FR2763951A1 - New phencyclidine derivatives with affinity for low affinity receptors - Google Patents

Abstract

Phencyclidine derivatives of formula (I), their isomers, enantiomers and diastereomers and acid and base addition salts, are new. Ar = aryl comprising 5-6 membered monocyclic or condensed ring structure, optionally containing heteroatoms and optionally substituted by \- 1 1-6C alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, or hydroxyalkyl, or hydroxyl, cyano, nitro, or amino (optionally substituted by 1 or 2 1-6C alkyl) or free, esterified or salified carboxy; R1, R2 = H or 1-6C alkyl (optionally substituted by \- 1 hydroxy, cyano, nitro or free, esterified or salified carboxy) or NR1R2 = a group of formula (i) or (ii); n = 0, 1 or 2; R3, R3', R4 = H, halo, hydroxyl, cyano, nitro, free, esterified or salified carboxy or 1-6C alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, or hydroxyalkyl; 1 of X, Y, Z = O or S and the others are methylene except when R3, R3' and R4 = H and: (1) NR1R2 is pyrrolidinyl, Ar is phenyl or 2-thienyl and 1 of X, Y and Z is O; (2) NR1R2 is piperidinyl, Ar is phenyl, methoxyphenyl, benzothienyl or 2-thienyl, Y is O and X and Y are each methylene; (3) NR1R2 is piperidinyl, Ar is phenyl, thienyl or benzothienyl, Y is S and X and Z are each methylene; (4) NR1R2 is piperidinyl, Ar is phenyl, methoxyphenyl or 2-thienyl, 1 of X and Z is O and the other is methylene and Y is methylene; (5) NR1R2 is piperidinyl, Ar is phenyl or 2-thienyl, 1 of X and Z is S and the other is methylene and Y is methylene; (6) NR1R2 is pyrrolidinyl, Ar is 2-thienyl, 1 of X and Z is S and the other is methylene and Y is methylene and (7) NR1R2 is ethylamino or pyrrolidinyl, Ar phenyl, y is S and X and Y are each methylene. Also claimed are N-1-(2-thienyl)-cyclohexan-1-yl-3-hydroxymethylpiperidine, N-1-(2-thienyl)-cyclohexan-1-yl-4-hydroxy-3-methylpiperidine, N-1-(2-benzothiophenyl)-cyclohexan-1-yl-4-hydroxy-3-methylpiperidine, N-ethyl-1-(2-thienyl)-cyclohexylamine and N-1-(2-furyl)-cyclohexan-1-ylpiperidine. 9 Compounds (I) are specifically claimed e.g: N-4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl-piperidine, N-4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-yl-piperidine, N-4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl-3-methylpiperidine and N-4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl-4-hydroxypiperidine.

Description

Novel phencyclidine derivatives, processes for their preparation and

  Pharmaceutical compositions containing them [N- (1-phenylcyclohexyl) piperidine (or PCP), developed as anesthetic agent and then removed because of psychotropic effects too important, is nowadays only a pharmacological tool, interesting at least by through 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 of the PCP receptor. In vitro and in vivo studies of the [3H] TCP binding to the PCP receptor revealed the existence of a second type of binding corresponding to so-called low affinity PCP sites compared to the first so-called sites.

  high affinity (Brain Res., 378, 133-141 (1986)).

  The present invention relates to novel 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 of cells of the central or peripheral nervous system against the

  acute or chronic degeneration, or as an anticonvulsant agent.

  The subject of the invention is thus the compounds of general formula I RI AR4

R1 R

X xIy / 11Z

Y I

  in which Ar represents a carbocyclic or heterocyclic aryl radical, monocyclic with 5 or 6 members or consisting of fused rings and optionally substituted with one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl, alkenyl and alkynyl radicals; alkoxy, alkylthio, haloalkyl, hydroxyalkyl, having not more than 6 carbon atoms; esterified or salified free carboxy; cyano; nitro; amino optionally substituted with one or two identical or different alkyl radicals containing at most 6 carbon atoms; R1 and R2, which may be identical or different, represent a hydrogen atom or an alkalkyl radical having at most 6 carbon atoms optionally substituted by one or more radicals;

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  identical or different radicals selected from hydroxyl, esterified or salified free carboxy, cyano, nitro or R1 and R2 together with the carbon atom to which they are attached form a radical H2) n R3 R13 or R3 in which n represents an integer of 0 to 2 and R3 and R'3 identical or different represent a hydrogen atom, a halogen atom or a hydroxyl radical, free carboxy esterified or salified, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl hydroxyalkyl having not more than 6 carbon atoms; R4 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 the three represent a methylene radical, with the exception of compounds in which R3, R ' 3 and R4 each represent a hydrogen atom and 1) R1 and R2 together with the nitrogen atom to which they are attached form a pyrrolidine radical, Ar represents a phenyl or 2-thienyl radical and one of X, Y or Z represents an oxygen atom, 2) R 1 and R 2 form, with the nitrogen atom to which they are bonded, a piperidine radical, Ar represents a phenyl, thienyl and benzothienyl radical; Y represents a sulfur atom, X and Z represent each a methylene radical, 3) R1 and R2 together with the nitrogen atom to which they are attached a piperidine radical, Ar represents a phenyl, methoxyphenyl, benzothienyl and 2thienyl radical and Y represents an oxygen atom, X and Z represent each a methylene radical, 4) R1 and R2 form with the nitrogen atom to which they are attached 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 radical methylene,) R1 and R2 together with the nitrogen atom to which they are attached 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) R1 and R2 together with the nitrogen atom to which they are attached form 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, -3-

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  and it being understood that when X, Y and Z each represents a methylene radical, Ar represents a monocyclic or fused ring heterocyclic aryl radical substituted with one or more identical or different radicals, said compounds of formula I being in all isomeric forms , racemic, enantiomers and diastereoisomers possible as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said compounds of formula I. The invention more particularly relates to compounds of general formula I such that defminie above in which Ar represents a monocyclic heterocyclic aryl radical with 5 members or consisting of two fused rings and optionally substituted with one or more identical or different alkyl radicals; R1 and R2, which may be identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms, or R1 and R2 form, with the carbon atom to which they are bonded, a radical ((5H2) nn 4; R3 '; or

I I

  in which n is equal to 1 and R3 and R'3, which may be 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 halogen expression represents a fluorine atom,

chlorine, bromine or iodine.

  The term alkyl having at most 6 carbon atoms represents a linear or branched alkyl radical such as the methyl, ethyl, propyl, isopropyl, butyl or isobutyl radical,

  sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl.

  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, mention may be made of ethynyl, propargyl, butynyl, pentynyl or hexynyl radicals. The alkoxy radical, linear or branched, preferably denotes radicals in which the alkyl radical is as defined above. We prefer radicals

  methoxy, ethoxy, propoxy, isopropyloxy or butoxy.

  The alkylthio radical preferably denotes radicals in which the alkyl radical is such

  as defined above, for example methylthio or ethylthio.

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  The haloalkyl radical preferably denotes radicals in which the alkyl radical is such

  as defined above and is substituted by one or more halogen atoms as defined above.

  as, for example, bromoethyl, trifluoromethyl, trifluoroethyl or pentafluoroethyl. The hydroxyalkyl radical preferably denotes the radicals in which the alkyl radical is

  as defined above such as hydroxymethyl or hydroxyethyl.

  The heterocyclic aryl radical may contain one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen and sulfur atoms. Examples of such aryl radicals include phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, diazolyl, oxadiazolyl, benzothienyl and benzofuryl radicals.

  benzopyrrolyl, benzimidazolyl or indolyl.

  The invention more particularly relates to compounds of general formula I as defined above wherein Ar represents thienyl, furyl, benzothienyl, benzofuryl and optionally substituted by one or more methyl or ethyl radicals; R1 and R2, which are identical or different, represent a hydrogen atom or a methyl or ethyl radical, or else R1 and R2 form, with the carbon atom to which they are bonded, a radical (CH2) n R3 or fCN; R'3 [9 R'3 NN R3 wherein n is 1 and R3 and R'3 are the same or different and represent an atom

  hydrogen or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical.

