 6

H

1 1 2 HC1 245 (d) 2A CHOH CH 3

C

6

H

11 2 HC1 230-244 (d) 3A CH08 H C 6

H

11 1 122-123 4A CHOR CR 3

C

6

H

11 1 HC1 262-264 SA CEOH CR 3

C

6

H

11 1 118-119 6A CR08 CR 3

C

6

H

11 2 114-115 7A CR08 H C 5

H

9 1 104-105 8A CR08 H C 6

H

11 0 135-136 9A CH08 H C 6

H

11 3 85-86 CHOH H C 6 Hjj 1I 140-141 11A 0808 H C 6 11 11 1 140-141 12A CR 2 H C 6

H

11 1 81 284-285 13A CR 2 H C 6

H

11 0 C1 300-301 14A CH 2 H C 6

H

11 2 HC1 290-291

CR

2 H C 6

H

11 3 HC1 241-242 16A CO H C 6

H

11 2 71-72 17A CO H 06811 3 C1 210-211 18A CHOH 8 C 7

IH

1 3 1 116-117 19A CR 2 H C 5

H

9 1 HC1 284-285 Note: the optical rotations of the compounds numbered and 11A are, respectively, +460 and -460 (c=l; CHC1 3 Table B C,

,,R

No.1 xI I JZ) R [7Isom. I al m.p. (OC) 3B 4B 6B 7B 8B 9B 11lB 12B 1 3B 145 16B 17B 18B 19B 21B 2 2B

(CH

2 2

(CE

2 2

(CE

2 2

CH

2

(CH-

2 2

(CE

2 3 (C'1 2 2

CH

2

CE

2

(CE

2 2

(CE

2 2

(CH

2 2

(CH

2 2

(CE

2 2

(CE

2 2

(CH

2 2

(CE

2 2

(CE

2 2

(CE

2 2

CE

2

CE

2

CE

2

CHOH

CHQE

CEOH

CE

2

CHOH

CO

CE

2

CO

CHQE

CO

CHOR

CE

2

CO

CHON

CE

2

CO

CE

2

CE

2

CO

CEON

CE

2

H

8-CE 3 8-F

H

E

H

E

H

1H

H

C

6

H

11

C

6

H

11

C

6

H

11 C 6

H

11

C

6

H

11

C

6

E

11

C

611

C

6

H

11

C

6

H

11

C

6

H

11

C

6

H

11

C

6

H

11

C

6

H

11

C

6

H

11

C

6

H

11

C

6

H

11 1±) 192-193 192-193 154-155 210-211 192-193 18 8-189 17 6-177 190-191 180-18 1 15 1-152 191-193 190-192 169-171 19 0-192 23 0-2 32 2 12-2 14 179 150-152 172-17 4 164-166 17 9-181 160-162 No. X Y Z R, R 2 n Isom. Salt IM.P. 23B CH 2 co H H C 6

H

11 0 179-181 24B CH 2 CHOR H H C 6

H

11 0 204-206

CH-

2 CO H H C 6 Hjj 3 154-156 26B CH- 2

CH

2 H H C 6

H

11 0 187-189 27B (CH 2 2 CHOR H H C 5

H

9 1 W± 189-191 28B (CH 2 2 CO H H C 5

H

9 1 162-164 29B (CH 2 2

CH

2 H H C7H 13 1 154-155

(CH

2 2 CHON H H C 7

H

1 3 1 W± 190-192 31B CH 2

CH

2 H H C 6

H

11 3 154-156 32B Cl- 2 CHOH H H C 6

H

11 3 W± 164-166 33B CH 2 co H H C 5

H

9 1 157-159 34B CH 2

CH

2 H H C 5

H

9 1I 162-164

CH

2 CH-OH H H C 5 Hq 1I 173-175 36B CH 2

CH

2 IH IH IC 7

H

13 1 156-158 38 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 effects on the regeneration of the sciatic nerve in rats.

