SK31198A3 - 4-(cycloalkyl)piperidine and 4-(cycloalkylalkyl)piperidine derivatives, preparation thereof and therapeutical applications thereof - 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

Technical field

The invention relates to derivatives of 4- (cycloalkyl) piperidines and 4- (cycloalkylalkyl) piperidines, to a process for their preparation and to their therapeutic use.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the general formula I

Ar

ⁿ 'R ² (II wherein Ar represents

(a) a phenyl group substituted by a halogen atom; or

b) a group of the general formula I '

in which

X represents a group of the formula -CH ₂ -, - (0 ' ^- or - (CH ₂ ) 3 ^- a

Z represents hydrogen or a halogen atom or a methyl group,

Y is -CH ₂ -, -CO- or CHOH-,

R ¹ represents a hydrogen atom or a methyl group,

R ² is C 3 -C 7 cycloalkyl and n is 0, 1, 2 or 3.

The compounds of the invention may exist in the form of free bases or acid addition salts.

Moreover, when Y represents a -CHOH- group, the carbon atom of the asymmetric analogously when R ¹ is methyl, it is also an asymmetric carbon atom carrying them. Accordingly, the compound of the invention may, depending on the circumstances, be in the form of a pure optical isomer or a mixture of these isomers.

According to the invention, the compound of formula (I) may be prepared by the methods illustrated in the following schemes.

According to Scheme 1, a haloketone of formula II in which Ar is as defined above and Hal is a halogen atom is first reacted with a substituted piperidine of

of formula III wherein n and R are as defined above to form a ketone of formula Ia, which corresponds to formula I, when Y is -CO-.

If desired, the ketone can then be reduced, for example, using an alkali metal borohydrin to give an alcohol of formula Ib, which corresponds to formula I, wherein Y is -CHOH-.

The reaction conditions of these two steps are well known to those skilled in the art.

To give a compound of formula I, wherein Y is -CH ₂ - and Ar is phenyl substituted with halo, can then be reduced to an alcohol of formula Ib by reaction with thionyl chloride, followed by reaction of the chloro intermediate with lithium aluminum hydride .

Scheme 1

(II) (III) (la)

(Ib)

(Ic)

In order to obtain a compound of formula I wherein Y is -CH2- and Ar is in accordance with Scheme 2, first a haloketone of formula II in which Ar is a group of formula I 'and Hal is a halogen atom is reduced by triethylsilane. 'nom. and trifluoroacetic acid as described in patent application EP-0 281 309 to give a halogenated derivative of the formula IV, which is then reacted with a substituted piperidine of the formula III in which R ² is as defined above under standard conditions , for example in a solvent such as N, N-dimethylformamide in the presence of a base such as sodium carbonate.

Scheme 2

Ar

Hal

R (II)

Et ₃ SiH / CF ₃ CO ₂ H

ⁿ ^ R ² (IV) (H 1) (1c)

The starting compounds of formula (II) are commercially available or described in EP-0 109 317, EP-0.281 309, EP-0 351 282 and FR-2 684 379.

A compound of formula III wherein n is 2 and R ² is a cyclohexyl group is described in J. Org. (1957) 22 1376 and in U.S. Patent 4,005,093, and US 4,028,366th compounds of formula III wherein n is 1 or ² and R @ 3 represents a cyclohexyl group are mentioned, but not described in US 4261891st

Other compounds of formula III are novel and form part of the invention as necessary intermediates in this process for the preparation of compounds of formula I.

The compounds of formula III wherein n is 0, 1 or ² and R @ 3 represents a cyclohexyl group, can be obtained by catalytic hydrogenation of analogous derivatives in which ^R2 represents phenyl, in the presence of, for example, rhodium on carbon.

Other compounds of formula III can be obtained, for example, by Wittig reaction of pyridine-4-carboxaldehyde and phosphorus ylide obtained by cycloalkyl halide followed by reduction of the intermediate by complete hydrogenolysis, i.e. by alkylation of 4-methylpyridine as described in U.S. Patent 3,914,227 followed by reduction of the by hydrogenation in the presence of platinum oxide.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate in detail the preparation of several compounds of the invention. Elemental microanalysis and NMR spectra confirmed the structure of the compounds obtained. The numerical designations of the compounds in brackets in the headings correspond to those in Tables A and B below.

Example 1 (Compound No. 16A)

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

1.1 4- [2- (cyclohexyl) ethyl] piperidine hydrochloride g (0.88 mol) 4- (2-phenylethyl) piperidine hydrochloride, 2 g of 5% are carbonated and 200 ml of 1N hydrochloric acid are placed in a Parr flask for 15 hours hydrogenates at about 50 psi (50 psi).

The catalyst was removed by filtration, the filtrate was evaporated and dried by adding a mixture of ethanol and toluene, which was distilled off in vacuo. 17 g of white crystalline product are obtained, which product is used as is in the following stage.

1.2 1- (4-Chlorophenyl) -2- [4- [2- (cyclohexyl) ethyl] piperidin-1-yl] ethanone

A mixture of 8 g (0.0343 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 6.7 g (0.0343 mol) of 4- [2- (cyclohexyl) ethyl] piperidine, 30 g of potassium carbonate and 150 ml of acetonitrile is stirred at room temperature for 8 hours and allowed to stand overnight.

The mixture was poured into water and the insoluble material was collected by filtration and dried. 10.1 g of product are obtained. Melting point 71-72 ° C.

Example 2 (Compound No. 1A) (±) -a- (4-Chlorophenyl) -4- [2- (cyclohexyl) ethyl] piperidine-1-ethanol hydrochloride

10.1 g (0.029 mol) of 1- (4-chlorophenyl) -2- [4- [2- (cyclohexyl) ethyl] piperid-1-yl] ethanone, 300 ml of ethanol and 30 ml of water are placed in a round-bottomed flask. The mixture is heated to dissolve the mixture, 5 g of potassium borohydride are added in portions and the mixture is stirred at room temperature for 6 hours.

Water was added followed by 3N hydrochloric acid and the mixture was allowed to stand overnight.

The solid is collected by filtration, washed with acetone and recrystallized from 2-propanol.

4.4 g of hydrochloride are obtained. Mp 245 ° C (dec.).