  More particularly, the subject of the invention is the compounds described hereinafter 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-methylpiperidine; N- [4- (2-benzothiophenyl) tetrahydro-4H-thiopyran-4yl] -3-methyl-piperidine; N- [1- (2-thienyl) -cyclohexan-1-yl] -3-hydroxymethyl-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-methylthiophen-2-yl) tetrahydro-4H-thiopyran-4-yl] piperidine; N- [4- (2-thienyl) tetrahydro-4H-thiopyran-4yl] -3-hydroxypiperidine; N- [4- (2-thienyl) tetrahydro-4H-thiopyran-4-yl] -4-hydroxypiperidine; N- [1- (2-thienyl) -cyclohexan-1-yl] -4-hydroxy-methylpiperidine; N- [1- (2-benzothiophenyl) -cyclohexan-1-yl] -4-hydroxy-3-methylpiperidine; - N-ethyl-1- (2-thienyl) -cyclohexylamine in all the isomeric, racemic, enantiomeric and diastereoisomeric forms possible as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said compounds. The subject of the invention is also a process for the preparation of the compounds of general formula I as defined above, characterized in that it comprises the reaction of a compound of formula ## STR1 ## in which wherein X, Y, Z and R4 have the meanings indicated above, with an aryl magnesium halide of formula Hal-Ar-Mg wherein Hal represents a halogen atom and Ar has the meaning indicated above, for obtaining the compound of formula II ## STR3 ## in which X, Y, Z, Ar and R 4 have the meanings indicated above, the conversion of the hydroxyl radical of the alcohol of formula 2 thus obtained, azide of the formula ## STR3 ## wherein X, Y, Z, Ar and R4 have the meanings indicated above,

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  and then reducing the azide of formula 3 to the primary amine of formula 4 H2N Ar H2 y.R 4

XYZ 4

  in which X, Y, Z, Ar and R4 have the meanings indicated above, and finally, if the desired compound of formula I is such that at least one of the radicals R1 or R2 is different from the hydrogen atom or else R1 and R2 form a ring with the carbon atom to which they are bonded, treating this compound of formula 4 to obtain the

  compound of formula I which is converted if desired into salt.

  In this preparation process, the first step, which consists in obtaining the compound of formula 2, is a classical Grignard reaction whose conditions of use are

known to those skilled in the art.

  The second step makes it possible to access azide 3 from alcohol 2. The reaction takes place in the presence of an excess of protonating organic agent such as trichloroacetic acid, an alkaline azide in a solvent aprotic polar. Preferably, the reaction takes place in the presence

  an excess of trichloroacetic acid and sodium azide in chloroform.

  For the reduction of the azides of formula 3 to primary amine 4, the standard methods known to those skilled in the art for the reduction of azides can be implemented. The reduction can thus be carried out using, for example, Raney nickel in 60 C isopropanol or lithium aluminum hydride in diethyl ether or tetrahydrofuran Si in the desired compound of formula I, R 1 and R 2 form a cycle with the carbon atom to which they are linked, the fourth step is then a cyclization; it is obtained by reacting, in a polar solvent, in an alkaline medium, the compound of formula 4 with the appropriate compound of formula Hal- (CH2) 2- (CH2) n- (CH2) 2-Hal or Hal- (CH2) ) -CH = CH- (CH2) 2-Hal of cis structure, substituted by the radicals R3 and R'3, and wherein n, R3 and R'3 have the meaning indicated above and Hal represents an atom of halogen. The alkaline conditions serve to trap the formed acid and can be obtained using, for example, potassium carbonate. The polar solvent used may be chosen from methanol, acetone, hexamethylphosphoramide or sulfolane and preferably hexamethylphosphoramide.

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  The primary amine of formula 4 thus corresponds to the compound of formula I in which R 1 and R 2 represent the hydrogen atom. If in the desired compound of formula I, R 1 and R 2 are the same or different and at least one of them is not hydrogen, then the compound of formula I is a secondary or tertiary amine according to the values of R 1 and R2; these amines can be obtained from the primary amine

  corresponding formula 4 according to conventional methods known to those skilled in the art.

  Thus, for example, for the preparation of the compound of formula I wherein one of the radicals R 1 or R 2 represents hydrogen atom and the other an alkyl radical, the corresponding primary amine of formula 4 is reacted with the appropriate acid anhydride then one

  reduces the amide obtained with, for example, LiAlIH4.

  The different isomeric, enantiomeric and diastereoisomeric forms may be obtained by resolution of either the starting material 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.

  The subject of the invention is also another process for the preparation of the compounds of general formula I as defined above, characterized in that it comprises the reaction of a compound of formula 1 ## STR2 ## in which X, Y, Z and R4 have the meanings indicated above, in an anhydrous medium, with a compound of formula RIR2NH in which R1 and R2 have the meanings indicated above, and a cyanide ion donor compound, to obtain the compound of formula 5 R1 R1

R <N CN

2 z

YZ 5

  wherein X, Y, Z, R1 and R2 have the meanings given above, and

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  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 cyanohydrin as a cyanide ion donor as a desiccant of the medium, it is possible to use, for example, sodium sulfate. anhydrous magnesium. The reaction is preferably carried out in a polar basic solvent such as acetamide, methylacetamide, dimethylacetamide, acetylpiperidine or piperidine, and

  preferably dimethylacetamide or piperidine.

  The second step of this second preparation process is a Bruylants reaction (P.

  Noisy, Bull. Soc. Chim. Belg., 33, 467 (1924); P. Bruylants, A. Castile, 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 the equatorial position. Therefore, it will only be used for the synthesis of compounds of formula I having no

  no particular stereochemistry.

  Given the lack of stereospecificity of this first reaction, this route of synthesis

  will preferably be used in the case where R4 represents a hydrogen atom.

  The possible 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 I wherein R 4 is hydrogen and Y is sulfur or oxygen or methylene are commercial products. The other starting compounds of formula 1 wherein R 4 represents hydrogen can be prepared according to the scheme described by T. E. 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 methods of

  substitution known to those skilled in the art.

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

  different therapeutic applications.

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  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 action of neurotoxic agents, endogenous and

  exogenous, directly or through secondary mechanisms.

  The compounds can also be used to protect central or peripheral nervous system cells against chronic degenerative diseases induced by disease and neurodegenerative processes such as pathological aging, dementia, disease

  Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis.

  The compounds are particularly interesting also as an anticonvulsant agent.

  The following is an illustration of the properties in the experimental section

  pharmacological compounds of the invention.

  These properties make the compounds of formula I suitable for pharmaceutical use. The subject of the present application is also, as medicaments, the compounds of formula I as defined above, in the form of all the isomeric, racemic, enantiomeric and diastereoisomeric forms possible, as well as the addition salts with mineral acids. or organic or pharmaceutically acceptable inorganic or organic bases of said compounds of formula I, as well as pharmaceutical compositions containing, as a

  active ingredient, at least one of the drugs 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 may be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories. Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, cellulose

  carboxymethyl sodium, polyvinylpyrrolidine and wax.

  The pharmaceutical compositions containing a compound of the invention may also be in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as mixtures thereof, in varying proportions, in water, added to pharmaceutically acceptable oils or fats. . Sterile liquid compositions can be used for intramuscular or subcutaneous injections and 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.

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  The subject of the invention is also the use of the compounds of formula I as defined above, for the preparation of medicaments intended to protect the cells of the central or peripheral nervous system against acute degeneration induced by accidents such as trauma, ischemia or action of neurotoxic agents, endogenous or exogenous, directly or through secondary mechanisms. The invention also relates to the use of medicaments for protecting the cells of the central or peripheral nervous system against chronic degeneration induced by diseases or pathological aging-type neurodegenerative processes, dementias, Alzheimer's disease, Parkinson's disease, sclerosis amyotrophic, as well as drugs

anticonvulsants.

