EP0986555A1

EP0986555A1 - Novel phencyclidine derivatives, preparation methods and pharmaceutical compositions containing same

Info

Publication number: EP0986555A1
Application number: EP98928415A
Authority: EP
Inventors: Jean-Marc Kamenka; Jacques Hamon; Jacques Vignon
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 1997-06-03
Filing date: 1998-06-02
Publication date: 2000-03-22
Also published as: JP2002502411A; CA2292642A1; AU8024998A; HUP0002302A3; US6342511B1; WO1998055478A1; HUP0002302A2; PL337178A1; NO995905L; NO995905D0

Abstract

The invention concerns novel phenycyclidine derivatives with selective affinity for low affinity receptors, methods for preparing them, pharmaceutical compositions containing them and their use as protective agents for central or peripheral nervous system cells against acute or chronic degeneration, or as anticonvulsant.

Description

New phencyclidin derivatives, processes for their preparation and pharmaceutical compositions containing them

[N- (1-phenylcyclohexyl) piperidine (or PCP), developed as an anesthetic agent and then withdrawn due to excessive psychotropic effects, is now only a pharmacological tool, interesting at least through of its derivatives or the like. One of the derivatives, N- (1- (2-thienyl) cyclohexyl) piperidine (or TCP), is, in its tritiated form, a ligand widely used as a marker for the PCP receptor. In vitro and in vivo studies of the [ ³ H] TCP binding to the PCP receptor have revealed the existence of a second type of binding corresponding to so-called low affinity PCP sites compared to the first so-called high affinity sites ( Brain Res., 378, 133-141 (1986)).

The present invention relates to new phencyclidine derivatives having a selective affinity for low affinity receptors, methods for their preparation, pharmaceutical compositions containing them and their use in particular as a protective agent for cells of the central or peripheral nervous system against acute or chronic degeneration, or as an anticonvulsant agent.

A subject of the invention is therefore the compounds of formula I characterized in that they correspond to either formula IA

in which

Ar represents a carbocyclic or heterocyclic aryl radical, monocyclic with 5 or 6 members or consisting of condensed rings and optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl radicals , alkoxy, alkylthio, haloalkyl, hydroxyalkyl, having at most 6 carbon atoms; esterified or salified free carboxy; cyano; nitro; amino optionally substituted by one or two identical or different alkyl radicals containing at most 6 carbon atoms; Ri and R _{2, which are} identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from hydroxyl, free esterified or salified carboxy, cyano, nitro or well Ri and R2 form with the nitrogen atom to which they are linked a radical

in which n represents an integer from 0 to 2 and R3 and R'3 which are identical or different represent a hydrogen atom, a halogen atom or a hydroxyl radical, free esterified or salified carboxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxy alkyl having at most 6 carbon atoms;

R4 has the same meaning as R3 or R'3;

X, Y and Z are such that at least one represents a sulfur or oxygen atom and the others represent a methylene radical, with the exception of the compounds in which R3, R'3 and R4 each represent a d atom hydrogen and

1) R 1 and R 2 form, with the nitrogen atom to which they are linked, a pyrrolidine radical, Ar represents a phenyl or 2-thienyl radical and one of X, Y or Z represents an oxygen atom,

2) Ri and R ₂ form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, thienyl and benzothienyl radical, Y represents a sulfur atom and

X and Z each represent a methylene radical,

3) Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, methoxyphenyl, benzothienyl and 2-thienyl radical, Y represents an oxygen atom and X and Z each represent a radical methylene, 4) Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, methoxyphenyl or 2-thienyl radical, one of X or Z represents an oxygen atom, l the other represents a methylene radical and Y represents a methylene radical,

5) Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl or 2 thienyl radical, one of X or Z represents a sulfur atom, the other represents a methylene radical and Y represents a methylene radical, 6) Ri and R2 form with the nitrogen atom to which they are linked a pyrrolidine radical, Ar represents a 2-thienyl radical, one of X or Z represents a sulfur atom, the other represents a methylene radical and Y represents a methylene radical,

7) Ri and R2 form, with the nitrogen atom to which they are linked, an ethylamino or pyrrolidine radical, Ar represents a phenyl radical, Y represents a sulfur atom and X and Z each represent a methylene radical, either to one following formulas:

- N- [1- (2-thienyl) -cyclohexan-1-yl] -3-hydroxymethyl-piperidine, - N- [1- (2-thienyl) -cyclohexan-1-yl] -4-hydroxy-3- methyl piperidine, - N- [1- (2-benzothiophenyl) -cyclohexan-1-yl] -4-hydroxy-3-methyl piperidine,

- N-ethyl-1- (2-thienyl) -cyclohexylamine or

- N- [1- (2-furyl) -cyclohexan-1-yl] piperidine, said compounds of formula I being in all the isomeric, racemic, enantiomeric and diastereoisomeric forms as well as the addition salts with mineral acids and organic or with the mineral and organic bases of the said compounds of formula I.

A more particular subject of the invention is the compounds of general formula IA as defined above in which

Ar represents a 5-membered monocyclic heterocyclic aryl radical or consisting of two condensed rings and optionally substituted by one or more identical or different alkyl or alkenyl radicals;

Ri and R2 identical or different represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms or Ri and R2 form with the nitrogen atom to which they are linked a radical

in which n is equal to 1 and R3 and R'3, which are identical or different, represent a hydrogen atom or a hydroxyl, alkyl or hydroxyalkyl radical having at most 6 carbon atoms.

In the definitions given above, the expression halogen represents a fluorine, chlorine, bromine or iodine atom. The expression alkyl having at most 6 carbon atoms represents a linear or branched alkyl radical such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl radical.

Among the alkenyl radicals, mention may be made of linear or branched alkyl radicals such as vinyl, allyl, 1-propenyl, butenyl, pentynyl or hexynyl.

Among the alkynyl radicals, there may be mentioned the ethynyl, propargyl, butynyl, pentynyl or hexynyl radicals. The alkoxy radical, linear or branched, preferably denotes the radicals in which the alkyl radical is as defined above. The methoxy, ethoxy, propoxy, isopropyloxy or butoxy radicals are preferred. The alkylthio radical preferably designates the radicals in which the alkyl radical is as defined above, for example methylthio or ethylthio.

The haloalkyl radical preferably designates the radicals in which the alkyl radical is as defined above and is substituted by one or more halogen atoms as defined above such as, for example, bromoethyl, trifluoromethyl, trifluoroethyl or alternatively pentafluoroethyl.

The hydroxyalkyl radical preferably designates the radicals in which the alkyl radical is as defined above, for example hydroxymethyl or hydroxyethyl.

The aryl radical can be carbocyclic or heterocyclic. The heterocyclic aryl radical can contain one or more heteroatoms, identical or different, chosen from oxygen, nitrogen and sulfur atoms. As an example of an aryl, carbocyclic or heterocyclic radical, mention may be made of phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, diazolyl, oxadiazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl or indolyl radicals.

Ar represents the thienyl, furyl, benzothienyl, benzofuryl radical and optionally substituted by one or more methyl, ethyl, propyl or allyl radicals;

Ri and R2, which are identical or different, represent a hydrogen atom or a methyl or ethyl radical, or else R and R2 form, with the nitrogen atom to which they are linked, a radical

in which n is equal to 1 and R3 and R'3, which are identical or different, represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical. More particularly, the subject of the invention is the compounds of formula IA described below in the examples, in particular the compounds corresponding to the following formulas:

- N- [4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl-piperidine; - N- [4- (2-benzothiophenyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl-piperidine;

- N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (2-benzofuranyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine; - N- [4- (5-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl] -piperidine; - N- [4- (4-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl] -piperidine; - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-hydroxy piperidine;

- N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxy piperidine

in all the isomeric, racemic, enantiomeric and diastereoisomeric forms possible as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said compounds.

The subject of the invention is also a process for preparing the compounds of general formula I as defined above, characterized in that it comprises

- the reaction of a compound of formula 1

in which X ", Y", Z "represent a sulfur or oxygen atom or a methylene radical, R ₄ has the meaning indicated above, with an aryl magnesium halide of formula Hal-Ar-Mg in which Hal represents a halogen atom and Ar has the meaning indicated above, to obtain the compound of formula 2

in which X ", Y", Z ", Ar and R ₄ have the meanings indicated above, - the transformation of the hydroxyl radical of the alcohol of formula 2 thus obtained, into azide of formula 3

3

in which X ", Y", Z ", Ar and R ₄ have the meanings indicated above,

- then the reduction of the azide of formula 3 to the primary amine of formula 4

4

in which X ", Y", Z ", Ar and R ₄ have the meanings indicated above,

- and finally, if the desired compound of formula I is such that at least one of the radicals Ri or R2 is different from the hydrogen atom or else Ri and R2 form a ring with the nitrogen atom to which they are linked , the treatment of this compound of formula 4 to obtain the compound of formula I which is transformed if desired into a salt.

In this preparation process, the first step which consists in obtaining the compound of formula 2, is a conventional Grignard reaction whose conditions of implementation are known to those skilled in the art.

The second step provides access to azide 3 from alcohol 2. The reaction takes place in the presence of an excess of protonating organic agent such as trichloroacetic acid, of an alkali azide in a solvent polar aprotic. Preferably, the reaction takes place in the presence of an excess of trichloroacetic acid and sodium azide in chloroform.

For the reduction of azides of formula 3 to primary amine 4, the conventional methods known to those skilled in the art for the reduction of azides can be used. The reduction can thus be carried out using, for example, Raney nickel in isopropanol at 60 ° C. or lithium aluminum hydride in diethyl ether or tetrahydrofuran.

