IE922090A1 - 2-(1-piperidyl)ethanol derivatives, their preparation and¹their therapeutic application - Google Patents

Abstract

Compound, in the form of a pure optical isomer or of a mixture of two enantiomers, corresponding to the general formula (I) in which R1 represents a hydrogen or halogen atom or a methyl group, R2 represents one or two substituents chosen from the hydrogen and halogen atoms and the (C1-4)alkyl, hydroxyl, (C1-4)alkoxy, trifluoromethyl, acetylamino and methylsulphonylamino groups, and either X represents a CH2 group and Y represents a CH2, (CH2)2 or CO group, or X represents a CO group and Y represents a CH2 group.

Description

The present invention relates to compounds which are 2-(1-piperidyl)ethanol derivatives or salts thereof, their preparation, their therapeutic application and to an intermediate useful in the preparation of the compounds.

The present invention provides a compound which is a 2-(1-piperidyl)ethanol derivative of the general formula (I) in which R, represents hydrogen, halogen atom or methyl R2 represents one or two substituents independently chosen from halogen, (CV4) alkyl, hydroxyl, (CV4) alkoxy, trifluoromethyl, acetylamino and methylsulphonylamino, and either X represents a CH2 group and Y represents a CH2, (CH2)2 or CO group, or X represents a CO group and Y represents a CH2 group, provided that R1 and R2 are not both hydrogen when X and Y each represent a CH2 group, or a pharmaceutically acceptable acid addition salt thereof. The present invention also provides a process for the preparation of the 2-(1-piperidyl)ethanol derivatives and the salts thereof, an intermediate useful in the synthesis of them and therapeutic application of them. The - 3 compound of formula (I) in which R, and R2 each represent a hydrogen atom and X and Y each represent a CH2 group is described in EP-A-481853, In a preferred embodiment R, represents hydrogen, fluorine or methyl and R2 represents one or two substituents independently chosen from fluorine, chlorine, methyl, hydroxy, methoxy, trifluoromethyl, acetylamino and methylsulphonylamino The pharmaceutically acceptable acid is preferably the fumarate or oxalate.

Examples of specific compounds of the present invention are: (±)-6-[l-hydroxy-2-[4-[2-(4-fluorophenyl)ethyl]-1-piperidyl]ethyl]-3,4-dihydroquinolin-2(It)-one; (±)-6-[l-hydroxy-2-[4-[2-(4-chlorophenyl) ethyl]-1-piperidyl]15 ethyl]-3,4-dihydroquinolin-2(lH)-one; (+)-8-fluoro-6-[l-hydroxy-2-[4-[2-(4-fluorophenyl)ethyl]1-piperidyl]ethyl]-3,4-dihydroguinolin-2(IB)-one; (±)-6-[l-hydroxy-2-[4-(3-phenylpropyl)-1-piperidyl]ethyl]-3,4 dihydroquinolin-2 (IB)-one; (±)-6-[l-hydroxy-2-[4-(2-phenyl-2-oxoethyl)-1-piperidyl]ethyl] 3,4-dihydroguinolin-2(lH)-one; (+)-6-(l-hydroxy-2-[4-(2-(4-fluorophenyl)-1-oxoethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one; (±)-8-fluoro-6-[l-hydroxy-2-[4-(2-phenylethyl)-1-piperidyl]25 ethyl]-3,4-dihydroquinolin-2(IH)-one; (±)-8-fluoro-6-[l-hydroxy-2-[4-[2-(3-fluorophenyl)ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one; (±)-6-[l-hydroxy-2-[4-[2-[4-(trifluoromethyl) phenyl]ethyl]IE 922090 1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one; (-)-6-[1-hydroxy-2-[4-[2-[4-(trifluoromethyl) phenyl]ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one; (+)-6-(l-hydroxy-2-[4-(2-(4-(tri fluoromethyl) phenyl]ethyl]5 1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one; (±)-6-[l-hydroxy-2-[4-(2-(4-(acetylamino)phenyl]ethyl)1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one.; (±)-6-[l-hydroxy-2-[4-(2-phenylethyl)-1-piperidyl]ethyl]7-fluoro-3,4-dihydroquinolin-2(IH)-one; (±)-6-[l-hydroxy-2-[4-[2-(2-methylphenyl) ethyl]-1-piperidyl]ethyl]-8-methyl-3,4-dihydroquinolin-2(IH)-one; and (+)-6-[l-hydroxy-2-[4-[2-(3,5-difluorophenyl)ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH) -one.

Given that the molecule represented by the general 15 formula (I) possesses an asymmetric carbon atom, the compounds of the invention may exist in the form of pure enantiomers or a racemic mixture. The compounds of the invention are in the form of free bases or addition salts with pharmaceutically acceptable acids.

The compounds of the invention may be prepared according to scheme 1 on the next page.

(V) Scheme (II) KN (IV) (la) (I) A compound of general formula (II) in which either A represents a CH2 group and B represents a CH2 or (CH2)2 group, or A or B represents a CH2 group and the other represents a 5 l,3-dioxolan-2,2-diyl group, is reacted with a compound of general formula (III), in which R, is as defined above, to give a compound of general formula (IV) .

The ketone functional group of the compound (IV) is 10 then reduced with a reducing agent such as potassium borohydride.

If A represents a CH2 group and B represents a CH2 or (CH2)2 group, the compound of formula (Ia) thus obtained corresponds to the general formula (I) in which X represents a CH2 group and Y represents a CH2 or (CH2)2 group.

If A or B represents a CH2 group and the other represents a 1,3-dioxolan-2,2-diyl group, the compound of general formula (Ia) is hydrolysed in acidic medium, and a compound of general formula (I) in which X or Y represents a CH2 group and the other represents a CO group is thus obtained. If desired, the compound of formula (I) thus obtained is converted into a pharmaceutically acceptable acid addition salt.

The starting compounds of general formula (II) are known or alternatively they can be prepared according to methods similar to methods which are known or which are described in the literature, for example in J. Org. Chem., 22, 1376 (1957)? C.A., 52, 8138a (1958); C. R. Acad. Sci., 255, 956 (1962); US-P-4254127; EP-A-12643 and EP-A-481853; FR-A-2459795.

Thus, for example, a compound of general formula (V) , in which V or W represents a CH2 group and the other represents a CO group, may be used as starting material.

In order to obtain a compound of general formula (II) in which A and B each represent a CH2 group, the CO group of the compound (V) is reduced by means of hydrazine in the presence of a base, and then the nitrogen of the piperidine ring is deprotected by debenzylation.

In order to obtain a compound of general formula (II) in which A or B represents a CH2 group and the other represents a 1,3-dioxolane-2,2-diyl group, the CO group of the compound (V) is converted by ketalisation by means of ethylene glycol in the presence of 4-methylbenzenesulphonic acid, and then the nitrogen of the piperidine is deprotected by debenzylation.

The compounds of general formula (II) in which A and B each represent a CH2 group and R2 is as defined above except hydrogen are new and form part of the invention as synthesis intermediates. They may be prepared according to the processes illustrated by Schemes 2 and 3 below.

Scheme 2 illustrates a similar process to that described in C. R. Acad. Sci., 255, 956 (1962); first, an ester of general formula (VI) in which Aik represents a (CV4)alkyl group, is reacted with a benzeneacetonitrile of general formula (VII) in which R2 is as defined above, in the presence of sodium amide. An enol of general formula (VIII) is obtained and treated in acidic medium in order to obtain a ketone of general formula (IX) which is reduced for example by means of hydrazine hydrate in the presence of potassium hydroxide and triethylene glycol in order to obtain a compound of general formula (X), and finally this compound is subjected to debenzylation by - 8 catalytic hydrogenation or by chemical deprotection by reaction with trichloroethyl chloroformate followed by treatment of the resultant product with zinc in acetic acid in order to obtain a compound of general formula (II') which corresponds to the general formula (II) when A and B each represent a CH2 group.

Scheme 3 illustrates a process similar to that described in J. Org. Chem., 22, 1376 (1957); first, 4-methylpyridine of formula (XI) is reacted with a benzaldehyde of general formula (XII) in which Rz is as defined above, in acetic anhydride. A compound of general formula (XIII) is obtained, and this compound is subjected to catalytic hydrogenation.

Scheme 2 (VI) (VII) (VIII) (IX) (X) (II·) (XI) Scheme 3 (XII) (XIII) (II’) The starting compounds of general formulae (VI), (VII), (XI) and (XII) are available commercially.

Details of the preparation of certain specific compounds are given in the examples below.

The starting compounds of general formula (III) are also known or may be prepared according to methods similar to methods which are known or which are described in the literature, for example in EP-A-0351282 and in J. Med. Chem., 29, 2433 (1986).

Thus, for example, a quinolin-2(1H)-one which is suitably substituted by R1 may be used as starting material, and is subjected to catalytic hydrogenation in order to obtain the corresponding 3,4-dihydroquinolin-2(IH)-one, and the compound of general formula (III) is obtained by reaction with chloroacetic acid chloride in the presence of aluminium chloride.

Finally, the enantiomers of a compound according to the invention may be prepared from the racemate according to conventional methods, for example by formation of an addition salt with an optically pure chiral acid, fractional crystallisation, and release of the base.

The following examples illustrate in detail the preparation of some compounds of the invention. Microanalyses and IR and NMR spectra confirm the structures of the compounds obtained. The compound numbers indicated in brackets in the titles correspond to those in the tables which are given further on.

The example and compound numbers given in Roman numerals correspond to the starting 4-(2-phenylethyl)piperidines of general formula (II'), and the example and compound numbers given in Arabic numerals correspond to final compounds of general formula (I).

Example I (Compound No. Ill) 4-(2-(4-Fluorophenyl) ethyl]piperidine, hydrochloride.