  -Il - 2763951 The following examples are presented to illustrate the above procedures and are not intended to

  no case be considered as a limit to the scope of the invention.

EXPERIMENTAL PART

  Example 1 N- [4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl] piperidine (31A, B) Step 1α: 3-methyl-tetrahydro-4H-thiopyran-4-one (27) In a 250 ml three-necked flask, diisopropylamine (8.4 ml, mmol) and 74 ml of THF were added under nitrogen. NBuLi (37.5 ml, 60 mmol) is added dropwise and the mixture is stirred for a further 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). After half an hour, methyl iodide (5.6 ml, 90 mmol) is added and the temperature is allowed to rise to 25 ° C. After stirring for 5 hours, a solution of sodium bicarbonate (5%) is added. ) saturated with salt, decanted, dried the organic phase over sodium sulphate and concentrated to dryness. The orange oil obtained is chromatographed on silica eluting with a 90/10 EP / AcOEt mixture. We obtain

a colorless oil (3.2 g).

  1H NMR: 2.8 (m, 3H); 2.4 (m, 4H); 0.95 (d, 3H, J = 6.1 Hz).

  13 C NMR: 209.52 (C4); 47.20 (C3); 43.45 (C5); 30.07 (C2); 30.38 (C6); 14, 41 (CH3).

  Step 1.b: 4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-ols (28) 2-Thienyl magnesium 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 anhydrous ether.

  The mixture is heated at 45 ° C. for 3 hours and then at room temperature the 3-methyl-

  tetrahydro-4H-thiopyran-4-one (4.2 g, 33 mmol) dissolved in ether (50 mL). The reaction medium is heated for 16 hours under reflux. After cooling, the reaction medium is poured into 100 ml of a saturated aqueous solution of NH 4 Cl. The mixture is stirred for half an hour in order to destroy the magnesium complex, the mixture is decanted and the aqueous phase is extracted with ether (3 × 50 ml), which is then neutralized with NH 4 OH (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.

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  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: major diastereoisomer: 153.65 (C 2 '); 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).

  minor 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 (CH3).

  Step 1. c: 4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl azides (29)

  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 mixture is cooled to 10 ° C. The diastereoisomeric alcohols obtained according to the preceding step (6.6 g, 8 mmol) are added dropwise. dissolved in chloroform (50 ml). The reaction medium is stirred for 72 hours while maintaining the temperature at 10-12 C. A solution of ammonia (10%) is then added until neutralization, and then the aqueous phase is extracted with dichloromethane (3x100 ml). The organic phase is washed with water (200 ml), dried over Na 2 SO 4 and concentrated to dryness. This gives a brown oil (6.8 g) which is subsequently used 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 (minor diastereoisomer: 28%) Step 1. d: 4- (2-thienyl) -3-methyl-tetrahydro-4H-thlopyran-4-yl-amines (30) In a 100 ml tricol lithium aluminum hydride (0.87 g, 23 mmol) in THF at 0 ° C. The mixture of the azides obtained in the preceding step (5.5 g, 23 mmol) dissolved in 30 ml of water is added dropwise. THF. The reaction medium is stirred for 24 hours at room temperature. The minimum amount of ammonia (10%) is added very slowly in order to destroy the excess of LiAlH4. It is filtered through 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 solution of HCl (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 MgSO4 and concentrated to dryness. The product obtained is purified by

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  chromatography on silica eluting with an EP / EA 50/50 mixture. We thus obtain a

colorless oil (3.7 g).

  Rf (silica, eluent EP / EA 60/40): 0.20 (majority) and 0.25 (minor) GC / MS (90-250 ° C (10 ° C / min)): Tr = 24.15 min (diastereoisomer majority 62.5%) Tr = 23.77 min (minority diastereoisomer: 37.5%) 13C 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 (CH3).

  13C 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 (CH3).

  Step 1. e: N- [4- (2-thienyl) -3-methyl-tetrahydro-4H-thiopyran-4-yl] piperidines (31A, B) The amine mixture from step 1d above ( 4.5 g, 21 mmol) is dissolved in HMPT (50 ml). Potassium carbonate (5.8 g, 42 mmol) and 1,5-dibromopentane (3.6 ml, 26.2 mmol) are added. The medium is stirred under nitrogen at 60 ° C. for 48 hours. After

  After cooling, this solution is poured into water (200 ml) and extracted with ether (3x100 ml).

  As before, an acid-base wash is carried out, extracted again with ether, the ether phase is washed with water, dried over magnesium sulphate and concentrated to dryness. The yellow oil obtained (6.2 g) is purified by chromatography on silica eluting with a mixture EP / EA (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 (majority) = 18.15 min and Tr (racemic) = 19.75 min Tr (minor) ) = 18.46 min and Tr (racemic) = 18.95 min 13 C NMR (majority): 145.88 (C2 '); 125.80-122.41 (C3 'to CS'); 61.51 (C4); 45.96 (Coa); 33.26 (C3); 29.47 (C5); 28.38 (C2); 26.90 (CO); 25.03 (C6); 22.93 (Cy); 15,10

(CH3).

  13C NMR (Minority): 142.70 (C2 '); 126.23-122.76 (C3 'to C5'); 62.08 (C4); 45.59 (Cta); 33.55 (C3); 32.88 (C5); 30.64 (C2); 26.87 (CO); 25.38 (C6); 25.03 (Cy); 13.41

(CH3).

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  ExemFl.2.2 (+) - N- [4- (2-thienyl) tetrahydro-4H-thiopyran-4-yl] -3-methyl-

  piperidine 33 Step 2α: 4- (3-methylpiperidino) -tetrahydro-4H-thiopyran-4-carbonitrile (32A) In a 250 ml well, magnesium sulfate (9.6 g, mmol) was added successively. 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 g, 23 mmol). 7 g, 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. Extraction is then carried out with ether (3 × 80 ml), the combined organic phases are washed with water (100 ml), dried over Na 2 SO 4, filtered and concentrated to dryness. This gives a brown oil (4.5 g, 20 mmol) consisting of a mixture of expected product

  with about 4% of the amino nitrile from acetone and 7% of tetrahydro-4H-thiopyran

  4-one remaining. The product is subsequently used without further purification 13 C NMR: 118.3 (CN); 59.43 (C4); 54.1 (Ca); 46.42 (Ca '); 34.3 (C3 +); 34.2 (C5 +);

  32.1 (C); 30.9; 25.1 (C2-C6); 22.8 (C3 '); 19.3 (CH3).

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

  piperidine 2-Thienylmagnesium bromide is prepared from magnesium in the form of magnesium (1 g, 40 mmol), 2-bromothiophene (6.52 g, 40 mmol) and 150 ml of anhydrous ether under nitrogen. The mixture is refluxed with ether for 3 hours and then added to

  room temperature the aminonitrile obtained according to the preceding step (2.25 g, 10 mmol).

  The reaction medium is heated for 20 hours under reflux. After the usual treatment, a brown oil is obtained which is chromatographed on 100 g of alumina, eluting with a mixture of

  EP / EA (95/5). This gives a colorless oil (1.6 g).

  13 C NMR: 146.6 (C2 '); 126.0-122.7 (C3 'to C5'); 58.2 (C4); 53.35 (Ca); 45.5 (Ca ');

  37.1 (C3 +); 36.8 (C5 +); 33.2 (C13 '); 31.8 (CI); 23.4 (C2-C6); 22.5 (C, 19.3 (CH3).

  The corresponding hydrochloride is prepared by treatment for 3 hours of the base in hydrochloric ether. after filtration and rinsing thoroughly 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 (Ca); 46.2 (Ca ')

  33.4 (C3 +); 33.2 (C5 +); 30.5 (C ['); 28.2 (CI); 24.9 (C2-C6); 22.1 (C, y) 18.9 (CH3).