These effects were evaluated after lesion by local freezing of the sciatic nerve in rats. Lesion by freezing destroys 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 process 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 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 (EthilonTM black 10-0) on the perineurium above the trifurcation of the sciatic nerve. The lesion of the sciatic nerve is made 1.-I 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 TM, 10 min and 6 h after the lesion, then twice a d&y 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 TM, 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 animals are slightly anaesthetized and the sciatic nerve is reexposed in order to carry out the pinch test. This test consists in pinching the nerve slightly using forceps, starting with the most distal region of the nerve and moving up 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 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 microtubules ensure axonal transport of newly synthesized macromolecules which need to be conveyed to the distal part of the nerve, in order to ensure th- 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.

s lr 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 (D 1 the animals receive a single administration of 0.2 mg/kg of vincristine and, on day D 7 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 D, in the control animals, not treated with the test compounds. These test compounds are administered to animals intraperitoneally, twice a day, from D o to D 6 (10 min and 6 h after the lesion, on Do, then morning and evening, with a 6 h interval, from D, to D 6 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 l 3 H]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-HC1 buffer (pH 7.4 at 25 0 by means of an Ultra-Turrax

T

(Ikawerk) or Polytron TM (Kinematica) machine. The homogenate is washed twice by centrifugation for minutes at 45000 x g, the pellet being resuspended I I I- It L- 42 in fresh buffer. The final pellet is taken up in volumes of the same buffer. A 100 Ai aliquot of this suspension is incubated in a final volume of 1000 Il with 0.5 nM [H]ifenprodil (specific activity: 30 to 35 Ci/mmol) for 30 minutes at 37 0 C, in the absence or in the presence of 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 pM ifenprodil, the data are analysed according to the usual methods and the IC, 0 concentration, the concentration which inhibits the binding of [3H]ifenprodil by 50 is determined.

The IC, 5 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 CD1) 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 "3second effective dose" (ED 3 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 untreated mice.

A 3-second increase in the survival time is both statistically significant and reproducible.

The ED 3 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 44 (section or crushing of a nerve) or ischaemic neuropathies, metabolic 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 thrombosis 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, sugarcoated 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.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

so 0 00 0

Claims

1. Compound, optionally in the form of a pure optical isomer or a mixture of such isomers, corresponding to the general formula (I) (CH 2 )R (I) Y N2 R ArY R, in which Ar represents a) a phenyl group substituted with a halogen atom or b) a group of general formula e X o H Z in which X represents a group of formula -CH 2 S 10 2 or -(CH 2 3 and Z represents a hydrogen or halogen atom or a methyl group, Y represents a group of formula -CO- or -CHOH-, R, represents a hydrogen atom or a methyl group, R 2 represents a C 3 -C 7 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) I I 47 0 Ar Hal (II) R i 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) (CH 2 ^R HN (CH) 2 (III) HN in which n and R 2 are as defined in Claim 1, to obtain the ketone of general formula (Ia) (CH 2 (Ia) Ar 0 n' R 2 (la) Ri which corresponds to the general formula when Y represents a -CO- group, followed, if so desired, by reduction of this ketone to obtain the alcohol of general formula (Ib) (CH R2 (Ib) Ar N R( L L_ 48 which corresponds to the general formula when Y represents a -CHOH- group, then, if it is desired to obtain a compound of general formula 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 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 in which Y represents a group of formula CH 2 and Ar represents a group of general formula as defined in Claim 1, a haloketone of general formula 15 in which Ar represents a group of general formula 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) Hal Ar Ar (IV) R i followed by reaction of the latter with a substituted piperidine of general formula (III), in which n and R 2 are as defined in Claim 1. I I':\1O'1IM1(1WDI 9,4 9Mi06 /2/99

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

4. Method for the treatment of a peripheral neuropathy in a patient comprising the administration of a compound as defined in claim 1 to a patient in need thereof.

Method for the treatment or prevention of a cerebral disorder in a patient, comprising the administration of a compound as defined in claim 1 to a patient in need thereof.

6. Use of a compound as defined in claim 1 for the manufacture of a medicament for the treatment of a peripheral neuropathy in 15 a patient. 9 *4*

7. Use of a compound as defined in claim 1 for the manufacture of a medicament for the treatment or prevention of a cerebral disorder in a patient.

8. A compound according to claim 1, or a process according to claim 2 substantially as hereinbefore described with reference to the Examples

9. A composition according to claim 3 or a method or use according to claims 4 and 6 respectively, substantially as hereinbefore described with reference to the Examples. DATED this 5th day of February 1999 Synthelabo. By its Patent Attorneys DAVIES COLLISON CAVE