I.1. 2-(4-Fluorophenyl)-3-hydroxy-3-[1-(phenylmethyl)-4piperidyl]prop-2-enenitrile. 13.5 g (0.1 mole) of 4-fluorobenzeneacetonitrile, ml of toluene and 4.4 g of sodium amide are introduced into a 500-ml round bottom flask. The mixture is stirred at room temperature for 30 minutes and then 27.2 g (0.11 mole) of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate are added by means of a dropping funnel. After the addition is completed, the mixture is heated at 80*C for 3 hours. It is then cooled in an ice bath and 300 ml of water are added, the mixture is stirred for 30 minutes and 15 ml of acetic acid are added. A yellow precipitate is obtained which is separated by filtration, washed with water and dried in the presence of phosphorus pentoxide. 17.6 g of compound are obtained which are used as such in the next stage. 1.2. 2-(4-Fluorophenyl)-1-[1-(phenylmethyl)4-piperidyl]ethanone. ml of water, 50 ml of concentrated sulphuric acid and 50 ml of acetic acid are introduced into a 500-ml round bottom flask placed in a water and ice bath and 24.4 g (0.072 mole) of 2-(4-fluorophenyl)-3-hydroxy3-[1-phenylmethyl)-4-piperidyl]prop-2-enenitrile are added. The 20 mixture is refluxed for 12 hours. The round bottom flask is cooled in a water and ice bath. 200 ml of ice are introduced into a 1-litre Erlenmeyer flask and the mixture prepared above is slowly added; 200 ml of ethyl acetate are added together with 200 ml of ammonium hydroxide in order to adjust the pH to 9. The mixture is decanted, the organic phase is recovered and the agueous phase is extracted three times with 150 ml of ethyl acetate. The organic phases are pooled and they are washed three times with 150 ml of water until a pH of 7 to 8 is obtained. The organic phase is dried over sodium sulphate, filtered and the ethyl acetate is evaporated under reduced pressure. 20.7 g of oily compound are obtained which are used as such in the next stage. 1.3. 4-[2-(4-Fluorophenyl)ethyl]-l-(phenylmethyl)piperidine. g (0.199 mole) of 2-(4-fluorophenyl)1-[1-(phenylmethyl)-4-piperidylJethanone in solution in 400 ml of ethanol are introduced into a 1-litre round bottom flask. 11.6 ml (0.23 mole) of hydrazine hydrate are added and the mixture is refluxed for 2.5 hours. It is cooled in an ice bath and then the solution is concentrated to half the volume. The product crystallises. 400 ml of water are then added, the mixture is stirred and the white precipitate is filtered. This precipitate is drained and dried in a desiccator in the presence of phosphorus pentoxide. 73.3 g of intermediate hydrazone are obtained. 64.8 g (about 0.199 mole) are taken up in 300 ml of triethylene glycol and 30 g of potassium hydroxide are added. The mixture is rapidly heated to 200‘C for 1 hour.

It is rapidly cooled in ice. 600 ml of water are then added and the mixture is extracted three times with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride. It is dried over sodium sulphate and then the solvent is evaporated under reduced pressure. A dark chestnutcoloured oil is obtained which is purified by chromatography on a silica gel column. 36.68 g of a pale oil are obtained which are used as such in the next stage. 1.4. 4-[2-(4-Fluorophenyl)ethyl)piperidine, hydrochloride. 9.8 g (about 0.033 mole) of - 14 ~ 4-[2-(4-fluorophenyl) ethyl]-l-(phenylmethyl)piperidine in solution in 100 ml of ethanol and 10 ml of a normal aqueous solution of hydrochloric acid are introduced into a Parr apparatus. 1 g of 10 % palladium on carbon is added.

Hydrogenation is carried out at 0.35 MPa and at 50*C for hours. The catalyst is removed by filtration, it is washed with water and ethanol, and 2 ml of concentrated hydrochloric acid are added. The mixture is evaporated and azeotropically dried with an ethanol/toluene mixture. It is again evaporated and the residue is taken up in 100 ml of tetrahydrofuran. The mixture is stirred for 15 minutes and the onset of precipitation is observed. 20 ml of diisopropyl ether are added and the mixture is further stirred for 15 minutes. The solid is rapidly filtered and then dried in a desiccator in the presence of phosphorus pentoxide. 5 g of compound are obtained.

Melting point: 131-132'C.

Example II (Compound No. IV) 4-[2-(4-Chlorophenyl)ethyl]piperidine, acetate.

II.1. 2-(4-Chlorophenyl)-3-hydroxy-3-[1-(phenylmethyl)-4piperidyl)prop-2-enenitrile. .3 g (0.2 mole) of 4-chlorobenzeneacetonitrile, 100 ml of toluene and 8.8 g of sodium amide are introduced into a 500-ml round bottom flask. The mixture is stirred at room temperature for 30 minutes and then 49.4 g (about 0.2 mole) of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate diluted in 40 ml of toluene are added by means of a dropping funnel. After the addition is completed, the mixture is heated at 80*C for hours. It is then cooled in an ice bath and 800 ml of water are added, the mixture is stirred for 30 minutes and 15 ml of acetic acid are added. A precipitate is obtained which is separated by filtration, washed with water and dried in the presence of phosphorus pentoxide. 65.67 g of compound are obtained which are used as such in the next stage. 11.2. 2-(4-Chlorophenyl)-1-[1-(phenylmethyl)4-piperidyl]ethanone. 50 ml of water, 100 ml of concentrated sulphuric acid and then 100 ml of acetic acid are introduced into a 500-ml round bottom flask placed in a water and ice bath and 30.21 g (0.086 mole) of 2-(4-chlorophenyl)-3-hydroxy3-[1-(phenylmethyl)-4-piperidyl]prop-2-enenitrile are added while stirring. The mixture is refluxed for 12 hours. 200 ml of ice are introduced into a 1-litre Erlenmeyer flask and the mixture prepared above is slowly added, and 400 ml of ammonium hydroxide are added in order to adjust the pH to between 8 and 9. The mixture is stirred in an ice bath and the precipitate formed is separated by filtration, washed with water and dried in the presence of phosphorus pentoxide. 28.75 g of compound are obtained which are used as such in the next stage. 11.3. 4-(2-(4-Chlorophenyl) ethyl]-1-(phenylmethyl)25 piperidine. 26.26 g (0.08 mole) of 2-(4-chlorophenyl)1-(1-(phenylmethyl)-4-piperidyl)ethanone in solution in 160 ml of ethanol are introduced into a 500-ml round bottom flask. 4.7 ml (0.093 mole) of hydrazine hydrate are added and the IE 922090 - mixture is refluxed for 1.5 hours. It is cooled in an ice bath and then the solution is concentrated to half the volume. The product crystallises. 160 ml of water and 200 ml of ethyl acetate are then added, the mixture is stirred and the organic phase is separated; the aqueous phase is extracted once more, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried over sodium sulphate, the solvent is evaporated under reduced pressure, and 28.3 g of intermediate hydrazone are obtained in the form of an oil which 10 crystallises. It is taken up in 130 ml of triethylene glycol and 14 g of potassium hydroxide are added. The mixture is rapidly heated to 200’C for 1 hour. It is rapidly cooled in ice. 260 ml of water are added and the mixture is extracted five times with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride. It is dried over sodium sulphate and then the solvent is evaporated under reduced pressure. 27.07 g of a chestnut-coloured oil are obtained which are used as such in the next stage.

II.4. 4-[2-(4-Chlorophenyl)ethyl]piperidine, acetate. .7 g (0.034 mole) of 4-[2-(4-chlorophenyl)ethyl]1-(phenylmethyl)piperidine, 14.4 g (0.068 mole) of trichloroethyl chloroformate, 0.5 g of potassium carbonate and 100 ml of toluene are introduced into a 500-ml round bottom flask. The mixture is refluxed for 5 hours and allowed to cool, 200 ml of water are added and the mixture is stirred, the aqueous phase is separated and extracted with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried over sodium sulphate and the solvent is evaporated under reduced pressure. 21.7 g of an oil are obtained which are introduced into a 500-ml round bottom flask, 150 ml of acetic acid and 9.13 g (0.139 mole) of powdered zinc are added, and the mixture is stirred overnight.

The zinc is separated by filtration and the filtrate is evaporated under reduced pressure; the residue is triturated with diethyl ether and the solid is separated by filtration, washed with diethyl ether and dried in the presence of phosphorus pentoxide. 7.6 g of crude product are finally isolated.

Melting point: 155’C.

Example III (Compound No. VII) 4-[2-(4-Methoxyphenyl) ethyl]piperidine, hydrochloride.

III.1. 4-[2- (4-Methoxyphenyl) ethenyl]piperidine. 46.56 g, equivalent to 48.6 ml (0.5 mole) of 4-methylpyridine, 122.5 g, equivalent to 109.5 ml (0.9 mole) of 4-methoxybenzaldehyde and 50 ml of acetic anhydride are introduced into a round bottom flask and the mixture is heated at 180’C for 3.5 hours. It is allowed to stand at room temperature overnight and then concentrated under reduced pressure. The residue is washed several times with diethyl ether and dried in the presence of phosphorus pentoxide. 35 g of compound are obtained which are used as such in the next stage.

Melting point: 122-123‘C.

III.2. 4-[2-(4-Methoxyphenyl)ethyl]piperidine, hydrochloride g (0.166 mole) of 4-(2-(4-methoxyphenyl)ethenyl)piperidine, a mixture of 175 ml of ethanol and 175 ml of 1 N hydrochloric acid and 3 g of 10 % palladised carbon are introduced into a Parr flask and hydrogenation is carried out at about 0.35 Mpa, at 50*C for 14 hours. The catalyst is separated by filtration, by washing it with ethanol, and the solvent is evaporated under reduced pressure. Traces of water are removed from the residue by azeotropic entrainment with toluene and the residue is washed with diethyl ether and dried in the presence of phosphorus pentoxide. 36.08 g of compound are obtained. 3 g of it are recrystallised from 2-propanol and the product is dried at 80“C in the presence of phosphorus pentoxide. 2.53 g of compound are obtained.