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

  piperidine Step 3a: S - (+) - 3-methylpiperidine Hot (+) mandelic acid (45.64 g, 0.3 mol) was dissolved in 300 ml of ethyl acetate in the hot state. 3-Methylpiperidine (29.8 g, 0.3 mol) is added with stirring and the solution is allowed to come to room temperature. After 24 hours, the salt obtained is filtered and rinsed with EA / AcOEt (1/1) and then recrystallized 3 times in AcOEt. The salt of (S) - (+) - 3-methylpiperidine mandelate (22.7 g) is thus obtained. Mp = 120-122 ° C; aD = + 58.0 o (methanol,

c = 1.0).

  These crystals are taken up in 50 ml of 25% aqueous sodium hydroxide solution and the solution is extracted with ether (3 × 50 ml). The combined organic phases are washed with a saturated solution of NaCl, dried over MgSO4 and then concentrated. The oil obtained is distilled at atmospheric pressure to give a colorless liquid (7.1 g). Mp = 92-97 C

  13 C NMR = 53.2 (C2); 45.1 (C6); 32.2 (C4); 30.6 (C3); 25.2 (C5); 18.0 (CH3).

  Step 3b: S-4- (3-methylpiperidino) -tetrahydro-4H-thiopyran-4-carbonitrile (32B)

  The procedure is identical to that illustrated in step 2a, using the S - (-) -

  3-methylpiperidine in place of () -3-methylpiperidine.

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

piperidine (35)

  The procedure is identical to that illustrated in step 2b, using S-4- (3-methyl)

  piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile in place of (+) 4- (3-methyl)

  piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile. A colorless oil (1.8 g) is obtained which

crystallizes in the cold. Mp: 53-55 ° C.

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

aD = - 10 o (methanol, c = 1.0)

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

  piperidine 34 Step 4a: R - (-) - 3-methyl-piperidine

  The filtrates of crystallization and recrystallization of mandelic salts of S - (+) - 3-methyl-

  piperidine of the previous step 3a are combined and treated with 100 ml of an aqueous solution of sodium hydroxide (25%). After stirring for half an hour, this aqueous phase is extracted with ether (4x50 ml). The combined organic phases are washed with a saturated solution of NaCl (100 ml), dried over MgSO4 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) and then recrystallized twice in ethyl acetate. The salt of the R - (-) -

  3-methyl-piperidine mandelate is obtained in the form of white crystals (17 g).

  Mp 121-123 ° C; (XD = - 56.5 ° C. (methanol, c = 1.0) These crystals are taken up in 50 ml of 25% aqueous sodium hydroxide solution and the solution is then extracted with ether (3 × 50 ml). The combined oil is washed with saturated NaCl solution, dried over MgSO 4 and concentrated.

  atmospheric pressure to give a colorless liquid (5.2 g).

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

4-carbonitrile 32B

  The procedure is identical to that illustrated in step 2a, using the R - (+) -

  3-methylpiperidine in place of () -3-methylpiperidine.

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

piperidine 34

  The procedure is the same as that illustrated in step 2b, using R-4- (3-methyl)

  piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile in place of () 4- (3-methyl)

  piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile. A colorless oil (1.65 g) is obtained

  which crystallizes in the cold. Mp = 54-56C.

  The hydrochloride is obtained according to the procedure described in step 2b. Mp = 170-172C.

"D = + 12 o (methanol, c = 1.0)

- 17 -

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  Example 5 () -N- [4- (2-benzothiophenyl) tetrahydro-4H-thiopyran-4-yl]

  3-methyl-piperidine 4- (3-Methylpiperidino) -tetrahydro-4H-thiopyran-4-carbonitrile (2 g, 8.9 mmol) dissolved in 50 ml of anhydrous ether is added dropwise to a solution of 2-benzothiophenylmagnesium bromide (44.7 mmol). The mixture is refluxed with 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). We obtain

  thus a white solid (1.2 g, 40%).

  Mp = 90-92 ° C 13 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 (Ca); 45.65 (Ca '); 36.78 (C3 +); 36.52 (C5 +); 33.17 (C1 '); 31.85

  (THIS); 26.14 (C); 23.52 (C2-C6); 19.77 (CH3).

  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 (Ca); 46.72 (Ca '); 33.48 (C3 +); 33.29 (C5 +); 30.57 (C3 '); 28.41

  (This); 25.06 (C2-C6); 22.21 (C); 18.92 (CH3).

  EXAMPLE 6 R - (+) - N- [4- (2-Benzothiophenyl) -tetrahydro-4H-thiopyran-4-yl]

3-methyl-piperidine 37

  The procedure is identical to that of Example 5 starting from R4- (3-methyl)

  piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile in place of 4- (3-methylpiperidino)

  tetrahydro-4H-thiopyran-4-carbonitrile. The same amounts of reagents are used. We

  gives colorless crystals (1.85 g) .Pf = 90-92 C.

  Characteristic of the corresponding hydrochloride: mp = 158-165 ° C .; IED = + 27.2% (methanol, c = 1.0)

  EXAMPLE 7 S - (-) - N- [4- (2-Benzothlophenyl) tetrahydro-4H-thiopyran-4-yl]

3-methyl-piperidine 38

  The procedure is identical to that of Example 5 starting from S4- (3-methyl)

  piperidino) -tetrahydro-4H-thiopyran-4-carbonitrile in place of 4- (3-methylpiperidino)

  tetrahydro-4H-thiopyran-4-carbonitrile. The same amounts of reagents are used. Colorless crystals (1.2 g) are obtained .pf = 91-93 ° C.

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  Characteristic of the corresponding hydrochloride:

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

  EXAMPLE N - [1- (2-thienyl) -cyclohexan-1-yl] -3-hydroxymethyl-piperidine Step 8a: 1- [1- (3-Hydroxymethyl-piperidino) -cyclohexan-1-yl] carbonitrile It is prepared from MgSO4 (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 previously described 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 (C1); 50.17 (Ca); 47.07 (Ca '); 34.75

  (Cf); 33.72 (C2 *); 33.60 (C6 *); 26.79 (CT); 24.65 (C3-C5); 21.83 (C4).

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

  heated at 45 C for 3 hours and then added at room temperature 1 [1- (3-

  hydroxymethyl-piperidino) -cyclohexan-1-yl] -carbonitrile (2 g, 9 mmol) dissolved in ether. The reaction medium is heated for 20 hours under reflux. After treatment of the reaction, 2.1 g of a yellow oil are obtained which is chromatographed on alumina, eluting with

  EP / EA mixture (50/50). This gives a colorless oil (1.4 g).

  13 C NMR: 145.45 (C2 '); 125.84 to 122.76 (C3 'to C5'); 66.66 (CH 2 OH); 60.06 (C1);

  49.26 (Ca); 46.08 (Ca '); 38.44 (CB); 35.89 (C2 *); 35.69 (C6 +); 27.73 (C ('); 25.22

(C7); 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 (C1);

  49.69 (Ca); 46.85 (Ca '); 36.60 (C [); 33.37 (C2 *); 33.00 (C6 *); 25.27 (Cl '); 23.97

(CT; 23.03 (C3-C5); 22.21 (C4).

- 2763951

  EXAMPLE 9 N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine Step 9a: 4-piperidino-tetrahydro-4H-thiopyran-4-carbonitrile 2 In a 250 ml bicol , magnesium sulphate (9.3 g, 77.4 mmol), DMA (2.25 g, 25.8 mmol), piperidine (4.4 g, 51.6 mmol), tetrahydro are introduced successively. 4H-thiopyran-4-one (3 g, 25.8 mmol) and acetone cyanohydrin (2.2 g,

  8 mmol). The reaction medium is stirred for 48 hours at 45 ° C.

  After cooling to room temperature, the resulting mixture is thrown on ice (about 100 g) and stirred for 1/2 hour. Extraction is then carried out with ether (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 (5.3 g, 25.2 mmol) is obtained which will be used by the

  continued without special purification.

  13 C NMR: 118.34 (CN); 59.61 (C4); 46.985 (Ca); 34.215 (C3-C5); 25.72 (C2C6);

23.77 (C [5]; 22.76 (CD.

