WO2004013100A2

WO2004013100A2 - N-[phenyl(piperidin-2-yl)methyl]benzamide derivatives, preparation thereof, and use thereof in therapy

Info

Publication number: WO2004013100A2
Application number: PCT/FR2003/002355
Authority: WO
Inventors: Emmanuelle Dachary; Gihad Dargazanli; Geneviève ESTENNE-BOUHTOU; Benoît MARABOUT; Nathalie Rakotoarisoa; Pierre Roger; Mireille Sevrin
Original assignee: Sanofi-Aventis
Priority date: 2002-07-29
Filing date: 2003-07-25
Publication date: 2004-02-12
Also published as: AU2003273474A8; FR2842805A1; AU2003273474A1; WO2004013100A3

Abstract

Disclosed are compounds of general formula (I) in which R1 represents H or an alkyl, cycloalkyl alkyl, phenylalkyl, alkenyl, or alkynyl, X represents H or one or several halogen atoms, alkyl, or alkoxy, R2 represents H or one or several halogen atoms or alkoxy groups, or optionally substituted amino, R3 represents an optionally substituted aminosulfonyl group, a cyano group or a group of formula S-alkyl, an alkylsulfonyl group, a carboxy or alkoxycarbonyl group, an optionally substituted carbamoyl group, an acetyl or benzoyl group, or an alkyl, cycloalkyl, alkenyl, phenyl, thienyl or thianthrenyl group. Said compounds are used for therapeutic purposes.

Description

N- [phenyl (piperidin-2-yl) methyl] benzamide derivatives, their preparation and their therapeutic use.

The compounds of the invention correspond to the general formula (I)

in which R _x represents either a hydrogen atom, or a linear or branched (C _j -C,) alkyl group optionally substituted by one or more fluorine atoms, or a (C ₄ -C ₇ ) cycloalkyl group, or a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₃ ) alkyl group, either a phenyl (C ₁ -C ₃ ) alkyl group, or a (C ₂ -C ₄ ) alkenyl group, or a (C ₂ - group) C ₄ ) alkynyl,

X represents a hydrogen atom or one or more substituents chosen from halogen atoms and trifluoromethyl groups, (C ₁ -C ₄ ) linear or branched alkyl and (C ₁ -C ₄ ) alkoxy,

R ₂ represents either a hydrogen atom or one or more substituents chosen from halogen atoms and (C ₁ -C ₄ ) alkoxy, methylenedioxy and amino groups of general formula NR ₄ R ₅ in which R ₄ and R ₅ each represent, independently of one another, a hydrogen atom or a (C ₁ -C ₄ ) alkyl group, or form, with the nitrogen atom which carries them, a pyrrolidine, piperidine ring, morpholine or piperazine,

R ₃ represents one or more substituents chosen from the following: either a group of general formula S0 ₂ NR ₆ R ₇ in which R ₆ and R ₇ each represent, independently of one another, a hydrogen atom or a (C ₁ -C ₄ ) linear or branched or cyclic alkyl group, (C ₁ _C ₃ ) alkylamino (C ₁ _C ₃ ) alkyl, (C ₁ .C ₃ ) alkoxy (C ₁ _C ₃ ) alkyl, (C ₁ _C ₃ ) alkylaminocarbonyl, or form, with the nitrogen atom which carries them, a pyrrolidine ring optionally substituted by one or two groups methyl, a piperidine ring or a morpholine ring, either a group of general formula S (C ₁ _C ₃ ) alkyl, or a (C ₁ .C ₃ ) alkylsulfonyl group, or a carboxy group or (C ₁ _C ₃ ) alkoxycarbonyl, either a group of general formula CONR ₆ R ₇ in which R ₆ and R ₇ are as defined above, either an acetyl or benzoyl group, or a cyano group or a linear or branched (^ -0 ₄ ) alkyl group, either a cyclo (C ₅ -C ₆ ) alkyl or cyclo (C ₅ -C ₆ ) alkenyl group, or a phenyl group substituted or not by one or more substituents chosen from halogen atoms, (C ₁ _C ₃ ) alkoxy groups, methylthio group, trifluoromethyl group, trifluoromethoxy group, cyano group, (C _x -C ₄ ) alkyl groups and phenyl group, either a thienyl, benzothienyl or thianthenyl.

The compounds of general formula (I) can exist in the form of the threo racemate (1R, 2R; 1S, 2S) or in the form of enantiomers (IR, 2R) or (1S, 2S); they can exist in the form of free bases or of addition salts with acids.

Compounds of structure analogous to that of the compounds of the invention are described in patent US Pat. No. 5,254,569 as analgesics, diuretics, anticonvulsants, anesthetics, sedatives, cerebroprotectors, by a mechanism of action on opiate receptors. Other compounds of similar structure are described in patent application EP-0 99995 as 5-HT ₃ antagonists useful in the treatment of psychotic disorders, neurological diseases, gastric symptoms, nausea and vomiting.

The compounds of the invention exhibit an activity particular as specific inhibitors of the glycine transporters glytl and / or glyt2.

The preferred compounds lacking activity on the opiate receptors or 5-HT ₃ as specific inhibitors of the glytl transporter are of configuration {S, S) with R ₃ representing one or more groups chosen from the groups

alkyls, cyano, S (C _x -C ₃ ) alkyls, aryls or heteroaryls and R ₂ representing a hydrogen or halogen atom. The preferred compounds as inhibitors of the glyt2 transporter are of configuration (R _r R), with R ₃ representing an aminosulfonyl group of general formula S0 ₂ NR ₆ R ₇ or aminocarbonyl of general formula CONR ₆ R ₇ and R ₂ representing one or more substituents chosen from halogen atoms and amino groups of general formula NR ₄ R ₅ .

The compounds of general formula (I) in which R _x is different from a hydrogen atom can be prepared by a process illustrated by scheme 1 which follows.

Diagram 1

A diamine of general formula (II), in which X is as defined above and R _x is different from a hydrogen atom, is coupled with an activated acid or an acid chloride of formula general (III) in which Y represents a nucleofuge group such as a halogen atom and R ₂ and R ₃ are as defined above, using the methods known to those skilled in the art. The diamine of general formula (II) can be prepared by a method illustrated by scheme 2 which follows.

Diagram 2

The Weinreb amide of formula (IV) is reacted with the phenyllithium derivative of general formula (V), in which X is as defined above, in an ethereal solvent such as diethyl ether, between -30 ° C and room temperature; a ketone of general formula (VI) is obtained which is reduced to alcohol of threo configuration of general formula (VII) by a reducing agent such as K-Selectride® or 'L-Selectride® (tri-sec- potassium or lithium butylborohydride), in an ethereal solvent such as tetrahydrofuran, between -78 ° C and room temperature ^' . The carbamate of general formula (VII) can then be reduced to iV-methylaminoalcohol threo of general formula (VIII) by the action of a mixed hydride such as 1 double lithium aluminum hydride, in an ethereal solvent such as tetrahydrofuran, between room temperature and reflux temperature. The threo alcohol of general formula (VIII) is then transformed into threo diamine of formula general (II) where R _x represents a methyl group in two stages: the alcohol function is first transformed into a nucleofuge group, for example a methanesulfonate group by the action of methylsulfonyl chloride, in a chlorinated solvent such as dichloromethane, and presence of a base such as triethylamine, between 0 ° C and room temperature, then reacting the nucleofuge group with liquefied ammonia at -50 ° C, in an alcohol such as et anol, in a closed environment such as an autoclave, between -50 ° C and room temperature.