Example 3 (Compound No. 4A) (±) -? - (4-Chlorophenyl) -4 - [(cyclohexyl) methyl] -? - methylpiperidine-1-ethanol hydrochloride, erythroisomer

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 charcoal are placed in an autoclave of 11 and hydrogenated for 6 hours at a pressure of about 7 MPa and a temperature of 80 ° C.

The mixture was allowed to cool, the catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was washed with acetone and dried.

49 g of white crystalline powder are obtained, which product is used in the next step without further purification.

Melting point: 303-305 ° C.

3.2 (+) -1- (4-chlorophenyl) -2- [4 - [(cyclohexyl) methyl] piperid-1-yl] propanone

A mixture of 9 g (0.0364 mol) of 2-bromo-1- (4-chlorophenyl) propanone, 6.5 g (0.0359 mol) of 4 - [(cyclohexyl) methyl] piperidine, 30 g of potassium carbonate and 150 ml of acetonitrile was added. After stirring at room temperature for one hour, the mixture was allowed to stand overnight. After addition of water, the insoluble component is separated by filtration, dried and used in the next step without further purification.

3.3 (±) -1- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] -p-methylpiperidine-1-ethanol hydrochloride, erythroisomer.

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 Place in a round-bottomed flask, add 4 g of potassium borohydride in portions and allow to stand overnight.

Water is added, followed by hydrochloric acid, some solvent is evaporated and the crystals formed are filtered off, washed with water recrystallized from 2-propanol and dried.

4.7 g of the hydrochloride are obtained. Melting point 262-264 ° C.

Example 4 (Compound No. 5A) (±) -? - (4-Chlorophenyl) -4 - [(cyclohexyl) methyl] -? - methylpiperidine-1-ethanol hydrochloride, threoisomer.

g (0.0172 mol) of (+) -1- (4-chlorophenyl) -2- [4 - [(cyclohexyl) methyl] piperid-1-yl] propanone, 200 ml of methanol, sufficient tetrahydrofuran to form a solution and then 20 ml of water are placed in a round-bottomed flask, 4 g of potassium borohydride are added in portions and the mixture is stirred at room temperature for 5 hours.

Water was added and the insoluble material was filtered off and purified by silica gel column chromatography, eluting with a 97: 3 mixture of dichloromethane and acetone.

Evaporation gave 2.3 g of the product. Melting point: 118-119 ° C.

Example 5 (Compound No. 8A) (±) -a- (4-Chloro-phenyl) -4- (cyclohexyl) -piperidine-1-ethanol

1.5 4- (cyclohexyl) piperidine hydrochloride g (0.0645 mol) of 4-phenylpyridine, 1 g of 5% carbon on charcoal, 100 ml of 1N hydrochloric acid and 10 ml of concentrated hydrochloric acid are placed in a Parr apparatus and the mixture is hydrogenated for 13 days at 0 35 MPa and 50 ° C (0.5 g of catalyst are added after the first week).

The catalyst is separated by filtration, a few drops of concentrated hydrochloric acid are added to the filtrate, concentrated by evaporation and taken up in ethanol, which is distilled off twice. After drying, 11.8 g of a white solid are obtained.

Melting point: 310-311 ° C.

2.5 (±) -? - (4-Chlorophenyl) -4- (cyclohexyl) piperidine-1-ethanol

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

The mixture was cooled, potassium borohydride (4.4 g) was added and stirred at room temperature for 2 days.

Water was added and the precipitate was collected by filtration, washed with water and dried. 2.88 g of product are obtained. Mp 135-136 ° C.

Example 6 (Compound No. 9A) (±) -? - (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- (3-phenylpropyl) piperidine, 2 g of 5% carbon on charcoal and 200 ml of 1N hydrochloric acid are placed in a Parr flask and the mixture is hydrogenated at 0.35 MPa and temperature 50 ° C for 40 hours.

The catalyst was removed by filtration, the filtrate was evaporated, the residue was taken up in toluene / ethanol and evaporated again, a crystalline white residue _; Dissolve in 50 ml of hot i

Of 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 product are obtained in the form of the hydrochloride. Mp 229 ° C.

2.6 (±) -a- (4-Chlorophenyl) -4- [3- (cyclohexyl) propyl] piperidine-1-ethanol

A suspension of 1.84 g (0.0075 mol) of 4- [3- (cyclohexylpropyl) piperidine hydrochloride, 1.75 g (0.0075 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 1.6 g was prepared. sodium carbonate, 40 ml of ethanol and 10 ml of water and refluxed for 1 hour 30 minutes.

The mixture was cooled, potassium borohydride (3.59 g) was added and the mixture was stirred at room temperature overnight.

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 product are obtained. Melting point: 85-86 ° C.

Example 7 (Compound No. 12A) 1- [2- (4-chlorophenyl) ethyl] -4 - [(cyclohexyl) methyl] piperidine Hydrochloride

3.0 g (0.0089 mol) of α- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] piperidine-1-ethanol suspended in 25 ml of toluene were placed in a round-bottomed flask, cooled in an ice bath. , a solution of 3 ml of thionyl chloride in 10 ml of toluene was added and the mixture was stirred at room temperature for 5 hours and 30 minutes. The solvent is evaporated under reduced pressure, the residue is washed with toluene to remove the last traces of thionyl chloride, the solvent is evaporated, the residue is taken up in 60 ml of tetrahydrofuran and the resulting slurry is poured dropwise into a suspension of lithium aluminum hydride in 15 ml of tetrahydrofuran. gradually heated to reflux with continuous stirring for 1 hour and 3 minutes. The mixture is cooled and taken up in 40 ml of water and 30 ml of ethyl acetate, the organic phase is separated and the solvent is evaporated off under reduced pressure.

The residue was purified by silica gel column chromatography, 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 product is 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 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 hours and 30 minutes. Then the solvent is evaporated under reduced pressure, the residue is washed with toluene to remove the last traces of thionyl chloride, the solvent is evaporated, the residue is taken up in 60 ml of tetrahydrofuran, the suspension is poured dropwise into a suspension of 0.7 g of lithium aluminum hydride in 10 ml of tetrahydrofuran. the mixture was refluxed with stirring for 1 hour and 30 minutes and allowed to stand overnight.

It is taken up in a mixture of 40 ml of water and 30 ml of ethyl acetate, the organic phase is separated and the solvent is evaporated off under reduced pressure.

The residue was purified by column chromatography on 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 product is isolated. Mp 290-291 ° C.