Melting point: 178-179'C.

Example IV (Compound No. VIII) - [ 2-(4-Trifluoromethylphenyl)ethyl]piperidine, hydrochloride.

IV.1. 4-[2-(4-Trifluoromethylphenyl) ethenyl]piperidine. 46.56 g, equivalent to 48.6 ml (0.5 mole) of 4-methylpyridine, 104.47 g, equivalent to 81.9 ml (0.6 mole) of 4-trifluoromethylbenzaldehyde and 50 ml of acetic anhydride are introduced into a round bottom flask and the mixture is heated at 180*C for 7.25 hours. It is concentrated under reduced pressure. The residue is triturated in 100 ml of isopropyl ether, drained and dried in the presence of phosphorus pentoxide. 73.65 g of compound are obtained which are used as such in the next stage.

Melting point: 72’C. - 19 IV. 2. 4-[2-(4-Trifluoromethylphenyl)ethyl]piperidine, hydrochloride. 73.15 g (0.293 mole) of 4-[2-(4-trifluoromethylpheny1)ethenyl]piperidine, a mixture of 350 ml of ethanol and 350 ml of 1 N hydrochloric acid and 5 g of 10 % palladised carbon are introduced into a Parr flask and hydrogenation is carried out at about 0.35 Mpa, at 50*C for 8 hours. The catalyst is separated by filtration, washed with ethanol and the solvent is evaporated under reduced pressure, and the residue is washed with diethyl ether and dried in the presence of phosphorus pentoxide. 37.2 g of compound are obtained. 3 g of it are recrystallised from 30 ml of toluene and the compound is taken up in 30 ml of diethyl ether, drained and dried at 80°C in the presence of phosphorus pentoxide. 2.72 g of compound are obtained.

Melting point: 166-167’C.

Example V (Compound No. XIV) N-[4-[2-(4-Piperidyl) ethyl]phenyl]acetamide, hydrochloride.

V. 1. 4-[2-(4-Nitrophenyl)ethenyl]pyridine. .11 g (0.1 mole) of 4-nitrobenzaldehyde, 9.3 g (0.1 mole) of 4-methylpyridine and 15 ml of acetic anhydride are introduced into a round bottom flask and the mixture is heated in an oil bath (bath temperature: 180*C) for 7 hours. It is concentrated under reduced pressure and the residue is taken up in petroleum ether and triturated. The solid is separated by filtration and dried. - 20 V.2. 4-(2-(4-Pyridyl) ethyl]benzeneamine.

The product from the preceding stage, 140 ml of ethanol, 100 ml of 1 N hydrochloric acid and 3 g of 10 % palladised carbon are introduced into a Parr flask and hydrogenation is carried out at 0.28 MPa for 8 hours, at room temperature. The catalyst is separated by filtration, the filtrate is evaporated and the residue is dried by entrainment with toluene and triturated in diethyl ether. 10.3 g of product are obtained after drying.

Melting point: 108-110’C.

V.3. N-(4-(2-(4-Pyridyl) ethyl]phenyl]acetamide. g (0.025 mole) of 4-[2-(4-pyridyl)ethyl]benzeneamine and 25 ml of dichloromethane are introduced into a round bottom flask and the mixture is stirred for 5 minutes at room temperature in order to obtain a solution; 10 ml of acetic anhydride are added and the mixture is stirred for 2 hours at room temperature.

The precipitate is separated by filtration, taken up in 50 ml of water and diluted ammonium hydroxide is added, the mixture is stirred for 30 minutes and the white precipitate is separated by filtration, washed with water and dried in the presence of phosphorus pentoxide. .35 g of compound are obtained.

Melting point: 178’C.

V.4. N-(4-(2-(4-Piperidyl) ethyl]phenyl]acetamide, hydrochloride. .25 g of N-(4-(2-(4-pyridyl)ethyl]phenyl]acetamide in solution in a mixture of 50 ml of ethanol and 25 ml of 1 N hydrochloric acid are introduced into a Parr flask and 0.5 g of 10 % palladised carbon are added and hydrogenation is carried out at 0.35 MPa at 50*C for 16 hours. The catalyst is separated by filtration, the solvents are evaporated and the residue is taken up in a mixture of ethanol and diethyl ether and triturated. .2 g of product are obtained after filtration and drying in the presence of phosphorus pentoxide. 1 g of it is recrystallised from propanol containing 1 % concentrated hydrochloric acid. 0.68 g of compound are obtained.

Melting point: 256-258’C.

Example VI (Compound No. XI) 4-(2-(3,5-Difluorophenyl)ethyl]piperidine, hydrochloride.

VI.1. 4-(2-(3,5-Difluorophenyl) ethenylj pyridine. g (0.176 mole) of 3,5-difluorobenzaldehyde, 16.37 g (0.176 mole) of 4-methylpyridine and 20 ml of acetic acid are introduced into a round bottom flask and the mixture is heated in an oil bath (bath temperature: 180*C) for 7 hours. The solvent is evaporated under reduced pressure and an oil is obtained which crystallises on cooling. This residue is taken up in 50 ml of diisopropyl ether, the mixture is triturated and the solid is separated by filtration, washed with diisopropyl ether and dried in the presence of phosphorus pentoxide. .94 g of product are obtained.

Melting point: 114’C.

VI.2. 4-[2-(3,5-difluorophenyl)ethyl]piperidine, hydrochloride. .90 g (0.142 mole) of 4-(2-(3,5-difluorophenyl)ethenyl]pyridine, 140 ml of ethanol, 140 ml of 1 N hydrochloric acid and 2.5 g of 10 % palladised carbon are introduced into a Parr flask and hydrogenation is carried out at 0.35 MPa for 14 hours.

The catalyst is separated by filtration, the filtrate is evaporated and the residue is dried by entrainment with toluene and then in the presence of phosphorus pentoxide. .88 g of compound are obtained. 1.5 g of it are purified by recrystallisation from 60 ml of toluene, washed with diethyl ether and then dried in the presence of phosphorus pentoxide. 1.28 g of pure hydrochloride are finally isolated.

Melting point 161-162‘C.

Table 1 below illustrates the chemical structures and the physical properties of some compounds of general formula (II').

In the salt” column, HC1 denotes a hydrochloride and AcOH denotes an acetate; in the m.p. (*C) column, * denotes a crude product, that is to say unpurified and whose structure has as yet not been confirmed by elemental microanalysis.

Table 1 4-(2-Phenylethyl)piperidines of general formula (II') Table 1 4-(2-Phenylethyl) piperidines of general formula (II') No. r2 Salt m.p. (*C) I 2-F HCl 151-152 II 3-F HCl 171-172 III 4-F HCl 131-132 IV 4-C1 AcOH 155* v 4-CH3 HCl 160-161 VI 3-CH3 HCl 119-120 VII 4-OCH3 HCl 178-179 VIII 4-CF3 HCl 166-167 IX 2-CF3 HCl 186-187 X 3-CF3 HCl 73-74 XI 3,5-Fj HCl 161-162 XII 2,4-F2 HCl 130-131 XIII 3,4-F2 HCl 137-138 XIV 4-NHCOCHj HCl 256-258 Example 1 (Compound No. 3) (±)-6-[l-Hydroxy-2-[4-[2-(4-fluorophenyl) ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one. 4.5 g (0.02 mole) of 6-(chloroacetyl)5 3,4-dihydroquinolin-2(1H)-one, 100 ml of ethanol and 20 ml of water are placed in a round bottom flask. 4.9 g (0.02 mole) of 4-[2-(4-fluorophenyl)ethyl]piperidine hydrochloride and then 4 g (about 0.04 mole) of sodium carbonate are added. The mixture is refluxed for 1.25 hours. It is allowed to cool and then 9 g of potassium borohydride are added. It is further stirred for 2 hours and then the mixture is allowed to stand overnight at room temperature. 200 ml of water are then added, the mixture is stirred for 1 hour and the precipitate formed is filtered. It is thoroughly washed with water and then drained and dried in a desiccator in the presence of phosphorus pentoxide. The product obtained is purified by chromatography on silica gel, eluting with a 9/1 dichloromethane/methanol mixture, and then it is recrystallised from 90 ml of ethanol.

It is dried in a desiccator in the presence of phosphorus pentoxide and then under vacuum at 80’C. 5.33 g of compound are obtained.

Melting point: 159-160'C.

Example 2 (Compound No. 4) ( + )-6-[l-Hydroxy-2-[4-[2-(4-chlorophenyl) ethyl]2 5 1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one. 2.1. 4-[2-(4-Chlorophenyl)ethyl]piperidine, hydrochloride. .14 g (0.08 mole) of 4-[2-(4-chlorophenyl)ethyl]1-(phenylmethyl)piperidine in solution in 100 ml of anhydrous dichlororoethane and 8.4 ml (0.088 mole) of ethyl chloroformate are introduced into a round bottom flask. The mixture is refluxed for 3.5 hours. The solvent is evaporated and the residue is purified by chromatography on a silica gel column, eluting with isopropyl ether. A pale oil is recovered to which 50 ml of an aqueous solution of sodium hydroxide at 30 % by volume and 100 ml of ethanol are added. The mixture is heated at 80*C for 26 hours. It is evaporated to dryness and then the residue is taken up in a solution of 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride. The mixture is extracted three times with ethyl acetate and then the organic phase is washed with a saturated aqueous solution of sodium chloride until a neutral pH is obtained. 5 ml of concentrated hydrochloric acid are added to the organic phase and it is then evaporated to dryness: a product crystallises.