It is also possible to deprotect the carbamate of general formula (VII) by means of a strong base such as aqueous potassium hydroxide, in an alcohol such as methanol to obtain the amino alcohol threo of general formula (IX), then proceed to a W -alkylation by means of a halogen derivative of formula R _X Z, in which R _x is as defined above, but different from a hydrogen atom, and Z represents a halogen atom, in the presence of a base such as potassium carbonate, in a polar solvent such as N, IV-dimethylformamide, between room temperature and 100 ° C. The alcohol of general formula (X) thus obtained is then treated as described with respect to the alcohol of general formula (VIII).

Another variant of the process, illustrated by diagram 3 which follows, can be used in the case where R _x represents a methyl group and X represents a hydrogen atom. The pyridineoxime of formula (XI) is quaternized, for example by the action of methyl trifluoromethanesulfonate, in an ethereal solvent such as diethyl ether at room temperature. The pyridinium salt thus obtained, of formula (XII) is then subjected to hydrogenation under a hydrogen atmosphere, in the presence of a catalyst such as platinum oxide, in a mixture of alcohol and aqueous acid such than ethanol and IN hydrochloric acid. The diamine of general formula (II) is obtained in which R _x represents a methyl group and X represents a hydrogen atom in the form of a mixture of the two threo / erythro 9/1 diastereoisomers. Diagram 3

It can be salified, for example with oxalic acid, then purified by recrystallization of the oxalate formed in a mixture of alcohol and an ethereal solvent such as methanol and diethyl ether, to obtain the threo diastereoisomer. (R, 2R; 1S, 2S) pure.

The compounds of general formula (I) in which R _x represents a hydrogen atom can be prepared by a process illustrated by scheme 4 which follows.

Diagram 4

From the amine of general formula (XIII), in which X is as defined above, coupling is carried out with an activated acid or an acid chloride, as described above, of general formula ( III), according to methods known to those skilled in the art, to obtain the compound of general formula (XIV). Finally, hydrogenation of the latter is carried out, for example with hydrogen in the presence of a - catalyst such as platinum oxide in a mixture of alcoholic solvent, such as ethanol, and hydrochloric acid, to finally obtain a compound of general formula (I) in which R _x represents a hydrogen atom.

Another method consists in modifying a compound of general formula (I) in which R _x represents either an optionally substituted phenylmethyl group and in deprotecting the nitrogen of the piperidine ring, for example by an oxidizing agent or by a Lewis acid, such as boron tribromide, or by hydrogenolysis, either an alkenyl group, preferably allyl, and deprotecting nitrogen with a Pd ° complex, to obtain a compound of general formula (I) in which R _x represents an atom of hydrogen.

Furthermore, the chiral compounds of general formula (I) corresponding to the enantiomers (1JR, 2.R) or (1S, 2S) of the threo diastereoisomer can also be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a column chiral, or by splitting the racemic amine of general formula (II) by using a chiral acid such as tartaric acid, camphorsulfonic acid, dibenzoyltartaric acid or W-acetylleucine, by fractional recrystallization and preferential of a diastereoisomeric salt, in an alcohol type solvent, or also by enantioselective synthesis. according to scheme 2 with the use of a chiral einreb amide of formula (IV).

The Weinreb amide of racemic or chiral formula (IV), as well as the ketone of general formula (VI), can be prepared according to a method analogous to that described in Eur. J. Med. Chem. (2000), 35, 979-988 and J. Med. Chem. (1998), 41, 591-601. The phenyllithium compound of general formula (V) where X represents a hydrogen atom is commercially available. Its substituted derivatives can be prepared according to a method analogous to that described in Tetrahedron. Lett. (1996), 57, 33, 5905-5908. The pyridineoxime of formula general (XI) can be prepared according to a method analogous to that described in patent application EP-0366006. The amine of general formula (IX) in which X represents a hydrogen atom can be prepared in chiral series according to a method described in patent US-2928835. Finally, the amine of general formula (XIII) can be prepared according to a method analogous to that described in Chem. Pharm. Bull. (1984), 32, 12, 4893-4906 and Synthesis, (1976), 593-595.

The benzoic acid derivatives of general formula (III) in which Y represents an OH group which are not commercially available can be prepared according to various methods known to those skilled in the art; a first approach consists in the synthesis of sulfonamide derivatives. Some of these are described in patents DE-2436263, BE-620741,

DE-1158957, US-3112337, GB-915259, US-3203987, DE-642758, EP-68700, FR-2396757, DE-2734270, and in J. Pharm. Pharmacol. (1962), 14, 679-685. Etachlorosulfonyl acids can be obtained according to a method analogous to those described in J. Chem. Soc.

(C), (1968), 13, and in patents US-2273444, DE-19929076, EP-0556674, by heating the acid in chlorosulfonic acid at 140 ° C for 1 to 2 days. The ^{'chlorosulfonylation} ortho or para position may be carried out from a diazonium salt by a method analogous to that described in US-3663615, with the 4-amino-3-chlorobenzoic acid by bubbling dioxide of sulfur in the presence of cupric salt, in a solvent such as acetic acid, when cold, on the corresponding diazonium salt.

The sulfonamides are obtained by reaction of the chlorosulfonylated derivatives in the presence of an excess of amine in a solvent such as tetrahydrofuran, at room temperature or at reflux. Secondary sulfonamides can be methylated according to a method analogous to that described in patent BE-620741, with the use of dimethylsulfate in the presence of a base such as concentrated soda, in an alcoholic solvent such as methanol. The primary sulfonamides can be reacted with an isocyanate, in a solvent such as tetrahydrofuran, in the presence of a base such as potassium carbonate. A second approach consists in the synthesis of sulfoxide derivatives of benzoic acids. Some of them are described in patents DE-2056912, DE-2901170 and US-3953476, or can be obtained by methods analogous to those described in patent BE-872585 and in J. Org. Chem. ((1991), 56 (1), 4976-4977. The synthesis of the sulfoxide is carried out by coupling a halogen derivative with an alkylsulfonyl chloride in the presence of copper.

The benzoic acid derivatives of general formula (III), in which R ₃ represents a branched alkyl group or a cycloalkenyl group, can be prepared according to methods analogous to that described in US Pat. No. 4,879,426 and in Syn. Lett. (1996), 473-474 and J. Med. Chem. (2001), 44, 1085-1098. Biphenyl type benzoic acid derivatives can be synthesized by Suzuki type coupling, by heating the benzoic acid derivative substituted on the phenyl ring by an iodine atom in the presence of a boronic acid, of a base such as potassium carbonate and a catalyst such as tris (dibenzylideneacetone) dipalladium in a solvent such as N, N-dimethylformamide.

Finally, the carbonyl benzoic acids can be synthesized according to methods analogous to those described in patents US-3725417 and GB-913100 and in Chem. Pharm. Bull. , (1988), 36 (9), 3462-3467 and J. Labeled Compd. Radiopharm. , (1997), 39 (6), 501-508.

The first conventional method of carbonylation uses a halogenated benzoic acid or ester derivative on which carbon onoxide is made to act in the presence of a catalyst such as palladium chloride bis (triphenylphosphine) and a base such as triethylamine, in a mixture of alkaline solvent, such as methanol or ethanol, and of N, N-dimethylformamide at 60 ° C.

Esters or amides can also be introduced by direct carbonylation with a strong base of para-acid, under the conditions described in Tetrahedron Lett. , (2000), 41, 3157-3160.

The deprotonation of the aromatic nucleus by a strong base such as Schlosser's base (butyllithium / potassium tert-butoxide, in a solvent such as tetrahydrofuran, at low temperature, followed by the addition of an electrophile of the alkyl chloroformate or chloride type of alkylcarbamoyl, leads to carbonyl compounds Finally, the cyano derivatives of benzoic acids are obtained by heating a halogenated benzoic acid or ester in the presence of potassium cyanide, of a catalyst of the palladiumtetrakis triphenylphosphine type in a solvent of the tetrahydrofuran type, according to a method analogous to that described in J. Org. Chem. (1967) 62, 25, 8634-8639.

