# Patent

## Title
Cyclic amine derivatives- CCR-3 receptor antagonists

## Abstract

medicinal products containing the same which are useful as facilitators of memory and cognition and antalgic agents.

## Background
The present invention relates to new 1-aza-2-alkyl-6-aryl-cycloalkanes.

Aging of the population due to increased life expectancy has brought with it a major increase in cognitive disorders associated with normal cerebral aging and with pathological cerebral aging occurring in the course of neurodegenerative diseases such as, for example, Alzheimer's disease.

The majority of substances used today in treating cognitive disorders associated with aging act by facilitating the central cholinergic systems--either directly, as in the case of acetylcholinesterase inhibitors (tacrine, donepezil) and cholinergic agonists (nefiracetam), or indirectly, as in the case of nootropic agents (piracetam, pramiracetam) and cerebral vasodilators (vinpocetine).

Besides their cognitive properties, substances acting directly on the central cholinergic systems often have antalgic properties but also have hypothermic properties, which can be undesirable.

It has been therefore been especially valuable to synthesise new compounds that are capable of opposing the cognitive disorders associated with aging and/or of improving cognitive processes and that can possess antalgic properties without having hypothermic activity.

4-Hydroxy- or 4-oxo-substituted 1-aza-2-alkyl-6-aryl-cycloalkanes and 1-aza-2-alkyl-6-aryl-cycloalkenes have already been described in the literature (J. Org. Chem. 1988, 53, 2426; Liebigs Ann. Chem. 1986, 11, 1823; Synlett 1993, 9, 657; Tet. Lett. 1998, 39(3/4), 217), but no pharmacological activity has been described for those compounds.

More specifically, the present invention relates to compounds of formula (I): ##STR2##

wherein: -C.sub.6)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C.sub.1 -C.sub.6)alkyl group, a linear or branched (C.sub.1 -C.sub.6)acyl group, a linear or branched (C.sub.1 -C.sub.6)alkoxycarbonyl group, an aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyl group in which the alkoxy moiety is linear or branched, or a trifluoro-acetyl group, -C.sub.6)alkyl group, OR.sub.3, SR.sub.4 or NOR.sub.5, -C.sub.6)alkyl group, a linear or branched (C.sub.1 -C.sub.6)acyl group, a linear or branched (C.sub.1 -C.sub.6)alkoxycarbonyl group or an aryl-(C.sub.1 -C.sub.6)alkoxycarbonyl group in which the alkoxy moiety is linear or branched, -C.sub.6)alkyl group or an aryl group, -C.sub.6)alkyl group optionally substituted by one or more identical or different groups selected from hydroxy, amino (optionally substituted by one or two linear or branched (C.sub.1 -C.sub.6)alkyl groups) and linear or branched (C.sub.1 -C.sub.6)alkoxy, it being understood that the valency of the atoms is respected,

their isomers and addition salts thereof with a pharmaceutically acceptable acid,

with the proviso that the compounds of formula (I) are other than: a methyl, ethyl, propyl or isopropyl group, isopropyl or butyl group.

Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoric acid etc.

An aryl group is understood to be phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C.sub.1 -C.sub.6)alkyl, hydroxy, linear or branched (C.sub.1 -C.sub.6)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (C.sub.1 -C.sub.6)alkyl groups).

A heteroaryl group is understood to be an aromatic, mono- or bi-cyclic, 5- to 12-membered group containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl group may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C.sub.1 -C.sub.6)alkyl, hydroxy, linear or branched (C.sub.1 -C.sub.6)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (C.sub.1 -C.sub.6)alkyl groups). Among the heteroaryl groups there may be mentioned, without implying any limitation, thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl groups.

Preferred compounds of formula (I) are those wherein n represents 0.

The group X as defined for formula (I) is preferably an oxygen atom or a group OR.sub.3 wherein R.sub.3 represents a hydrogen atom.

The group R.sub.1 as defined for formula (I) is preferably a hydrogen atom.

The term "aryl" used in respect of the group Ar as defined for formula (I) is preferably an optionally substituted phenyl group.

The term "heteroaryl" used in respect of the group Ar as defined for formula (I) is preferably an optionally substituted thienyl group or an optionally substituted pyridyl group.

The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that a compound of formula (II): ##STR3##

wherein Ar and n are as defined for formula (I), which is reacted with a compound of formula (III): ##STR4##

wherein R.sub.2 is as defined for formula (I), ##STR5##

wherein Ar, n and R.sub.2 are as defined hereinbefore and HA represents a proton donor acid, which compound of formula (IV) is then reacted in a basic medium to yield the compound of formula (Ia), a particular case of the compounds of formula (I): ##STR6##

wherein Ar, n and R.sub.2 are as defined hereinbefore, formula R'.sub.1 -Y, wherein R'.sub.1 represents an aryl-(C.sub.1 -C.sub.6)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C.sub.1 -C.sub.6)alkyl group, a linear or branched (C.sub.1 -C.sub.6)acyl group, a linear or branched (C.sub.1 -C.sub.6)alkoxycarbonyl group, an aryl-(C.sub.1 -C.sub.6)alkoxycarbonyl group in which the alkoxy moiety is linear or branched, or a trifluoroacetyl group and Y represents a leaving group, to yield the compound of formula (Ib), a particular case of the compounds of formula (I): ##STR7##