If in the desired compound of formula I, R 1 and R ₂ form a ring with the nitrogen atom to which they are linked, the fourth step is then cyclization; it is obtained by doing react, in a polar solvent, in an alkaline medium, the compound of formula 4 with the appropriate compound of formula Hal- (CH ₂ ) ₂ - (CH ₂ ) _n - (CH ₂ ) ₂ -Hal or Hal- (CH ₂ ) -CH = CH- (CH ₂ ) ₂ -Hal of cis structure, substituted by the radicals R3 and R'3, and in which n, R3 and R'3 have the meaning indicated above and Hal represents an atom of halogen. The alkaline conditions allow the acid formed to be trapped and can be obtained using, for example, potassium carbonate. The polar solvent used can be chosen from methanol, acetone, hexamethylphosphoramide or sulfolane and preferably hexamethylphosphoramide.

The primary amine of formula 4 therefore corresponds to the compound of formula I in which R 1 and R ₂ represent the hydrogen atom. If in the compound of formula I desired, R] and R ₂ are identical or different and at least one of the two does not represent the hydrogen atom, then the compound of formula I is a secondary or tertiary amine depending on the values of Ri and R ₂ ; these amines can be obtained from the corresponding primary amine of formula 4 according to the conventional methods known to those skilled in the art. Thus, for example, for the preparation of the compound of formula I in which one of the radicals Ri or R represents the hydrogen atom and the other an alkyl radical, the corresponding primary amine of formula 4 is reacted with the appropriate acid anhydride and then the amide obtained is reduced with, for example, LiAlH

The various isomeric, enantiomeric and diastereoisomeric forms can be obtained by splitting either the starting product or the final product according to methods known to those skilled in the art. For example, the two diastereoisomers can be separated at the final stage by simple chromatography. This separation can also be carried out after obtaining the compounds of formula 4. The resolution can also be carried out by the use of optically active acids such as tartaric or mandelic acids.

Another subject of the invention is another process for preparing the compounds of general formula I as defined above, characterized in that it comprises

- the reaction of a compound of formula 1

in which X ", Y", Z "and R ₄ have the meanings indicated above, in an anhydrous medium, with a compound of formula RιR ₂ NH in which Rj and R have the meanings indicated above, and a donor compound of cyanide ions, to obtain the compound of formula 5

in which X ", Y", Z ", Ri and R2 have the meanings indicated above, and

the reaction of the compound of formula 5 thus obtained, with an aryl magnesium halide of formula Hal-Ar-Mg in which Ar has the meaning indicated above and Hal represents a halogen atom, to obtain the compound of formula I according to the invention.

In this second preparation process, the reaction for obtaining the compound of formula 5 can be carried out in the presence of acetone cyanhydrin as a donor of cyanide ions; as dehydrating agent of the medium, one can use, for example, anhydrous magnesium sulfate. The reaction is preferably carried out in a basic polar solvent such as acetamide, methylacetamide, dimethylacetamide, acetylpiperidine or piperidine, and preferably dimethylacetamide or piperidine.

The second stage of this second preparation process is a Bruylants reaction (P. Bruylants, Bull. Soc. Chim. Belg., 33, 467 (1924); P. Bruylants, A. Castille, Bull. Soc. Chim. Belg. ., 34, 261-284 (1925)). On an experimental level, this reaction is stereospecific and leads to the introduction of the aryl radical in an equatorial position. Consequently, it will only be used for the synthesis of compounds of formula I which do not have any particular stereochemistry.

Given the lack of stereospecificity of this first reaction, this synthetic route will preferably be used in the case where R ₄ represents a hydrogen atom.

The optional salification of the compounds of formula I is carried out according to the usual methods indicated below in the experimental part.

The starting compounds of formula 1 in which R4 represents the hydrogen atom and Y "represents a sulfur or oxygen atom or a methylene radical, are commercial products. The other starting compounds of formula 1 in which R4 represents the hydrogen atom, can be prepared according to the scheme described by TE Young (J. Org. Chem., 38, 1562-1566 (1973)). The starting compounds in which R4 is different from the hydrogen atom can be obtained from the corresponding compounds of formula 1 in which R4 represents the hydrogen atom, according to the substitution methods known to man of art.

The compounds of the present invention have very good affinity and selectivity for a new type of low affinity sites. The action on these sites inhibits the neurotoxicity induced by glutamate responsible for certain pathological consequences such as acute or chronic degeneration of cells of the central or peripheral nervous system. The compounds of the present invention can thus be used in various therapeutic applications.

Thus, the compounds of the present invention can be used to protect the cells of the central or peripheral nervous system against acute degeneration induced by accidents such as trauma, ischemia or the action of endogenous and exogenous neurotoxic agents, directly or through secondary mechanisms.

The compounds can also be used to protect the cells of the central or peripheral nervous system against chronic degenerations induced by neurodegenerative diseases and processes such as pathological aging, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis. They can also be used as anticonvulsants or antidepressants or to stimulate alertness, to treat states of dependence on different substances such as drug addicts.

The following is an illustration of the pharmacological properties of the compounds of the invention in the experimental section.

These properties make the compounds of formula I suitable for pharmaceutical use. The present application also relates, as medicaments, to the compounds of formula I as defined above, in all the isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral acids or pharmaceutically acceptable organic or inorganic or organic bases of said compounds of formula I, as well as pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above.

The invention thus relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable acid or base additive salt thereof, in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition can be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories. The appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water, added to pharmaceutically acceptable oils or fats . The sterile liquid compositions can be used for intramuscular or subcutaneous injections and the sterile compositions can also be administered intravenously. The compositions according to the invention can also be administered by other conventional routes such as oral administration.

A subject of the invention is also the use of the compounds of formula I ', characterized in that they correspond

either to formula I'A

the A in which

Ar 'represents a carbocyclic or heterocyclic aryl radical, 5 or 6-membered monocyclic or consisting of condensed rings and optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl radicals, alkoxy, alkylthio, haloalkyl, hydroxy alkyl, having at most 6 carbon atoms; esterified or salified free carboxy; cyano; nitro; amino optionally substituted by one or two identical or different alkyl radicals containing at most 6 carbon atoms; R'i and R'2 identical or different represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from hydroxyl radicals, free esterified or salified carboxy, cyano , nitro or R'i and R'2 form with the nitrogen atom to which they are linked a radical

R'4 has the same meaning as R3 or R'3;

X ', Y' and Z 'are such that at least one represents a sulfur or oxygen atom or a methylene radical and the others represent a methylene radical, or to one of the following formulas: - N- [ l- (2-thienyl) -cyclohexan-1-yl] -3-hydroxymethyl-piperidine,

- N- [1 - (2-thienyl) -cyclohexan- 1 -yl] -4-hydroxy-3-methyl piperidine,

- N- [1- (2-benzothiophenyl) -cyclohexan-1-yl] -4-hydroxy-3-methyl piperidine or

- N-ethyl- 1 - (2-thienyl) -cyclohexy lamin,

- N- [1- (2-furyl) -cyclohexan-1-yl] piperidine, - N- [1- (2-thienyl) -cyclohexan-1-yl] -3-methyl-piperidine, said compounds of formula I 'being in all the isomeric, racemic, enantiomeric and diastereoisomeric forms possible as well as the use of addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula I,

for the preparation of medicaments intended to protect the cells of the central or peripheral nervous system against acute degenerations induced by accidents such as trauma, - ischemia or the action of neurotoxic agents, endogenous or exogenous, directly or through secondary mechanisms .

The invention also relates to the use of the compounds of formula l as defined above, for the preparation of medicaments intended to protect the cells of the central or peripheral nervous system against the chronic degenerations induced by diseases or neurodegenerative processes such as pathological aging, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic sclerosis, as well as anticonvulsant or antidepressant drugs or drugs to stimulate alertness, to treat states of dependence on various substances such than addicts like cocaine.

The invention relates more particularly to the use of the compounds of formula I'A as defined above in which

Ar 'represents a 5-membered monocyclic heterocyclic aryl radical or consisting of two condensed rings and optionally substituted by one or more identical or different alkyl or alkenyl radicals;

R'i and R'2, which are identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms, or else Ri and R2 form, with the nitrogen atom to which they are linked, a radical

in which n is equal to 1 and R3 and R'3 which are identical or different, represent a hydrogen atom or a hydroxyl, alkyl or hydroxyalkyl radical having at most 6 carbon atoms, for the preparation of medicaments as defined above .

The invention relates more particularly also to the use of the compounds of formula A as defined above in which Ar 'represents the thienyl, furyl, benzothienyl, benzofuryl radical and optionally substituted by one or more methyl, ethyl, propyl radicals or allyl;

R'i and R'2, identical or different, represent a hydrogen atom or a methyl or ethyl radical, or else Ri and R2 form, with the nitrogen atom to which they are linked, a radical

in which n is equal to 1 and R3 and R'3 which are identical or different, represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical, for the preparation of medicaments as defined above. More particularly, the subject of the invention is the use of the compounds of formula I'A corresponding to the following formulas:

- N- [4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxy piperidine

- N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] piperidine

- N- [4- (2-thienyl) -tetrahydro-4H-pyran-4-yl] piperidine

- N- [3- (2-thienyl) -tetrahydro-4H-thiopyran-3-yl] piperidine,

for the preparation of medicaments as defined above.