The examples which follow illustrate the preparation of some compounds of the invention. Elementary microanalyses, and I.R. and R.M.N. and HPLC on a chiral column confirm the enantiometric structures and purities of the compounds obtained.

The numbers indicated in parentheses in the titles of the examples correspond to those in the 1st column of the table given below. In the names of the compounds, the dash "-" is part of the word, 5 and the dash "_" is only used for breaking at the end of the line; it must be deleted in the absence of a break, and must not be replaced either by a normal dash or by a space.

Example 1 (Compound No. 25). _Q Threo-3-bromo-4- hydrochloride [[(cyclopropyl) (methyl) _ amino] suifonyl] -N- [(1-methylpiperidin-2-yl) phenylmethyl] benz_ amide 1: 1.

1.1. 3-Bromo-4- [[(cyclopropyl) (methyl) _ 5 amino] sulfonyl] benzoic acid.

1.1.1. 3-Bromo-4-chlorosulfonylbenzoic acid.

35 g (0.162 mole) of 4-amino-3-bromobenzoic acid (J. Med. Chem. (2000), 43,) are placed in a 500 ml three-necked flask 21, 3820-3823) in 82 ml of acetic acid and 41 ml of concentrated hydrochloric acid and the mixture is cooled to 0 ° C. A solution of 11.3 g (0.164 mole) of sodium nitrite in 27 ml of water is added dropwise, without exceeding 5 ° C, and the mixture is stirred at 0 ° C for 20 min.

On the other hand, in a three-necked flask of 1 1, 164 ml of acetic acid are placed, the medium is cooled to 0 ° C and bubbled with sulfur dioxide until saturation. To this solution is added 21.8 g (0.162 mole) of copper chloride in 41 ml of water. At 0 ° C the solution of the diazonium salt is added slowly and the mixture is left at 0 ° C for 2 h. The precipitate formed is collected by filtration and dried under reduced pressure. 35.8 g of 3-bromo-4-chlorosulfonylbenzoic acid are obtained in the form of a beige solid.

1.1.2. Benzoic 3-bromo-4- [[(cyclopropyl) amino] sulfonyl] acid.

4.2 ml (60 mmol) of cyclopropylamine dissolved in 50 ml of tetrahydrofuran are placed in a 150 ml flask, 6 g (20 mmol) of 3-bromo-4-chlorosulfonyl benzoic acid are added in small portions, and the mixture is heated at reflux overnight.

After evaporation of the tetrahydrofuran under reduced pressure, the residue is taken up with dichloromethane, and the mixture is acidified with IN hydrochloric acid.

After filtration of the precipitate formed and drying, one obtains

3.27 g of 3-bromo-4- [[(cyclopropyl) amino] sulfonyl] benzoic acid. Melting point: 194-200 ° C.

1.1.3. 3-Bromo-4- [[(cyclopropyl) (methyl) amino] sul_ fonyl] benzoic acid.

2 g (6.3 mmol) of 3-bromo-4- [[(cyclopropyl) amino] sulfonyl] benzoic acid in solution in 12 l of methanol and 1.8 ml of concentrated sodium hydroxide are placed in a 100 ml flask , 1.78 ml (18.8 mmol) of dimethyl sulphate are added and the mixture is heated at 55 ° C for 30 min. 3.6 ml of sodium hydroxide and 1.78 ml of dimethyl sulphate are added. so that the mixture remains basic, and is left at 55 ° C for 2 h.

After evaporation of the solvents under reduced pressure, the residue is taken up in water and concentrated hydrochloric acid, the precipitate is collected by filtration and dried under reduced pressure.

1.89 g of 3-bromo-4 ~ [[(cyclopropyl) (methyl) _ amino] sulfonyl] benzoic acid are obtained.

1.2. Threo- (1-methylpiperidin-2-yl) phenylmethanamine.

1.2.1. 1,1-Dimethylethyl threo [hydroxy (phenyl) methyl] piperidine-1-carboxylate. 2.0 g (6.9 mmol) of 2-benzoylpiperidine-1, 1-dimethylethylcarboxylate in 30 ml of anhydrous diethyl ether are introduced into a 250 ml flask under an argon atmosphere. the solution is cooled to -78 ° C, 20.7 ml (20.7 mmol) of a 1M solution of lithium tri-sec-butylborohydride in diethyl ether are added dropwise. for 3 h.

The mixture is hydrolyzed with 16 ml of water and 16 ml of a 35% aqueous solution of hydrogen peroxide, and the mixture is allowed to return to room temperature with stirring for 2 h. It is diluted with water and ethyl acetate, the aqueous phase is separated, and extracted with ethyl acetate. After washing the combined organic phases, drying over sodium sulfate and evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a mixture of ethyl acetate and cyclohexane. 2.0 g of oily product are obtained.

1.2.2. Threo (1-methylpiperidin-2-yl) phenylmethanol. 2.96 g (78.1 mmol) of aluminum and lithium double hydride in 50 ml of anhydrous tetrahydrofuran are introduced into a 200 ml two-necked flask under nitrogen, the mixture is heated to reflux, 4.49 g (15.4 mmol) of a solution of threo [hydroxy (phenyl) methyl] piperidine are added 1, 1-Dimethylethyl 1-carboxylate in 35 ml of tetrahydrofuran and the mixture is maintained at reflux for 3.5 h. ^'

It is cooled, hydrolyzed slowly with a 0.1M solution of potassium and sodium double tartrate and the mixture is left to stir overnight. It is filtered and the precipitate is rinsed with tetrahydrofuran, then the filtrate is concentrated under reduced pressure. 2.95 g of a colorless oily product are obtained.

1.2.3. Threo- (1-methylpiperidin-2-yl) phenylmethanamine. 0.8 g (3.65 mmol) of threo (1-methylpiperidin-2-yl) phenylmethanol and 0.48 ml (3.65 mmol) are introduced into a 100 ml flask under an argon atmosphere. triethylamine in 20 ml of anhydrous dichloromethane, the mixture is cooled to 0 ° C., 0.28 ml (3.63 mmol) of methanesulfonyl chloride is added and the mixture is allowed to slowly return to room temperature for 2 h and concentrated under reduced pressure.

In an autoclave equipped with magnetic stirring and cooled to -50 ° C., liquefied ammonia is introduced and the methanesulfonate previously prepared in solution in 10 ml of absolute ethanol is added, the autoclave is closed and the stirring for 48 h.

The mixture is transferred to a flask, concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.3 g of oily compound is obtained, which is used as it is in the next step.

1.3. Threo-3-bromo-4- [[(cyclopropyl) _ hydrochloride

(methyl) amino] sulfonyl] -N- [(1-methylpiperidin-2-yl) _ phenylmethyl] benzamide 1: 1.

To a solution of 610 mg (1.82 mmol) of 3-bromo-4- [[(cyclopropyl) (methyl) amino] sulfonyl] benzoic acid, 350 mg (1.82 mmol) of hydrochloride of 1- ( dimethylamino_ propyl) -3-hylcarbodiimide, 250 mg (1.82 mmol) of hydroxybenzotriazole in 20 ml of dichloromethane stirred for 10 min, a solution of 372 mg (1.82 mmol) of threo (1-methylpiperidin-2-yl) phenylmethanamine in 5 ml of dichloromethane is added, and the mixture is stirred overnight.

It is hydrolyzed with water and IN sodium hydroxide, and it is extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. An oil is obtained which corresponds to the coupling product. The hydrochloride is prepared by dissolving it in a few ml of propan-2-ol and adding 10 ml of a 0.1N solution of hydrochloric acid in propan-2-ol, then concentrating the mixture under reduced pressure. After trituration with isopropyl ether, 219 mg of threo-3-bromo-4- [[(cyclopropyl) (methyl) amino] sulfonyl]] -N- [(1-methylpiperidin-2-yl) phenylmethyl hydrochloride are finally isolated. ] benzamide 1: 1. Melting point: 163-165 ° C.