An azeotropic entrainment is carried out with ethanol, the precipitate is taken up in ether, the mixture is filtered and the precipitate is washed with ether and then dried in a desiccator in the presence of phosphorus pentoxide. 8.35 g of hydrochloride are obtained which are used as such in the next stage. 2.2 (±)-6-[l-Hydroxy-2-[4-[2-(4-chlorophenyl)ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one. 3.35 g (0.015 mole) of 6-chloroacetyl3,4-dihydroquinolin-2(1H)-one, 3.90 g (0.015 mole) of 4-[2-(4-chlorophenyl)ethyl]piperidine hydrochloride and 4.24 g (0.04 mole) of sodium carbonate in a solution of 80 ml of ethanol and 20 ml of water are placed in a 500-ml round bottom - 26 flask. The mixture is refluxed for 1 hour. It is allowed to cool to room temperature and then 7.25 g of potassium borohydride are added. The mixture is stirred and then allowed to stand overnight. 160 ml of water are then added, the mixture is stirred and the precipitate is collected by filtration. It is washed with water, drained and dried in a desiccator in the presence of phosphorus pentoxide. The product obtained is recrystallised from 350 ml of ethanol and then it is again recrystallised from 80 ml of propanol. 4.12 g of compound are obtained.

Melting point: 189-190‘C.

Example 3 (Compound No. 18) (±)-8-Fluoro-6-[l-hydroxy-2-[4-[2-(4-fluorophenyl)ethyl]15 1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one. 3.6 g (0.015 mole) of 6-(chloroacetyl)-8-fluoro3,4-dihydroquinolin-2 (1H)-one, 3.65 g (0.015 mole) of 4-[2-(4-fluorophenyl)ethyl]piperidine hydrochloride and 3 g (about 0.03 mole) of sodium carbonate in a mixture of 80 ml of ethanol and 20 ml of water are placed in a round bottom flask. The mixture is refluxed for 1.25 hours. It is cooled and then 7 g of potassium borohydride are added. The mixture is stirred for 3 hours and then allowed to stand overnight. 160 ml of water are added, the mixture is stirred for 30 minutes and then the precipitate is collected by filtration. It is washed with water, dried in a desiccator in the presence of phosphorus pentoxide and then purified by chromatography on a silica gel column, eluting with a 9/1 dichloromethane/methanol mixture.

The product is recrystallised from 70 ml of 2-propanol and then dried at 80*C in the presence of potassium hydroxide. 2.93 g of compound are obtained.

Melting point: 163-164’C.

Example 4 (Compound No. 10) (±)-6-[1-Hydroxy-2-[4-(3-phenylpropyl)-1-piperidyl)ethyl)-3,4dihydroguinolin-2 (IH)-one. 3.35 g (0.015 mole) of 6-(chloroacetyl)3,4-dihydroguinolin-2(lH)-one in solution in 100 ml of ethanol and 20 ml of water, 3.05 g (0.015 mole) of 4-(3-phenylpropyl)piperidine and 2.12 g (0.02 mole) of sodium carbonate are placed in a 500-ml round bottom flask. The mixture is refluxed for 1 hour. It is allowed to cool to room temperature and then 6.4 g of potassium borohydride are added.

The mixture is stirred and then allowed to stand overnight at room temperature. 200 ml of water are added and the mixture is stirred; the precipitate formed is filtered, thoroughly washed with water and dried in a desiccator in the presence of phosphorus pentoxide and then recrystallised from ethanol. 4.04 g of compound are obtained after drying.

Melting point: 164-165'C.

Example 5 (Compound No. 11) (+)-6-[1-Hydroxy-2-[4-(2-phenyl-2-oxoethyl)-1-piperidyl)ethyl]25 3,4-dihydroquinolin-2(IH)-one. .1. 1-Pheny1-2-(1-(phenylmethyl)-4-piperidyl]ethanone. 2.35 g (0.0966 at.-g) of magnesium turnings and 40 ml of diethyl ether are introduced into a 500-ml round bottom flask and the mixture is stirred slowly and 1 ml of bromobenzene and then an iodine crystal are added. The stirring is increased and 9.2 ml of bromobenzene (equivalent to a total of 0.0966 mole) in 20 ml of diethyl ether are added at reflux temperature. The reflux is maintained for 30 minutes and then the mixture is allowed to cool to room temperature. A solution of 10 g (0.0466 mole) of l-(phenylmethyl)4-piperidineacetonitrile in 10 ml of diethyl ether is then gently added while heating so as to maintain a slight reflux.

The reflux is maintained for 3.25 hours. The mixture is cooled in an ice-cold bath and 100 ml of water and then 50 ml of 5 N hydrochloric acid are slowly added and the mixture is stirred for 1.5 hours at room temperature. A precipitate is formed which is recovered by filtration and washed with water. After drying in the presence of phosphorus pentoxide, 15.8 g of product are obtained which are used as such in the next stage. .2. 4-[(2-Phenyl-1,3-dioxolan-2-yl)methyl)1-(phenylmethyl)piperidine. .8 g (0.0466 mole) of 1-phenyl2-[1-(phenylmethyl)-4-piperidyl]ethanone in solution in 150 ml of toluene are introduced into a round bottom flask. 30 g k27 ml) of ethylene glycol and 16 g of 4-methylbenzenesulphonic acid are added. The mixture is refluxed for 3.5 hours using a Dean-Stark apparatus. The toluene is evaporated under reduced pressure and 150 ml of ethyl acetate and then 50 ml of a solution of ammonium hydroxide at 30 % by volume are added. The mixture is stirred, decanted and extracted a second time with ethyl acetate and the organic phases are pooled, washed with a saturated solution of sodium chloride, dried over sodium sulphate and the solvent is evaporated under reduced pressure. 14.56 g of an oil are obtained which are used as such in the next stage. .3. 4-((2-Phenyl-l,3-dioxolan-2-yl)methyl]piperidine. 14.56 g (0.043 mole) of 4-((2-phenyl-l,3-dioxolan2-yl)methyl]-l-(phenylmethyl)piperidine in solution in 100 ml of ethanol and 20 ml of water are introduced into a Parr apparatus. 1 g of 10 % palladium on carbon is added. The mixture is hydrogenated at 0.35 MPa and at 50’C for 5 hours.

The catalyst is separated by filtration and washed with water and with ethanol; the filtrate is recovered and the solvent evaporated under reduced pressure. 10.26 g of an oil are obtained which are used as such in the next stage. .4. (+)-6-(l-Hydroxy-2-(4-((2-phenyl-l,3-dioxolan2-yl) methyl)-1-piperidyl) ethyl]-3,4-dihydroquinolin2 (IK) -one. .13 g (0.0207 mole) of 4-((2-phenyl-l,3-dioxolan2-yl)methyl]piperidine in solution in 100 ml of ethanol and 20 ml of water, 4.64 g (0.0207 mole) of 6-(chloroacetyl) 3,4--dihydroquinolin-2 (IH) -one and 2.2 g (0.0207 mole) of sodium carbonate are placed in a 500-ml round bottom flask. The mixture is heated at 80'C for 1.25 hours. It is allowed to cool to room temperature and then 9.8 g of potassium borohydride are added. The stirring is continued at room temperature and then the mixture is allowed to stand overnight. 200 ml of water are then added. The mixture is stirred and then the beige precipitate formed is filtered. This precipitate is washed with water and drained. 7.54 g of a moist compound are obtained which are used as such in the next stage. .5. (±)-6-[l-Hydroxy-2-[4-(2-phenyl-2-oxoethyl)-l-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one. 7.54 g (0.0173 mole) of 6-[1-hydroxy2-[4-[(2-phenyl-l,3-dioxolan-2-yl)methyl]-1-piperidyl]ethyl]3,4-dihydroguinolin-2(1H)-one are introduced into a 500-ml round bottom flask. The compound is suspended in 150 ml of a normal aqueous solution of hydrochloric acid, 50 ml of ethanol are added and the mixture is heated at 80'C for 1 hour and then at 100’C for 1 hour. It is evaporated to dryness and a gummy residue is obtained which is taken up in a mixture of 25 ml of ethanol, 25 ml of ethyl acetate and 150 ml of an ammoniated solution (26 to 28 % of ammonium hydroxide by volume). The mixture is stirred at room temperature for 1 hour and then the chestnut-coloured precipitate obtained is filtered. It is dried in a desiccator in the presence of phosphorus pentoxide and then purified by chromatography on a silica gel column, eluting with a 9/1 dichloromethane/methanol mixture. The product obtained is recrystallised from 45 ml of propanol. 1.45 g of compound are obtained.

Melting point: 186-187’C.