The following examples are presented to illustrate the above procedures and should in no way be taken as limiting the scope of the invention.

EXPERIMENTAL PART

Example 1 N- [4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yI] piperidine

Step 1 a: 3-methyl-tetrahydro-4H-thiopyran-4-one

In a three-necked flask of 250 ml, diisopropylamine (8.4 ml, 60 mmol) and 74 ml of THF are introduced under nitrogen. NBuLi (37.5 ml, 60 mmol) is poured in dropwise and the mixture is stirred for an additional half hour at 25 ° C. The lithium diisopropylamide solution (0.5 M) obtained is cooled to -80 ° C. Tetrahydro-4H-thiopyran-4-one (6.96 g, 60 mmol) is added slowly. After half an hour, methyl iodide (5.6 ml, 90 mmol) is added and the temperature rises to 25 ° C. After five hours of stirring, a sodium bicarbonate solution (5%) saturated with salt is added, decanted, the organic phase is dried over sodium sulfate and concentrated to dryness. The orange oil obtained is chromatographed on silica, eluting with an EP / AcOEt 90/10 mixture. A colorless oil (3.2 g) is thus obtained.

NMR ^! H: 2.8 (m, 3H); 2.4 (m, 4H); 0.95 (d, 3H, J = 6.1 Hz).

¹ C NMR: 209.52 (C4); 47.20 (C3); 43.45 (C5); 30.07 (C2); 30.38 (C6); 14.41 (CH ₃ ). Step 1.b: 4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-ols

2-thienylmagnesium bromide is prepared under nitrogen from magnesium (0.9 g, 37.2 mmol), 2-bromo-thiophene (6.1 g, 37.2 mmol) and 100 ml of ether anhydrous. The mixture is heated at 45 ° C. for 3 hours and then 3-methyltetrahydro-4H-thiopyran-4-one (4.2 g, 33 mmol) dissolved in ether (50 ml) is added at room temperature. The reaction medium is heated for 16 hours at reflux. After cooling, the reaction medium is poured into 100 ml of an aqueous solution saturated with NH4Cl. It is stirred for half an hour in order to destroy the magnesium complex, it is decanted and the aqueous phase is extracted with ether (3 × 50 ml) which is then neutralized with NH4OH (25%). After extraction with ether (3 × 50 ml), the combined organic phases are washed with water until neutral, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The green oil obtained (7.6 g) is chromatographed on silica, eluting with an EP / EA mixture (90/10). A clear oil is thus obtained.

Rf (silica, eluent EP / EA 60/40): 0.4

GC / MS (90-250 ° C (10 ° C / min)): Tr = 14.40 min (majority diastereoisomer: 87%)

Tr = 14.71 min (minority diastereoisomer: 13%)

¹³ C NMR: majority diastereoisomer: 153.65 (C2 '); 126.88-121.80 (C3 'to C5'); 74.52 (C4); 43.33 (C5); 42.68 (C3); 30.67 (C2); 23.89 (C6); 15.86 (CH3).

minority diastereoisomer: 153.0 (C2 '); 126.43-122.98 (C3 'to C5'); 73.33 (C4); 40.25 (C3); 33.84 (C5); 30.17 (C2); 23.89 (C6); 15.04 (CH ₃ ).

Step 1. c: 4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl-azides

The trichloroacetic acid (15.1 g, 92.4 mmol) is dissolved in chloroform (100 ml). Sodium azide (4 g, 61.7 mmol) is added and the medium is cooled to 10 ° C. The diastereoisomeric alcohols obtained according to the preceding step (6.6 g, 30.8 mmol) dissolved in chloroform (50 ml) are poured dropwise. The reaction medium is stirred for 72 hours while maintaining the temperature at 10-12 ° C. An ammonia solution (10%) is then added until neutralization, then the aqueous phase is extracted with dichl oromethane (3x100 ml). The organic phase is washed with water (200 ml), dried over Na ₂ SO ₄ and concentrated to dryness. A brown oil (6.8 g) is thus obtained which is used subsequently without further purification.

Rf (silica, eluent EP / EA 60/40): 0.37 GC / MS (60-250 ° C (10 ° C / min)): Tr = 18.31 min (majority diastereoisomer: 72%)

Tr = 18.08 min (minority diastereoisomer: 28%)

Step 1. d: 4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl-amines

In a 100 ml three-necked flask, lithium aluminum hydride (0.87 g, 23 mmol) is introduced into THF at 0 ° C. The mixture of azides obtained in the previous step (5.5 g, 23 mmol) dissolved in 30 ml of THF is poured in dropwise. The reaction medium is stirred for 24 hours at room temperature. The minimum ammonia (10%) is added very slowly in order to destroy the excess LiAlH ₄ . Filtered on celite, the precipitate is washed with dichloromethane (300 ml) and concentrated to dryness. The brown oil obtained is taken up in ether and extracted with a HCl solution (10%) (3x100 ml). The aqueous phase is then neutralized with ammonia (20) and extracted with ether (3x100 ml). The organic phase is washed with water, dried over MgSO ₄ and concentrated to dryness. The product obtained is purified by chromatography on silica, eluting with an EP / EA 50/50 mixture. A colorless oil (3.7 g) is thus obtained.

Rf (silica, eluent EP / EA 60/40): 0.20 (majority) and 0.25 (minority)

GC / MS (90-250 ° C (10 ° C / min)): Tr = 24.15 min (majority diastereoisomer: 62.5%)

Tr = 23.77 min (minority diastereoisomer: 37.5%)

¹³ C NMR (majority): 155.11 (C2 '); 125.99-121.94 (C3 'to C5'); 54.80 (C4); 40.72 (C3); 34.51 (C5); 30.66 (C2); 23.44 (C6); 15.34 (CH ₃ ).

¹³ C NMR (minority): 156.60 (C2 '); 126.41-121.26 (C3 'to C5'); 55.84 (C4); 43.92 (C5); 42.40 (C3); 30.04 (C2); 23.35 (C6); 15.97 (CH ₃ ).

Step 1. e: N- [4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl] piperidines

The mixture of amines from step ld above (4.5 g, 21 mmol) is dissolved in HMPT (50 ml). Add potassium carbonate (5.8 g, 42 mmol) and 1,5-dibromopentane (3.6 ml, 26.2 mmol). The medium is stirred under nitrogen at 60 ° C for 48 hours. After cooling, this solution is poured onto water (200 ml) and extracted with ether (3x100 ml). An acid-base wash is carried out as previously, extracted again with ether, washing the ethereal phase with water, drying over magnesium sulphate and concentrating to dryness. The yellow oil obtained (6.2 g) is purified by chromatography on silica, eluting with an EP / EA mixture (90/10). The two diastereoisomers are thus obtained separately: the majority (2 g, 34%) and the minority (0.7 g, 12), both in the form of a white solid.

Rf (silica, eluent EP / AP 90/10): 0.6 (trans), 0.4 (cis)

CPV: Tr 18.15 min and Tr (racemic) = 19.75 min

Tr (minority) = 18.46 min and Tr (racemic) = 18.95 min

1 ³ C NMR (majority): 145.88 (C2 '); 125.80-122.41 (C3 'to C5'); 61.51 (C4); 45.96 (Cα); 33.26 (C3); 29.47 (C5); 28.38 (C2); 26.90 (Cβ); 25.03 (C6); 22.93 (Cγ); 15.10

(CH ₃ ).

¹³ C NMR (minority): 142.70 (C2 '); 126.23-122.76 (C3 'to C5'); 62.08 (C4); 45.59 (Cα); 33.55 (C3); 32.88 (C5); 30.64 (C2); 26.87 (Cβ); 25.38 (C6); 25.03 (Cγ); 13.41

(CH ₃ ).

Example 2 (±) -N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine

Step 2 a: 4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile In a 250 ml bicol, magnesium sulfate (9.6 g, 80 mmol) is successively introduced, DMA ( 2 g, 23 mmol) (±) -3-methylpiperidine (4 g, 40 mmol), tetrahydro-4H-thiopyran-4-one (2.3 g, 20 mmol) and acetone cyanohydrin (1.7 g, 20 mmol). The reaction medium is stirred for 48 hours at 45 ° C. After cooling to room temperature, the pasty mixture obtained is thrown on ice (about 150) and stirred for half an hour. An ether extraction is then carried out (3 × 80 ml), the combined organic phases are washed with water (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. A brown oil is thus obtained (4.5 g, 20 mmol) consisting of a mixture of the expected product with approximately 4% of the amino nitrile derived from acetone and 7% of tetrahydro-4H-thiopyran- 4- one remaining. The product is used subsequently without additional purification

¹³ C NMR: 118.3 (CN); 59.43 (C4); 54.1 (Cα); 46.42 (Cα '); 34.3 (C3 *); 34.2 (C5 *); 32.1 (Cγ); 30.9; 25.1 (C2-C6); 22.8 (Cβ '); 19.3 (CH ₃ ).

Step 2b: (±) -N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine

2-Thienylmagnesium bromide is prepared under nitrogen from magnesium in turnings (1 g, 40 mmol), 2-bromothiophene (6.52 g, 40 mmol) and 150 ml of anhydrous ether. The ether is refluxed for 3 hours and then raminonitrile obtained according to the preceding step (2.25 g, 10 mmol) is added at room temperature. The reaction medium is heated for 20 hours at reflux. After the usual treatment, a brown oil is obtained which is chromatographed on 100 g of alumina, eluting with an EP / EA mixture (95/5). A colorless oil (1.6 g) is thus obtained.