Example 9 (Compound No. 7A) (±) -a- (4-Chlorophenyl) -4 - [(cyclopentyl) methyl] piperidine-1-ethanol

9.1. 4 - [(cyclopentyl) methyl] piperidine hydrochloride (variant 1)

9.1.1.

4 - [(cyclopentyl) methyl] pyridine

300 ml of ammonia are condensed in a three-necked flask with 1 l at

J Or round bottom containing diethyl ether and still at -78 ° C is

-78 ° C, 8.28 g (0.36 mol) of sodium are added portionwise. The color changes from blue to yellow. 47.68 g (0.32 mol) of bromocyclopentane dissolved in 100 ml of diethyl ether are still added at -78 ° C and stirring is continued for 2 hours at -78 ° C.

Ammonium chloride and ammonia were added and the ether was evaporated using a hot water bath.

The residue is taken up in 200 ml of diethyl ether and 100 ml of water and extracted three times with ether. The organic phase is washed twice with water, dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure. 10 g of crude oil are obtained which is distilled under reduced pressure. Yield: 2 g of product, which is used as is in the following stage.

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 is introduced into a Parr flask and 300 mg of platinum oxide are hydrogenated at 0.35 MPa at 25 ° C. .

The catalyst was removed by filtration and the solvent was removed. it is evaporated under reduced pressure, a 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, filtered and the solvent is evaporated off under reduced pressure.

1.6 g of product are obtained, which product is purified by silica gel column chromatography, eluting with a 95: 5 mixture of methanol and 25% aqueous ammonia.

1.6 g of purified product are obtained in the form of the free base. 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 ° C.

9.2 4 - [(cyclopentyl) methyl] piperidine hydrochloride (2nd variant)

9.2.1. cyclopentyl triphenylphosphonium

The mixture is separated with 17.57 g (0.067 mol) of triphenylphosphine and 10 g (0.067 mol) of bromocyclopentane are heated at room temperature 200 ° C (bath temperature) under an inert atmosphere for two hours. The mixture was cooled, benzene was added with stirring, and the resulting precipitate was collected by filtration and recrystallized from ethyl acetate-methanol. 16 g of product are obtained. Mp 260 ° C.

9.2.2 4 - [(cyclopentylidene) methyl] pyridine

A suspension of 8.88 g (0.022 mole) of cyclopentyltriphenylphosphonium bromide in 100 ml of tetrahydrofuran is placed in an inert atmosphere in a 250 ml three-necked round-bottomed flask, the temperature is lowered to -78 ° C, 13.75 ml of 1 is added dropwise. Of a 6M solution of butyllithium in hexane, the mixture turns red and stirred for 30 minutes, then 2.359 g (0.022 mol) of pyridine-4-carboxaldehyde dissolved in 50 ml of tetrahydrofuran is added dropwise and the mixture is stirred at -7 8 ° for 1 hour. C and then 3 hours at room temperature.

50 ml of water and 100 ml of ethyl acetate are added, the aqueous phase is separated and extracted three times with ethyl acetate, the organic phase is washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulphate, filtered and the solvent is evaporated under reduced pressure.

10 g of crude product are obtained, which, after purification by silica gel column chromatography, gives 2.69 g of the title compound.

9.2.3. 4 - [(cyclopentyl) methyl] piperidine hydrochloride

A solution of 4.815 g (0.038 mol) of 4 - [(cyclopentylidene) methyl] pyridine in 180 ml of a 1: 1 mixture of ethanol and 1N hydrochloric acid is introduced into a Parr flask, 2.5 g of Adams catalyst (platinum oxide) are added. and the mixture is hydrogenated at 25 ° C and 0.35 MPa. The catalyst is separated 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, dried over magnesium sulfate, filtered. the solvent was evaporated under reduced pressure.

5 g of crude product is obtained, which is purified by column chromatography on silica gel, eluting with a 95: 5 mixture of methanol and 25% aqueous ammonia.

4.9 g of pure base are obtained, from which the hydrochloride is prepared from a 0.1N solution of hydrochloric acid in 2-propanol. Mp 275-276 ° C.

9.3. (±) -a- (4-chlorophenyl) -4 - [(cyclopentyl) methyl] piperidin-1-ethanol

0.57 g (0.0024 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 500 mg (0.0024 mol) of 4 - [(cyclopentyl) methyl] piperidine hydrochloride, 0.52 g (0.0049 mol) of carbonate Sodium chloride, 13 ml of ethanol and 3 ml of water are placed in a 100 ml round bottom flask and the mixture is heated at 80 ° C (bath temperature) for 1 hour 30 minutes.

The mixture is cooled, 1 g of potassium borohydride is added and the mixture is stirred and then left to stand overnight.

26 ml of water are added, the suspension is stirred and the solid phase is separated by filtration, washed with water and dried in the presence of phosphorus pentoxide.

0.7 g of product is obtained, which product is purified by column chromatography on silica gel, eluting with a 95: 5 mixture of dichloromethane and methanol.

After recrystallization and drying, 0.366 g of product is isolated. Melting point 104-105 ° C.

Example 10 (Compound No. 3A) (±) -a- (4-Chlorophenyl) -4 - [(cyclohexyl) methyl] piperidine-1-ethanol g (0.03 mol) 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 placed in a round-bottomed flask. The mixture was refluxed for 2 hours. _;

The mixture was allowed to cool at room temperature, while stirring, 10 g of potassium borohydride was added at room temperature for 30 minutes and the mixture was allowed to stand overnight.

The mixture was poured into 320 ml of water and the yellow precipitate was collected by filtration and dried in the presence of phosphorus pentoxide. 8.8 g of crude product are obtained, which product is purified by column chromatography on silica gel, eluting with a dichloromethane / methanol (90/10) mixture.

6.36 g of product are obtained, which product is recrystallized from ethanol. Melting point: 122-123 ° C.

Example 11 (Compound No. 10A) (±) -a- (4-Chlorophenyl) -4 - [(cyclohexyl) methyl] piperidine-1-ethanol

2.8 g (0.0083 mol) of (±) -a- (4-chlorophenyl) -4 - [(cyclohexyl) methyl] piperidine-1-ethanol, 2.37 mol (0.01 mol) of diisopropyl (-) of tartrate and 80 ml of dichloromethane are placed in a 500 ml round bottom flask under nitrogen and 4.95 mol (5.174 ml, 0.0174 mol) of titanium tetraisopropyloxide are added and the mixture turns yellow. The mixture was cooled to -25 ° C in an acetone / dry ice bath (solid carbon dioxide) and 1.53 ml of a 3.3M solution of tert-butyl hydroperoxide in toluene was added and stirring was continued at -25 ° C for 2 hours and 30 minutes.