wherein Ar, n, R'.sub.1 and R.sub.2 are as defined hereinbefore, partial reduction with the aid of an appropriate reducing agent, followed, if desired, by alkylation, acylation or esterification of the hydroxy function to yield the compound of formula (Ic), a particular case of the compounds of formula (I): ##STR8##

wherein Ar, n and R.sub.2 are as defined hereinbefore and R.sub.1 and R.sub.3 are as defined for formula (I), yield the compound of formula (Id), a particular case of the compounds of formula (I): ##STR9##

wherein Ar, n, R.sub.1 and R.sub.2 are as defined hereinbefore, compound of formula R'.sub.3 -Y, wherein R'.sub.3 represents a linear or branched (C.sub.1 -C.sub.6)alkyl group, a linear or branched (C.sub.1 -C.sub.6)acyl group, a linear or branched (C.sub.1 -C.sub.6)alkoxycarbonyl group or an aryl-(C.sub.1 -C.sub.6)alkoxycarbonyl group in which the alkoxy moiety is linear or branched and Y represents a leaving group, to yield the compound of formula (Ie), a particular case of the compounds of formula (I): ##STR10##

wherein Ar, n, R.sub.1, R.sub.2 and R'.sub.3 are as defined hereinbefore, an oxo group, yielding the compound of formula (If), a particular case of the compounds of formula (I): ##STR11##

wherein Ar, n, R.sub.1 and R.sub.2 are as defined hereinbefore, either with a chlorinating agent such as, for example, thionyl chloride to yield the compound of formula (Ig), a particular case of the compounds of formula (I): ##STR12##

wherein Ar, n, R.sub.1 and R.sub.2 are as defined hereinbefore and {character pullout} is as defined for formula (I), R.sub.4 is as defined for formula (I), to yield the compound of formula (Ih), a particular case of the compounds of formula (I): ##STR13##

wherein Ar, n, R.sub.1, R.sub.2, R4 and {character pullout} are as defined for formula (I), defined for formula (I), to yield the compound of formula (Ii), a particular case of the compounds of formula (I): ##STR14##

wherein Ar, n, R.sub.1, R.sub.2, R.sub.5 and {character pullout} are as defined hereinbefore, and (Ii) constituting the totality of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their isomers according to a conventional separation technique and are converted, if desired, into their addition salts with a pharmaceutically acceptable acid.

The compound of formula (II) is obtained by starting from the compound of formula (VI):

wherein Ar is as defined hereinbefore, which is converted into a compound of formula (VII): ##STR15##

wherein Ar and n are as defined hereinbefore, Th. Malewinskaya in Ber. 1926, 59, 2952 and T. B. Johnson, J. E. Livak in J. Am. Chem. Soc. 1936, 58, 299 Specification CH 449046, to obtain the compound of formula (I) in its enantiomerically pure form) according to a conventional resolution technique before being converted into a compound of formula (II) by reaction with trifluoroacetic anhydride.

In addition to the fact that the compounds of the present invention are new, they exhibit properties facilitating cognitive processes and antalgic properties, rendering them of use in the treatment of cognitive deficiencies associated with cerebral aging and with neurodegenerative pathologies, such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoffs disease and frontal lobe and subcortical dementias and in the treatment of pain.

The invention relates also to pharmaceutical compositions comprising as active ingredient a compound of formula (I) together with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) and nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.

The dosage used can be adapted to the nature and the severity of the disorder, the administration route and the age and weight of the patient. The dosage varies from 1 to 500 mg per day in one or more administrations.

The following Examples illustrate the invention without limiting it in any way. DMSO is to be understood as meaning dimethylsulfoxide.

A compound having the relative configuration (2R*, 4S*, 6R*) is understood to be a racemic mixture of the compounds having the absolute configurations (2R, 4S, 6R) and (2S, 4R, 6S).

The starting materials used are products that are known or prepared according to known procedures.

The structures of the compounds described in the Examples were determined according to customary spectrophotometric techniques (infrared, NMR, mass spectrometry).

Step A: (.+-.)-3-(3-Chlorophenyl)-.beta.-alanine

The expected product is obtained according to the procedure described in Ber. 1926, 59, 2952 and JACS 1936, 58, 299, starting from 3-chlorobenzaldehyde.

Step B: (.+-.)-3-(3-Chlorophenyl)-N-trifluoroacetyl-.beta.-alanine

Trifluoroacetic anhydride (11 mmol) is added to 10 mmol of the compound obtained in the preceding Step. After stirring for 30 minutes, the solvent and the excess reagent are evaporated off under reduced pressure to yield the expected product.

Step C: (.+-.)-3-(3-Chlorophenyl)-3-trifluoroacetylaminopropionic acid chloride

20 ml of thionyl chloride are added to 10 mmol of the compound described in the preceding Step and the mixture is then heated to reflux. After 80 minutes, the thionyl chloride is evaporated off and the residue is then taken up in 50 ml of petroleum ether. The precipitate obtained is filtered off and washed with petroleum ether.