Example 6 (Compound No. 13) (±) — 6 — [l-Hydroxy-2-[4-[2-(4-fluorophenyl)-1-oxoethyl]1-piperidylJ ethylj-3,4-dihydroquinolin-2(1H)-one. 6.1. 2-(4-Fluorophenyl)-3-hydroxy-3-[1-(phenylmethyl) 4-piperidyl]prop-2-enenitrile. 13.5 g (0.1 mole) of (4-fluorophenyl)acetonitrile, 50 ml of toluene and 4.4 g of sodium amide are introduced into a 500-ml round bottom flask. The mixture is stirred at room temperature for 30 minutes and then 27.2 g (0.11 mole) of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate are added by means of a dropping funnel. After the addition is completed, the mixture is heated at 80*C for 3 hours. It is then cooled in an ice bath and 300 ml of water are added, the mixture is stirred for 30 minutes and 15 ml of acetic acid are added. A yellow precipitate is obtained which is separated by filtration, washed with water and dried in the presence of phosphorus pentoxide. 17.6 g of compound are obtained which are used as such in the next stage. 6.2. 2-(4-Fluorophenyl)-1-[1-(phenylmethyl)4-piperidyl]ethanone. ml of water, 50 ml of concentrated sulphuric acid and 50 ml of acetic acid are introduced into a 500-ml round bottom flask placed in a water and ice bath and 24.4 g (0.072 mole) of 2-(4-fluorophenyl)-3-hydroxy3-[1-phenyImethyl)-4-piperidyl]prop-2-enenitrile are added. The mixture is refluxed for 12 hours. The round bottom flask is cooled in a water and ice bath. 200 ml of ice are introduced into a 1-litre Erlenmeyer flask and the mixture prepared above is slowly added? 200 ml of ethyl acetate are added together with 200 ml of ammonium hydroxide in order to adjust the pH to 9. The mixture is decanted, the organic phase is recovered and the aqueous phase is extracted three times with 150 ml of ethyl acetate. The organic phases are pooled and they are washed three times with 150 ml of water until a pH of 7 to 8 is obtained. The organic phase is dried over sodium sulphate and filtered and the ethyl acetate is evaporated under reduced pressure. 20.7 g of oily compound are obtained which are used as such in the next stage. 6.3. 4-[2-[(4-Fluorophenyl)methyl]-l,3-dioxolan-2-yl)-110 (phenylmethyl)piperidine. .35 g (0.033 mole) of 2-(4-fluorophenyl)1-[1-(phenylmethyl)-4-piperidyl]ethanone, 100 ml of toluene, g of ethylene glycol and 10.35 g of 4-methylbenzenesulphonic acid are introduced into a 500-ml round bottom flask equipped with a Dean-Stark apparatus and the mixture is refluxed for 1.75 hours. The toluene is evaporated and the residue is taken up in 200 ml of ethyl acetate. 100 ml of a 30 % solution of ammonium hydroxide are added and the organic phase is decanted, washed three times with 100 ml of water and dried and the solvent is evaporated under reduced pressure. 13.4 g of an oily product are obtained which are used as such in the next stage. 6.4. 4-[2-[(4-Fluorophenyl) methyl]-1,3-dioxolan-2-yl]piperidine. 13.4 g (0.033 mole) of 4-[2-[(4-fluorophenyl ) methyl]-1,3-dioxolan-2-yl)-1-(phenylmethyl) piperidine in solution in 100 ml of ethanol and 20 ml of water are introduced into a Parr apparatus and 2 g of 10 % palladium on carbon are added and hydrogenation is carried out at 50*C at a hydrogen pressure of 0.35 MPa for 5 hours. The catalyst is separated by filtration and washed with water and with ethanol, the filtrate is evaporated under reduced pressure and the residue is dried under vacuum. 9.74 g of an oily compound are obtained which crystallise and which are used as such in the next stage. 6.5. (±)-6-[l-Hydroxy-2-[ 4- [2-(4-fluorophenyl)-1,3-dioxolan2-yl]-1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one. 4.37 g (0.0165 mole) of 4-(2-[(4-fluoro10 phenyl)methyl]-1,3-dioxolan-2-yl]piperidine in solution in 80 ml of ethanol and 20 ml of water are introduced into a 500-ml round bottom flask. 3.69 g (0.0165 mole) of 6(chloroacetyl)-3,4-dihydroguinolin-2(IH)-one and 2 g (about 0.02 mole) of sodium carbonate are added. The mixture is refluxed for 50 minutes. The mixture is cooled and then 8.56 g of potassium borohydride are added. The stirring is continued at room temperature and then the mixture is allowed to stand overnight at room temperature. 160 ml of water are added and the mixture is stirred for 30 minutes. The precipitate is separated by filtration and washed with water. 8.14 g of moist product are obtained which are used as such in the next stage. 6.6. (+)-6-[l-Hydroxy-2-[4-[2-(4-fluorophenyl)-1-oxoethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one. 7.5 g (0.0165 mole) of 6-[l-hydroxy-2-[4-[2-(4fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidyl]ethyl]3,4-dihydroguinolin-2(IH)-one in suspension in 150 ml of a normal aqueous solution of hydrochloric acid are introduced into a 500-ml round bottom flask. 50 ml of ethanol are added - 34 and the mixture is stirred at 80’C for 1 hour. It is allowed to cool and then evaporated to dryness. The crystallised residue is taken up in a mixture of 25 ml of ethanol, 25 ml of ethyl acetate and 150 ml of an ammoniated aqueous solution (26 to 28 % ammonium hydroxide by volume). The mixture is stirred at room temperature for 2 hours and filtered and the residue is taken up in ethanol. The mixture is stirred, a small amount of water is added and the insoluble matter is separated by filtration. The product is dried in a desiccator in the presence of phosphorus pentoxide and then purified by chromatography on a silica gel column, eluting with a 70/15/15 dichloromethane/methanol/ethyl acetate mixture. The product is recrystallised from 10 ml of propanol and dried. 0.8 g of compound is obtained.

Melting point: 171-172 °C.

Example 7 (Compound No. 15) (±)-8-Fluoro-6-[1-hydroxy-2-[4-(2-phenylethyl)-1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one. 7.1. N-(2-Fluorophenyl)-3-phenylprop-2-enamide.

A round bottom flask containing a solution of 33.3 g (0.3 mole) of 2-fluorobenzeneamine in 300 ml of toluene is introduced into an ice bath. 25.5 ml of pyridine are added followed dropwise by a solution of 50 g (0.3 mole) of phenylprop-2-enoyl chloride in 300 ml of toluene. The mixture is stirred for 1 hour while maintaining the round bottom flask in the ice bath, and then the mixture is allowed to stand overnight at room temperature. The precipitate formed is filtered, washed with water and then with petroleum ether and dried in a desiccator in the presence of phosphorus pentoxide. 36.2 g of compound are obtained.

Melting point: 116*C. 7.2. 8-Fluoroquinolin-2(1H)-one. g (0.141 mole) of N-(2-fluorophenyl) 3-phenylprop-2-enamide are suspended in 180 ml of chlorobenzene. 93 g (0.7 mole) of aluminium chloride are added, with stirring, in small fractions. The mixture is then refluxed for 3.5 hours. It is slightly cooled and slowly poured into 1 litre of a water/ice mixture while stirring. The precipitate obtained is washed with water and then with petroleum ether. It is dried in a desiccator in the presence of phosphorus pentoxide. 22.5 g of compound are obtained.

Melting point: 193”C. 7.3. 8-Fluoro-3,4-dihydroquinolin-2(1H)-one. g (0.134 mole) of 8-fluoroquinolin-2(1H)-one are introduced into a mixture of 100 ml of ethanol and 50 ml of a normal aqueous solution of hydrochloric acid containing 2 g of 10 % palladium on carbon, and hydrogenation is carried out at 50’C at a pressure of 0.35 MPa for 10 hours. The suspension is filtered in the heated state and the catalyst is washed with hot ethanol. A white mass crystallises from the filtrate. It is evaporated to dryness and the residue is triturated with a small amount of petroleum ether. The mixture is filtered, drained and then dried in a desiccator. 17.85 g of compound are obtained. - 36 Melting point: 140’C. 7.4. 6-(Chloroacetyl)-8-fluoro-3,4-dihydroquinolin-2 (IH)-one. 42.4 g (0.318 mole) of aluminium chloride, 30 ml of 5 dichloromethane and 23.9 g, equivalent to 17 ml (0.212 mole) of chloroacetyl chloride are placed in a 500-ml round bottom flask. The mixture is stirred at room temperature for 30 minutes and then 17.5 g (0.106 mole) of 8-fluoro3.4- dihydroquinolin-2(IH)-one are added rapidly and in small fractions. It is heated at 80*C for 3.5 hours. A blackish solution is obtained which is poured slowly into 1 litre of a water/ice mixture. The mixture is stirred for 15 minutes and the precipitate is collected by filtration, thoroughly washed with water, drained and dried in a desiccator. 25 g of compound are obtained.

Melting point: 194CC. 7.5. (±)-8-Fluoro-6-[l-hydroxy-2-[4-(2-phenylethyl)1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one. 3.62 g (0.015 mole) of 6-(chloroacetyl)-8-fluoro3.4- dihydroquinolin-2(IH)-one, 3.38 g (0.015 mole) of 4-(2-phenylethyl)piperidine hydrochloride and 4 g (about 0.04 mole) of sodium carbonate are placed in a round bottom flask. 80 ml of ethanol and 20 ml of water are added. The mixture is refluxed for one hour. It is cooled and then 7 g of potassium borohydride are added all at once. The mixture is stirred at room temperature for 2.5 hours. 150 ml of water are added, the mixture is stirred and then the precipitate formed is filtered. It is dried, recrystallised from 50 ml of - 37 2-propanol and dried. 2.5 g of solid are obtained.

Melting point: 138-140’C.

Example 8 (Compound No. 17) (±)-8-Fluoro-6-[l-hydroxy-2-[4-[2-(3-fluorophenyl) ethyl]1-piperidyl]ethyl]-3,4-dihydroguinolin-2(IH)-one. 3.6 g (0.015 mole) of 6-(chloroacetyl)-8-fluoro3,4-dihydroquinolin-2(IH)-one, 3.6 g (0.015 mole) of 4-[2-(3-fluorophenyl)ethyl]piperidine hydrochloride, 3 g (about 0.03 mole) of sodium carbonate and a mixture of 80 ml of ethanol and 20 ml of water are placed in a round bottom flask. The mixture is refluxed for 1.5 hours. It is cooled and then 7 g of potassium borohydride are added. The mixture is stirred overnight at room temperature, poured into 160 ml of water and stirred for 1 hour. The precipitate formed is then filtered, washed with water, drained and dried in a desiccator in the presence of phosphorus pentoxide. 4.9 g of product are obtained which are purified by chromatography on a silica gel column, eluting with a 9/1 dichloromethane/methanol mixture. 4 g of an oily product are obtained which crystallise and which are recrystallised from 30 ml of 2-propanol. 2.4 g of pure compound are obtained after drying.

Melting point: 116-117*C.

Example 9 (Compound No. 9, 9a and 9b) (±)-6-[l-Hydroxy-2-[4-[2-[4-(trifluoromethyl) phenyl]ethyl] — 1-piperidyl]ethyl]-3,4-dihydroquinolin-2(lH)-one and its (-) and (+) enantiomers. 9.1. (±)-6-(l-Hydroxy-2-[4-[2-[4-(trifluoromethyl) phenyl]ethyl]-1-piperidyl]ethyl]-3,4-dihydroquinolin-2 (1H)-one. 22.3 g (0.1 mole) of 6-(chloroacetyl)3,4-dihydroquinolin-2(1H)-one , 29.3 g (0.1 mole) of 4-(2-(4-(tri fluoromethyl) phenyl)ethyl]piperidine hydrochloride, 21.2 g (0.2 mole) of sodium carbonate, 400 ml of ethanol and 100 ml of water are introduced into a 1-litre round bottom flask and the mixture is heated in an oil bath (bath temperature: 120°C) for 1 hour. It is cooled using a cold water bath, poured into 800 ml of water and the chestnut-coloured precipitate is separated by filtration and washed with water, and 4 g of this intermediate ketone are collected for other uses.