80 ml of diethyl ether, 4 ml of water and 5 ml of 30% sodium hydroxide are added, the mixture is allowed to warm to room temperature with vigorous stirring and allowed to stand overnight.

The white titanium salt precipitate was collected by filtration and the filtrate was evaporated. 1.67 g of a white crystalline solid is obtained, and this product is purified by silica gel column chromatography, followed by elution with ethyl acetate. 0.53 g of white crystals are obtained, which are recrystallized twice from ethanol to isolate 0.21 g of the dextrorotatory enantiomer (ee = 92.6%). Melting point: 140-141 DEG C. [a] _D ²⁰ = +46, 0 ⁰ (c = 1, CHC1 ₃₎ ·

Example 12 (Compound No. 11A) (-) -? - (4-Chlorophenyl) -4 - [(cyclohexyl) methyl] piperidine-1-ethanol

The preparation is the same as in the previous case, but the dextrorotatory diisopropyl tartrate is used instead of the levorotatory isomer. The amount of racemate initially used is 3.36 g (0.01 mol), at the end of the preparation 0.38 g of the left-handed enantiomer is obtained (ee = 90.5%). Mp 140-141 ° C [α] _D ²⁰ = -46.0 ^° (c = 1, CHCl ₃ ).

Example 13 (Compound No. 18A) (±) -a- (4-chlorophenyl) -4 - [(cycloheptyl) methyl] piperidine-1-ethanol

13.1. 4 - [(cycloheptyl) methyl] piperidine hydrochloride

The second variant of the method described for 4 - [(cyclopentyl) methyl] piperidine hydrochloride is used, but the starting compound is bromocycloheptane instead of bromocyclopentane. Melting point: 260 ° C.

13.2. (±) -a- (4-chlorophenyl) -4 - [(cycloheptyl) methyl] piperidine-1-ethanol

A mixture of 0.4 g (0.00171 mol) of 2-bromo-1- (4-chlorophenyl) ethanone, 0.4 g (0.00171 mol) of 4 - [(cycloheptyl) methyl] piperidine hydrochloride and 0.4 g of sodium carbonate in 20 ml of ethanol and 5 ml of water are refluxed for 2 hours with stirring.

The mixture is cooled and 0.8 g of potassium borohydride is added while stirring overnight at room temperature.

40 ml of water are added, the aqueous phase is extracted with ethyl acetate, the organic phase is washed with water and then with a saturated aqueous sodium chloride solution, dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 95: 5 mixture of dichloromethane and methanol. Recrystallization from ethanol then gave the title compound (0.097 g). 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 carbonate Sodium hydroxide, 80 ml of ethanol and 20 ml of water are placed in a 500 ml round bottom flask and the mixture is refluxed for 1 hour 30 minutes.

It is allowed to cool and poured into 200 ml of water and the precipitate is collected by filtration, washed with diethyl ether and dried in the presence of phosphorus pentoxide.

4 g of product are obtained, by chromatography on silica gel, dichloromethane and methanol in the ratio from ethanol.

After washing with phosphorus diethyl ether, 0.96 g of melting is isolated at 180-181 ° C.

Example 15 (Compound No. 4B) which was purified by column elution with 95: 5 followed by recrystallization drying in the presence of the oxide of the title compound. Temperature (±) -5- [2- [4- (2-cyclohexylethyl) piperid-1-yl] -1-hydroxyethyl] -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, 3.18 g (0.03 mol) of carbonate Sodium (100 ml), ethanol (100 ml) and water (20 ml) were placed in a 500 ml round bottom flask and the mixture was heated at 120 ° C (bath temperature) for 1 hour 30 minutes.

The mixture was cooled in an ice bath and 6.61 g of potassium borohydride was added while stirring overnight at room temperature.

The mixture was poured into 200 ml of water and stirred for 10 minutes, and the precipitate was collected by filtration, washed with water and petroleum ether, and dried in the presence of phosphorus pentoxide. 4.34 g of crude product are obtained, which product is purified by column chromatography on silica gel, eluting with dichloromethane / methanol (90/10).

After recrystallization and drying, 1.48 g of product is isolated. Mp 210-211 ° C.

Example 16 (Compound # 8B)

5- [2- [4- (2-Cyclohexylethyl) piperid-1-yl] ethyl] -3H-indol-2-one

16.1. 5- (2-Chloroethyl) -3H-indol-2-one g (0.0715 mol) of 5- (chloroacetyl) -3H-indol-2-one suspended in 60 ml of trifluoroacetic acid is introduced into a round-bottomed flask containing 500 ml, cooled in an ice bath, 23.13 ml (0.164 mol) triethylsilane was added dropwise and the mixture was allowed to warm to room temperature overnight with continuous stirring.

The mixture was poured into 300 ml of ice water with stirring for 15 minutes and the beige precipitate was collected by filtration, washed with water and hexane and dried in the presence of phosphorus pentoxide.

13.75 g of compounds are obtained, which compounds are used as is in the following stage.

16.2. 5- [2- [4- (2-Cyclohexylethyl) piperid-1-yl] -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, 3.17g (0.03 mol) of sodium carbonate and 50 ml of N, N-dimethylformamide are introduced into a 500 ml round-bottom flask and the mixture is heated at 120 ° C (bath temperature) for 5 hours.

150 ml of water are added with stirring for 30 minutes and the resulting brown precipitate is collected by filtration and dried in the presence of phosphorus pentoxide.

4.56 g of crude product are obtained, which product is purified by column chromatography on silica gel, eluting with dichloromethane / methanol (90/10).

After recrystallization from 2-propanol, washing with diethyl ether and drying in the presence of phosphorus pentoxide, 0.85 g of product is isolated. Melting point 190-191 ° C.