¹ C NMR: 146.6 (C2 '); 126.0-122.7 (C3 'to C5'); 58.2 (C4); 53.35 (Cα); 45.5 (Cα '); 37.1 (C3 *); 36.8 (C5 *); 33.2 (Cβ '); 31.8 (Cβ); 23.4 (C2-C6); 22.5 (Cγ); 19.3 (CH ₃ ).

The corresponding hydrochloride is prepared by treating the base for 3 hours in hydrochloric ether. after filtration and rinsing abundantly with anhydrous ether, a white powder (1.42 g) is obtained. Mp = 168 ° C

¹³ C NMR: 134.5 (C2 '); 130.3-127.9 (C3 'to C5'); 68.9 (C4); 52.3 (Cα); 46.2 (Cα '); 33.4 (C3 *); 33.2 (C5 *); 30.5 (Cβ '); 28.2 (Cβ); 24.9 (C2-C6); 22.1 (Cγ); 18.9 (CH ₃ ).

Example 3 S - (-) - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine

Step 3 a: S - (+) - 3-methyl-piperidine

Hot (+) mandelic acid (45.64 g, 0.3 mol) is dissolved in 300 ml of ethyl acetate. 3-methylpiperidine (29.8 g, 0.3 mol) is added with stirring and the solution is allowed to return to room temperature. After 24 hours, the salt obtained is filtered and rinsed with an EA / AcOEt mixture (1/1) then recrystallized 3 times from AcOEt. The salt of (S) - (+) - 3-methylpiperidine mandelate (22.7 g) is thus obtained. Mp = 120-122 ° C; α _D = + 58.0 ° (methanol, c = 1.0).

These crystals are taken up in 50 ml of a 25% aqueous sodium hydroxide solution and then the solution is extracted with ether (3 × 50 ml). The combined organic phases are washed with a saturated NaCl solution, dried over MgSθ ₄ and then concentrated. The oil obtained is distilled at atmospheric pressure to give a colorless liquid (7.1 g). Mp = 92-97 ° C

1 ³ C NMR = 53.2 (C2); 45.1 (C6); 32.2 (C4); 30.6 (C3); 25.2 (C5); 18.0 (CH ₃ ).

Step 3b: S-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile

The procedure is identical to that illustrated in step 2a, using S - (-) - 3-methylpiperidine in place of (±) -3-methylpiperidine.

Step 3 c: S - (-) - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine

The procedure is identical to that illustrated in step 2b, using S-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile instead of (±) -4- ( 3-methyl- piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile. A colorless oil (1.8 g) is obtained which crystallizes when cold. Mp = 53-55 ° C.

The hydrochloride is obtained according to the procedure described in step 2b. Mp = 169-171 ° C.

_D = - 10 ° (methanol, c = 1.0)

Example 4 R - (+) - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine

Step 4 a: R - (-) - 3-methyl-piperidine

The crystallization and recrystallization filtrates of the mandelic salts of S - (+) - 3-methyl-piperidine from the preceding stage 3a are combined and treated with 100 ml of an aqueous sodium hydroxide solution (25%). After half an hour with stirring, this aqueous phase is extracted with ether (4x50 ml). The combined organic phases are washed with saturated NaCl solution (100 ml), dried over MgSO ₄ and then concentrated. A liquid enriched in (R) - (+) - 3-methylpiperidine is thus obtained, which is added to 30 g of (-) mandelic acid dissolved in 180 ml of hot ethyl acetate. After 24 hours, the salt obtained is filtered and rinsed with an EA / AcOEt mixture (1/1) then recrystallized 2 times from ethyl acetate. The salt of R - (-) - 3-methyl-piperidine mandelate is obtained in the form of white crystals (17 g).

Mp = 121-123 ° C; α _D = - 56.5 ° (methanol, c = 1.0)

These crystals are taken up in 50 ml of a 25% aqueous sodium hydroxide solution and then the solution is extracted with ether (3 × 50 ml). The combined organic phases are washed with a saturated NaCl solution, dried over MgSO ₄ and then concentrated. The oil obtained is distilled at atmospheric pressure to give a colorless liquid (5.2 g).

Step 4b: R-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran- 4-carbonitrile

The procedure is identical to that illustrated in step 2a, using R - (+) - 3-methylpiperidine in place of (±) -3-methylpiperidine.

Step 4 c: R - (+) - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl- piperidine

The procedure is identical to that illustrated in step 2b, using R-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile instead of (±) -4- ( 3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile. A colorless oil (1.65 g) is obtained which crystallizes when cold. Mp = 54-56 ° C. The hydrochloride is obtained according to the procedure described in step 2b. Mp = 170-172 ° C.

ŒD = + 12 ° (methanol, c = 1.0)

Example 5 (±) -N- [4- (2-benzothiophenyl) -tetrahydro-4H-thiopyran-4-yl] - 3-methyl-piperidine

4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile (2 g, 8.9 mmol) dissolved in 50 ml of anhydrous ether is poured in dropwise over 2- bromide solution benzothiophenylmagnesium (44.7 mmol). The mixture is heated under reflux of the ether for 20 hours. After the usual treatment, a brown oil (1.7 g) is obtained which is chromatographed on 60 g of alumina, eluting with an EP / EA mixture (95/5). A white solid is thus obtained (1.2 g, 40%).

Mp = 90-92 ° C

1 ³ C NMR: 147.99 (C2 '); 139.19 (C7'a); 138.32 (C3'a); 123.90 to 119.96 (C3 'to C7'); 58.88 (C4); 53.45 (Cα); 45.65 (Cα '); 36.78 (C3 *); 36.52 (C5 *); 33.17 (Cβ '); 31.85 (Cβ); 26.14 (Cγ); 23.52 (C2-C6); 19.77 (CH ₃ ).

The corresponding hydrochloride is prepared. Mp = 160 ° C

¹³ C NMR: 139.45 (C2 '); 138.63 (C7'a); 135.04 (C3'a); 127.89 to 121.86 (C3 'to C7'); 69.26 (C4); 52.75 (Cα); 46.72 (Cα '); 33.48 (C3 *); 33.29 (C5 *); 30.57 (Cβ '); 28.41 (Cβ); 25.06 (C2-C6); 22.21 (Cγ); 18.92 (CH ₃ ).

Example 6 R - (+) - N- [4- (2-benzothiophenyl) -tetrahydro-4H-thiopyran-4-yl] - 3-methyl-piperidine

The procedure is identical to that of Example 5, starting with R-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile instead of 4- (3-methyl-piperidino) - tetrahydro-4H-thiopyran-4-carbonitrile. The same amounts of reagents are used. Colorless crystals are obtained (1.85 g). Mp = 90-92 ° C.

Characteristic of the corresponding hydrochloride:

Mp = 158-165 ° C; 0C _D = + 27.2 ° (methanol, c = 1.0)

Example 7 S - (-) - N- [4- (2-benzothiophenyl) -tetrahydro-4H-thiopyran-4-yl] - 3-methyl-piperidine

The procedure is identical to that of Example 5, starting from S-4- (3-methyl-piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile instead of 4- (3-methyl-piperidino) - tetrahydro-4H-thiopyran-4-carbonitrile. The same amounts of reagents are used. Colorless crystals are obtained (1.2 g). Mp = 91-93 ° C

Characteristic of the corresponding hydrochloride:

Mp = 162-168 ° C; CC _D = - 23.6 ° (methanol, c = 1.0).

Example 8 N- [1- (2-thienyl) -cyclohexan-1-yl] -3-hydroxymethyl-piperidine

Step 8 a: l- [l- (3-hydroxymethyl-piperidino) -cyclohexan-l-yl] -carbonitrile

It is prepared from MgSO ₄ (9 g, 75 mmol), (2.2 g, 25 mmol), 3-hydroxymethyl-piperidine (5.8 g, 38 mmol), cyclohexanone (2.5 g , 25 mmol) and acetone cyanohydrin (2.2 g, 25 mmol) as described previously in step 2a. After treatment of the reaction, a white solid (4.5 g) is obtained.

¹³ C NMR: 118.89 (CN); 64.94 (CH ₂ OH); 60.93 (Cl); 50.17 (Cα); 47.07 (Cα '); 34.75 (Cβ); 33.72 (C2 *); 33.60 (C6 *); 26.79 (Cγ); 24.65 (C3-C5); 21.83 (C4).

Step 8b: N- [1- (2-thienyl) -cyclohexan-1-yl] -3-hydroxymethyl-piperidine

2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (0.66, 27.2 mmol), 2-bromothiophene (4.4 g, 9.5 mmol) and 80 ml of anhydrous ether, heated at 45 ° C for 3 hours then added at room temperature l- [l- (3-hydroxymethyl-piperidino) -cyclohexan-1-yl] -carbonitrile (2 g, 9 mmol) dissolved in ether. The reaction medium is heated for 20 hours at reflux. After treatment of the reaction, 2.1 g of a yellow oil are obtained which is chromatographed on alumina, eluting with an EP / EA mixture (50/50). A colorless oil (1.4 g) is thus obtained.

¹³ C NMR: 145.45 (C2 '); 125.84 to 122.76 (C3 'to C5'); 66.66 (CH ₂ OH); 60.06 (Cl); 49.26 (Cα); 46.08 (Cα '); 38.44 (Cβ); 35.89 (C2 *); 35.69 (C6 *); 27.73 (Cβ '); 25.22 (Cγ); 24.70 (C3-C5); 22.08 (C4).

Characteristic of the corresponding hydrochloride:

Mp = 176-178 ° C.