  Step 9b: N- [4- (2-furyl) -tetrahydro-4H-thiopyran-4-yl] piperidine 40

  A solution of MgBr 2 is prepared by dropwise addition under nitrogen of 1,2-dibromo

  ethane (6.76 g, 36 mmol) diluted in 80 ml of anhydrous ether with magnesium

  turnings (0.88 g, 36 mmol). The solution is kept for 2 hours at room temperature.

  A solution of 2-thiourofuran is prepared simultaneously at -20 ° C. and under nitrogen by dropwise addition of a solution of 1,6 M ntutyl lithium in hexane (28 ml, 45 mmol).

  on a furan mixture (3.1 g, 45 mmol). This mixture is heated for 2 hours under reflux.

  This solution is transferred to room temperature. The aminonitrile from step 9a (1.9 g, 9 mmol) dissolved in 50 ml of anhydrous ether is dripped onto the 2-furylmagnesium bromide solution. The mixture is refluxed with 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 (1.6 g,

71%).

Mp = 79-81C.

13 C NMR: 156.49 (C2 '); 141.05 (C5 '); 109.27 (C3 '); 106.10 (C5 '); 57.47 (C4); 46.44

  (It); 33.57 (C3-C5); 26.58 (C2-C6); 24.55 (C, 23.30 (C [3).

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  Characteristic of the corresponding hydrochloride:

Mp 171-173 ° C.

  13 C NMR: 145.25 (C2 '); 143.49 (C5 '); 113.71 (C3 '); 110.74 (C4 '); 66.84 (C4); 46.74

  (It); 30.25 (C3-C5); 24.52 (C2-C6); 21.96 (CI); 21,33 (Cy.

  EXAMPLE 10 N- [4- (2-Benzofuryl) -tetrahydro-4H-thiopyran-4-yl] -piperidine The preparation method is identical to that of step 9b but using a solution of

  2-lithio-benzofuran in place of a 2-lithio-furan solution.

  After the usual treatment, a yellow solid is obtained which is chromatographed on alumina

  eluting with EP / EA mixture (98/2). This gives a white solid (67%).

M.p. 109-111 C.

  13 C NMR: 159.78 (C2 '); 154.0 (C7'a); 127.83 (C3'a); 123.42 to 102.8 (C3 'to C7');

  57.76 (C4); 46.62 (Ca); 33.78 (C3-C5); 26.81 (C2-C6); 24.64 (C); 23.17 (CP3).

  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 (Ca); 30.77 (C3-C5); 24.99 (C2-C6); 22.47 (CP); 24.64 (C).

  EXAMPLE 11 N- [4- (5S-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl]

  The process of preparation is identical to that of step 9b but using a solution of

  2-lithio-5-methyl-thiophene in place of a 2-lithio-furan solution.

  After the usual treatment, a yellow solid is obtained which is chromatographed on alumina

  eluting with EP / EA mixture (98/2). This gives a white solid (67%).

Pf = 93-95C.

  13 C NMR: 144.04 (C2 '); 136.95 (C5 '); 124.05 (C3 '); 123.05 (C4 '); 58.44 (C4); 45,96

  (It); 36.65 (C3-C5); 26.74 (C2-C6); 24.88 (C); 23.37 (Cg); 15.09 (CH3).

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  Characteristic of the corresponding hydrochloride:

Mp = 160-162C.

  13 C NMR: 142.88 (C2 '); 131.34 (C5 '); 130.25 (C3 '); 125.82 (C4 '); 68.83 (C4); 46.47

  (It); 32.89 (C3-C5); 24.68 (C2-C6); 22.27 (CO3); 21.69 (CD); 14.75 (CH3).

  Example 12 N- [4- (4-methyl-thiophen-2-yl) -tetrahydro-4H-thiopyran-4-yl] piperidine 43 The preparation method is identical to that of step 9b but using a solution of

  2-lithio-4-methyl-thiophene instead of a 2-lithio-furan solution.

  After the usual treatment, a brown solid is obtained which is chromatographed on alumina

  eluting with EP / EA mixture (90/10). This gives a white solid (55%).

Pf = 89-91 C.

  13 C NMR: 146.04 (C2 '); 136.32 (C4 '); 125.63 (C3 '); 118.05 (C5 '); 58.34 (C4); 45.95

  (It); 36.66 (C3-C5); 26.74 (C2-C6); 24.68 (CO, 23.32 (Cl), 15.78 (CH3).

  Characteristic of the corresponding hydrochloride:

Mp = 144-146 ° C.

  13 C NMR: 138.86 (C2 '); 134.17 (C5 '); 132.68 (C3 '); 123.93 (C4 '); 69.43 (C4); 47.17

  (CoA); 33.57 (C3-C5); 25.21 (C2-C6); 22.84 (C [); 21.14 (C, 15.61 (CH3).

  Example 13 N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-hydroxypiperidine Step 13a: 4- (3-Hydroxypiperidino) -tetrahydro-4H-thiopyran-4-carbonitrile In a 100 ml bicol, 3-hydroxy-piperidine hydrochloride (6.5 g, 47.3 mmol) is added to 30 ml of water. Potassium cyanide (1.85 g, 5 mmol) was added and 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 soda (10%).

  After stirring for 24 hours at room temperature, extraction with ether (3 × 80 ml) is then carried out, the combined organic phases are washed with water (100 ml) and dried over Na 2 SO 4.

  filter and dry concentrate. This gives a colorless oil (3.9 g, 17.2 mmol).

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  13 C NMR: 117.87 (CN); 66.25 (C [); 59.19 (C4); 53.20; 45.96 (Ca '); 33.94 (C3-C5);

  31.79 (Cy); 22.70 (C2-C6); 21.90 ((Cg ').

  Step 13b: N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -3-hydroxy-piperidine 2-Thienyl magnesium bromide is prepared under nitrogen from magnesium (1.3 g. 53.2 mmol), 2-bromothiophene (8.7 g, 53.2 mmol) and 100 ml anhydrous ether. The mixture is heated at 45 ° C. for 3 hours and the aminonitrile obtained in step 13a (3 g, 13.3 mmol) dissolved in ether is then added at ambient temperature. The reaction medium is heated for 20 hours under 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). We thus obtain a

white solid (42%).

Mp = 84-87C.

  13 C NMR: 145.82 (C2 '); 126.71 to 123.13 (C3 'to C5'); 66.83 (CO); 58.23 (C4); 52.52

  (It); 45.89 (Ca '); 36.40 (C3-C5); 32.18 (Cy); 23.40 (C2-C6); 22.36 (Cp ').

  Characteristic of the corresponding hydrochloride:

Mp = 169-172C.

  13 C NMR: 134.26 (C2 '); 130.78 to 128.29 (C3 'to C5'); 69.69 (C4); 63.75 (CO); 51.31

  (It); 46.18 (Ca '); 34.10 (C3-C5); 31.22 (Cy); 25.28 (C2-C6); 20.38 (Cg ').

  Example 14 N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxypiperidine Step 14a: 4- (4-Hydroxypiperidino) tetrahydro-4H-thiopyran-4-carbonitrile

  It is prepared from MgSO4 (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 treatment of the reaction, a white solid (4.7 g) is obtained which is crystallized from anhydrous ether. We obtain

  white crystals (3.6 g, 79%), mp = 79-81 ° C.

  13 C NMR: 118.28 (CN); 66.67 (Cy); 59.42 (C4); 43.87 (Ca); 33.96 (C3-C5 *); 34.33

(C [5 *); 22.91 (C2-C6).

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  Step 14b: N- [4- (2-thienyl) -tetrahydro-4H-thiopyran-4-yl] -4-hydroxypiperidine 47 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. The mixture is heated at 45 ° C. for 3 hours and the aminonitrile obtained in step 14a (1.4 g, 6.2 mmol) dissolved in ether is then added at ambient temperature. The reaction medium is heated for 20 hours under reflux. After treatment of the reaction, 1.5 g of a brown solid are obtained which is chromatographed on alumina, eluting with anhydrous ether. This gives a solid

white (0.85g, 49%).