Example 17 (Compound 7B)

6- [2- [4- (2-Cyclohexylethyl) piperid-1-yl] oxoethyl] -3,4-dihydro-1H-quinolin-2-one

3.35 g of 6- (chloroacetyl) -3,4-dihydro-1H-quinolin-2-one, 3.47 g (0.015 mol) of 4- (2-cyclohexylethyl) piperidine hydrochloride, 3.17 g ( Sodium carbonate (0.03 mol), ethanol (80 ml) and water (20 ml) were placed in a 500 ml round bottom flask and the mixture was refluxed for 1 hour 30 minutes.

The mixture is allowed to cool, poured into 200 ml of water, stirred for 15 minutes and the precipitate is collected 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 column chromatography on silica gel, eluting with dichloromethane / methanol (90/10), followed by recrystallization from ethanol.

After washing with diethyl ether and drying in the presence of phosphorus pentoxide, 3.82 g of product are isolated. Melting point: 176-177 ° C.

Example 18 (Compound 3B) (±) -6- [2- [4- (2-Cyclohexylethyl) piperid-1-yl] -1-hydroxyethyl] -8-fluoro-3,4-dihydro-1H-quinolin-2-one

3.62 g of 6- (chloroacetyl) -8-fluoro-3,4-dihydro-1H-quinolin-2-one; 3.47 g (0.015 mol) of 4- (2-cyclohexylethyl) piperidine hydrochloride; 18 g (0.03 mol) of sodium carbonate, 80 ml of ethanol and 20 ml of water are placed in a 500 ml round-bottomed flask and the mixture is refluxed for 1 hour 30 minutes.

The mixture is allowed to cool, 6.5 g of potassium borohydride are added and stirred overnight at room temperature.

160 ml of water are added, stirred for 15 minutes and the beige precipitate is collected by filtration, washed with water and petroleum ether and dried in the presence of phosphorus pentoxide.

5 g of crude product is obtained, which is purified by column chromatography on silica gel, eluting with dichloromethane / methanol (90/10).

After recrystallization and drying in the presence of phosphorus pentoxide, 2.7 g of product are isolated. Mp 154-155 ° C.

Example 19 (Compound No. 5B)

6- [2- [4- (2-Cyclohexylethyl) piperid-1-yl] ethyl] -3,4-dihydro-1H-quinolin-2-one

1.19 6- (2-chloroethyl) -3,4-dihydro-lH-quinolin-2-one

5.36 g (0.024 mol) of 6- (chloroacetyl-3,4-dihydro-1H-quinolin-2-one) and 18.5 ml of trifluoroacetic acid are placed in a round-bottomed flask, the suspension is cooled in an ice bath and dropwise 8.77 ml (0.055 mol) of triethylsilane are added under stirring at room temperature for 16 hours.

The mixture was poured into 100 ml of ice water for 15 minutes and the precipitate was collected by filtration, washed with water and hexane and dried in the presence of phosphorus pentoxide.

5 g of product are obtained. Melting point: 163-164 ° C.

2.19 6- [2- [4- (2-cyclohexylethyl) piperid-1-yl] ethyl] -3,4-dihydro-1H-quinolin-2-one

3.14 g (0.015 mol) of 6- (2-chloroethyl) -3,4-dihydro-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 placed in a 500 ml round-bottom flask and the mixture is heated at 120 ° C (bath temperature) for 4 hours and 30 minutes.

150 ml of water are added, the mixture is stirred in an ice bath for 30 minutes and the precipitate is collected by filtration, washed with water and dried in the presence of phosphorus pentoxide. 4.70 g of crude product are obtained, which is purified by column chromatography on silica gel, eluting with dichloromethane / methanol (90/10).

After recrystallization from 2-propanol, washing with diethyl ether and drying in the presence of phosphorus pentoxide, 2.5 g of product are isolated. Mp 192-193 ° C.

Example 20 (Compound 6B) (±) -7- [2- [4- (2-Cyclohexylethyl) piperid-1-yl] -1-hydroxyethyl] -1,3,4,5-tetrahydrobenzo [b] azepine -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 placed in a 500 ml round bottom flask and the mixture is refluxed for 2 hours.

Allow to cool, then add 6 g of potassium borohydride with stirring at room temperature overnight.

160 ml of water are added, the mixture is stirred for 2 hours and the precipitate is collected by filtration, washed with water and dried in the presence of phosphorus pentoxide.

5.1 g of crude product are obtained, which is purified by column chromatography on silica gel, eluting with dichloromethane / methanol (90/10).

After recrystallization from propanol and drying, 3 g of product are isolated. Melting point 188-189 ° C.

Example 21 (Compound No. 17B)

6- [2- [4- (3-cyclohexylpropyl) piperid-1-yl] -1-oxoethyl] -3,4-dihydro-1H-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-1H-quinolin-2-one, 0.87 g (0.0082 mol) of sodium carbonate, 20 ml of ethanol and 5.5 ml of water are placed in a round-bottom flask and the mixture is refluxed for 2 hours 30 minutes.

The mixture is cooled to 0 ° C where it is stirred for 20 minutes, 35 ml of water are added with continuous stirring at 0 ° C for 15 minutes and the light brown precipitate is collected by filtration, the crystals are washed with water and dried in the presence of phosphorus pentoxide. during the night.

After recrystallization from 2-propanol, washing with water, washing with hexane and drying, 1.23 g of product is isolated. Mp 179 ° C.

Example 22 (Compound No. 10) (±) -6- [2- [4- (3-Cyclohexylpropyl) piperid-1-yl] -1-hydroxyethyl] -3,4-dihydro-1H-quinolin-2-one

5.5 g (0.0138 mol) of 6- [2- [4- (3-cyclohexylpropyl) piperid-1-yl] -1-oxoethyl] -3,4-dihydro-1H-quinolin-2-one, 80 ml of ethanol and 20 ml of 0.5N hydrochloric acid are placed in 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 30 minutes and the precipitate is collected by filtration, washed with water and dried. 5.2 g of crude product are obtained, which is purified by column chromatography on silica gel, eluting with dichloromethane / methanol (90/10).

After recrystallization from ethanol and drying, 4.24 g of product is isolated. Mp 151-152 ° C.

Example 23 (Compound No. 16B)

6- [2- [4- (3-cyclohexyl) piperid-1-yl] ethyl] -3,4-dihydro-1H-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-bromomethyl) -3,4-dihydro-1H-quinolin-2-one is prepared, 0.59 g (0.0055 mol) of sodium carbonate and 9.5 ml of N, N-dimethylformamide were heated at 120 ° C (bath temperature) for 5 hours and 30 minutes.