¹³ C NMR: 135.76 (C2 '); 130.57 to 127.92 (C3 'to C5'); 69.74 (CH ₂ OH); 64.20 (Cl); 49.69 (Cα); 46.85 (Cα '); 36.60 (Cβ); 33.37 (C2 *); 33.00 (C6 *); 25.27 (Cβ '); 23.97 (Cγ); 23.03 (C3-C5); 22.21 (C4). Example 9 N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine

Step 9 a: 4-piperidino-tetrahydro-4H-thiopyran-4-carbonitrile

Magnesium sulfate (9.3 g, 77.4 mmol), DMA (2.25 g, 25.8 mmol), piperidine (4.4 g, 51, 6 mmol), tetrahydro-4H-thiopyran-4-one (3 g, 25.8 mmol) and acetone cyanohydrin (2.2 g, 25.8 mmol). The reaction medium is stirred for 48 hours at 45 ° C.

After cooling to room temperature, the mixture obtained is thrown on ice (about 100 g) and stirred for 1/2 hour. An ether extraction is then carried out (3 × 80 ml), the combined organic phases are washed with water (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. An orange oil is obtained (5.3 g, 25.2 mmol) which will be used subsequently without particular purification.

¹³ C NMR: 118.34 (CN); 59.61 (C4); 46.985 (Cα); 34.215 (C3-C5); 25.72 (C2-C6); 23.77 (Cβ); 22.76 (Cγ).

Step 9b: N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine

A solution of MgBr ₂ is prepared by adding dropwise and under nitrogen 1,2-dibromoethane (6.76 g, 36 mmol) diluted in 80 ml of anhydrous ether on magnesium in turns (0.88 g , 36 mmol). The solution is kept for 2 hours at room temperature.

A solution of 2-lithio-furan is simultaneously prepared, at -20 ° C. and under nitrogen, by dropwise addition of a solution of 1.6 M n-butyllithium in hexane (28 ml, 45 mmol) on a mixture of furan (3.1 g, 45 mmol). This mixture is heated for 2 hours at reflux.

This solution is transferred at room temperature. Raminonitrile from step 9a (1.9 g, 9 mmol) dissolved in 50 ml of anhydrous ether is poured in dropwise over the solution of 2-furylmagnesium bromide. The mixture is heated under reflux of the ether for 16 hours. After the usual treatment, a brown solid (1.8 g) is obtained which is chromatographed on 60 g of alumina, eluting with an EP / EA mixture (98/2). A white solid is thus obtained (1.6 g, 71%).

Mp = 79-81 ° C.

¹³ C NMR: 156.49 (C2 '); 141.05 (C5 '); 109.27 (C3 '); 106.10 (C4 '); 57.47 (C4); 46.44 (Cα); 33.57 (C3-C5); 26.58 (C2-C6); 24.55 (Cγ); 23.30 (Cβ). Characteristic of the corresponding hydrochloride:

Mp = 171-173 ° C.

1 ³ C NMR: 145.25 (C2 '); 143.49 (C5 '); 113.71 (C3 '); 110.74 (C4 '); 66.84 (C4); 46.74 (Cα); 30.25 (C3-C5); 24.52 (C2-C6); 21.96 (Cβ); 21.33 (Cγ).

Example 10 N- [4- (2-benzofuryl) -tetrahydro-4H-thiopyran-4-yl] -piperidine

The preparation process is identical to that of step 9b but using a 2-lithio-benzofuran solution instead of a 2-lithio-furan solution.

After the usual treatment, a yellow solid is obtained which is chromatographed on alumina, eluting with an EP EA mixture (98/2). A white solid is thus obtained (67%).

Mp = 109-111 ° C.

¹³ C NMR: 159.78 (C2 '); 154.0 (C7 ^* a); 127.83 (C3'a); 123.42-102.8 (C3 'to c7'); 57.76 (C4); 46.62 (Cα); 33.78 (C3-C5); 26.81 (C2-C6); 24.64 (Cγ); 23.17 (Cβ).

Characteristic of the corresponding hydrochloride:

Mp = 171-173 ° C.

¹³ C NMR: 154.18 (C2 '); 147.88 (C7'a); 126.65 (C3'a); 125.80 to 111.07 (C3 'to C7'); 67.83 (C4); 47.55 (Cα); 30.77 (C3-C5); 24.99 (C2-C6); 22.47 (Cβ); 24.64 (Cγ).

Example 11 N- [4- (5-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yI] - piperidine

The preparation process is identical to that of step 9b but using a solution of 2-lithio-5-methyl-thiophene in place of a solution of 2-lithio-furan.

After the usual treatment, a yellow solid is obtained which is chromatographed on alumina, eluting with an EP / EA mixture (98/2). A white solid is thus obtained (67%).

Mp = 93-95 ° C.

¹³ C NMR: 144.04 (C2 '); 136.95 (C5 '); 124.05 (C3 '); 123.05 (C4 '); 58.44 (C4); 45.96 (Cα); 36.65 (C3-C5); 26.74 (C2-C6); 24.88 (Cγ); 23.37 (Cβ); 15.09 (CH ₃ ).

Characteristic of the corresponding hydrochloride:

Mp = 160-162 ° C. ¹³ C NMR: 142.88 (C2 '); 131.34 (C5 '); 130.25 (C3 '); 125.82 (C4 '); 68.83 (C4); 46.47 (Cα); 32.89 (C3-C5); 24.68 (C2-C6); 22.27 (Cβ); 21.69 (Cγ); 14.75 (CH ₃ ).

Example 12 N- [4- (4-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl] - piperidine

The preparation process is identical to that of step 9b but using a 2-Uthio-4-methyl-thiophene solution in place of a 2-lithio-furan solution.

After the usual treatment, a brown solid is obtained which is chromatographed on alumina, eluting with an EP / EA mixture (90/10). A white solid (55%) is thus obtained.

Mp = 89-91 ° C.

¹³ C NMR: 146.04 (C2 '); 136.32 (C4 '); 125.63 (C3 '); 118.05 (C5 '); 58.34 (C4); 45.95 (Cα); 36.66 (C3-C5); 26.74 (C2-C6); 24.68 (Cγ); 23.32 (Cβ); 15.78 (CH ₃ ).

Characteristic of the corresponding hydrochloride:

Mp = 144-146 ° C.

³ C NMR: 138.86 (C2 '); 134.17 (C5 '); 132.68 (C3 '); 123.93 (C4 '); 69.43 (C4); 47.17 (Cα); 33.57 (C3-C5); 25.21 (C2-C6); 22.84 (Cβ); 21.14 (Cγ); 15.61 (CH ₃ ).

Example 13: N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-hydroxy piperidine

Step 13 a: 4- (3-hydroxypiperidino) -tetrahydro-4H-thiopyran-4-carbonitrile

In a 100 ml bicol, the 3-hydroxy-piperidine hydrochloride (6.5 g, 47.3 mmol) is introduced into 30 ml of water. Add potassium cyanide (1.85 g,

35.5 mmol) and drip tetrahydro-4H-thiopyran-4-one (2.7 g,

23.6 mmol). The pH of the medium is adjusted to 11 with a few drops of sodium hydroxide (10%). After 24 hours with stirring at room temperature, an extraction with ether is then carried out (3 × 80 ml), the combined organic phases are washed with water (100 ml), dried over Na SO ₄ , filtered and concentrated to dryness. A colorless oil is thus obtained (3.9 g, 17.2 mmol).

¹³ C NMR: 117.87 (CN); 66.25 (Cβ); 59.19 (C4); 53.20; 45.96 (Cα '); 33.94 (C3-C5); 31.79 (Cγ); 22.70 (C2-C6); 21.90 ((Cβ '). Step 13b: N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-hydroxy piperidine

2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (1.3 g, 53.2 mmol), 2-bromothiophene (8.7 g, 53.2 mmol) and 100 ml of anhydrous ether. The mixture is heated at 45 ° C. for 3 hours and then the aminonitrile obtained in step 13a (3 g, 13.3 mmol) dissolved in ether is added at room temperature. The reaction medium is heated for 20 hours at reflux. After treatment of the reaction, 2.3 g of a brown oil are obtained which is chromatographed on silica eluting with an EP / EA mixture (30/70). A white solid is thus obtained (42%).

Mp = 84-87 ° C.

¹³ C NMR: 145.82 (C2 '); 126.71 to 123.13 (C3 'to C5'); 66.83 (Cβ); 58.23 (C4); 52.52 (Cα); 45.89 (Cα '); 36.40 (C3-C5); 32.18 (Cγ); 23.40 (C2-C6); 22.36 (Cβ ').

Characteristic of the corresponding hydrochloride:

Mp = 169-172 ° C.

¹³ C NMR: 134.26 (C2 '); 130.78 to 128.29 (C3 'to C5'); 69.69 (C4); 63.75 (Cβ); 51.31 (Cα); 46.18 (Cα '); 34.10 (C3-C5); 31.22 (Cγ); 25.28 (C2-C6); 20.38 (Cβ ').

Example 14: N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxy piperidine

Step 14 a: 4- (4-hydroxypiperidino) -tetrahydro-4H-thiopyran-4-carbonitrile

It is prepared from MgSO ₄ (7.2 g, 60 mmol), DMA (2.62 g, 30 mmol), 4-hydroxy-piperidine (3.03 g, 20 mmol), tetrahydro-4H -thiopyran-4-one (2.32 g, 20 mmol) and acetone cyanohydrin (1.7 g, 20 mmol). After treating the reaction, a white solid (4.7 g) is obtained which is crystallized from anhydrous ether. White crystals are thus obtained (3.6 g, 79%), mp = 79-81 ° C.