Step D: (.+-.)-1-(3-Chlorophenyl)-3-hydroxy-5-oxo-3-hexenylammonium chloride

11 mmol of samarium and 16.5 mmol of iodine are reacted in dry acetonitrile. After stirring for 12 hours at ambient temperature, the solution is cooled to 0.degree. C., and then the acid chloride obtained in the preceding Step (10 mmol) and 11 mmol of pentane-2,4-dione are added. The reaction mixture is stirred for 6 hours at 0.degree. C. 50 ml of hydrochloric acid solution (6N) are added, the acetonitrile is evaporated off and then 50 ml of hydrochloric acid (6N) are added. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated sodium bicarbonate solution and then with saturated sodium thiosulphate solution and they are then dried and evaporated. The solid residue is taken up in a 50/50 mixture of hydrochloric acid and ethanol; the suspension is heated at reflux for 12 hours and then evaporated to yield the expected product in the foim of yellow crystals.

Melting point: 97.degree. C.

IR (KBr): OH band at 3415 cm.sup.-1

Step E: (.+-.)-2-(3-Chlorophenyl)-6-methyl-2,3-dihydro-4(1H)-pyridinone

Concentrated ammonium hydroxide solution is added dropwise to 10 mmol of the compound obtained in the preceding Step dissolved in dichloromethane, until the pH of the mixture is .gtoreq.10.

The aqueous phase is extracted with dichloromethane; the combined organic phases are then dried and evaporated. The oily residue is taken up in 50 ml of ether. By filtering off the precipitate obtained, the expected product is obtained in the form of beige-coloured crystals.

Melting Point: 163.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       65.02        5.91         6.32 found           64.89        6.02         6.25

A 1.6M solution of n-butyllithium in hexane (11 mmol) is added dropwise, at -78.degree. C., to 10 mmol of the compound described in Example 1 dissolved in tetrahydrofuran. After stirring for half an hour at -78.degree. C., 11 mmol of iodomethane are added. Stirring is continued at -78.degree. C. for a further 30 minutes and then at ambient temperature for 1 hour. After hydrolysing by adding saturated sodium hydrogen carbonate solution, the aqueous phase is extracted with dichloromethane. The combined organic phases are washed, dried and evaporated to yield the expected product in the form of orange crystals.

Melting Point: 82.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       57.39        6.23         3.94 found           57.82        6.21         3.78

Step A: (2R*,4S*,6R*)-N-Methyl-2-(3-chlorophenyl)-6-methyl-4-piperidinol

80 mmol of sodium borohydride are added to a solution, at 0.degree. C., in ethanol, of 10 mmol of the compound described in Example 2. After stirring for 12 hours at ambient temperature, the ethanol is evaporated off and the white residue is taken up in dichloromethane. The organic phase is washed with 2N hydrochloric acid solution; the combined aqueous phases are then saturated with sodium chloride, rendered alkaline with concentrated ammonium hydroxide solution and then extracted with dichloromethane. The combined organic phases are dried and then evaporated to yield the expected product in the form of a colourless oil.

Step B: (2R*,4S*,6R*)-N-Methyl-2-(3-chlorophenyl)-6-methyl-4-piperidinol fumarate

11 mmol of fumaric acid are added to a solution, in isopropanol, of 10 mmol of the compound obtained in the preceding Step. After stirring for 1 hour at ambient temperature, the solvents are evaporated off to yield the expected product in the form of white crystals.

Melting Point: 182.degree. C.

10 mmol of the compound described in Example 3 are added, at 0.degree. C., to 11 mmol of sodium hydride suspended in tetrahydrofuran. After stirring for half an hour at 0.degree. C., 100 mmol of iodomethane are added. Stirring is then continued at ambient temperature for 2 days; the solution is then hydrolysed by adding 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the combined organic phases are then washed, dried and evaporated to yield the expected product in the form of a pale yellow oil. ol

To a solution, in ethanol, of 10 mmol of the compound described in Example 2 there are added 10 mmol of CeCl.sub.3 heptahydrate and then, at 0.degree. C. and in portions, 10 mmol of sodium borohydride. After stirring for half an hour at 0.degree. C. and then for 1 hour at ambient temperature, the ethanol is evaporated off and the white residue is taken up in dichloromethane. The organic phase is washed with 2N hydrochloric acid solution; the combined aqueous phases are then saturated with sodium chloride, rendered basic with concentrated ammonium hydroxide solution and then extracted with dichloromethane. The combined organic phases are dried and then evaporated to yield the expected product.

Step A: (2R*,4S*,6R*)-2-(3-Chlorophenyl)-6-methyl-4-piperidinol

The expected product is obtained according to the procedure described in Step A of Example 3, starting from the compound described in Example 1.

Step B: (2R*,4S*,6R*)-2-(3-Chlorophenyl)-6-methyl-4-piperidinol hydrochloride

11 ml of a 1M solution of ethereal HCl are added to a solution, in isopropanol, of 10 mmol of the compound obtained in the preceding Step. After stirring for 1 hour at ambient temperature, the solvents are evaporated off to yield the expected product in the form of beige-coloured crystals.