The rest is taken up in 400 ml of ethanol and 100 ml of water, 80 g of potassium borohydride are added and the mixture is stirred for two days at room temperature.

The mixture is poured into 800 ml of water and stirred for 30 minutes and the precipitate is filtered, washed with water and dried in the presence of phosphorus pentoxide. 34.64 g of product are obtained which are recrystallised from 440 ml of 2-propanol and 31.18 g of product are obtained after drying in the presence of phosphorus pentoxide. g of it are collected for separation of the enantiomers and the remaining 11.18 g are recrystallised for the last time from 120 ml of 2-propanol. 9.94 g of purified compound are finally isolated after drying in the presence of phosphorus pentoxide.

Melting point: 163-164 °C. - 39 9.2. (-)-6-[1-Hydroxy-2-[4-[2-[4-(trifluoromethyl)phenyl]ethyl]-1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one. g (0.0448 mole) of (±)-6-[l-hydroxy2-[4-[2-[4-(trifluoromethyl) phenyl) ethyl]-1-piperidyl]ethyl]5 3,4-dihydroquinolin-2(IH)-one, 6.8 g (0.0448 mole) of L(+)mandelic acid and 100 ml of ethanol are introduced into an Erlenmeyer flask. The mixture is stirred, thus forming into a mass, it is refluxed and ethanol is added until the salt dissolves, equivalent to about 1500 ml of ethanol.

The mixture is filtered in the heated state and the filtrate is heated in order to redissolve the precipitate; 60 ml of ethanol are added in order to obtain a clear solution which is allowed to stand, without stirring, at room temperature for 4 hours.

The crystals formed are filtered, washed with a small amount of ethanol and dried in the presence of phosphorus pentoxide. 14.56 g of product are obtained which are recrystallised two times from ethanol thus leaving 7.09 g of salt.

Melting point: 234-234.5’C.

The base is released in a conventional manner in dichloromethane and using agueous ammonium hydroxide. After separation of the organic phase and evaporation of the solvent, the base is recrystallised from 50 ml of propanol and dried in the presence of phosphorus pentoxide. 4.34 g of compound are finally isolated.

Melting point: 172-173’C. [a]20 = -34.0’ (c = 1.0; CHClj). 9.3. (+)-6-(l-Hydroxy-2-[4-[2-[4 -(trifluoromethyl)phenylethyl ]-1-piperidyl ] ethyl]-3 ,4-dihydroquinolin-2(IH)-one.

All the mother liquors from the preceding stage are pooled, the solvent is evaporated, dichloromethane and ammonium hydroxide are added to the evaporation residue, the organic phase is separated and the solvent is evaporated. g (0.0336 mole) of base are obtained which are suspended in 100 ml of ethanol, 5.11 g of D(-)-mandelic acid are added, the mixture is refluxed and ethanol is added until the salt dissolves, equivalent to about 1300 ml of ethanol.

The mixture is filtered in the heated state, the filtrate is 10 heated in order to redissolve the precipitate and the solution is allowed to stand, without stirring, at room temperature for hours.

The crystals formed are filtered, washed with a small amount of ethanol and dried in the presence of phosphorus pentoxide. .96 g of product are obtained which are recrystallised twice from ethanol thus leaving 6.11 g of salt.

Melting point: 234-235’C.

The base is released in a conventional manner in dichloromethane and using aqueous ammonium hydroxide. After separation of the organic phase and evaporation of the solvent, the base is recrystallised from 50 ml of propanol and dried in the presence of phosphorus pentoxide. 3.78 g of compound are finally isolated.

Melting point: 174-175’C. [a]20 = +35.0’ (c = 1.0; CHClj). - 41 Example 10 (Compound No. 51) (±)-6-[l-Hydroxy-2-[4-(2-(4-(acetylamino)phenyl]ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2 (1H)-one. 3.35 g (0.015 mole) of 6-(chloroacetyl)5 3,4-dihydroquinolin-2(1H)-one, 4.23 g (0.015 mole) of N—[4—[2— (4-piperidyl)ethyl]phenyl]acetamide hydrochloride, 3.18 g (0.03 mole) of sodium carbonate, 80 ml of ethanol and 20 ml of water are introduced into a round bottom flask and the mixture is refluxed for 2 hours.

It is allowed to cool and 7 g of potassium borohydride are added and the mixture is stirred overnight at room temperature. 160 ml of water are added, the mixture is stirred for minutes and the precipitate is separated by filtration, washed with water and dried. .5 g of product are obtained, which are recrystallised from propanol and dried at 90°C. 3.8 g of compound are finally obtained.

Melting point: 205-206’C.

Example 11 (Compound No. 39) (±)-6-[1-Hydroxy-2-[4-(2-phenylethyl)-1-piperidyl]ethyl]7-fluoro-3,4-dihydroquinolin-2(1H)-one. 11.1. N-(3-Fluorophenyl)-3-phenylprop-2-enamide. g (0.27 mole) of 3-fluorobenzenamine, 300 ml of toluene and 25 ml of pyridine are introduced into an Erlenmeyer flask, cooled using an ice bath, and then a solution of 45 g (0.27 mole) of 3-phenylprop-2-enoyl chloride in 300 ml of toluene is added dropwise without allowing the temperature to - 42 exceed 10'C.

The mixture is stirred for another 15 minutes in an ice bath and then overnight at room temperature.

A precipitate is removed by filtration and 50 ml of water are 5 added to the filtrate and the mixture is vigorously stirred for hour. The precipitate is separated by filtration, washed with water and dried in the presence of phosphorus pentoxide. g of product are obtained.

Melting point: 115*C. 11.2. 7-Fluoroquinolin-2(IH)-one. g (0.211 mole) of N-(3-fluorophenyl) 3-phenylprop-2-enamide and 200 ml of chlorobenzene are introduced into a round bottom flask followed by 140 g (1.05 mole) of aluminium chloride in small fractions, the mixture is refluxed for 4 hours and allowed to stand overnight. It is poured into a mixture of water and ice and filtered, and the solid is washed with water and then with petroleum ether and allowed to dry in the open air. 34 g of compound are obtained. 11.3. 7-Fluoro-3,4-dihydroguinolin-2(IH)-one. g (C.208 mole) of 7-fluoroquinolin-2(IH)-one, 150 ml of ethanol, 50 ml of 1 N hydrochloric acid and 3 g of % palladised carbon are introduced into a Parr flask and hydrogenation is carried out at 0.42 MPa at 50*C for 16 hours. The catalyst is separated by filtration, the filtrate is evaporated and the white residue is triturated with 50 ml of ethanol, separated by filtration and dried in the presence of phosphorus pentoxide. 27.03 g of product are obtained which are used as such in the next stage. 11.4. 6-(Chloroacetyl)-7-fluoro-3,4-dihydroquinolin5 2(lH)-one. g (0.49 mole) of aluminium chloride, 50 ml of dichloromethane and 26 ml (0.327 mole) of chloroacetyl chloride are introduced into a 500-ml round bottom flask and the mixture is stirred at room temperature for 30 minutes. 27 g (0.163 mole) of 7-fluoro-3,4-dihydroquinolin-2(IH)-one are then added in small fractions and the mixture is refluxed for 4 hours and allowed to stand overnight at room temperature.

It is slowly poured into 300 ml of ice-cold water, the mixture is stirred for 10 minutes and the precipitate is separated by filtration, washed with water and then with hexane, drained and dried in the presence of phosphorus pentoxide. g of product are obtained which are used as such in the next stage. 11.5. (±)-6-[l-Hydroxy-2-[4-(2-phenylethyl)-l-piperidyl]ethyl]-7-fluoro-3,4-dihydroquinolin-2(IH)-one. 3.6 g (0.015 mole) of 6-(chloroacetyl)-7-fluoro3,4-dihydroguinolin-2(IH)-one, 3.38 g of 4-(2-phenylethyl)piperidine hydrochloride, 3.18 g (0.03 mole) of sodium carbonate, 160 ml of water, 40 ml of water and 50 ml cf Ν,Ν-dimethylformamide are introduced into a round bottom flask and the mixture is stirred at room temperature for 3 days. g of potassium borohydride are added and the mixture is - 44 stirred overnight at room temperature. It is poured into 350 ml of water, the mixture is stirred for 30 minutes and the precipitate is separated by filtration, dried and purified by chromatography on a silica gel column, eluting with a 9/1 dichloromethane/ methanol mixture, recrystallised from 60 ml of propanol and dried in the presence of phosphorus pentoxide. 1.48 g of compound are finally obtained.

Melting point: 199-200*C.

Example 12 (Compound No. 36) (+)-6-(l-Hydroxy-2-[4-[2-(2-methylphenyl) ethyl]1- piperidyl]ethyl]-8-methyl-3,4-dihydroquinolin-2(lH)-one. 12.1. K-(2-Methylphenyl)-3-phenylprop-2-enamide. 32.15 g (0.3 mole) of 2-methylbenzeneamine, 300 ml of toluene and 25.5 ml of pyridine are introduced into a 2- litre round bottom flask cooled using an ice bath, and then a solution of 50 g (0.3 mole) of 3-phenylprop-2-enoyl chloride in 300 ml of toluene is added dropwise.

The ice bath is removed and then the mixture is stirred for 3.5 hours at room temperature and allowed to stand overnight.

A white precipitate is obtained which is separated by filtration, washed several times with water and then with diethyl ether and dried in the presence of phosphorus pentoxide. 69.47 g of product are obtained.