¹³ C NMR: 118.28 (CN); 66.67 (Cγ); 59.42 (C4); 43.87 (Cα); 33.96 (C3-C5 *); 34.33 (Cβ *); 22.91 (C2-C6).

Step 14b: N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxy piperidine

2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (0.45 g, 18.5 mmol), 2-bromothiophene (3 g, 18.5 mmol) and 50 ml of anhydrous ether. We heated at 45 ° C for 3 hours then raminonitrile obtained in step 14a (1.4 g, 6.2 mmol) dissolved in ether is added at room temperature. The reaction medium is heated

20 hours at reflux. After treatment of the reaction, 1.5 g of a brown solid are obtained which is chromatographed on alumina, eluting with anhydrous ether. A white solid is thus obtained (0.85 g, 49%).

Mp = 145-148 ° C.

¹³ C NMR (D ₂ O): 146.19 (C2 '); 126.07 to 122.98 (C3 'to C5'); 68.18 (Cγ); 58.24 (C4); 42.67 (Cα); 36.92 (C3-C5 *); 35.19 (Cβ *); 23.40 (C2-C6).

Characteristic of the corresponding hydrochloride:

Mp = 182-185 ° C.

¹ C NMR: 136.63 (C2 '); 134.19 to 130.98 (C3 'to C5'); 72.05 (C4); 67.53 (Cγ); 48.04 (Cα); 36.71 (C3-C5); 33.87 (Cβ); 27.45 (C2-C6).

Example 15: N- [1- (2-thienyl) -cyclohexan-1-yI] -4-hydroxy-3-methyl piperidine

Step 15 a: Ethyl N-benzoyl-4-piperidone-3-carboxylate

Benzamide (12.1 g, 0.1 mmol) in 200 ml of toluene is introduced under nitrogen into a 250 ml three-necked flask and sodium hydride (4 g, 0.1 mol) is added. The mixture is heated for one hour at reflux, then cooled to 0 ° C. and ethyl acrylate (32.6 ml, 0.3 moles) is poured rapidly. The reaction medium is stirred for 24 hours at 60 ° C. Cool to 0 ° C and add 100 ml of ice water. After 1/2 hour with stirring, the two phases are decanted and the aqueous phase is washed with 50 ml of ether. The aqueous phase is acidified to pH 3 and then extracted with dichloromethane (3x50 ml). The combined organic phases are dried over Na ₂ SO ₄ and concentrated to dryness. A yellow oil is thus obtained which is chromatographed on silica, eluting rapidly with anhydrous ether. An oil slightly colored red (9.4 g, 34) is thus obtained with traces of benzamide.

¹ C NMR: 201.63 (C4); 197.5 (C4enol); 170.89 and 170.4 (CO amide and ester); 135.25 to 126.87 (Caromatics); 95.73 (C3enol); 61.4 and 60.46 (CH enol and ketone); 56.01 (C3); 41.05 (C6); 34.55 (C2); 28.78 (C5); 13.95 and 13.76 (CH ₃ enol and ketone).

Step 15b: Ethyl N-benzoyl-4-piperidone-3-carboxylate

The mixture consisting of the keto-ester from step 15a (9.3 g, 33.8 mmol) and sodium hydride (1.35 g, 34 mmol) in 50 ml of dimethoxyethane is heated under reflux for 2 hours with stirring. The mixture is cooled to 0 ° C. and methyl iodide (5.2 ml,

84 mmol). The reaction medium is heated for 40 hours at 60 ° C. Concentrate to dryness and take up the residue in water (100 ml). Dichloromethane extraction is carried out

(3x50 ml), wash the combined organic phases with 50 ml of NaOH (5%), 50 ml of HCl (5%) and 50 ml of water. Sir Na2SO4 is dried and concentrated to dryness. The brown oil obtained

(9.4 g) is chromatographed on silica eluting with anhydrous ether. A slightly yellow oil is obtained (7.7 g, 79%).

¹³ C NMR: 203.89 (C4); 170.54 (CO amide and ester); 134.76 to 126.87 (Caromatics); 61.56 (CH ₂ Et); 57.11 (C3); 39.05 (C6); 17.15 (CH ₃ ); 13.60 (CH ₃ Et).

Step 15 c: 3-methyl-4-piperidone hydrochloride

The compound from step 15b (7.7 g, 26.6 moles) is heated to reflux of an aqueous HCl solution (6N) for 72 hours. The precipitate of benzoic acid formed is filtered, the aqueous phase is extracted with ether (3 × 50 ml) and the aqueous phase is concentrated to dryness. The brown solid obtained is crystallized from ethanol and thus white crystals are obtained (2.85 g, 72%). Mp = 180-182 ° C.

¹³ C NMR: 210.38 (C4); 54.58 (C2); 47.67 (C6); 47.01 (C3); 42.98 (C5); 11.18 (CH ₃ ).

Step 15 d: 3-methyl-4-piperidol

The compound of step 15c (2.85 g, 19 mmol) and 30 ml of methanol are introduced into a 100 ml three-necked flask. 7.6 ml of a sodium hydroxide solution (5%) are poured dropwise. After 1/2 hour with stirring, a solution of sodium borohydride (2.46 g, 6.5 mmol) is poured into 30 ml of methanol. The reaction medium is stirred for 4 hours at room temperature. The medium is cooled to 0 ° C., a few drops of HCl solution are added and concentrated to dryness. The yellow solid obtained is taken up in hot ethanol and the product is precipitated by adding a few drops of ether. The precipitate is filtered and a white solid is thus obtained (1.9 g, 87%). Mp = 169-170 ° C.

¹³ C NMR (D ₂ O): - Majority diastereoisomer: 73.24 (C4); 50.75 (C2); 45.69 (C6); 38.45 (C3); 32.92 (C5); 16.8 (CH ₃ ).

- Minority diastereoisomer: 67.94 (C4); 46.97 (C2); 41.32 (C6); 34.89 (C3); 31.29 (C5); 16.47 (CH ₃ ).

Step 15 e: l- (4-hydroxy-3-methyl-piperidino) -cycIohexan-l-carbonitrile

The compound of step 15d (0.8 g, 7 mmol) is introduced into 10 ml of water in a 50 ml bicol. Cyclohexanone (2.7 g, 23.6 mmol) and a few drops of HCl are added. in order to bring the pH to 3. Then pour the potassium cyanide (0.47 g, 7.3 mmol). The pH of the medium is then close to 11. After 24 hours with stirring at room temperature, an extraction is carried out with dichloromethane, dried over Na2Sθ4, filtered and concentrated to dryness. A colorless oil is thus obtained (1.43 g, 6.4 mmol) representing only one of the two diastereoisomers.

1 C NMR: 118.97 (CN); 73.69 (Cγ); 60.57 (Cl); 52.43 (Cα); 45.37 (Cα '); 38.57 (Cβ); 34.22 (Cβ '*); 33.98 (C2-C6 *); 33.87 (C4 *); 21.91 (C3-C5); 15.61 (CH ₃ ).

Step 15 f: N- [1- (2-thienyl) -cyclohexan-1-yl] -4-hydroxy-3-methyl piperidine

2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (0.38 g, 15.7 mmol), 2-bromothiophene (2.57 g, 15.7 mmol) and 60 ml of anhydrous ether. The mixture is heated at 45 ° C. for 3 hours and then the aminonitrile obtained in step 15e (0.7 g, 3.15 mmol) dissolved in THF is added at room temperature. The reaction medium is heated for 20 hours at reflux. After treatment of the reaction, a brown oil is obtained which is chromatographed on alumina, eluting with anhydrous ether. A white solid is thus obtained (0.48 g, 54%).

¹³ C NMR: 146.14 (C2 '); 125.86 to 122.61 (C3 'to C5'); 74.76 (Cγ); 59.34 (Cl); 51.17 (Cα); 43.98 (Cα '); 39.36 (Cβ); 36.0 (C3-C5); 25.85 (C4 *); 21.96 (C3-C5 *); 15.75

(CH ₃ ).

Characteristic of the corresponding hydrochloride:

¹³ C NMR: 135.09 (C2 '); 129.98 to 127.55 (C3 'to C5'); 70.60 (Cγ); 69.00 (Cl); 50.59 (Cα); 45.30 (Cα '); 35.37 (Cβ); 32.80 (C3-C5); 30.77 (C2-C6); 23.43 (C4); 22.53 (C3-C5); 15.06 (CH ₃ ).

Example 16 N- [1- (2-benzothiophenyl) -cyclohexan-1-yl] -4-hydroxy-3-methyl piperidine

The aminonitrile from step 15e (0.7 g, 3.15 mmol) dissolved in 50 ml of anhydrous ether is poured in dropwise over a solution of 2-benzothiophenylmagnesium bromide (15.75 mmol). The mixture is heated under reflux of the ether for 16 hours. After the usual treatment, a yellow oil (0.85 g) is obtained which is chromatographed on alumina, eluting with an EP / EA mixture (20/80). A white solid is thus obtained (0.74 g, 71%).

Mp = 120-122 ° C. ¹³ C NMR: 147.60 (C2 '); 139.44 (C7'a); 138.64 (C3'a); 123.77 to 120.44 (C3 'to C7'); 74.89 (Cγ); 59.98 (Cl); 51.29 (Cα); 44.16 (Cα '); 39.55 (Cβ); 33.84 (C2-C6); 35.27 (Cβ '); 25.86 (C4); 22.14 (C3-C5); 15.85 (CH ₃ ).