Example 2 (Compound No. 29).

Threo-3-bromo-4- [[[(ethylamino) carbonyl] amino] sulfonyl] -N- [(1-methylpiperidin-2-yl) hénylméthyl] benzamide.

2.1. 3-Bromo-4- [[[(ethylamino) carbonyl] amino] _ sulfonyl] benzoic acid.

In a Schlenk tube, 1 g (3.4 mmol) of methyl 4- (aminosulfonyl) -3-bromobenzoate is placed in solution.

15 ml of tetrahydrofuran, in the presence of 0.45 g (3.4 mmol) of potassium carbonate and 0.27 ml (3.4 mmol) of ethyl isocyanate, and the mixture is heated to reflux for one night. The solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of cyclohexane and ethyl acetate, then ethyl acetate and methanol.

We obtain 0.9 g of 3-bromo-4- [[[(ethylamino) carbonyl] acid _ amino] suifonyl] benzoic as a white solid.

2.2. Threo-3-bromo-4- [[[(ethylamino) carbonyl] amino] sul_ fonyl] -N- [(1-methylpiperidin-2-yl) phenylmethyl] _ benzamide.

In the same way as in Example 1.3, starting from 640 mg (1.82 mmol) of 3-bromo-4- [[[(ethylamino) carbonyl] amino] sulfonyl] benzoic acid, 350 mg ( 1.82 mmol) of 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 250 mg (1.82 mmol) of hydroxybenzotriazole and 371 mg (1.82 mmol) of threo- (1-methylpiperidin-2- yl) phenyl_methanamine, 482 mg of a solid corresponding to the coupling product are obtained. Melting point: 215-220 ° C.

Example 3 (Compound No. 134).

2-chloro-6-fluoro-3-methyl-ΛJ- hydrochloride [[1S) - [(2S) -

[(1-methylpiperidin-2-yl) phenylmethyl] benzamide 1: 1.

3.1. (2S) -2-benzoylpiperidine-l-carboxylate of 1,1-dimethylethyl. 11.8 g (43.3 mmol) of (2S) -2- (IV-methoxy-W-methylcarbamoyl) piperidine-1-carboxylate of 1.1 are introduced into a 500 ml flask under a nitrogen atmosphere -dimethylethyl in 100 ml of anhydrous diethyl ether, the medium is cooled to -23 ° C, 21.6 ml (43.2 mmol) of a 1.8M solution of phenyllithium in a mixture are added dropwise 70/30 of cyclohexane and diethyl ether and the mixture is stirred at room temperature for 3 h. After hydrolysis with a saturated aqueous solution of sodium chloride, the aqueous phase is separated and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of ethyl acetate and cyclohexane. 4.55 g of solid product are obtained. Melting point: 123-125 ° C. [] _D ²⁵ = -25.4 ° (c = 2.22; CH ₂ C1 ₂ ) ee = 97.2%. 3.2. (1S) -2- [(2S) -hydroxy (phenyl) methyl] piperidine-1-1-dimethylethylcarboxylate. 4.68 g (16.2 mmol) of (S) -2-benzoylpiperidine-1-1, 1-dimethylethylcarboxylate in 170 ml of anhydrous tetrahydrofuran are introduced into a 500 ml flask under a nitrogen atmosphere. the solution is cooled to -78 ° C., 48.5 ml (48.5 mmol) of a 1M solution of L-Selectride® (tri-sec-lithium butylborohydride) in tetrahydrofuran is added dropwise and the mixture is stirred at room temperature for 5 h.

It is hydrolysed cold slowly with 34 ml of water and 34 ml of a 35% aqueous solution of hydrogen peroxide, and the mixture is allowed to return to room temperature with stirring for 2 h. It is diluted with water and ethyl acetate, the aqueous phase is separated, it is extracted with ethyl acetate. After washing the combined organic phases, drying, drying over sodium sulfate, filtration and evaporation, the residue is purified by chromatography on a column of silica gel, eluting with a mixture of ethyl acetate and cyclohexane. 4.49 g of a pale yellow oil are obtained. [] ²⁵ = + 63.75 ° (c = 0.8; CH ₂ C1 ₂ ) ee = 97.8%.

5 3.3. (1S) - [(2 S) - (1-methylpiperidin-2-yl] phenylmethanol 2.96 g (78.1 mmol) of double hydride are introduced into a 200 ml two-necked flask aluminum and lithium in 50 ml of anhydrous tetrahydrofuran, the mixture is heated to reflux, 4.49 g (15.4 mmol) _Q - of a solution of (1S) -2- [(2 S) are added -hydroxy (phenyl) methyl] _ 1,1-dimethylethyl piperidine-1-carboxylate in 35 ml of tetrahydrofuran and the mixture is maintained at reflux for 3.5 h. It is cooled, hydrolysed slowly with a solution 5 0.1M potassium and sodium double tartrate and the mixture is left to stir overnight, filtered and the precipitate is rinsed with tetrahydrofuran, then the filtrate is concentrated under reduced pressure. 2.95 g of a colorless oily product are obtained.

3.4. (1S) - [(2S) - (1-methylpiperidin-2-yl)] phenyl_ methanamine. 2.95 g (14.4 mmol) of (1S) - [(2S) - (l-methyl_ piperidin-2-yl)] phenylmethanol and 2 ml are introduced into a 250 ml flask under a nitrogen atmosphere. (14.4 mmol) of triethylamine in 70 ml of anhydrous dichloromethane, the medium is cooled to 0 ° C., 1.1 ml (14.4 mmol) of methane sulfonyl chloride are added, the mixture is allowed to slowly return to temperature ambient for 2 h and concentrated under reduced pressure.

In an autoclave fitted with a magnetic stirrer and cooled to -50 ° C., liquefied ammonia is introduced, a solution of the crude methanesulfonate previously prepared in solution in 30 ml of absolute ethanol is added, the autoclave is closed and maintains agitation for 48 h.

The mixture is transferred to a flask and the amine is isolated in the form of an oily product which is used as it is in the next step.

3.5. 2-chloro-6-fluoro-3-methyl- hydrochloride

N- [(1S) - [[2 S) [(1-ethylpiperidin-2-yl)] phenyl_methyl] benzamide 1: 1. 0.48 g (2 mmol) of

(1S) - [(2 S) - (1-methylpiperidin-2-yl)] phenylmethanamine dissolved in 10 ml of dichloromethane, 0.3 ml of triethylamine and 0.49 g of 2-chloro-6 acid chloride -fluoro-3-methylbenzoic acid, and the mixture is stirred for 12 h.

After hydrolysis with water, the mixture is extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol.

700 mg of oily product are obtained, corresponding to the coupling product. The hydrochloride is prepared by dissolving it in a few ml of propan-2-ol, adding 20 ml of a 0.1 IN solution of hydrochloric acid in propan-2-ol and concentrating the mixture under reduced pressure.

After trituration with isopropyl ether, 700 mg of hydrochloride are finally isolated. Melting point: 164-166 ° C. [α] _D ²⁵ = + 51.5 ° (c = 0.506; CH ₃ OH).

Example 4 (Compound No. 42). 0 Threo-4-chloro-3- [(dimethylamino) sulfonyl] - IV- [(piperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1.

4.1. 4-chloro-3- [(dimethylamino) suifonyl] -

N- [phenyl (pyridin-2-yl) methyl] benzamide. _5 To a solution of 2.9 g of 4-chloro-3- [(dimethyl_ amino) sulfonyl] benzoic acid in 20 ml of dichloromethane is added 1/47 g (10.85 mmol) of hydroxybenzotriazole and 2.1 g

(10.85 mmol) hydrochloride

1- (dimethylaminopropyl) -3-ethylcarbodiimide. The mixture is left for 15 min at room temperature, then added

2 g (10.85 mmol) of phenyl (pyridin-2-yl) methanamine and the mixture is stirred at room temperature for 6 h.