Mp = 145-148 ° C.

  13C NMR (D2O): 146.19 (C2 '); 126.07 to 122.98 (C3 'to C5'); 68.18 (C; 58, 24 (C4)

  42.67 (Ca); 36.92 (C3-C5 *); 35.19 (C13 *); 23.40 (C2-C6).

  Characteristic of the corresponding hydrochloride:

Mp = 182-185C.

  13 C NMR: 136.63 (C2 '); 134.19 to 130.98 (C3 'to C5'); 72.05 (C4); 67.53 (CY); 48,04

  (CoA); 36.71 (C3-C5); 33.87 (Cg); 27.45 (C2-C6).

  Example 15 N- [1- (2-thienyl) -cyclohexan-1-yl] -4-hydroxy-3-methylpiperidine Step 15a: N-Benzoyl-4-piperidone-3-carboxylic acid ethyl ester 48 To a 250 ml three-necked layer, benzamide (12.1 g, 0.1 mmol) in ml of toluene was introduced under nitrogen and sodium hydride (4 g, 0.1 mol) was added. The mixture is refluxed for one hour and is then cooled to 0.degree. C. and ethyl acrylate (32.6 ml, 0.3 mol) is rapidly run in. The reaction medium is stirred for 24 hours at 60 ° C. It is cooled to 0 ° C. and ml of ice-cold water is added. After stirring for half an hour, 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 (3 × 50 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. This gives a lightly colored oil

  red (9.4 g, 34%) with traces of benzamide.

  13 C NMR: 201.63 (C4); 197.5 (C4enol); 170.89 and 170.4 (CO amide and ester); 135.25 to 126.87 (Caromatic); 95.73 (C3enol); 61.4 and 60.46 (CH 2 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).

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  Step 15b: Ethyl N-benzoyl-4-piperidone-3-carboxylate The mixture consisting of the ketoester of step 15a (9.3 g, 33.8 mmol) and sodium hydride (1 35 g, 34 mmol) in 50 ml of dimethoxyethane is refluxed for 2 hours with stirring. It is cooled to 0 ° C. and methyl iodide (5.2 ml, 84 mmol) is added. The reaction medium is heated for 40 hours at 60 ° C. It is concentrated to dryness and the residue is taken up in water (100 ml). Extraction is carried out with dichloromethane (3 × 50 ml), the combined organic phases are washed with 50 ml of NaOH (5%), 50 ml of HCl (5%) and 50 ml of water. Na 2 SO 4 is dried and concentrated to dryness. The brown oil obtained (9.4 g) is chromatographed on silica eluting with anhydrous ether. We get a

  slightly yellow oil (7.7 g, 79%).

  13 C NMR: 203.89 (C4); 170.54 (CO amide and ester); 134.76 to 126.87 (Caromatic); 61.56

  (CH2Et); 57.11 (C3); 39.05 (C6); 17.15 (CH3); 13.60 (CH3Et).

  Step 15 c: 3-methyl-4-piperidone hydrochloride The compound of step 15b (7.7 g, 26.6 moles) is refluxed with an aqueous solution of HCl (6N) for 72 hours. hours. The formed benzofacic acid precipitate is filtered off, the aqueous phase is extracted with ether (3 × 50 ml) and the aqueous phase is concentrated to dryness. We crystallize the solid

  brown obtained in ethanol and thus obtained white crystals (2.85 g, 72%). Pf = 180-

182 C.

  13 C NMR: 210.38 (C4); 54.58 (C2); 47.67 (C6); 47.01 (C3); 42.98 (C5); 11, 18 (CH3).

  Step 15 d: 3-methyl-4-piperidol 51 In a 100 ml tricol, the compound from step 15c (2.85 g, 19 mmol) and ml of methanol are introduced. 7.6 ml of a sodium hydroxide solution (5%) are added dropwise. After stirring for half an hour, 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 a solution of HCl are added and the mixture is 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 thus obtained

  a white solid (1.9 g, 87%). Mp = 169-170C.

  13 C NMR (D 2 O): - Major diastereoisomer: 73.24 (C4); 50.75 (C2); 45.69 (C6);

38.45 (C3); 32.92 (C5), 16.8 (CH3).

  - Minor diastereoisomer: 67.94 (C4); 46.97 (C2); 41.32 (C6);

34.89 (C3); 31.29 (C5), 16.47 (CH3).

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  Step 15 e: 1- (4-Hydroxy-3-methyl-piperidino) -cyclohexan-1-carbonitrile In a 50 ml bicot, the compound of step 15d (0.8 g, 7 mmol) is introduced into ml of water. Cyclohexanone (2.7 g, 23.6 mmol) and a few drops of HCl were added to bring the pH to 3. The potassium cyanide (0.47 g, 7.3 mmol) was then run. The pH of the medium is then close to 11. After stirring for 24 hours at room temperature,

  extraction is carried out with dichloromethane, dried over Na 2 SO 4, filtered and concentrated to dryness.

  This gives a colorless oil (1.43 g, 6.4 mmol) representing only one of

two diastereoisomers.

  13 C NMR: 118.97 (CN); 73.69 (Cy); 60.57 (Cl); 52.43 (Ca); 45.37 (Ca '); 38.57 (CO)

  ; 34.22 (Cid '*); 33.98 (C2-C6 *); 33.87 (C4 +); 21.91 (C3-C5); 15.61 (CH3).

  Step 15 f: N- [1- (2-thienyl) -cyclohexan-1-yl] -4-hydroxy-3-methylpiperidine Nitrogen bromide of 2-thienylmagnesium is prepared from magnesium (0.38 g. , 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 the aminonitrile obtained in step 15e (0.7 g, 3.15 mmol) dissolved in THF is then added at ambient temperature. The reaction medium is heated at reflux. After treatment of the reaction, a brown oil is obtained which is chromatographed on alumina, eluting with anhydrous ether. This gives a solid

white (0.48g, 54%).

  13 C NMR: 146.14 (C2 '); 125.86 to 122.61 (C3 'to C5'); 74.76 (Cy); 59.34 (C1); 51.17 (Ca); 43.98 (Ca '); 39.36 (C [); 36.0 (C3-C5); 25.85 (C4 +); 21, 96 (C3-C5 *); 15.75

(CH3).

  Characteristic of the corresponding hydrochloride: 13 C NMR: 135.09 (C2 '); 129.98 to 127.55 (C3 'to C5'); 70.60 (Cy); 69.00 (C1); 50.59

  (It); 45.30 (Ca '); 35.37 (Cl); 32.80 (C3-C5); 30.77 (C2-C6); 23.43 (C4); 22.53 (C3-

C5); 15.06 (CH3).

  Example 16 N- [1- (2-Benzothiophenyl) -cyclohexan-1-yl] -4-hydroxy-3-methylpiperidine The aminonitrile from Step 15e (0.7 g, 15 mmol) dissolved in 50 ml of anhydrous ether over a solution of 2-benzothiophenylmagnesium bromide (15.75 mmol). The mixture is refluxed with ether for 16 hours. After the usual treatment, a yellow oil (0.85 g) is obtained, which is chromatographed on alumina, eluting with

  with an EP / EA mixture (20/80). This gives a white solid (0.74 g, 71%).

- 26 -

-26- 2763951

Mp = 120-122C.

  13C NMR: 147.60 (C2 '); 139.44 (C7'a); 138.64 (C3'a); 123.77 to 120.44 (C3 'to C7') 74.89 (C); 59.98 (C1); 51.29 (Ca); 44.16 (Cat '); 39.55 (C); 33.84 (C2-C6); 35.27

  (CP '); 25.86 (C4); 22.14 (C3-C5); 15.85 (CH3).

  Characteristic of the corresponding hydrochloride:

Mp = 170-172C.

  13 C NMR: 139.60 (C2 '); 139.02 (C7'a and C3'a); 126.16 to 120.02 (C3 'to C7'); 71.85 (C7), 66 (C1); 51.33 (Coa); 45.66 (Cat '); 36.54 (C5); 33.58 (C2C6); 31.99 (C5 '); 24,12

(C4); 22.80 (C3-C5); 15.54 (CH3).