The mixture is allowed to cool, 20 ml of water are added over 15 minutes of stirring and the solid phase is separated by filtration and the crystals are washed with water.

0.73 g of product is obtained, which product is purified by column chromatography on silica gel, eluting with dichloromethane: methanol (94: 6).

After recrystallization from 200 ml of acetone containing some methanol, filtration, washing with water and then hexane and drying, 0.466 g of product crystals are isolated. Melting point 212-214 ° C.

Example 24 (Compound No. 19B)

6- [2- [4 - [(cyclopentyl) methyl] piperid-1-yl] ethyl] -3,4-dihydro-1H-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-bromomethyl) -3,4-dihydro-1H-quinolin-2-one is prepared. 0.313 mol (0.00298 mol) of sodium carbonate and 5.5 ml of N, N-dimethylformamide and the mixture was heated at 130 ° C (bath temperature) for 3 hours.

The mixture is allowed to cool, water (12 ml) is added over 15 minutes, the solid phase is separated by filtration and the crystals are washed with water and then with hexane.

0.39 g of product is obtained, which product is purified by column chromatography on silica gel, eluting with dichloromethane: methanol (94: 6).

After recrystallization from 60 ml of acetone containing some methanol, filtration, washing with water and then hexane and drying, 0.217 g of crystalline product is isolated. Melting point: 172-174 ° C.

Example 25 (Compound # 29B)

6- [2- [4- (Cycloheptyl) methyl] piperid-1-yl] ethyl-3,4-dihydro-1H-quinolin-2-one

Suspension of 0.2 g (0.000864 mol) of 4 - [(cyclohexyl) methyl] piperidine hydrochloride, 3.5 ml of N, N-dimethylformamide, 0.22 g (0.000864 mol) of 6- (2-bromomethyl) -3,4 of dihydro-1H-quinolin-2-one and 0.184 g (0.001728 mol) of sodium carbonate were introduced into a round-bottomed flask and the mixture was refluxed for 3 hours 15 minutes.

The mixture was cooled, diluted with 8 ml of water and the precipitate was collected by filtration and dried.

0.23 g of product is obtained, which product is purified by column chromatography on silica gel, eluting with dichloromethane: methanol (96: 4).

0.21 g of solid product is isolated, which is recrystallized from 80 ml of acetone to give 0.146 g of compound. Mp 154-155 ° C.

The following Tables A and B show the chemical composition and physical properties of some of the compounds of the invention. In the columns "R ² " means "C ₅ H ₉ cyclopentyl", "C ₆ Hu cyclohexyl" and "C ₇ H ₁₃ cycloheptyl".

In the column "Isom stands for (±) racemate," + dextrorotatory enantiomer, "-" left-handed enantiomer, "/ achiral compound," E stands for erythrodiastereoisomers and "T threodiastereoisomers.

In the column "salt" means "-" a compound in the form of a base and "HCl" means a hydrochloride.

In the column "m.p. (° C) means "(d) melting point with decomposition.

Table A

no. Y R ¹ R ² n Izom. salt temperature Melting point (° C) IA CHOH H C ₆ H _u 2 (±) HC1 245 d 2A CHOH ch ₃ C ₆ Hh 2 (+) E HC1 230-244 (d) 3A CHOH H CgHn 1 (±) - 122-123 4A CHOH ch ₃ CgHn 1 (±) E HC1 262-264 5A CHOH ch ₃ CgHn 1 (±) T - 118-119 6A CHOH ch ₃ CgHn 2 (±) T - 114-115 7A CHOH H C5H9 1 (±) - 104-105 8A CHOH H CgH _u 0 (±) - 135-136 9A CHOH H CgHn 3 . (±) - 85-86 10A CHOH H CgHn 1 (+) - 140-141 11A CHOH H CgHn 1 (-) - 140-141 12A ch ₂ H CgHn 1 / HC1 284-285 13A ch ₂ H CgHn 0 / HC1 300-301 14A ch ₂ H CgHn 2 / HC1 290-291 15A ch ₂ H CgHn 3 / HC1 241-242 16A WHAT H CgHn 2 / - 71-72 17A WHAT H CgHn 3 / HC1 210-211 18A CHOH H ' C ₃ Hi ₃ 1 (+) - 116-117 19A ch ₂ H c ₅ h ₉ 1 / HC1 284-285

Note: the optical rotations of compounds with numbers 10A and 11A are + 46 ° and -46 ° (c = 1, CHCl ₃ ).

Table B

FROM

no. X Y R ¹ FROM R ² n Izom. salt temperature mp (° C) 1B (CH ₂ ) ₂ CHOH H H CgHn 2 (±) - 192-193 2B (CH ₂ ) ₂ CHOH 8-CH 3 H CgHn 2 (±) - 192-193 3B (CH ₂ ) ₂ CHOH 8-F H CgHn 2 (±) - 154-155 4B ch ₂ CHOH H H C ₆ H _n 2 (±) - 210-211 5B (CH ₂ ) ₂ ch ₂ H H CgHn 2 / - 192-193 6B (CH ₂ ) ₂ CHOH H H c ₅ h _u 2 (±) - 188-189 7B (CH ₂ ) ₂ WHAT H H CgHn 2 / - 176-177 8B ch ₂ ch ₂ H H CgHn 2 / - 190-191 9B ch ₂ WHAT H H CgHn 2 / - 180-181 10B (CH ₂ ) ₂ CHOH H H CgH _n 3 (±) - 151-152 11B (CH ₂ ) ₂ WHAT H H C ₆ H _u 1 / - 191-193 12B (CH ₂ ) ₂ CHOH H H CgHn 1 (±) - 190-192 13B (CH ₂ ) ₂ ch ₂ H H c ₆ h _u 1 / - 169-171 14B (ch ₂ ) ₂ WHAT H H CgHn 0 T - 190-192 15B ' (ch ₂ ) ₂ CHOH H H C ₆ Hn 0 (±) - 230-232 16B (CH ₂ ) ₂ ch ₂ H H CgHn 0 / - 212-214 17B (CH ₂ ) ₂ WHAT H H CgHn 3 / - 179 18B (CH ₂ ) ₂ ch ₂ H H CgHn 3 / - 150-152 19B (ch ₂ ) ₂ ch ₂ H H c ₅ h ₉ 1 / - 172-174 20B ch ₂ - WHAT H H CgHn 1 / - 164-166 21B ch ₂ - CHOH H H CgHn 1 (±) - 179-181 22B ch ₂ - ch ₂ H H CgHn 1 / - 160-162 23B ch ₂ WHAT H H CgHn 0 / - 179-181