The mixture is hydrolyzed with IN sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure.

3 g of compound are obtained which is used as it is in the next step.

0 4.2. Threo-4-chloro-3- [(dimethylamino) _ sulfonyl] -N- [(piperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1. 1 g (2.32 mmol) of 4-chloro-3- [(dimethylamino) sulfonyl] -N- [phenyl (pyridin-2-yl) methyl]) benzamide in solution in 20 ml is placed in a Parr flask of ^'methanol and 20 ml of hydrochloric acid in the presence of 0.05 g of platinum oxide, and hydrogenation is carried out during 6 h. The catalyst is filtered off, the filtrate is concentrated to dryness, the residue is taken up with dichloromethane and treat the solution with ammonia. The organic phase is separated, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 5. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ^' methanol.

2 fractions are obtained: the least polar (320 mg) and the most polar (325 mg) corresponding to the threo diastereoisomer. 0 The hydrochloride is prepared by dissolving it in a few ml of propan-2-ol, adding 10 ml of a 0.1N solution of hydrochloric acid in propan-2-ol and concentrating the mixture under reduced pressure.

After trituration with isopropyl ether, 230 mg of hydrochloride are finally isolated.

Melting point: 232-236 ° C.

Example 5 (Compound No. 59).

Threo-4-chloro-3-ethylsulfonyl-ΛJ- 0 hydrochloride [(1-methylpiperidin-2-yl) phenylmethyl] benzamide 1: 1.

5.1. 4-chloro-3- (ethylsulfonyl) benzoic acid.

In a three-necked 250 ml flask, under a nitrogen atmosphere, 2.52 g (40 mmol) of copper are placed in 12 ml of 5 N, anhydrous ΔJ-dimethylformamide, the suspension is cooled to 0 ° C. and added, dropwise, a solution of 2.52 ml (27 mmol) of ethanesulfonyl chloride in 16 ml of N, N-dimethylformamide while maintaining the temperature at 0 ° C, and the mixture is stirred at this temperature for 1 h. 0 is added, still at 0 ° C, dropwise, a solution of 5 g (18 mmol) o ^f 4-chloro-3-iodobenzoic acid (J. Chem. Soc. (1925) 25) in 56 ml of N, N-dimethylformamide anhydrous, allowed to return to room temperature and the mixture is heated to 50 ° C overnight. The solvent is evaporated off under reduced pressure, and the residue is taken up with hydrochloric acid. A precipitate is formed which is collected by filtration and which is dried under reduced pressure. It is purified by chromatography on silica gel, eluting with a mixture of dichloromethane and methanol.

4.4 g of solid are obtained.

Melting point: 208-210 ° C.

5.2. Threo- (1-methylpiperidin-2-yl) phenylmethanamine.

5.2.1. 2- (Benzyloxyiminophenyl_methyl) -1-methylpyridinium trifluoromethanesulfonate.

To a suspension of 35 g (120 mmol) of phenyl (pyridin-2-yl) methanone O-benzyloxime in 200 ml of diethyl ether is added dropwise and at 0 ° C, 17.4 ml (120 mmol) of methyl trifluoromethane sulfonate and the mixture is stirred at room temperature for 3 h.

The precipitate formed is collected by filtration and dried under reduced pressure.

49 g of product are obtained, which product is used as it is in the next step.

5.2.2. Threo (1-methylpiperidin-2-yl) ethanedioate _ phenylmethanamine 2: 1.

14.8 g (31.89 mmol) of 2- (benzyloxyiminophenyl methyl) -1-methylpyridinium and 0.74 g of platinum oxide in 50 ml of ethanol and 50 ml are placed in a Parr flask 14.8 g (31.89 mmol) hydrochloric acid IN and hydrogenation is carried out for 5 h.

The ethanol is evaporated off under reduced pressure, the residue is extracted with dichloromethane, the aqueous phase is separated, an ammonia solution is added thereto and it is extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulfate, filtration and evaporation of the solvent under reduced pressure, 6.7 g of oily product are obtained comprising 10% of erythro diastereoisomer. The ethanedioate is prepared by dissolving the 6.7 g of base in methanol and adding 2 equivalents of oxalic acid dissolved in the minimum amount of methanol, and the salt obtained is purified by recrystallization from a mixture of methanol and diethyl ether.

Finally isolated 4.7 g of ethanedioate from diastero [(1-methylpiperidin-2-yl) phenylmethyl] isomer threo pure. Melting point: 156-159 ° C.

5.3. Threo-4-chloro-3-ethylsulfonyl-W- hydrochloride

[(1-methylpiperidin-2-yl) phenylmethyl] benzamide 1: 1. As described in Example 1.3, starting from 550 mg (1.82 mmol) of 4-chloro-3- (ethylsulfonyl) benzoic acid, from 350 mg (1.82 mmol) of 1- hydrochloride (dimethylaminopropyl) -3-ethylcarbodiimide, 250 mg (1.82 mmol) of hydroxybenzotriazole and 371 mg (1.82 mmol) of threo (1-methylpiperidin-2-yl) phenylmethanamine, an oil corresponding to coupling product. The hydrochloride is prepared by dissolving it in a few ml of propan-2-ol and adding 10 ml of a 0.1N solution of hydrochloric acid in propan-2-ol and concentrating the mixture under reduced pressure. After trituration with isopropyl ether, 413 mg of hydrochloride are finally isolated. Melting point: 231-233 ° C.

Example 6 (Compound No. 117).

Threo-4-chloro-3- (thien-2-yl) -N- hydrochloride

[(1-methylpiperidin-2-yl) phenylmethyl] benzamide 1: 1.

6.1. 4-chloro-3- (thien-2-yl) benzoic acid. 4 g (13.5 mmol) of methyl 4-chloro-3-iodobenzoate, 3.73 g (27 mmol) of potassium carbonate, 1.9 g (14.8 mmol) are introduced into a 100 ml flask 2-thiopheneboronic acid and 1.24 g (1.3 mmol) of tris (dibenzylideneacetone) dipalladium in 40 ml of • W, ÎV-dimethylformamide, and the mixture is heated at 70 ° C for 24 h.

The solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of cyclohexane and ethyl acetate. 3 g of a transparent oil are obtained which is saponified under conventional conditions to obtain the acid in the form of a white solid. Melting point: 200-202 ° C. 6.2. Threo-4-chloro-3- (thien-2-yl) hydrochloride -

N- [(1-methylpiperidin-2-yl) phenylmethyl] benzamide 1: 1. As described in Example 1.3, starting with 412 mg (1.82 mmol) of 4-chloro-3- (thien-2-yl) benzoic acid, 350 mg (1.82 mmol) of 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 250 mg (1.82 mmol) of hydroxybenzotriazole and 371 mg (1.82 mmol) of threo- (1-methylpiperidin-2-yl) phenylmethanamine, an oil corresponding to the coupling product.

The hydrochloride is prepared by dissolving it in a few ml of propan-2-ol and _. by adding 10 ml of a 0.1N solution of hydrochloric acid in propan-2-ol and concentrating the mixture under reduced pressure. After trituration with isopropyl ether, 413 mg of hydrochloride are finally isolated. Melting point: 156-158 ° C.

Example 7 (Compound No. 67). Threo-2-chloro-5- (methoxycarbonyl) hydrochloride -

N- [(1-methylpiperidin-2-yl) phenylmethyl] benzamide 1: 1.