Melting Point: 248.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       45.82        6.53         5.34 found           45.54        6.62         5.41

11 mmol of oxalic acid are added to a solution, in isopropanol, of 10 mmol of the compound obtained in Step A of Example 6. After stirring for 1 hour at ambient temperature, the solvents are evaporated off to yield the expected product in the form of crystals.

Melting Point: 224.degree. C. hydrochloride

Step A: (.+-.)-N-Trifluoroacetyl-2-(3-chlorophenyl)-6-methyl-2,3-dihydro-4(1H)-pyr idinone

The expected product is obtained according to the procedure described in Example 2, starting from the compound described in Example 1 and replacing the iodomethane by trifluoroacetyl chloride.

Step B: (2R*,4S*,6R*)-N-Trifluoroacetyl-2-(3-chlorophenyl)-6-methyl-4-piperidinol hydrochloride

Starting from the compound obtained in the preceding Step, the expected product is obtained according to the procedure described in Example 6.

The expected product is obtained according to the procedure described in Example 5, starting from the compound described in Example 1. (2R*,4S*,6R*)-2-(3-chlorophenyl)-6-methyl-4-oxo-3,4-dihydro-1(2H)-pyridine carboxylate

The expected product is obtained according to the procedure described in Example 2, starting from the compound described in Example 1 and replacing the iodomethane by benzyl chloroformate. (2R*,4S*)-2-(3-chlorophenyl)-4-hydroxy-6-methyl-3,4-dihydro-1(2H)-pyridine carboxylate

The expected product is obtained according to the procedure described in Example 5, starting from the compound described in Example 10.

Step A: (2R*,6R*)-2-(3-Chlorophenyl)-6-methyl-4-piperidinone

20 mmol of orthophosphoric acid and then 20 mmol of chromic anhydride are added dropwise to a solution, in acetone, at 0.degree. C., of 10 mmol of the compound described in Step A of Example 6.

After stirring for 1 hour at 0.degree. C. and then for 12 hours at ambient temperature, the acetone is evaporated off; the residue is taken up in 20 ml of ice and then rendered alkaline (pH>10) using 28% ammonium hydroxide solution. The solution is then extracted with dichloro-methane. The combined organic phases are dried and then evaporated to yield the expected product.

Step B: (2R*,6R*)-2-(3-Chlorophenyl)-6-methyl-4-piperidinone oxalate

The expected product is obtained according to the procedure described in Example 7, starting from the compound obtained in the preceding Step.

Melting Point: 183.degree. C.

Step A: (2R*,4R*,6R*)-4-Chloro-2-(3-chlorophenyl)-6-methyl-piperidine

To a solution, in chloroform, of 10 mmol of the compound described in Step A of Example 12 there are added 20 mmol of triethylamine followed by 20 mmol of thionyl chloride. The reaction mixture is heated at reflux for 2 hours. After returning to ambient temperature, the organic phase is washed; the combined aqueous phases are rendered alkaline by the addition of ammonium hydroxide solution and then extracted with dichloromethane, and the combined organic phases are washed, dried and evaporated to yield the expected product.

Step B: (2R*,4R*,6R*)-4-Chloro-2-(3-chlorophenyl)-6-methyl-piperidine fumarate

The expected product is obtained according to the procedure described in Step B of Example 3, starting from the compound obtained in the preceding Step.

Melting Point: 203.degree. C. Step A: (2R*,4S*,6R*)-2-(3-Chlorophenyl)-6-methyl-4-phenylthio-piperidine

To 30 mmol of sodium hydride suspended in dimethylformamide there are added, at 0.degree. C., 13 mmol of thiophenol and then, after stirring for 30 minutes, 10 mmol of the compound described in Step A of Example 13. The reaction mixture is then heated at reflux for 2 hours and the solution is subsequently hydrolysed by adding 1N hydrochloric acid solution. The aqueous phase is washed with ether and is then rendered alkaline by the addition of ammonium hydroxide solution and extracted with ether. The combined organic phases are washed with water, dried and then evaporated to yield the expected product.

Step B: (2R*,4S*,6R*)-2-(3-Chlorophenyl)-6-methyl-4-phenylthio-piperidine fumarate

The expected product is obtained according to the procedure described in Step B of Example 3, starting from the compound obtained in the preceding Step.

Melting Point: 181.degree. C.

40 mmol of hydroxylamine hydrochloride and 40 mmol of sodium acetate are added to a solution, in ethanol, of 10 mmol of the compound described in Example 1, and the reaction mixture is then heated at reflux for 2 hours. After hydrolysis, the aqueous phase is extracted with dichloromethane; the combined organic phases are then washed, dried and evaporated to yield the expected product in the form of orange crystals.