Melting point: 166*C. 12.2. 8-Methylquinolin-2(1H)-one. 67.5 g (0.284 mole) of N-(2-methylphenyl)3-phenylprop-2-enamide and 370 ml of chlorobenzene are introduced into a 2-litre round bottom flask; the mixture is stirred and 188.1 g (1.409 mole) of aluminium chloride are added in small fractions. The mixture is refluxed for 4 hours and allowed to stand overnight.

It is slowly poured into 1 litre of water and ice and the chestnut-coloured precipitate is separated by filtration, washed several times with water and then with hexane, and dried in the presence of phosphorus pentoxide. 42.76 g of compound are obtained.

Melting point: 224'C. 12.3 . 8-Methyl-3,4-dihydroquinolin-2(IH)-one. 42.76 g (0.266 mole) of 8-methylguinolin-2(IH)-one, 200 ml of ethanol, 100 ml of 1 N hydrochloric acid and 4.2 g of 10 % palladised carbon are introduced into a Parr flask and hydrogenation is carried out at 0.25 MPa at 50 *C for 15 hours. The catalyst is separated by filtration in the heated state, by washing it with hot ethanol, the filtrate is evaporated and the residue is washed with petroleum ether and dried in the presence of phosphorus pentoxide. 38.15 g of product are obtained which are used as such in the next stage.

Melting point: 131-132’C. 12.4. 6-(Chloroacetyl)-8-methyl-3,4-dihydroquinolin2(IH)-one. 57.21 g (0.429 mole) of aluminium chloride, 45 ml of dichloromethane and 32.32 g, equivalent to 22.8 ml, (0.286 mole) of chloroacetyl chloride are introduced into a 500-ml round bottom flask and the mixture is stirred at room temperature for 30 minutes. 23.02 g (0.286 mole) of 8-methyl3,4-dihydroquinolin-2(1H)-one are then added in small fractions and the mixture is refluxed for 3.5 hours.

It is slowly poured into 1 litre of ice-cold water, the mixture is stirred for 10 minutes and the chestnut-coloured precipitate is separated by filtration, washed several times with water and then with petroleum ether, drained and dried in the presence of phosphorus pentoxide. 33.45 g of product are obtained which are used as such in the next stage. 12.5. (±)-6-[l-Hydroxy-2-[4-[2-(2-methylphenyl)ethyl]15 1-piperidyl]ethyl]-8-methyl-3,4-dihydroquinolin2 (1H) -one. 3.56 g (0.015 mole) of 6-(chloroacetyl)-8-methyl3,4-dihydroquinolin-2(1H)-one, 3.6 g (0.015 mole) of 4-[2(2-methylphenyl)ethyl]piperidine hydrochloride, 4.24 g (0.04 mole) of sodium carbonate, 100 ml of ethanol and 20 ml of water are introduced into a 500-ml round bottom flask and the mixture is refluxed for 1 hour.

The mixture is cooled, 7.16 g of potassium borohydride are added and the mixture is stirred overnight at room temperature. 200 ml of water are added, the mixture is stirred for minutes and the precipitate is separated by filtration, dried and purified by chromatography on a silica gel column, eluting with a 9/1 dichloromethane/ methanol mixture. 4.09 g of product are obtained which are recrystallised from 130 ml of propanol and dried in the presence of phosphorus pentoxide. 3.68 g of product are obtained which are recrystallised for a second time from 325 ml of ethanol. 3.29 g of compound are finally obtained.

Melting point: 185-186’C.

Example 13 (Compound No. 40) (±)-6-[l-Hydroxy-2-[4-[2-(3,5-difluorophenyl)ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one. 3.35 g (0.015 mole) of 6-(chloroacetyl)3,4-dihydroguinolin-2(IH)-one, 3.9 g (0.015 mole) of 4-[2-(3,5-difluorophenyl)ethyl]piperidine hydrochloride, 80 ml of ethanol and 20 ml of water are introduced into a round bottom flask and the mixture is refluxed for 2 hours.

It is allowed to cool, 7 g of potassium borohydride are added and the mixture is stirred overnight at room temperature. 160 ml of water are added, the mixture is stirred for 15 minutes and the solid is separated by filtration, washed with water and then with hexane, dried and purified by chromatography on a silica gel column, eluting with a 9/1 dichloromethane/methanol mixture. 3.7 g of product are obtained which are recrystallised from 60 ml of ethanol. 3.08 g of compound are finally isolated after drying.

Melting point: 173-174‘C.

The following table illustrates the chemical structures and the physical properties of some compounds of general formula (I).

All the compounds are in the racemic state except compounds No 9a and No. 9b which are the laevorotatory and dextrorotatory enantiomers of compound No. 9, respectively.

In the salt*' column, denotes a compound in the form of a base, wfum.M denotes a compound in the form of a fumarate and ox. denotes a compound in the form of an oxalate.

Table 2 Compounds of general formula (I) No . R. *2 X Y Salt m.p. (eC) 1 H 2-F ch2 ch2 - 161-162 2 H 3-F ch2 ch2 - 165-166 3 H 4-F ch2 ch2 159-160 4 H 4-C1 ch2 ch2 189-190 10 5 H 3-CH3 ch2 ch2 163-164 6 H 4-CH3 ch2 ch2 174-176 7 H 4-OH ch2 ch2 225-226 8 H 4-OCHj ch2 ch2 192-193 9 H 4-CF3 ch2 ch2 163-164 15 9a lae vorotatory enantiomer 172-173 9b dextrorotatory enantiomer 174-175 10 H H ch2 ch2ch2 164-165 11 H H ch2 co 186-187 12 H H co ch2 183-184 20 13 H 4-F co ch2 171-172 No. R: r2 X Y Salt m.p. (*C) 14 H 4.CH3 CO ch2 - 199-200 15 8-F H ch2 ch2 - 138-140 16 8-F 2-F ch2 ch2 - 139-140 17 8-F 3-F ch2 ch2 - 116-117 18 8-F 4-F ch2 ch2 - 163-164 19 8-F 4-OCH3 ch2 ch2 - 166-167 20 8-F 4-CF3 ch2 ch2 - 172-173 21 8-F 4-C1 ch2 ch2 fuir,. 215-216 22 H 3-C1 ch2 ch2 ox . 219-220 23 H 4-F ch2 co 192-193 2-4 8-F 4-F ch2 co 176-177 25 8-F 2-CH3 ch2 ch2 139-140 2 6 8-CK, H ch2 ch2 195-196 27 8-CK3 3-CF3 ch2 ch2 164-165 28 H 2-CF3 ch2 ch2 172-173 29 8-CH3 2-F ch2 ch2 166-167 30 H 2-CH3 ch2 ch2 161-162 31 8-CH3 4-F ch2 ch2 180-181 32 8-CH3 4-CFj ch2 ch2 190-191 33 8-CH3 4-CH3 ch2 ch2 206-207 34 8-F 2-CF3 ch2 ch2 123-124 35 8-CH3 2-CF3 ch2 ch2 172-173 36 8-CH3 2-CH3 ch2 ch2 185-186 37 8-CH3 3-CH3 ch2 ch2 - 186-187 No . Ri r2 X Y Salt m.p. (*C) 38 8-CHj 4-F ch2 co - 178-179 39 7-F H ch2 ch2 - 199-200 40 H 3,5-F2 ch2 ch2 - 173-174 41 8-F 3,5-F2 ch2 ch2 146-147 42 8-CH3 3,5-F2 ch2 ch2 162-163 43 7-F 2-F ch2 ch2 198-199 44 H 2,4-F2 ch2 ch2 171-172 45 H 3,4-F2 ch2 ch2 L63.5-164.5 A 6 7-F 2-CH, ch2 ch2 199-200 47 6-CH3 2,4 - F2 CK2 ch2 161-162 48 8-CH3 3,4 - F2 ch2 ch2 156-157 49 8-F 3,4 - F2 ch2 ch2 148-149 50 8-F 2.4-F2 ch2 ch2 164-165 51 H 4 - NHCOCHj ch2 ch2 205-206 52 H 4-CF3 CHj co 192-193 53 H 4-NHS02CH3 ch2 ch2 208-209 54 8-F H ch2 ch2ch2 131-132 55 8-CH3 H ch2 ch2ch2 152-153 The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof have been the subject of pharmacological trials which have demonstrated their usefulness as active substances of neuroprotective medicinal products.

From herein the compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof are referred to as the active compounds of the invention.

Thus, in particular, the neuroprotective activity 10 of the active compounds of the invention has been shown in a focal ischaemia model by ligature of the middle cerebral artery in mice according to a method similar to that described in Brain Research, 522, (1990), 290-307.

Six days after occlusion of the middle cerebral artery by 15 electrocoagulation under halothane anaesthesia, the mice are again anaesthetised and the cerebral cortex ipsilateral to the occlusion is removed. After homogenisation of the tissue, the extent of the cerebral infarction is evaluated by measuring the increase in the density of peripheral benzodiazepine sites (0J3) using the compound [3H]PK 11195 from New England Nuclear. The treatments are curatively administered via the intraperitoneal route at the following times: 5 minutes, 3 hours, 6 hours, hours and 24 hours.

Some active compounds of the invention decrease the density of the peripheral benzodiazepine sites by about 70 % at a dose of 10 mg/kg.

The active compounds of the invention have also been the subject of a test of inhibition of the binding of [3H)ifenprodil to rat cerebral cortex polyamine-sensitive receptors, according to the procedure described by Schoemaker et al., Eur. J. Pharmacol , 176, 249-250, (1990).

The 150- to 230-g male Sprague-Dawley rat is sacrificed and the cerebral cortex is homogenised in 20 volumes of ice-cold 50 mM Tris-HCl buffer (pH 7.4 at 0*C), by means of an Ultra-Turrax™ (Ikawerk) or Polytron™ (Kinematica) apparatus.