7.1. 2-chloro-5- (methoxycarbonyl) benzoic acid. 4 g (12.3 mmol) of phenylmethyl 5-bromo-2-chlorobenzoate, 5.74 g (5.47 mmol) of triethylamine, 0.52 g (0.734 mmol) of chloride are placed in a 250 ml flask of palladiumbis (triphenylphosphine) in 56 ml of methanol and 28 ml of N, IV-dimethylformamide. The flask is purged with carbon monoxide, it is placed under a carbon monoxide atmosphere and it is heated at 60 ° C. for 24 h.

The solvents are evaporated off under reduced pressure, the residue is taken up in water and dichloromethane, the organic phase is separated, dried over sodium sulfate, filtered, evaporated under reduced pressure and the residue is purified. residue by chromatography on a column of silica gel, eluting with a mixture of cyclohexane and ethyl acetate. 1.5 g of benzyl ester of 2-chloro-5- (methoxycarbonyl) benzoic acid are thus isolated. This mixture is placed in a Parr flask with 150 ml of methanol, a tip of a platinum oxide spatula, and hydrogenation is carried out under pressure for 4 h.

The catalyst is separated by filtration, rinsing with dichloromethane, the filtrate is concentrated under reduced pressure, and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.48 g of acid is obtained in the form of a white solid.

7.2. Threo-2-chloro-5- (methoxycarbonyl) - N- [(1-methylpiperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1. As described in Example 1.3, starting from 400 mg (1.82 mmol) of 2-chloro-5- (methoxycarbonyl) benzoic acid, from 350 mg (1.82 mmol) of hydrochloride

1- (dimethylaminopropyl) -3-ethylcarbodiimide, 250 mg (1.82 mmol) of hydroxybenzotriazole and 371 mg (1.82 mmol) of threo- (1-methylpiperidin-2-yl) phenylmethanamine, an oil is obtained corresponding to the coupling product. The hydrochloride is prepared by dissolving it in a few ml of propan-2-ol and adding 10 ml of a 0.1N solution of hydrochloric acid in propan-2-ol and concentrating the mixture under reduced pressure. After trituration with isopropyl ether, 320 mg of hydrochloride are finally isolated.

Melting point: 228-230 ° C.

Example 8 (Compound No. 70).

Threo-4- (aminocarbonyl) -3,5-dichloro-N- [(1-methylpiperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1.

8.1. 4- (aminocarbonyl) -3,5-dichlorobenzoic acid. 0.79 g (2.377 mmol) of methyl 3, 5-dichloro-4-iodobenzoate are placed in a Schlenk tube [Chem Ber. (1941), 74, 807-821), 0.17 g (2.61 mmol) of potassium cyanide,

0.045 g (0.237 mmol) of copper iodide and 0.137 g (0.119 mmol) of palladiumtetrakistriphenylphosphine in 5 ml of degassed tetrahydrofuran, and the mixture is heated at 80 ° C for 4 h. The solvent is evaporated off under reduced pressure, the residue is taken up in water and dichloromethane, the organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. 0.47 g of methyl 4-cyano-3,5-dichlorobenzoate is obtained in the form of a beige solid.

1.1 g (4.8 mmol) of methyl 4-cyano-3, 5-dichlorobenzoate in 12 ml of ethanol and 1.85 ml of concentrated sodium hydroxide are placed in a 100 ml flask and the mixture is heated at reflux for 5 h.

The solvent is evaporated off under reduced pressure, the residue is taken up with water and concentrated hydrochloric acid, the precipitate is collected by filtration and dried under reduced pressure. 1 g of product is obtained in the form of a beige solid.

8.2. Threo-4- (aminocarbonyl) -3,5-dichloro-N- [(1-methylpiperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1. As described in Example 1.3, starting from

393 mg (1.82 mmol) 4- (aminocarbonyl) -3.5-dichloro_ benzoic acid, 350 mg (1.82 mmol) 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 250 mg ( 1.82 mmol) of hydroxybenzotriazole and 371 mg (1.82 mmol) of threo (1-methylpiperidin-2-yl) phenylmethanamine, an oil corresponding to the coupling product is obtained. The hydrochloride is prepared by dissolving it in a few ml of propan-2-ol and adding 10 ml of a 0.1N solution of hydrochloric acid in propan-2-ol and concentrating the mixture under reduced pressure. After trituration with isopropyl ether, 86 mg of hydrochloride are finally isolated. Melting point: 297-299 ° C. Example 9 (Compound No. 73).

Threo-3, 5-dichloro-4- (morpholin-4-yl_ carbonyl) -N- [(1-methylpiperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1.

9.1. 3, 5-dichloro-4- (morpholin-4-ylcarbonyl) _ benzoic acid. In a three-necked flask under a nitrogen atmosphere, 940 mg (8.37 mmol) of potassium tert-butoxide is placed in 15 ml of anhydrous tetrahydrofuran at -76 ° C, the mixture is stirred for 30 min, added dropwise drop, 400 mg (2.09 mmol) of 3,5-dichlorobenzoic acid in solution in 5 ml of anhydrous tetrahydrofuran, 5.3 ml (8.37 mmol) of n-butyllithium 1 are added dropwise, 6M in hexane, and stirring is continued at -76 ° C for 1 h.

0.55 ml (4.7 mmol) of morpholinylcarbonyl chloride is added dropwise, the temperature is allowed to return to ambient and the stirring is continued overnight. The mixture is hydrolyzed with a solution of ammonium chloride and 1N hydrochloric acid and extracted with diethyl ether. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol.

428 mg of crude acid are obtained, which is used as it is in the next step.

9.2. Threo-3, 5-dichloro-4- (morpholin-4-yl_ carbonyl) -N- [(1-methylpiperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1. To a solution of 428 mg (1.4 mmol) of 3,5-dichloro-4- (morpholin-4-ylcarbonyl) benzoic acid, of 270 mg (1.4 mmol) of 1- (dimethylaminopropyl) hydrochloride - 3-ethyl_carbodiimide, 190 mg (1.4 mmol) of hydroxybenzotriazole in 20 ml of dichloromethane stirred for 10 min, a solution of 290 mg (1.4 mmol) of threo (1-methylpiperidin-2) is added yl) phenylmethanamine in 5 ml of dichloromethane, and the mixture is stirred overnight. The mixture is hydrolyzed with water and IN sodium hydroxide, it is extracted with dichloromethane, the organic phase is separated, it is washed with water, it is dried over sodium sulfate, it is filtered and it is concentrated. under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 370 mg of an oily product corresponding to the coupling product are obtained. The hydrochloride is prepared by dissolving it in a few ml of propan-2-ol and adding 10 ml of a 0.1N solution of hydrochloric acid in propan-2-ol and concentrating the mixture under reduced pressure. After trituration with isopropyl ether, 422 mg of hydrochloride are finally isolated. Melting point: 210-220 ° C.

Example 10 (Compound No. 152).

2-chloro-6-fluoro-3-methyl-1V- [(S) -phenyl [(2 S) -piperidin-2-yl] methyl] benzamide.

10.1. (S) -phenyl [(2S) -piperidin-2-yl] methanol. A solution of 2.0 g (6.9 mmol) of (1S) -2- [(2 S) -hydroxy (phenyl) methyl] piperidine- 1-carboxylate of 1, 1- is placed in a 250 ml flask. dimethylethyl (obtained according to the procedure described in step 1.2.1 in Example 1) in 40 ml of methanol, an aqueous solution of potassium hydroxide prepared from 2 g of potassium hydroxide pellets and 20 ml of water is added , and the mixture is heated at reflux for 2 h. It is cooled, the solvent is evaporated off under reduced pressure, water is added and the mixture is extracted several times with dichloromethane. After washing the combined organic phases, drying over magnesium sulfate, filtration and evaporation of the solvent under reduced pressure, 1 g of white solid is obtained. Melting point: 148-150 ° C. [α] _D ²⁵ = + 38.4 ° (c = 0.98; CHC1 ₃ ).