no. X Y R ¹ FROM R ² n Izom. Sol temperature mp (° C) 24B ch ₂ CHOH H H CgHn 0 (±) - 204-206 25B ch ₂ WHAT H H CsHii 3 / - 154-156 26B ch ₂ ch ₂ H H C ₆ Hn. 0 / - 187-189 27B (CH ₂ ) ₂ CHOH H H c ₅ h ₉ 1 (±) - 189-191 28B (CH ₂ ) ₂ WHAT H H C5H9 1 / - 162-164 29B (CH ₂ ) ₂ ch ₂ H H c ₇ h ₁₃ 1 / - 154-155 30B (CHJ 2 CHOH H H C7H13 1 (±) - 190-192 31B ch ₂ ch ₂ H H C ₆ Hh 3 / - 154-156 32B ch ₂ CHOH H H c ₆ h _u 3 (±) - 164-166 33B ch ₂ WHAT H H c ₅ h ₉ 1 / - 157-159 34B ch ₂ ch ₂ H H c ₅ h ₉ 1 / - 162-164 35B ch ₂ CHOH H H c ₅ h ₉ 1 (±) - 173-175 36B ch ₂ CH ₂ H H c ₇ h ₁₃ 1 / - 156-158

The compounds of the invention were tested in the assays described below to determine their therapeutic value.

The neurotrophic properties of the compounds of the invention were demonstrated in vivo based on their effects on rat sciatic nerve regeneration.

These effects were evaluated after a lesion performed by local freezing of the rat sciatic nerve. The lesion by freezing destroys the sciatic nerve fibers, which suffer from Wallerian-type degeneration at the lesion and distal region. This type of lesion keeps the nerve sheath intact and allows nerve regeneration under reproducible conditions. The regeneration process begins in the hours following the lesion on the proximal side. The rate of regeneration of the sensitive nerve fibers is measured by a compression test 8 days after the lesion.

The test animals are adult male Sprague Dawley rats (Iffa Credo) weighing about 250 g. After anesthesia of the animals with pentobarbital Na (60 mg / kg), the thigh skin is disinfected with alcohol and cut to connect the femoral (femur) biceps muscle. The sciatic nerve is exposed by removing the femoral lateral biceps muscle. The lesion point is labeled with a microstrain (black Ethilon ™ 10-0) on the nerve sheath above the sciatic nerve trifurcation. Sciatic nerve lesion is performed over 1 mm by 6 freeze-thaw cycles using copper cryode pre-cooled in liquid nitrogen. The wound is then closed and treated with an antibiotic (Exoseptoplix ©). The animals are placed in individual cages and inspected daily. After surgery, the animals are divided into groups of six individuals:

- lesion-injected control animals injected intraperitoneally (peritoneally) with 0.1% Tween 80 ™ 10 minutes after the lesion, then 6 hours after the lesion, from day two to eight days twice a day.

- lesion-treated animals injected intraperitoneally with test compound at doses of 0.3 mg / kg, 1 mg / kg or 3 mg / kg in 0.1% Tween 80 ™ 10 minutes and 6 hours after the lesion, then from day two to day eight twice a day.

Eight days after surgery, the animals are poorly anesthetized and the sciatic nerve is re-exposed to perform a compression test. This test involves a slight compression of the nerve by means of pliers, first on the outermost part of the nerve, then repeatedly shifting the compression site by 0.5 mm. The reflex response (contraction of the muscles of the hindquarters of the animal) is reflected at the point where the regenerated sensitive fiber band begins. This point is marked with a microstitch. The nerve is then dissected and the distance between the lesion site and the distal microstitch indicating the onset of sensitivity is measured on a millimeter paper under an operating microscope. After nerve surgery, the animals are sacrificed by an overdose of pentobarbital.

It has been found that in treated animals by administration of the compounds of the invention, the onset distance of the sensitive nerve fiber band increases by more than 10% compared to control animals.

The neurotrophic properties of the compounds of the invention were studied in vivo based on their effects on the sciatic nerve regeneration following a crush associated with vincristine administration.

Vincristine is an alkaloid isolated from zimozel used in the treatment of certain cancers, whose mechanism of action is well known. Vincristine binds to the cytoplasmic protein tubulin and prevents its polymerization into microtubules (microchannels), which are major factors in nerve regeneration after lesion. This is because microtubules provide axonal transport of newly synthesized macromolecules that need to be delivered to the distal part of the nerve in order to ensure the formation and extension of growth cones. For vincristine administration, it inhibits rapid axonal transport and, depending on the dose administered, either slows down or impedes nerve regeneration after the lesion.

Experimental Case Model: On D °, the right sciatic nerve of the rat was crushed for one and a half minutes after desensitization with pentobarbital. The following day D ¹ , animals are given a single dose of 0.2 mg / kg vincristine, and on D ⁷ the regeneration rate is determined by a compression test. The 0.2 mg / kg dose of vincristine reduces by about 20% the distance from the lesion to the onset of sensitivity measured on day 7 in control animals not treated with test compounds. These test compounds are administered to animals by intraperitoneal injections twice daily from D 0 to D ⁶ (day D 0 10 minutes and 6 hours after lesion, from D ¹ to D ⁶ at six hour intervals in the morning and evening).

In this assay, the most active compounds increase the rate of regeneration of the damaged sciatic nerve of animals receiving vincristine by 12-14%.

The compounds of the invention have also been tested to inhibit the binding of ( ³ H) ifenprodil to rat cerebral cortex (Shoemaker et al., Eur. J. Pharmacol. (1990) 183, 1670).