  EXAMPLE 17 N-ethyl-1- (2-thienyl) -cyclohexylamine Step 17 a: 1- (2-thienyl) -cyclohexanol N-thienylmagnesium bromide was prepared under nitrogen from magnesium (2.92 g, mmol), 2bromothiophene (19.6 g, 120 mmol) and 200 ml of anhydrous ether. The mixture is heated at 45 ° C. for 3 hours and then at room temperature cyclohexanone (7.84 g, 80 mmol) dissolved in ether is added. The reaction medium is heated for 16 hours under reflux. After cooling, the reaction medium is poured into 100 ml of a saturated aqueous solution of NH 4 Cl. Stir 1/2 hour to destroy the magnesium complex, decant and extract the aqueous phase with ether (3 × 50 ml). Acid-basic extraction is carried out with a 15% aqueous solution of HCl (3 × 50 ml), which is then neutralized with NH 4 OH (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 brown oil obtained is chromatographed on silica eluting with an EP / EA mixture (70/30). We

  thus obtaining a limpid, slightly yellow oil (12.1 g, 83%).

  13 C NMR: 153.52 (C2 '); 128.38 to 121.78 (C3 'to C5'); 71.78 (C1); 39.73 (C2-C6); 25.2

(C4); 22.15 (C3-C5).

  Step 17b: 1- (2-thienyl) -cyclohexylazide 56

  Trichloroacetic acid (31.9 g, 195 mmol) is dissolved in chloroform (200 ml).

  The sodium azide (8.45 g, 130 mmol) is added and the mixture is cooled to 10 ° C. The alcohol obtained in step 17a is poured dropwise (11.8 g, 65 mmol). dissolved in chloroform (50 ml). The reaction medium is stirred for 48 hours while maintaining the temperature at -12 ° C. A solution of ammonia (10%) is then added until neutralization, and then the aqueous phase is extracted with dichloromethane (3 × 100 ml). The organic phase is washed with water

-27- 2763951

  (200 ml), dried over Na 2 SO 4 and concentrated to dryness. We obtain a brown oil that we

  subsequently used without further purification.

  Step 17 c: 1- (2-thienyl) -cyclohexylamine 57. In a 500 ml tricolor, lithium aluminum hydride (2.28 g, 60 mmol) is introduced into 250 ml of THF at 0 ° C. dropwise the azide obtained in the previous step 17b (13.5 g, 65 mmol) dissolved in 30 ml of THF. The reaction medium is stirred for 24 hours at room temperature. The minimum amount of ammonia (10%) is added very slowly in order to destroy the excess of LiAlH4. It is filtered through 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 solution of HC1 (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 MgSO4 and concentrated to dryness. The product obtained is purified by chromatography on alumina, eluting with an EP / EA mixture (60/40). This gives an oil slightly

yellow (8.1 g, 69%).

  NMR 13 C 156.70 (C2 '); 125.99 to 120.85 (C3 'to C5'); 52.82 (Cl); 40.39 (C2-C6)

17 (C4); 22.10 (C3-C5).

  Step 17 d: N-acetoxy-1- (2-thienyl) -cyclohexylamine In a 250 ml tricol, the amine from step 17c (3 g, 16.6 mmol) is introduced into the pyridine (100 ml and dripping the acetic anhydride (51 g, 50 mmol). After stirring for 4 hours at room temperature, 100 ml of a solution of HCl (10%) are added and the product formed is extracted. ether (3x50 ml). The organic phase is washed with a solution of HCl (10%) (2 × 80 ml) and then with water (2 × 80 ml), dried over MgSO 4 and concentrated to

  dry. This gives a white solid (3.1 g, 84%).

  13 C NMR: 169.44 (CO); 152.48 (C2 '); 126.32 to 122.68 (C3 'to C5'); 56.69 (C1); 37.32

  (C2-C6); 25.22 (C4); 24.10 (CH3); 22.11 (C3-C5).

  Step 17e: N-ethyl-1- (2-thienyl) -cyclohexylamine 60 Lithium aluminum hydride (0.51 g, 13.4 mmol) in 80 ml THF is introduced into a 500 ml three-necked flask. at 0 ° C. The amine obtained in the previous step 17d (3 g, 13.4 mmol) dissolved in 30 ml of THF is added dropwise. The reaction medium is stirred for 48 hours under reflux. The minimum amount of ammonia (10%) is added very slowly in order to destroy the excess of LiAIH4. It is filtered through 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 solution of HCl (10%) (3x100 ml). The aqueous phase is then neutralized with ammonia (20%) and

-28- 2763951

  extracted with ether (3x100 ml). The organic phase is washed with water, dried over MgSO4 and concentrated to dryness. The product obtained is purified by chromatography on alumina, eluting with

  an EP / EA mixture (90/10). This gives a colorless oil (1.7 g, 61%).

  13C NMR: 154.18 (C2 '); 125.81 to 122.52 (C3 'to C5'); 56.60 (C1); 37.60 (CH 2); 35.74

  (C2-C6); 25.51 (C4); 21.86 (C3-C5); 15.48 (CH3).

  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 (C1); 36.30 (CH 2); 34.46

  (C2-C6); 24.30 (C4); 21.94 (C3-C5); 11.53 (CH3).

  Using the method indicated above, the following compounds which also form part of the invention can also be prepared: EXAMPLE X Y Z R4 R1R2N-Ar A C S C 1 1 CH3

B C S C 5 -CH 3 Et 2 N

C C O C H CH2OH

D C C C H CH3

E C O C H CH3 C2H5

F C C C H N

N. l

-29- 2763951

G C C H OH CZH

H C O C H EtMeN- CH CH3

I C S C 3 -CH 3 OH

K C C C H C H3 NO

-30- 2763951

  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 assessed by quantifying their displacement power of a specific tritiated marker of a given site. Competition binding experiments are carried out between the test molecule 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 KO, 5.

  For PCP1 sites, the tritiated marker used is [3H] TCP and the tests performed on

  membrane preparations from rat anterior brain homogenates.

  For the experimental conditions and the membrane preparation techniques used, reference may be made to the literature (Brain Res., 378, 133-141 (1986), Eur J. Pharm.

531-542 (1982)).

  For low affinity sites, the monosite treatment employed led to inconsistent results. The experimental data were therefore reprocessed by non-linear regression (MarquardtLevenberg algorithm) with the Sigma Plot software (Jandel) according to a model with two interaction sites noted PCP2 and PCP3. This treatment proved to be more suitable than a monosite treatment (Student's test: p <0.05) over a set of 3 to 4 experiments for each of the compounds tested. For all experiments, the two site populations are in a relative proportion of 68.0% (+1.5) for the PCP2 sites and 31.2% (1, 5) for the PCP3 sites (the nomenclature adopted for PCP receptor sites is as follows: PCP1 = high affinity sites in the forebrain, PCP2 = high sites

  affinity in the cerebellum and PCP3 = sites of low affinity in the cerebellum).

  For the PCP2 and PCP3 sites, the preparation comes from rat cerebellum. Not having a specific marker, only [3H] TCP can be used. A higher concentration of tritiated ligand (2.5 nM versus 1 nM in the cortex) will be used to be sure to occupy

all PCP2 and PCP3 sites.