10.2. (S) - [(2S) -1-allylpiperidin-2-yl] (phenyl) methanol. In a 500 ml flask fitted with magnetic stirring and 2.6 g (13.58 mmol) of (S) -phenyl [(2 S) -piperidin-2-yl] methanol and 100 ml of acetonitrile are introduced from a circulation of argon. 2.8 g of potassium carbonate and 1.4 ml (1.2 eq.) Of allyl bromide are then added to the suspension obtained, and stirring is continued at 25 ° C. for 6 h. 100 ml of water and 100 ml of ethyl acetate are added, the aqueous phase is separated, it is extracted three times with 50 ml of ethyl acetate, the combined organic phases are washed with 100 ml of water then 100 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. 3 g of yellow oil are obtained which are purified by chromatography on a silica gel column (120 g, elution gradient from 2% to 10% of methanol in dichloromethane in 30 min).

2.7 g of product are isolated in the form of a yellow oil.

10.3. (S) - [(2 S) -1-allylpiperidin-2-yl] (phenyl) methanamine. 2.7 g (11.67 mmol) of (S) - [(2S) -1-allylpiperidin-2-yl] (phenyl) methanol and 1 are introduced into a 250 ml flask under a nitrogen atmosphere. 62 ml of triethylamine in 80 ml of anhydrous dichloromethane, the medium is cooled to 0 ° C., 0.9 ml of methanesulfonyl chloride is added, the mixture is allowed to slowly return to room temperature for 2 h and concentrated under reduced pressure .

In an autoclave fitted with magnetic stirring and cooled to -50 ° C., liquefied ammonia is introduced, a solution of crude methanesulfonate previously prepared in solution in 30 ml of absolute ethanol is added, the autoclave is closed and stirring is continued for 48 h.

The mixture is transferred to a flask, it is concentrated under reduced pressure, water and dichloromethane are added to the residue, the aqueous phase is separated, it is extracted three times with dichloromethane, the combined organic phases are washed with water then with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. 1.5 g of amine are isolated in the form of an oily product which is used as it is in the next step. 10.4. N- [(S) - [(2S) -1-allylpiperidin-2-yl] (phenyl) methyl] -2-chloro-6-fluoro-3-methylbenzamide.

0.13 g (0.68 mmol) of 2-chloro-6-fluoro-3-methylbenzoic acid, 0.13 g (0.68 mmol) are successively introduced into 5 ml of dichloromethane in a 10 ml flask ) of 1- [3- (dimethylamino) propyl] -3-éthylcarbo_ diimide and 0.085 g of dimethylaminopyridine and stirred at room temperature for 30 ^m in. 0 _Λ 18 g of (S) - [(2S) -l-allylpiperidin-2-yl] (phenyl) _ methanamine are added in solution in 2 ml of dichloromethane and stirring is continued for 24 h.

5 ml of water are added, filtered on a Whatman® cartridge (PTFE) and purified directly on a cartridge of 10 g of silica, eluting with a 98/2 to 90/10 mixture of dichloromethane and methanol.

0.12 g of base is isolated in the form of a colorless oil.

10.5. 2-chloro-6-fluoro-3-methyl-N- [(S) -phenyl [(2S) -pipéri_ din-2-yl] methyl] benzamide. 0.14 g (3 eq.) Of 1,3-dimethylbarbituric acid dissolved in 3 ml of anhydrous dichloromethane is introduced into a 10 ml flask fitted with a magnetic stirrer, under an argon atmosphere. 0.004 g (0.01 eq.) of tetrakis (triphenylphosphine) palladium (0) is added and the mixture is heated to 30 ° C.

A solution of 0.12 g (0.3 mmol) of IV- [(S) - [(2S) -l-allylpiperidin-2-yl] (phenyl) methyl] - 2-chloro-6-fluoro- is added. 3-methylbenzamide in 1 ml of dichloromethane and the mixture is allowed to stir for 24 h.

5 ml of a saturated aqueous solution of sodium hydrogen sulphate are added, filter on Whatman® cartridge (PTFE filter) and purify directly on cartridge of 10 g of silica, eluting with dichloromethane containing 0.4% of 33% ammonia.

0.1 g of base is isolated and salified with a 0.1N solution of hydrochloric acid in propan-2-ol. 0.05 g of hydrochloride is obtained which is purified in reverse phase on an XTerra® MS C18 column (pH 10). 0.020 g of base is finally isolated in the form of white crystals.

Melting point: 152-154 ° C.

The following table illustrates the chemical structures of some compounds of the invention.

In the columns "R ₂ " and "R ₃ ", "pyrrolid" denotes a pyrrolidin-1-yl group. In the column "R ₃ ", "C ₆ H ₅ " denotes a phenyl group, "C ₆ H ₄ " denotes a monosubstituted phenyl group and "C ₆ H ₃ " denotes a disubstituted phenyl group, the substituents and their positions being indicated , "cC ₃ H ₅ " denotes a cyclopropyl group, "cC ₅ H ₇ " denotes a cyclopentyl group, "morphol" denotes a morpholin-1-yl group, "piperid" denotes a piperidin-1-yl group.

In the "Salt" column, "-" denotes a compound in the basic state, "HCl" denotes a hydrochloride and "tfa" denotes a trifluoroacetate. In the "stereo" column, "S, S; R, R" denotes the mixture of diastereoisomers lS, 2S, lR, 2R _r S, S denotes the isomer IS, 2S and R, R denotes the isomer lR, 2 .R.

The rotary power of compound N ° 134 is [] _L ²⁰ = + 51.5 ° (c = 0.806; CH ₃ OH), the rotary power of compound N ° 135 is [u] £ ⁰ = -9, ll ° ( c = 0.515; CH ₃ 0H) ^' and the rotary power of compound No. 144 is [α] _D ²⁰ = -79.9 ° (c = 0.97; CH ₃ OH).

X _ ι R, 3 Stereo Salt F (° C) H CH ₃ 4 -Cl 3-S0 ₂ N (CH ₂ CH ₂ OCH ₃ ) ₂ S, SR, R HCl M + H = 539 H CH ₃ 4 -Cl 3-S0 ₂ NHCH ₃ S, SR, R 69-70 2-F CH ₃ 4 -Cl 3-S0 ₂ NH ₂ S, SR, R 269-271 H (CH ₂ ) ₂ CH ₃ 4 -Cl 3-S0 ₂ N (CH ₃ ) ₂ S, SR, R HCl 243-244.5 H CH ₃ 4 -Cl 3-S0 ₂ NHCH ₂ cC ₃ H ₅ S, SR, R HCl 200-202 H CH ₃ 4- -Cl 3-S0 ₂ - [2,5- (CH ₃ ) ₂ -pyrrolid] S _r SR, R HCl 140-148 H CH ₃ 4- -Cl 3-S0 ₂ -morphol S, SR, R 156-160 H CH ₃ 4- -Cl 3-S0 ₂ NHCONHCH ₂ CH ₃ S, SR, R HCl 210-214 H CH ₃ 4- -Cl 3-S0 ₂ N (CH ₃ ) CH ₂ CH ₂ N (CH ₃ ) ₂ S, SR, R 2HC1 M + H = 508 H CH ₃ 4- -Cl 3-S0 ₂ N (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ S, SR, R HCl 112-120 H CH ₃ 2- -Cl 5 -S0 ₂ N (CH ₃ ) CH (CH ₃ ) ₂ S, SR, R HCl 175-177 H CH ₃ 2- -Cl 5-S0 ₂ N (CH ₃ ) (cC ₃ H ₅ ) S, SR, R HCl 220-222 H CH ₃ 3- -Br 4-S0 ₂ NH (cC ₃ H ₅ ) S, SR, R HCl 197-199 H CH ₃ 3- -Br 4-S0 ₂ N (CH ₃ ) (cC ₃ H ₅ ) S, SR, R HCl 163-165 H CH ₃ 2,4 -Cl ₂ 5-S0 ₂ NH ₂ S, SR, R HCl 280-282 H CH ₃ H 3-S0 ₂ NH ₂ S _r SR, R 75-78 H CH ₃ 4- -Cl 3-S0 ₂ NH ₂ S, s R, R 138-140 H CH ₃ 3- -Br 4-S 0 ₂ NHCONHCH ₂ CH ₃ s, s R, R 215-220 H CH ₃ 3- -Cl 4-S0 ₂ -piperid s, s R, R HCl 250-252