Melting Point: 88.degree. C. (Z/E mixture 20/80)

Elementary Microanalysis: % C          % H         % N calculated       60.89        5.54        11.83 found           60.95        5.62        11.15

Step A: (.+-.)-N-Phenylacetyl-3-(3-chlorophenyl)-.beta.-alanine

To a solution, in a 3/1 mixture of water/acetone, of 10 mmol of (.+-.)-3-(3-chlorophenyl)-.beta.-alanine described in Step A of Example 1 there are added 24 mmol of triethylamine and then, at -5.degree. C., 13 mmol of phenylacetyl chloride. After stirring for 2 hours at -5.degree. C. and then for 3 hours at ambient temperature, the solution is filtered; the acetone is evaporated off, the aqueous phase is washed with ether and is then acidified to pH=1 and extracted with ethyl acetate. The combined organic phases are dried and then evaporated. The residue obtained is washed with hexane, precipitated in a minimum of ether and then filtered to yield the expected product.

Step B: (3R)-3-(3-Chlorophenyl)-.beta.-alanine hydrochloride

Penicillin amidase (20 mg) is introduced into 10 mmol of the compound described in the preceding Step in saturated sodium bicarbonate solution at 37.degree. C. after adjustment of the pH to from 7.4 to 7.6 using concentrated hydrochloric acid. After stirring for 24 hours at a pH of from 7.5 to 8, the mixture is brought to pH=1 with hydrochloric acid. The aqueous phase is washed with ether and then evaporated. The white solid obtained is taken up in ethanol and then filtered. The filtrate is then evaporated to yield the expected product.

Step C: (2R)-2-(3-Chlorophenyl)-6-methyl-2,3-dihydro-4-(1H)-pyridinone

The expected product is obtained according to the procedure described in Steps B to E of Example 1, starting from the compound described in the preceding Step.

Rotatory Power: [.alpha.].sup.20.sub.D =-176.92 (c=0.0039; CH.sub.3 OH)

Step A: (2R,4S,6R)-2-(3-Chlorophenyl)-6-methyl-4-piperidinol

The expected product is obtained according to the procedure described in Step A of Example 3, starting from the compound described in Example 16.

Step B: (2R,4S,6R)-2-(3-Chlorophenyl)-6-methyl-4-piperidinol oxalate

The expected product is obtained according to the procedure described in Example 7, starting from the compound obtained in the preceding Step.

Rotatory Power: [.alpha.].sup.20.sub.D =-9.58 (c=0.0024; H.sub.2 O)

Step A: (3S)-3-(3-Chlorophenyl)-.beta.-alanine hydrochloride

Penicillin amidase (20 mg) is introduced into 10 mmol of the compound described in Step A of Example 16 in saturated sodium bicarbonate solution at 37.degree. C. after adjustment of the pH to from 7.4 to 7.6 using concentrated hydrochloric acid. After stirring for 24 hours at a pH of from 7.5 to 8, the mixture is brought to pH=1 with hydrochloric acid. The aqueous phase is extracted with ether and then the organic phases obtained are combined, dried and evaporated. The residue is taken up in hexane and precipitated using a minimum of ether. After filtration, the solid obtained is heated at 50.degree. C. for 24 hours in 2N hydrochloric acid to yield the expected product.

Step B: (2S)-2-(3-Chlorophenyl)-6-methyl-2,3-dihydro-4-(1H)-pyridinone

The expected product is obtained according to the procedure described in Steps B to E of Example 1, starting from the compound described in the preceding Step.

Rotatory Power: [.alpha.].sup.20.sub.D =+179.7 (c=0.080; CH.sub.3 OH)

Step A: (2S,4R,6S)-2-(3-Chlorophenyl)-6-methyl-4-piperidinol

The expected product is obtained according to the procedure described in Step A of Example 3, starting from the compound described in Example 18.

Step B: (2S,4R,6S)-2-(3-Chlorophenyl)-6-methyl-4-piperidinol fumarate

The expected product is obtained according to the procedure described in Step B of Example 3, starting from the compound obtained in the preceding Step.

Rotatory Power: [.alpha.].sup.20.sub.D =+9.8 (c=0.067; DMSO)

The expected product is obtained according to the procedure described in Example 12, starting from the compound described in Step A of Example 19.

Melting Point: 184.degree. C.

Rotatory Power: [.alpha.].sup.20.sub.D =-24.2 (c=0.065; DMSO)

Step A: (.+-.)-2-Phenyl-6-methyl-2,3-dihydro-1H-4-pyridinone

The expected product is obtained according to the procedure described in Example 1, starting from benzaldehyde.

Yellow Crystals.

Melting Point: 156.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       76.97        7.00         7.18 found           76.69        7.11         7.39

Step B: (2R*,4S*,6R*)-2-Phenyl-6-methyl-4-piperidinol

The expected product is obtained according to the procedure described in Step A of Example 3, starting from the compound obtained in the preceding Step.

Step C: (2R*,4S*,6R*)-2-Phenyl-6-methyl-4-piperidinol hydrochloride

The expected product is obtained according to the procedure described in Step B of Example 6, starting from the compound obtained in the preceding Step.

Beige Crystals.

Melting Point: 236.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       63.29        7.97         6.15 found           62.95        8.09         5.99

The expected product is obtained according to the procedure described in Example 7, starting from the compound described in Step B of Example 21.

The expected product is obtained according to the procedure described in Example 1, starting from 2-chloro-benzaldehyde.

Beige Crystals.