-31- 2763951

  cortex cerebellum 1 site 2 sites Compound K0.5 nH n KO, 5 PCP2 KO, 5 PCP3 n (nM) (nM) (%) (nM) (%)

TCP - - - 59 72.6 3716 29.8 5

  Ex 9 133 0.87 3 1015 68.3 13.8 32.3 5

Ex 1 17233 0.94 3 - - - - -

  (majority) Ex 1 26.8 0.89 3 1355 62.8 17.6 34.7 4 (minority) Ex 2 132 1.14 3 265 69.1 2850 31.6 3 Ex 4 24 0.84 3 53 , 2 66.3 2076 34.6 4 Ex 5> 10OM - 3> 100 pM 66.2 581 32.2 3 Ex 6> 1001 M - 3> 100 pM 55.6 280 39.4 3 Ex 7 82825 0.73 4 84000 57.8 639 40.7 3 Ex 8 28.4 0.96 3 2240 69 12.4 31 3 Ex 10 27467 0.9 3 26633 65.0 59.1 33.4 3 Ex 11il 462 0.97 3 532 83> 0l0M 15.3 3 Ex 12 77.8 772 76.4 5.4 21.8 4 Ex 17 20.9 0.77 3 55 56.6 47600 44.6 3

- 32 -

-32- 2763951

Claims (11)

  1. The compounds of formula I 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 radicals or different ones selected from halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl radicals, having at most 6 carbon atoms; esterified or salified free carboxy; cyano; nitro; amino optionally substituted with one or two identical or different alkyl radicals containing at most 6 carbon atoms; R1 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 or nitro radicals; R1 and R2 together with the carbon atom to which they are attached form a radical q2) nR3R3 or Ro3 in which n represents an integer from 0 to 2 and R3 and R'3, which may be identical or different, represent a hydrogen atom, a halogen atom or a hydroxyl radical, carboxy free esterified or salified, 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 either one represents a sulfur or oxygen atom and the other two represent a methylene radical, or the three represent a methylene radical, -33 - 2763951   with the exception of compounds in which R 3, R '3 and R 4 each represent a hydrogen atom and 1) R 1 and R 2 form, with the nitrogen atom to which they are bonded, a pyrrolidine radical, Ar represents a phenyl radical or 2-thienyl and one of X, Y or Z represents an oxygen atom 2) R1 and R2 together with the nitrogen atom to which they are attached a piperidine radical, Ar represents a phenyl, thienyl and benzothienyl Y radical represents a sulfur atom, X and Z each represent a methylene radical; 3) R1 and R2 together with the nitrogen atom to which they are attached form a piperidine radical; Ar represents a phenyl, methoxyphenyl, benzothienyl and 2-thienyl radical and Y represents an oxygen atom, X and Z each represent a methylene radical, 4) R and R 2 form, with the nitrogen atom to which they are bonded, 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;) Ri and R2 form, with the nitrogen atom to which they are bonded, a piperidine radical, Ar represents a phenyl or 2 thienyl radical, one of X or Z represents an atom of sulfur, the other represents a methylene radical and Y represents a methylene radical, 6) R1 and R2 form, with the nitrogen atom to which they are bonded, 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, and it being understood that when X, Y and Z each represent a methylene radical, Ar represents a monocyclic heterocyclic aryl radical or constituted by fused rings and substituted with one or more identical or different radicals, said compounds of formula I being in all isomeric, racemic, enantiomeric and diastereoisomeric forms possible, and addition salts with the inorganic and organic acids or with the inorganic and organic bases of said compounds of formula I. 2. The compounds of formula I as defined in claim 1, wherein Ar represents a monocyclic heterocyclic aryl radical with 5 members or consisting of two fused rings and optionally substituted with one or more identical or different alkyl radicals; -34- 2763951   R1 and R2, which are identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms, or R1 and R2 form with the carbon atom to which they are bonded a radical (CH2) n R3 R13 or RN Wherein n is 1 and R3 and R'3, which may be identical or different, represent a hydrogen atom or a hydroxyl, alkyl or hydroxyalkyl radical having at most 6 carbon atoms.   3. The compounds of formula I as defined in one of claims 1 or 2, in   wherein Ar represents thienyl, furyl, benzothienyl, benzofuryl and optionally substituted by one or more methyl or ethyl radicals; R1 and R2, which are identical or different, represent a hydrogen atom or a methyl or ethyl radical, or else R1 and R2 form, with the carbon atom to which they are bonded, a radical (CH2) n R3 or CNXR'3 N R3 I I   in which n is 1 and R3 and R'3 identical or different represent an atom   hydrogen 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   having 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-methylpiperidine; N- [4- (2-benzothiophenyl) tetrahydro-4H-thiopyran-4-yl] -3-methylpiperidine; N- [1- (2-thienyl) cyclohexan-1-yl] -3-hydroxymethylpiperidine; N- [4- (2-furyl) -tetrahydro4H-thiopyran-4-yl] piperidine; N- [4- (2-benzofuranyl) -tetrahydro-4H-thiopyran-4-yl] -piperidine; N- [4- (5-methylthiophen-2-yl) tetrahydro4H-thiopyran-4-yl] piperidine; N- [4- (4-methylthiophen-2-yl) tetrahydro-4H-thiopyran-4-yl] piperidine; N- [4- (2-thienyl) tetrahydro4H-thiopyran-4-yl] -3-hydroxypiperidine; N- [4- (2-thienyl) tetrahydro4H-thiopyran-4-yl] -4-hydroxypiperidine; N- [1- (2-thienyl) cyclohexan-1-yl] -4-hydroxy-3-methylpiperidine; -35 - 2763951   N- [1- (2-benzothiophenyl) -cyclohexan-1-yl] -4-hydroxy-3-methylpiperidine;   N-ethyl-1- (2-thienyl) -cyclohexylamine.   5. Process for the preparation of 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 ## STR2 ## in which X, Y , Z and R4 have the meanings indicated above, with an aryl magnesium halide of formula Hal-Ar-Mg wherein Hal represents a halogen atom and Ar has the meaning indicated above, to obtain the compound of formula 2 HO Ar XV - R4   Xyvz 2 in which X, Y, Z, Ar and R4 have the meanings indicated above, - the conversion of the hydroxyl radical of the alcohol of formula 2 thus obtained into the azide of formula 3 N 3 Ar X..yR 4 Y 3 in which X, Y, Z, Ar and R4 have the meanings indicated above, -36- 2763951   and then reducing the azide of formula 3 to the primary amine of formula 4 H 2 N Ar r> S R 4 X.YZ 4   in which X, Y, Z, Ar and R4 have the meanings indicated above, and finally, if the desired compound of formula I is such that at least one of the radicals R1 or R2 is different from the hydrogen atom or else R1 and R2 form a ring with the carbon atom to which they are bonded, treating this compound of formula 4 to   obtain the compound of formula I which is converted if desired into salt.   either B) - the reaction of a compound of formula 1 Y1   wherein X, Y, Z and R4 have the meanings indicated above, in anhydrous medium, with a compound of formula R1R2NH wherein R1 and R2 have the meanings indicated above, and a cyanide ion donor compound, for obtain the compound of formula 5 R1 R N CN   wherein X, Y, Z, R 1 and R 2 are as defined above, and the reaction of the compound of formula 5 thus obtained with an aryl halide.   magnesium of formula Hal-Ar-Mg in which Ar has the meaning indicated below.   above and Hal represents a halogen atom, to obtain the compound of formula I according to the invention. - 37 -2763951   6. As medicaments, the compounds of formula I as defined in claim 1, as well as the addition salts with inorganic or organic acids or the pharmaceutically acceptable inorganic or organic bases of said compounds of formula I. 7. As medicaments, the compounds of formula I as defined in one of the   2 to 4, as well as the addition salts with the mineral or organic acids or   the pharmaceutically acceptable inorganic or organic bases of said compounds of formula I. 8. Pharmaceutical compositions containing, as active ingredient, at least one of the   medicaments as defined in one of claims 6 or 7.   9. Use of the compounds of formula I as defined in any one of   claims 1 to 4 for the preparation of medicaments for protecting the cells of the   central or peripheral nervous system against acute degeneration induced by accidents such as trauma, ischemia or action of neurotoxic agents, endogenous and   exogenous, directly or through secondary mechanisms.   10. Use of the compounds of formula I as defined in any one of   claims I to 4 for the preparation of medicaments for protecting the cells of the   central or peripheral nervous system against chronic degeneration induced by pathological aging neurodegenerative diseases, dementia, disease   Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis.   11. Use of compounds of formula I as defined in any one of   Claims 1 to 4 for the preparation of anticonvulsant drugs.