Characteristic of the corresponding hydrochloride:

Mp = 170-172 ° C.

¹³ C NMR: 139.60 (C2 '); 139.02 (C7'a and C3'a); 126.16 to 120.02 (C3 'to C7'); 71.85 (Cγ); 65.66 (Cl); 51.33 (Cα); 45.66 (Cα '); 36.54 (Cβ); 33.58 (C2-C6); 31.99 (Cβ '); 24.12 (C4); 22.80 (C3-C5); 15.54 (CH ₃ ).

Example 17 N-ethyl-1- (2-thienyl) -cyclohexylamine

Step 17 a: 1- (2-thienyl) -cyclohexanol

2-Thienylmagnesium bromide is prepared under nitrogen from magnesium (2.92 g, 120 mmol), 2-bromothiophene (19.6 g, 120 mmol) and 200 ml of anhydrous ether. The mixture is heated at 45 ° C. for 3 hours and then cyclohexanone (7.84 g, 80 mmol) dissolved in ether is added at ambient temperature. The reaction medium is heated for 16 hours at reflux. After cooling, the reaction medium is poured into 100 ml of an aqueous solution saturated with NH4Cl. It is stirred for 1/2 hour in order to destroy the magnesium complex, it is decanted and the aqueous phase is extracted with ether (3x50 ml). An acid-base extraction is carried out with a 15% aqueous HCl solution (3 × 50 ml) which is then neutralized with NH4OH (25%). After extraction with ether (3 × 50 ml), the combined organic phases are washed with water until neutral, dried over Na2Sθ4, filtered and concentrated to dryness. The brown oil obtained is chromatographed on silica eluting with an EP / EA mixture (70/30). A clear, slightly yellow oil (12.1 g, 83%) is thus obtained.

³ C NMR: 153.52 (C2 '); 128.38 to 121.78 (C3 'to C5'); 71.78 (Cl); 39.73 (C2-C6); 25.2 (C4); 22.15 (C3-C5).

Step 17b: 1- (2-thienyl) -cyclohexylazide

The trichloroacetic acid (31.9 g, 195 mmol) is dissolved in chloroform (200 ml). Sodium azide (8.45 g, 130 mmol) is added and the medium is cooled to 10 ° C. The alcohol obtained in step 17a (11.8 g, 65 mmol) dissolved in chloroform (50 ml) is poured in dropwise. The reaction medium is stirred for 48 hours while maintaining the temperature at 10-12 ° C. An ammonia solution (10%) is then added until neutralization, then the aqueous phase is extracted with dichloromethane (3x100 ml). The organic phase is washed with water (200 ml), dried over Na2Sθ4 and concentrated to dryness. A brown oil is thus obtained which is used subsequently without further purification. Step 17 c: 1- (2-thienyl) -cyclohexylamine

In a 500 ml three-necked flask, the lithium aluminum hydride (2.28 g, 60 mmol) is introduced into 250 ml of THF at 0 ° C. The azide obtained in the preceding step 17b (13.5 g, 65 mmol) dissolved in 30 ml of THF is poured in dropwise. The reaction medium is stirred for 24 hours at room temperature. The minimum ammonia (10%) is added very slowly in order to destroy the excess LiAiï i. Filtered on celite, the precipitate is washed with dichloromethane (300 ml) and concentrated to dryness. The oil obtained is taken up in ether and extracted with a HCl solution (10%) (3x100 ml). The aqueous phase is then neutralized with ammonia (20%) and extracted with ether (3x100 ml). The organic phase is washed with water, dried over MgSθ4 and concentrated to dryness. The product obtained is purified by chromatography on alumina, eluting with an EP / EA mixture (60/40). A slightly yellow oil is thus obtained (8.1 g, 69%).

¹³ C NMR: 156.70 (C2 '); 125.99 to 120.85 (C3 'to C5'); 52.82 (Cl); 40.39 (C2-C6); 25.17 (C4); 22.10 (C3-C5).

Step 17 d: N-acetoxy-1- (2-thienyl) -cyclohexylamine

In the 250 ml three-necked flask, the amine from step 17c (3 g, 16.6 mmol) is introduced into the pyridine (100 ml) and the acetic anhydride (51 g, 50 mmol) is added dropwise. After 4 hours with stirring at room temperature, 100 ml of a HCl solution (10%) are added and the product formed is extracted with ether (3 × 50 ml). The organic phase is washed with an HCl solution (10%) (2x80 ml), then with water (2x80 ml), dried over MgSθ4 and concentrated to dryness. A white solid is thus obtained (3.1 g, 84%).

¹³ C NMR: 169.44 (CO); 152.48 (C2 '); 126.32 to 122.68 (C3 'to C5'); 56.69 (Cl); 37.32 (C2-C6); 25.22 (C4); 24.10 (CH ₃ ); 22.11 (C3-C5).

Step 17 e: N-ethyl-1- (2-thienyl) -cyclohexylamine

In a 500 ml three-necked flask, the lithium aluminum hydride (0.51 g, 13.4 mmol) is introduced into 80 ml of THF at 0 ° C. The amine obtained in the preceding step 17d (3 g, 13.4 mmol) dissolved in 30 ml of THF is poured in dropwise. The reaction medium is stirred for 48 hours at reflux. The minimum ammonia (10%) is added very slowly in order to destroy the excess LiAlH-4. Filtered on celite, the precipitate is washed with dichloromethane (300 ml) and concentrated to dryness. The oil obtained is taken up in ether and extracted with a HCl solution (10%) (3x100 ml). The aqueous phase is then neutralized with ammonia (20%) and extracted with ether (3x100 ml). The organic phase is washed with water, dried over MgSθ4 and concentrated to dryness. The product obtained is purified by chromatography on alumina, eluting with an EP / EA mixture (90/10). A colorless oil is thus obtained (1.7 g, 61%). ¹³ C NMR: 154.18 (C2 '); 125.81 to 122.52 (C3 'to C5'); 56.60 (Cl); 37.60 (CH ₂ ); 35.74 (C2-C6); 25.51 (C4); 21.86 (C3-C5); 15.48 (CH ₃ ).

Characteristic of the corresponding hydrochloride:

Mp = 214-216 ° C.

¹³ C NMR: 139.53 (C2 "); 128.49 to 126.65 (C3 'to C5'); 62.12 (Cl); 36.30 (CH ₂ ); 34.46 (C2-C6) ; 24.30 (C4); 21.94 (C3-C5); 11.53 (CH ₃ ).

Example 18 N- [1- (2-furyl) -cyclohexan-1-yI] piperidine

A MgBr2 solution is prepared from 1,2-dibromoethane (6.76 g, 36 mmol,

4 eq) and magnesium (0.88 g, 36 mmol, 4 eq) in ether (80 ml) under a nitrogen atmosphere. A solution of 2-lithio-furan is prepared under a nitrogen atmosphere by the dropwise addition of a solution of 1.6 M n-butyl lithium in hexane (28 ml, 45 mmol,

5 eq) to a mixture of furan (3.1 g, 45 mmol, 5 eq) and TMEDA (5.2 g, 45 mmol, 5 eq) in anhydrous ether (100 ml) at -20 ° C . The mixture is then brought to reflux for 2 hours, cooled to room temperature and added dropwise to the solution of MgBr2 in ether. A solution of 1-piperidin-1-yl-cyclohexanecarbonitrile (1.7 g, 9 mmol, 1 eq) in ether is added dropwise at room temperature. The mixture is brought to reflux for 16 hours, cooled to room temperature and then treated as follows: the mixture is poured gently into an ice-cold saturated NH4Cl solution, stirred for 30 minutes, extracted with ether; the ethereal phases are combined and then extracted three times with 10% HCl, and 20% NH4OH is added to the aqueous phase until neutral. The aqueous phase is extracted with ether, the organic phase washed with water, dried over Na ₂ S04, filtered and concentrated in vacuo. The crude product is purified by chromatography on alumina with CH2Cl2 as eluent to give an oil (1.7 g, 76%).

¹³ C NMR: 146.46 (C2 '); 143.0 (C5 '); 113.7 (C3 '); 110.7 (C4 '); 67.6 (C4); 47.0 (Cα); 29.8 (C3-C5); 23.4 (Cl); 22.5 (C2-C6); 22.3 (Cβ); 21.7 (Cγ).

The corresponding hydrochloride is obtained in the form of a white solid. Mp = 166-167 ° C.

Example 19 N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] piperidine

Example 20 N- [4- (2-thienyl) -tetrahydro-4H-pyran-4-yl] piperidine

Example 21 N- [3- (2-thienyl) -tetrahydro-4H-thiopyran-3-yl] piperidine Example 22 N- [1- (2-thienyl) -cyclohexan-1-yl] -3-methyl piperidine

The compounds corresponding to Examples 19 and 20 are described in Eur. J. Med. Chem. (1996) 31, pp 488-495. The compounds corresponding to Examples 21 and 22 are described in Arch. Pharm. (1987) vol.320, n ° 4 pp 348-361 and Eur. J. Med. Chem. (1995) 30, pp 463-470 respectively.

Using the process indicated above, the following compounds can also be prepared, which are also part of the invention:

Pharmacological study of the compounds of the invention

Principle of in vitro affinity measurements

The affinity of the compounds for their potential binding site can be appreciated by quantifying their power of displacement of a tritiated marker specific for a given site. Binding experiments are carried out by competition between the molecule to be tested and the appropriate radioligand on a membrane preparation enriched in sites to be studied. The concentration of the tested derivative which inhibits 50% of the binding of the radioligand to the receptor is noted IC50.