Male Sprague-Dawley rats weighing 150-230 g are sacrificed and the cerebral cortex is homogenized in 20 volumes of cold (50 ° C) Tris-HCl buffer at pH 7.4 at 25 ° C with either Ultra-Turrax. ™ (Ikawerk) or Polytron (Kinematica). The homogenate is washed twice by centrifugation at 45,000 xg for 10 minutes, the resulting pellet (the centrifuged solid residue is resuspended in fresh buffer. The final pellet is transferred to 20 volumes of the same buffer. 100 μΐ of this suspension is incubated for 30 minutes at 37 °. C in 0.5 nM ( ³ H) ifenprodil with a specific activity of 30 to 35 Ci / mmol in a final volume of 1000 μΐ, either with or without interfering substances After incubation, membranes are recovered by filtration on Whatman gF / B filters ™ treated with 0.05% polyethyleneimine and then washed twice with 5 ml ice-cold buffer.

Non-specific binding is determined with 10 μprod ifenprodil, the data are analyzed by conventional methods and IC ₅₀ concentrations, the concentration that inhibits 50% ( ³ H) ifenprodil binding, are determined.

IC ₅₀ values of the most active compounds are below 25 nM. The compounds of the invention were then tested for effects on global brain ischemia in mice.

Ischemia results from cardiac arrest due to rapid intravenous injection of magnesium chloride. In this test, the survival time, i.e. the interval between the time of magnesium chloride injection and the last observable respiratory movement, is tested on each test mouse. This last movement is considered to be the last indication of central nervous system function. Respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride.

Male Charles River CD1 mice were used in groups of ten. Prior to testing, they were fed and fed. Survival time is measured 10 minutes after intraperitoneal administration of the compounds of the invention. Results were discontinued as the difference between the survival time measured in the group of ten mice treated with test compounds and the survival time measured in the group receiving only liquid vehicle. The relationships between the different survival times and compound doses are plotted graphically in a semi-logarithmic curve.

This curve allows the calculation of the "three-second effective dose (ED3), which is the dose (in mg / kg) that results in a three-second increase in survival time compared to a control group of ten mice not treated with the compounds of the invention."

The three-second survival time increase is both statically significant and reproducible.

In said intraperitoneal method, the ED ₃ values of the most active compounds are at most 25 mg / kg.

The results show that the compounds of the invention have both neurotrophic and neuroprotective properties.

They can be used to treat peripheral neuropathies such as traumatic neuropathy (section or crushing of the nerve), or ischemic neuropathy, metabolic neuropathy (diabetes, uremia), infectious, alcoholic or medical neuropathy, genetic neuropathy, motoneuronic disorders such as spinal (spinal) amyotrophies and lateral amyotrophic sclerosis.

They can also be used for the treatment and prevention of brain disorders following, for example, ischemic attacks, cardiac and respiratory disruption, thrombosis or brain embolism, for the treatment of cerebral senility, dementia after multiple infarctions, senile dementia such as Alzheimer's disease or Pick's disease, treatment of olivopontocerebellar atrophy or other neurodegenerative diseases such as Huntington's chorea, lateral amyotrophic sclerosis, for traumatic treatment of the skull or spine, or prevention of neural beams that follow convulsive attacks (convulsions) or are a result of tumors in the neurological system, for the prevention and treatment of diabetic retinal diseases (retinopathies), in the case of optic nerve degeneration and

retinopathy associated with glaucoma. Compounds according to invention can combine with thrombo- lytic agents such as rt-PA (recombined tissue plasminogen activator human origin) in treatment brain thromboembolic type infarction; or in combination with bad

a medicine that reduces intraocular pressure in the treatment of glaucoma (glaucoma), or alternatively in combination with an anti-cancer agent, to reduce its side effects (neuropathy and the like).

For this purpose, the compounds of the invention may be prepared in any pharmaceutical form suitable for enteral or parenteral administration, in combination with suitable vehicles, for example in the form of tablets, sugar-coated tablets, gelatin or wafer capsules, rectal suppositories, solutions or suspensions for oral or injections, dosed so that they can be administered daily in doses of 1 to 1000 mg of the active ingredient.

Industrial usability

The industrial applicability of the invention is unquestionable, since the compounds of the invention belong to the group of active substances of similar chemical nature already supplied to the chemical industry. They allow the widening of the range of drugs with neurotrophic effects to a wide range of diseases that arise as a result of nerve damage through mechanical, metabolic, infectious, degenerative and others. The innovation consists in replacing the aromatic substituent of the piperidine at the 4-position of the active ingredient with a cycloaliphatic group. The importance is given by the fundamental importance of drugs for a wide range of neuropathies, degenerative processes in gerontology and traumatology.

Claims (4)

A compound of formula I wherein Ar is (a) a phenyl group substituted by a halogen atom; or (b) a group of formula (I ') in which: X is -CH ₂ -, ^- () 2) 2 ^- or - (CH 2) 3 -a Z represents a hydrogen atom or a halogen atom or a methyl group, Y is -CH ₂ -, -CO- or -CHOH-, R ¹ represents a hydrogen atom or a methyl group, R ² represents a C 3 -C 7 cycloalkyl group and n is 0, 1, 2 or 3, in the form of the free base or addition salt, optionally in the form of the pure optical isomer or a mixture of such isomers. 2. A process for the preparation of compounds according to claim 1, characterized in characterized in that a haloketone of formula II * wherein Ar is as defined in Claim 1 and Hal represents halo, by first reacting with a substituted piperidine of formula III, (CH ₂ ) X ¹ (III) wherein R ² is as defined in claim 1 to form a ketone of formula Ia, which corresponds to formula I, wherein Y is -CO-, and then, if desired, this ketone is reduced to form an alcohol of formula Ib, Ar ⁿ Y (Ib) which corresponds to the general formula I wherein Y represents a -CHOH- group, then, if desired, a compound of the general formula I wherein Y represents a group of the formula -CH 2 - and Ar represents a phenyl group substituted by a halogen atom, of formula (1b) wherein Y is -CHOH- and Ar is a halogen-substituted phenyl group by reaction with thionyl chloride, followed by reaction of the chlorinated intermediate with lithium aluminum hydride, or alternatively, if desired to yield a compound of formula (I), wherein Y is -CH 2 - and Ar is 1 'as defined in claim 1, a haloketone of formula II wherein Ar is 1' and Hal is halogen first reduced with trimethylsilane and trifluoroacetic acid to form a halogenated derivative of the general formula IV, Ar R Hal (IV) which is then reacted with a substituted piperidine of formula III wherein n and R 2 are as defined in claim 1. Medicinal product comprising a compound according to claim 1. A pharmaceutical composition comprising a compound of claim 1 combined with a suitable vehicle.