The homogenate is washed twice by centrifuging for 10 minutes at 45000 x g, the pellet being resuspended in fresh buffer. The final pellet is taken up in 20 volumes of the same buffer. Α 100-μ1 aliquot of this suspension is incubated in a final volume of 1000 μΐ with 1 nM of [3H] ifenprodil (specific activity: 30 to 35 Ci/mmol) for 120 minutes at 0’C, in the presence of 3 μΜ of GBR 12909 (Research Biochemicals Inc. , Natick, MA, USA), in the absence or in the presence of competing substance.

After incubation, the mixture is diluted with 5 ml of ice-cold, 50 mM Tris-HCl buffer (pH = 7.4 at 0’C) and the membranes are recovered by filtration on Whatman GF/B™ filters pretreated with 0.05 % polyethylenimine, and then washed with two times ml of ice-cold buffer.

Nonspecific binding is determined using 10 μΜ ifenprodil, the data are analysed according to the usual methods and the IC50 concentration, which inhibits the binding of [3H] ifenprodil by 50 %, is calculated.

The IC50 values range from 2 nM to 10 μΜ (2 x 109 to 1 x 10'5 M) .

The active compounds of the invention were also the subject of a test of inhibition of the binding of [3H]ifenprodil to rat cerebral cortex sigma receptors - 54 (Schoemaker et al., Eur J Pharmacol , 183, 1670, (1990).

The 150- to 230-g male Sprague-Dawley rat is sacrificed and the cerebral cortex is homogenised in 20 volumes of ice-cold 50 mM Tris-HCl buffer (pH = 7.4 at 0'C), by means of an Ultra-Turrax™ (Ikawerk) or Polytron™ (Kinematica) apparatus. The homogenate is washed twice by centrifuging for 10 minutes at 45000 x g, the pellet being resuspended in fresh buffer. The final pellet is taken up in 20 volumes of the same buffer.

A 100-μ1 aliquot of this suspension is incubated in a final volume of 1000 μΐ with 0.5 nM of [3H] ifenprodil (specific activity: 30 to 35 Ci/mmol) for 30 minutes at 37'C, in the absence or in the presence of competing substance. After incubation, the membranes are recovered by filtration on Whatman GF/B™ filters pretreated with 0.05 % polyethylenimine, and then washed with two times 5 ml of ice-cold buffer.

Nonspecific binding is determined using 10 μΜ ifenprodil, the data are analysed according to the usual methods and the IC50 concentration, which inhibits the binding of [3H]ifenprodil by 50 %, is calculated.

The IC50 values of the active compounds of the invention range from 2.5 to 800 nM (2.5 x 10'9 to 8 x 10'7 M) .

Finally, the active compounds of the invention were tested with respect to their activity towards maximum convulsions induced in mice by supermaximal electroshock.

The procedure for this test is described by E.A. Swinyard and J.H. Woodhead in Antiepileptic Drugs, Raven Press, New York, 111-126 (1982). minutes after intraperitoneal administration of the test compound, the number of mice with convulsions (extensions of the hind legs) immediately after application of an electric current (0.4 s, 60 mA, 50 Hz) using transcorneal electrodes, is noted. The results are expressed as the AD50, the dose which protects 50 % of the animals, calculated according to the method of J.T. Lichtfield and F. Wilcoxon (J. Phara Exp. Ther. , 96, 99-113 (1949)) from 3 to 4 doses each administered to a group of 8 to 10 mice.

The AD50 values of the most active compounds in this test are of the order of 10 mg/kg by the intraperitoneai route.

The results of the tests carried out on the active compounds of the invention suggest that they can be used for the treatment and prevention of cerebral disorders such as those resulting for example from an ischaemic attack, cardiac or respiratory failure, cerebral thrombosis or embolism, for the treatment of dementia resulting from multiple infarctions, for the treatment of 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, for the treatment of schizophrenia, for the treatment of cranial or spinal traumas, for the treatment of convulsive states, as antiemetics during the treatment of certain cancers with cisplatin, and for the treatment of AIDS (sec Science, 250, 1593 (1990)).

For this purpose, they may be formulated as pharmaceutical compositions, in which they are the active ingredient.

To this effect, the active compounds of the invention may be provided in all pharmaceutical forms which are suitable for enteral or parenteral administration, in - 56 combination with appropriate excipients, for example in the form of tablets, sugared pills, gelatin capsules, capsules, suppositories or in solutions or suspensions to be taken orally or injected, containing doses which permit a daily administration of 1 to 1000 mg of active substance.

Claims (12)

1. CLAIMS derivative
1. I. A compound which is a 2-(1-piperidyl)ethanol of the general formula (I) (I) in which R, represents hydrogen, halogen or methyl, R z represents one or two substituents independently chosen from halogen, (C V4 )alkyl, hydroxyl, (C V4 )alkoxy, trifluoromethyl, 15 acetylamino and methylsulphonylamino, and either X represents a CH 2 group and Y represents a CH 2 , (CH 2 ) 2 or CO group, or X represents a CO group and Y represents a CH Z group, provided that R, and R 2 are not both hydrogen when X and Y each 20 represent a CH 2 group, or a pharmaceutically acceptable acid addition salt thereof.
2. 2. A compound according to claim 1, which is in the form of a pure enantiomer or a racemic mixture.
3. 3. A compound according to claim 1 or 2, in 25 which R, represents hydrogen, fluorine or methyl and R 2 represents one or two substituents independently chosen from fluorine, chlorine, methyl, hydroxy, methoxy, trifluoromethyl, acetylamino and methylsulphonylamino.
4. 4. A compound according to any one of the - 58 preceding claims, in which the pharmaceutically acceptable acid addition salt is the fumarate or oxalate. 5. The treatment of certain cancers with cisplatin. 5 (+)-6-(l-hydroxy-2-(4-(2-(3,5-difluorophenyl) ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IH)-one. 5 (±)-6-(l-hydroxy-2-[4-[2-(4-fluorophenyl)ethyl]-1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one;
5. 5. A compound according to any one of the preceding claims which is:
6. 6. A pharmaceutical composition comprising, as active ingredient, a compound as claimed in any one of claims 1 to 5. 10 (±)-6-[l-hydroxy-2-(4-[2-(2-methylphenyl)ethyl]-1-piperidyl]ethyl]-8-methyl-3,4-dihydroquinolin-2(IH)-one? or (+)-6-[l-hydroxy-2-[4-(2-phenylethyl)-1-piperidyl]ethyl]7-fluoro-3,4-dihydroquinolin-2(IH)-one; (±)-6-[l-hydroxy-2-[4-[2-[4-(acetylamino)phenyl]ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one.; (-) - 6 - [i-hydroxy-2-[4-[2-[4-(tri fluoromethyl) phenyl]ethyl]1-piperidyl]ethyl]-3,4-dihydroguinolin-2(1H)-one; 25 (+)-6-[l-hydroxy-2-[4-[2-[4-(trifluoromethyl) phenyl]ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one; (±)-6-[l-hydroxy-2-[4-[2-[4-(trifluoromethyl) phenyl]ethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2 (1H)-one; (±)-6-[l-hydroxy-2-[4-(2-phenyl-2-oxoethyl)-1-piperidyl]ethyl]3,4-dihydroquinolin-2 (1H)-one; 15 (±)-6-[l-hydroxy-2-[4-(2-(4-fluorophenyl)-1-oxoethyl]1-piperidyl]ethyl]-3,4-dihydroquinolin-2(IK)-one; (+)-6-[l-hydroxy-2-[4-(3-phenylpropyl)-1-piperidyl]ethyl]-3,4dihydroquinolin-2 (1H)-one; (±)-6-[l-hydroxy-2-[4-[2-(4-chlorophenyl) ethyl]-1-piperidyl]ethyl]-3,4-dihydroquinolin-2 (1H)-one;
7. 7. A process for preparing a compound as claimed in claim 1, which process comprises reacting a compound of general formula (II) HN in which either A is a CH 2 group and B is a CH 2 or (CH 2 ) 2 group or A or B is a CH 2 group and the other is a 1,3-dioxolan-2,2-diyl group, and R 2 is as defined in claim 1, with a compound of general formula (III) (Hi) in which R, is as defined in claim 1, to give a compound of (IV) general formula (IV) B' in which R v R 2 , A and B are as hereinbefore defined, which compound is then reduced and, if necessary, the 1,3-dioxolan2,2-diyl group hydrolysed to a CO group to yield a compound of formula (I) and, if desired, converting the compound of formula (I) into a pharmaceutically acceptable acid addition salt.
8. 8. A process according to claim 7, in which the compound of formula (IV) is reduced with potassium borohydride. ( + )-8-fluoro-6-[l-hydroxy-2-[4-[2-(3-fluorophenyl) ethyl]20 1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one; (±)-8-fluoro-6-[l-hydroxy-2-[4-(2-phenylethyl)-1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one; (±)-8-fluoro-6-[l-hydroxy-2-[4-[2-(4-fluorophenyl)ethyl]10 1-piperidyl]ethyl]-3,4-dihydroquinolin-2(1H)-one;
9. 9. A process according to claim 7 or 8, in which, if necessary, the hydrolysis of the 1,3-dioxolan-2,2diyl group to a CO group takes place in an acidic medium.
10. 10. A compound of formula (II) KN (II) in which A and B each represent a CH 2 group and R 2 is one or 25 two substituents independently chosen from halogen, (C V4 ) alkyl, hydroxyl, (C V4 ) alkoxy, trifluoromethyl, acetylamino and methylsulphonylamino.
11. 11. A compound as claimed in any one of claims 1 to 5, for use in the treatment and prevention of cerebral disorders and in the treatment of dementia resulting from multiple infarctions, senile dementia, olivopontocerebellar atrophy and other neurodegenerative diseases, cranial or spinal traumas, convulsive states, AIDS and as an antiemetic during
12. 12. A process for the preparation of a compound of formula (I) as claimed in claim 1, substantially as hereinbefore described in any one of Examples 1 to 13.