For PCPi sites, the tritiated marker used is [ ³ H] TCP and the tests carried out on membrane preparations originating from homogenates of anterior rat brains.

For the experimental conditions and the techniques of membrane preparations used, reference may be made to the literature (Brain Res., 378, 133-141 (1986); Eur. J. Pharm., 81, 531-542 (1982)).

For sites with low affinity, the monosite treatment used has led to inconsistent results. The experimental data have therefore been reprocessed by non-linear regression (Marquardt-Levenberg algorithm) with the Sigma Plot software (Jandel) according to a model with two interaction sites denoted PCP2 and PCP3. This treatment proved to be better suited than a single site treatment (Student test: p <0.05) on a set of 3 to 4 experiments for each of the compounds tested. Out of all the experiments, the two populations of sites are found in a relative proportion of 68.0% (± 1.5) for PCP ₂ sites and 31.2% (± 1.5) for PCP3 sites.

For the PCP2 and PCP3 sites, the preparation comes from rat cerebellums. Having no specific marker, only [ ³ H] TCP can be used. A higher concentration of tritiated ligand (2.5 nM against 1 nM in the cortex) will be used in order to be sure to occupy all the PCP2 and PCP3 sites. The IC50 values are presented in Table 1 below.

Percent inhibition on PCP receptors:

The tritiated marker used is [ ³ H] TCP and the tests are carried out on membrane preparations originating from the cerebral cortex of rats (Brain Res., 378, 133-141 (1986).

Claims

1. The compounds of formula I characterized in that they correspond to either formula IA:

in which

Ar represents a carbocyclic or heterocyclic aryl radical, 5 or 6-membered monocyclic or consisting of condensed rings and optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy radicals , alkylthio, haloalkyl, hydroxyalkyl, having at most 6 carbon atoms; esterified or salified free carboxy; cyano; nitro; amino optionally substituted by one or two identical or different alkyl radicals containing at most 6 carbon atoms;

Ri and R2, which are identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from hydroxyl, free esterified or salified carboxy, cyano, nitro or else Ri and R2 form with the nitrogen atom to which they are linked a radical

in which n represents an integer from 0 to 2 and R3 and R'3 which are identical or different represent a hydrogen atom, a halogen atom or a hydroxyl radical, free esterified or salified carboxy, cyano, nitro, alkyl, alkenyl alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl having at most 6 carbon atoms;

R4 has the same meaning as R3 or R'3; X, Y and Z are such that one represents a sulfur or oxygen atom and the other two represent a methylene radical, with the exception of the compounds in which R3, R'3 and R ₄ each represent a hydrogen atom and

2) Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, thienyl and benzothienyl radical, Y represents a sulfur atom and X and Z each represent a methylene radical

3) Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, methoxyphenyl, benzothienyl and 2-thienyl radical, Y represents an oxygen atom and X and Z each represent a radical methylene,

4) Ri and R ₂ form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, methoxyphenyl or 2-thienyl radical, one of X or Z represents an oxygen atom, the other represents a methylene radical and Y represents a methylene radical,

5) Ri and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl or 2-thienyl radical, one of X or Z represents a sulfur atom, the other represents a radical methylene and Y represents a methylene radical,

6) Ri and R ₂ form with the nitrogen atom to which they are linked a pyrrolidine radical, Ar represents a 2-thienyl radical, one of X or Z represents a sulfur atom, the other represents a methylene radical and Y represents a methylene radical,

- N- [1 - (2-thienyl) -cyclohexan- 1 -yl] -3-hydroxymethyl-piperidine, - N- [1- (2-thienyl) -cyclohexan-1-yl] -4-hydroxy-3- methyl piperidine,

- N-ethyl- 1 - (2-thienyl) -cyclohexy lamine, - N- [1 - (2-furyl) -cyclohexan- 1 -yl] piperidine,

said compounds of formula I being in all the isomeric, racemic, enantiomeric and diastereoisomeric forms as well as the addition salts with mineral and organic acids or with mineral and organic bases of said compounds of formula I.

2. The compounds of formula I as defined in claim 1, in which

3. The compounds of formula I as defined in one of claims 1 or 2, in which

Ri and R2, which are identical or different, represent a hydrogen atom or a methyl or ethyl radical, or else Ri and R2 form, with the nitrogen atom to which they are linked, a radical

in which n is equal to 1 and R3 and R'3, which are identical or different, represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical.

4. The compounds of formula I as defined in one of claims 1 to 3 and corresponding to the following formulas:

- N- [4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl-piperidine;

- N- [4- (2-benzothiophenyl) -tetrahydro-4H-thiopyran-4-yl] -3-methyl-piperidine; - N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (2-benzofuranyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (5-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (4-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl] -piperidine; - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-hydroxy piperidine;

- N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxy piperidine;

5. Process for preparing the compounds of general formula I as defined in claim 1, characterized in that it comprises

either A)

- the reaction of a compound of formula 1

in which X ", Y", Z "represent a sulfur or oxygen atom or a methylene radical, R ₄ has the meaning indicated above, with an aryl magnesium halide of formula Hal-Ar-Mg in which Hal represents a halogen atom and

Ar has the meaning indicated above, to obtain the compound of formula 2

in which X ", Y", Z ", Ar and R ₄ have the meanings indicated above,

- the transformation of the hydroxyl radical of the alcohol of formula 2 thus obtained, into azide of formula 3

in which X ", Y", Z ", Ar and R ₄ have the meanings indicated above, 38

in which X ", Y", Z ", Ar and R ₄ have the meanings indicated above,

either B)

- the reaction of a compound of formula 1

in which X ", Y", Z "and R ₄ have the meanings indicated above, in an anhydrous medium, with a compound of formula RιR ₂ NH in which Rj and R ₂ have the meanings indicated above, and a compound cyanide ion donor, to obtain the compound of formula 5

in which X ", Y", Z ", Ri and R2 have the meanings indicated above, and

6. As medicaments, the compounds of formula I as defined in claim 1, as well as the addition salts with mineral or organic acids or the pharmaceutically acceptable mineral or organic bases of said compounds of formula I.

7. As medicaments, the compounds of formula I as defined in one of claims 2 to 4, as well as the addition salts with mineral or organic acids or the pharmaceutically acceptable mineral or organic bases of said compounds of formula IA-

8. Pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined in one of claims 6 or 7.

9. Use of the compounds of formula I 'characterized in that they respond

either to formula I'A

in which

Ar ′ represents a carbocyclic or heterocyclic aryl radical, 5 or 6-membered monocyclic or consisting of condensed rings and optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl radicals, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, having at most 6 carbon atoms; esterified or salified free carboxy; cyano; nitro; amino optionally substituted by one or two identical or different alkyl radicals containing at most 6 carbon atoms;

R'i and R'2 identical or different represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from hydroxyl radicals, free esterified or salified carboxy, cyano , nitro or R'i and R'2 form with the nitrogen atom to which they are linked a radical

in which n represents an integer from 0 to 2 and R3 and R'3 which are identical or different represent a hydrogen atom, a halogen atom or a hydroxyl radical, free esterified or salified carboxy, cyano, nitro, alkyl, alkenyl alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl having at most 6 carbon atoms; R'4 has the same meaning as R3 or R'3;

X ', Y' and Z 'are such that either one represents a sulfur or oxygen atom and the other two represent a methylene radical, or all three represent a methylene radical, or one of the following formulas:

- N-ethyl- 1 - (2-thienyl) -cyclohexylamine,

- N- [1- (2-furyl) -cyclohexan-1-yl] piperidine, - N- [1- (2-thienyl) -cyclohexan-1-yl] -3-methyl-piperidine,

said compounds of formula I 'being in all the isomeric, racemic, enantiomeric and diastereoisomeric forms as well as the use of addition salts with mineral and organic acids or with mineral and organic bases of said compounds of formula I',

for the preparation of medicaments intended to protect the cells of the central or peripheral nervous system against acute degenerations induced by accidents such as trauma, ischemia or the action of endogenous and exogenous neurotoxic agents, directly or through secondary mechanisms.

10. Use of the compounds of formula I ′ as defined in claim 9 for the preparation of medicaments intended to protect the cells of the central or peripheral nervous system against chronic degenerations induced by neurodegenerative diseases and processes of the pathological aging type, dementias, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis.

11. Use of the compounds of formula I 'as defined in claim 9 for the preparation of anticonvulsant or antidepressant drugs or to stimulate alertness, to treat states of dependence on different substances such as addictive drugs.

12. Use according to one of claims 9 to 11 of the compounds of formula I'A in which

R 'and R'2, which are identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms, or else Ri and R2 form, with the nitrogen atom to which they are linked, a radical

13. Use according to one of claims 9 to 11 of the compounds of formula I'A in which

Ar 'represents the thienyl, furyl, benzothienyl, benzofuryl radical and optionally substituted by one or more methyl, ethyl, propyl or allyl radicals;

in which n is equal to 1 and R3 and R'3, which are identical or different, represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical, for the preparation of medicaments as defined above.

14. Use according to one of claims 9 to 11 of the compounds of formula I'A and corresponding to the following formulas:

- N- [4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine; - N- [4- (2-benzofuranyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine; - N- [4- (5-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl] -piperidine; - N- [4- (4-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl] -piperidine;

- N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-hydroxy piperidine; - N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxy piperidine.