Melting Point: 98.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       65.02        5.91         6.32 found           65.20        5.93         6.32

The expected product is obtained according to the procedure described in Example 1, starting from 4-chloro-benzaldehyde.

Beige Crystals.

Melting Point: 104.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       65.02        5.91         6.32 found           64.90        5.92         6.31

4-Amino-3-(4-chlorophenyl)butyric acid (baclofen) is subjected to the operations described in Steps B to E of Example 1, to yield the expected product in the form of cream crystals.

Melting Point: 118.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       66.24        5.99         5.84 found           66.25        5.84         6.17

The expected product is obtained according to the procedure described in Example 1, starting from 3,4-dichlorobenzaldehyde.

Beige Crystals.

Melting Point: 163.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       56.27        4.33         5.47 found           56.27        4.33         5.45

The expected product is obtained according to the procedure described in Example 1, starting from 3-methoxybenzaldehyde.

Beige Crystals.

Melting Point: 98.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       71.87        6.96         6.45 found           71.82        6.66         6.72

The expected product is obtained according to the procedure described in Example 1, starting from thiophene-2-carboxaldehyde.

Beige Crystals.

Melting Point: 114.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       62.15        5.74         7.25 found           62.30        5.81         7.08

The expected product is obtained according to the procedure described in Example 6, starting from the compound described in Example 28.

Beige Crystals.

Melting Point: 248.degree. C.

Elementaay Microanalysis: % C          % H         % N calculated       51.38        6.90         5.99 found           51.16        7.01         5.79

The expected product is obtained according to the procedure described in Example 1, starting from thiophene-3-carboxaldehyde.

Brown Crystals.

Melting Point: 103.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       62.15        5.74         7.25 found           62.27        5.82         7.20

Step A: (2R*,4S*,6R*)-6-Methyl-2-(3-thienyl)-4-piperidinol

The expected product is obtained according to the procedure described in Step A of Example 3, starting from the compound described in Example 30.

Step B: (2R*,4S*,6R*)-6-Methyl-2-(3-thienyl)-4-piperidinol hydrochloride

The expected product is obtained according to the procedure described in Step B of Example 6, starting from the compound described in the preceding Step.

Beige Crystals.

Melting Point: 241.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       51.38        6.90         5.99 found           51.26        6.81         5.81

The expected product is obtained according to the procedure described in Example 7, starting from the compound described in Step A of Example 31.

Melting Point: 246.degree. C.

The expected product is obtained according to the procedure described in Example 12, starting from the compound described in Step A of Example 31.

Melting Point: 184.degree. C.

The expected product is obtained according to the procedure described in Example 1, starting from 4-bromo-thiophene-2-carboxaldehyde.

Beige Crystals.

Melting Point: 170.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       44.13        3.70         5.15 found           44.01        3.78         5.06

The expected product is obtained according to the procedure described in Example 1, starting from 4-chloro-thiophene-2-carboxaldehyde.

Beige Crystals.

Melting Point: 141.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       52.75        4.43         6.15 found           52.52        4.49         6.01

The expected product is obtained according to the procedure described in Example 1, starting from nicotinaldehyde.

Yellow Crystals.

Melting Point: 141.degree. C.

Elementary Microanalysis: % C          % H         % N calculated       52.75        4.43         6.15 found           52.52        4.49         6.01

Step A: (2R*,4S*,6R *)-6-Methyl-2-(3-pyridyl)-4-piperidinol

The expected product is obtained according to the procedure described in Step A of Example 3, starting from the compound described in Example 36.

Step B: (2R*,4S*,6R*)-6-Methyl-2-(3-pyridyl)-4-piperidinol dioxalate

22 mmol of oxalic acid are added to a solution, in isopropanol, of 10 mmol of the compound obtained in the preceding Step. After stirring for 1 hour at ambient temperature, the solvents are evaporated off to yield the expected product in the form of crystals.

Elementary Microanalysis: % C          % H         % N calculated       48.39        5.41         7.52 found           48.26        5.46         7.55

The expected product is obtained according to the procedure described in Example 2, starting from the compound described in Example 36 and replacing the iodomethane by acetyl chloride.

The expected product is obtained according to the procedure described in Step A of Example 3, starting from the compound described in Example 38.

Step A: (2R*,4S*,6R*)-N-Acetyl-6-methyl-2-(3-pyridyl)-4-piperidinone

The expected product is obtained according to the procedure described in Step A of Example 12, starting from the compound described in Example 39.

Step B: (2R*,4R*,6R*)-N-Acetyl-4-chloro-6-methyl-2-(3-pyridyl)-piperidine

The expected product is obtained according to the procedure described in Step A of Example 13, starting from the compound obtained in the preceding Step.

The expected product is obtained according to the procedure described in Step A of Example 14, starting from the compound described in Example 40 and methanethiol. ne

The expected product is obtained according to the procedure described in Example 4, starting from the compound described in Example 39 and replacing the iodomethane by methyl chloroformate.

Step A: (.+-.)-6-Propyl-2-(3-pyridyl)-2,3-dihydro-4(1H)-pyridinone

The expected product is obtained according to the procedure described in Example 1, starting from nicotinaldehyde and nonane-4,6-dione.

Step B: (.+-.)-N-Benzyl-6-propyl-2-(3-pyridyl)-2,3-dihydro-4(1H)-pyridinone

The expected product is obtained according to the procedure described in Example 2, starting from the compound obtained in the preceding Step and replacing the iodomethane by benzyl chloride. O-[2-(dimethylamino)-ethyl]-oxime

The expected product is obtained according to the procedure described in Example 15, starting from the compound described in Example 43 and replacing the hydroxylamine hydrochloride by 2-(aminooxy)-N,N-dimethylethanamine.

Locomotion in the Wistar Rat

The effects of the compounds of the invention on motor activity were assessed in the adult male Wistar rat. Wistar rats (180-200 g) were treated (intraperitoneal route) with the compounds being studied or their carriers (2 ml/kg). Thirty minutes after pharmacological treatment, the animals were placed in an open-field (40.times.40.times.60 cm) located in a controlled-environment experimentation room. The motor activity of the animals was assessed by measuring the distance they covered (cm) in the open-field over 30 minutes. The measurement was carried out automatically by a video-surveillance system coupled to a micro-computer (Videotrack system, View-Point, France). The results were expressed as means plus or minus the standard errors of the means, and inter-group comparisons were made by a single-factor variance analysis test followed, where appropriate, by a Dunnett test.

The results show that the compounds of the invention do not have any activity on the locomotion in the rat at a dose of 10 mg/kg or below.

Body Temperature in the NMRI Mouse

The effects of the compounds of the invention on body temperature were assessed in the adult male NMRI mouse. The rectal temperature of the mice (18-20 g) was measured just before pharmacological treatment (intraperitoneal route) with the compounds being studied or their carriers (20 mg/kg). The mice were then placed in individual cages (10.times.10.times.10 cm) and their rectal temperature was measured every 30 minutes during the 2 hours following treatment. The values were the means (.degree. C.) plus or minus the standard errors of the means, and inter-group comparisons were carried out by a single-factor variance analysis test followed, where appropriate by a Dunnett test.

The results show that the compounds of the invention do not have hypothermic activity at a dose of 20 mg/kg or below.

Abdominal Contractions Induced by Phenyl-p-benzoquinone (PBQ) in the NMRI Mouse

Intraperitoneal administration of an alcoholic solution of PBQ causes abdominal cramps in the mouse (SIEGMUND et al., Proc. Soc. Exp. Biol., 1957, 95, 729-731). The cramps are characterised by repeated contractions of the abdominal musculature, accompanied by extension of the hind limbs. Most analgesics antagonise these abdominal cramps (COLLIER et al., Brit. J. Pharmacol. Chem., 1968, 32 295-310). At t=0 min., the animals are weighed and the compound being studied is administered by the IP route. A group of control animals is given the solvent used for the compound. At t=30 min., an alcoholic solution of PBQ (0.2%) is administered by the IP route in a volume of 0.25 ml/mouse. Immediately after administration of the PBQ, the animals are placed in cylinders of plexiglass (L=19.5 cm; I.D.=5 cm). From t=35 min. to t=45 min., the animals' reaction is observed and the experimenter notes the total number of abdominal cramps per animal. The Table hereinbelow gives the percentage inhibition of the number of abdominal cramps measured in the control animals, at the active dose of the compound studied. The results obtained show that the compounds of the invention possess antalgic properties. Example        Dose (mg/kg)       Inhibition (%) 1                10                  51 25               20                  69 26               10                  55 30               20                  51

Social Recognition in the Wistar Rat

Initially described in 1982 by THOR and HOLLOWAY, (J. Comp. Physiol., 1982, 96, 1000-1006), the social recognition test has subsequently been proposed by various authors (DANTZER et al., Psychopharmacology, 1987, 91, 363-368; PERIO et al., Psycho-pharmacology, 1989, 97, 262-268) for studying the mnemocognitive effects of new compounds. The test is based on the natural expression of the olfactory memory of the rat and its natural tendency to forget and allows evaluation of memorisation, by recognition of a young congeneric animal, by an adult rat. A young rat (21 days), taken at random, is placed for 5 minutes in the cage housing an adult rat. With the aid of a video device, the experimenter observes the social recognition behaviour of the adult rat and measures its overall duration. The young rat is then removed from the adult rat's cage and is placed in its own cage until the second introduction. The adult rat is given the compound under test by intraperitoneal route and, after 2 hours, is again brought into the presence (5 minutes) of the young rat. The social recognition behaviour is then observed again and its duration measured.

The Table hereinbelow gives the difference (T.sub.2 -T.sub.1), expressed in seconds, between the "recognition" times of the 2 encounters. The results obtained show that the compounds of the invention very greatly enhance memorisation, even at a low dose. Example         Dose (mg/kg)   T.sub.2 -T.sub.1 (s) 1                  3                -36 21                 3                -33 24                 3                -32 36                 3                -36

Object Recognition in the Wistar Rat

The object recognition test in the Wistar rat was initially developed by ENNACEUR and DELACOUR (Behav. Brain Res., 1988, 31, 47-59). The test is based on the spontaneous exploratory activity of the animal and has the characteristics of episodic memory in humans. This memory test is sensitive to aging (SCALI et al., Eur. J. Pharmacol., 1997, 325, 173-180) and to cholinergic dysfunctions (BARTOLINI et al., Pharm. Biochem. Behav. 1996, 53(2), 277-283) and is based on the differences in the exploration of 2 objects of fairly similar shape--one familiar, the other new. Prior to the test, the animals are habituated to the environment (an enclosure without an object). In the course of a first session, the rats are placed (3 minutes) in the enclosure, in which there are 2 identical objects. The duration of exploration is measured for each object. In the course of the second session (3 minutes), 24 hours later, 1 of the 2 objects is replaced by a new object. The duration of exploration is measured for each object. The assessment criterion is the difference, Delta, expressed in seconds, between the exploration times for the new object and for the familiar object in the course of the second session. The control animals, previously treated with the carrier by the IP route or p.o. 30 minutes before each session, explore the familiar object and the new object in an identical manner, which indicates that the object introduced earlier has been forgotten. Animals treated with a compound that facilitates mnemocognition preferentially explore the new object, which indicates that the object introduced earlier has been remembered.

The Table hereinbelow gives the difference, Delta, expressed in seconds, between the exploration times of the 2 objects. The results obtained show that the compounds of the invention greatly enhance memorisation, even at a very low dose, not only by i.p. but also by p.o. route. Example       Dose (mg/kg)      Delta (s)     Route 1               0.3              7.5       i.p. 0.3              9.95      p.o. 18               1                6.2       p.o. 22               0.3              9.98      i.p. 3                5.93      p.o. 24               3                7.55      i.p. 27               3                6.68      i.p.

Pharmaceutical Composition

Formulation for the preparation of 1000 tablets each comprising 10 mg of active ingredient:

## Claims

1. A compound selected from those of formula (I): ##STR16## wherein: alkyl moiety is linear or branched, linear or branched (C.sub.1 -C.sub.6)alkyl, linear or branched (C.sub.1 -C.sub.6)acyl, linear or branched (C.sub.1 -C.sub.6)alkoxycarbonyl, aryl-(C.sub.1 -C.sub.6)alkoxycarbonyl in which the alkoxy moiety is linear or branched, or trifluoroacetyl, linear or branched (C.sub.1 -C.sub.6)acyl, linear or branched (C.sub.1 -C.sub.6)alkoxycarbonyl, or aryl-(C.sub.1 -C.sub.6)alkoxycarbonyl in which the alkoxy moiety is linear or branched, aryl, optionally substituted by one or more identical or different groups selected from hydroxy, amino (optionally substituted by one or two linear or branched C.sub.1 -C.sub.6)alkyl groups), and linear or branched C.sub.1 -C.sub.6)alkoxy, valency of the atoms is respected, acid, with the proviso that the compound of formula (I) is other than: a methyl, ethyl, propyl, or isopropyl group, isopropyl or butyl group, naphthyl, or tetrahydronaphthyl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched C.sub.1 -C.sub.6)alkyl, hydroxy, linear or branched C.sub.1 -C.sub.6)alkoxy, trihalomethyl, and amino (optionally substituted by one or more linear or branched C.sub.1 -C.sub.6)alkyl groups), to 12-membered group containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl group may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched C.sub.1 -C.sub.6)alkyl, hydroxy, linear or branched C.sub.1 -C.sub.6)alkoxy, trihalomethyl, and amino (optionally substituted by one ore more linear or branched C.sub.1 -C.sub.6)alkyl groups).

2. Compound of claim 1, in which X represents oxygen or OR.sub.3 wherein R.sub.3 is as defined in claim 1.

3. Compound of claim 1, in which X represents NOR.sub.5 wherein R.sub.5 is as defined in claim 1.

4. Compound of claim 1, in which X represents SR.sub.4 wherein R.sub.4 is as defined in claim 1.

5. Compound of claim 1, in which X represents chlorine.

6. Compound of claim 2, in which X represents oxygen or OR.sub.3 wherein R.sub.3 represents hydrogen.

7. Compound of claim 1, in which R.sub.1 represents hydrogen.

8. Compound of claim 1, in which Ar represents optionally substituted phenyl.

9. Compound of claim 1, in which Ar represents optionally substituted thienyl.

10. Compound of claim 1, in which Ar represents optionally substituted pyridyl.

11. Compound of claim 1 which is (.+-.)-2-(3-chlorophenyl)-6-methyl-2,3-dihydro-4(1H)-pyridinone, its isomers and addition salts thereof with a pharmaceutically-acceptable acid.

12. Compound of claim 1 which is (2R*,4S*,6R*)-2-phenyl-6-methyl-4-piperidinol, its isomers and addition salts thereof with a pharmaceutically-acceptable acid.

13. Pharmaceutical composition comprising as active principle an effective amount of a compound as claimed in claim 1, together with one or more pharmaceutically-acceptable excipients or vehicles.

14. Method for treating a mammal afflicted with a condition requiring an antalgic agent or a facilitator of memory and cognition, comprising the step of administering to the mammal an amount of a compound of claim 1 which is effective for alleviation of said condition.