N ° XR! R, R, Stereo Salt F (° C) H CH ₃ 4-Cl 3-CH ₃ 137.5-13? H CH ₃ 2-Cl 5-CH ₃ 217

90 H CH ₃ 2-Cl, 6-F 5-CH ₃ 149 91 H CH ₃ 4-Cl 2-CH ₃ HCl 228 92 H CH ₃ 3-F 2-CH ₃ HCl 52 93 H CH ₃ 3-Cl 2 -CH ₃ 250 94 H CH ₃ 5-C1 2-CH ₃ HCl 263-264 H CH ₃ H 2,3- (CH ₃ ) ₂ HCl 263 H CH ₃ 2-Cl 3-CH ₃ HCl 365 H CH ₃ 5 -F 2-CH ₃ HCl 260 H CH ₃ H 2-CH ₃ HCl 252 H CH ₃ H 2.5- (CH ₃ ) ₂ HCl 251 H CH ₃ H 2.4- (CH ₃ ) ₂ HCl 246 H CH ₃ 4-Br 2- (CH ₂ ) ₂ CH ₃ HCl 172-174 H CH ₃ 2-Cl, 6-F 3-CH ₃ HCl 149-150 H CH ₃ 3,5-Cl ₂ 4-C ₆ H ₅ HCl 163-165 H CH ₃ 4-Cl 3- (4-FC ₆ H ₄ ) tfa 176 H CH ₃ 4-Cl 3- (thianthren-1-yl tfa 146.5 H CH, 4-Cl 3 ~ C ₆ H ₅ tfa 147

N 'X R! R, Ra Stereo Salt F (° C)

H CH ₃ 4 -Cl 3- [3-CH (CH ₃ ) ₂ -C ₆ H ₄ ] S, SR, R HCl 221

H CH ₃ 4 -Cl 3- (3-OCH ₃ -C ₆ H ₄ ) S _f SR, R HCl 182

H CH ₃ 4- -Cl 3- (4-CN-C ₆ H ₄ ) S _f SR _f R HCl 216

H CH ₃ 4- -Cl 3- (2,3-Cl ₂ -C ₆ H ₃ ) S _f S; R _f R HCl 294

H CH ₃ 4- -Cl 3- (3,4-Cl ₂ -C ₆ H ₃ ) S, S; R _f R HCl 239

H CH ₃ 4- -Cl 3- (4-C ₆ H ₅ -C ₆ H ₄ ) S, S; R _f R HCl 235

H CH ₃ 4- -Cl 3- (3-Cl, 6-OCH ₃ -C ₆ H ₃ ) S _f S; R _f R HCl 179

H CH ₃ 4- -Cl 3- (2,4-Cl ₂ -C ₆ H ₃ ) S, S; R, R HCl 292

H CH ₃ 2-Cl, 6 -F 3-CH ₃ lS _r 2S HCl 164-166

H CH ₃ 4- -Cl 3-S0 ₂ NH ₂ lR _r 2R HCl 281-287

H CH ₃ 4- -Cl 3-S0 ₂ N (CH ₃ ) ₂ 1R, 2R tfa 85-86

H CH ₃ 4- -Cl 3-S0 ₂ N (CH ₃ ) ₂ 1S, 2S HCl 140-150

H CH ₃ 4- -Cl 3-S0 ₂ NH ₂ ! S _r 2S 135-137

H CH ₃ 3- -Cl -C0 ₂ CH ₃ S, SR _f R HCl 170-171

H CH ₃ H 3-S0 ₂ CH ₃ S _f SR _f R 92-95

H CH ₃ H 3- [3,4- (OCH ₃ ) ₂ -C ₆ H ₃ ] S, SR _f R HCl 233

H CH ₃ 2- -NH ₂ , 5- -Cl 3-CH ₃ S, S; R _f R HCl 172-173

H CH ₃ 2- -NH ₂ , 3- -Cl 6-CH ₃ S _f S; _f R HCl 301-302

H CH ₃ 2- -NH ₂ r 3- -Cl 6-CH, 1R, 2R HCl 168-169

The compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.

Study of glycine transport in SK-N-MC cells expressing the native glytl human transporter. The uptake of [ ¹⁴ C] glycine is studied in SK-N-MC cells (human neuroepithelial cells) expressing the native glytl human transporter by measuring the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured in a monolayer for 48 h in plates pretreated with 0.02% fibronectin. On the day of the experiment, the culture medium is eliminated and the cells are washed with a Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4. After 10 min of preincubation at 37 ° C in the presence of either buffer (control batch), or of test compound at different concentrations or 10 mM glycine (determination of non-specific capture), 10 μM of [ ¹⁴ C] glycine (specific activity 112 mCi / mmol) are then added. Incubation continues for 10 min at 37 ° C, and the reaction is stopped by 2 washes with Krebs-HEPES buffer at pH 7.4. The radioactivity incorporated by the cells is then estimated after adding 100 μl of liquid scintillant and stirring for 1 h. The counting is carried out on a Microbeta Tri-lux ™ counter. The effectiveness of the compound is determined by the IC ₅₀ , concentration of the compound which decreases the specific glycine uptake by 50%, defined by the difference in radioactivity incorporated by the control batch and the batch which received the glycine at 10 mM.

The compounds of the invention, in this test, have an IC ₅₀ of the order of 0.001 to 10 μM.

Ex vivo study of the inhibitory activity of a compound on the capture of [ ¹⁴ C] glycine in the cortical homogenate of mice.

Increasing doses of the test compound are administered orally (preparation by trituration of the test molecule in a mortar in a Tween / Methocel ™ solution at 0.5% in distilled water) or intraperitoneally (dissolution of the test molecule in physiological saline or preparation by trituration in a mortar in a Tween / methocel solution at 0.5% in water, depending on the solubility of the molecule) on male OFl Iffa Credo mice of 20 to 25 g on the day of the experiment. The control group is treated by the vehicle. The doses in mg / g, the route of administration and the treatment time are determined according to the molecule to be studied. After euthanasia by decapitation of the animals at a given time after administration, the cortex of each animal is quickly removed on ice, weighed and stored at 4 ° C or frozen at -80 ° C (in both cases the samples are kept 1 maximum day). Each sample is homogenized in a Krebs-HEPES buffer at pH 7.4 at a rate of 10 ml / g of tissue. 20 μl of each homogenate are incubated for 10 min at room temperature in the presence of 10 mM L-alanine and buffer. Nonspecific uptake is determined by adding 10 mM glycine to the control group. The reaction is stopped by vacuum filtration and the radioactivity retained is estimated by solid scintillation by counting on a Microbeta Tri-lux ™ counter.

A [ ¹⁴ C] glycine uptake inhibitor will decrease the amount of radioligand incorporated into each homogenate. The activity of the compound is evaluated by its ED ₅₀ , a dose which inhibits 50% of the capture of [ ¹⁴ C] glycine compared to the control group.

The most powerful compounds of the invention, in this test, have an ED ₅₀ of 0.1 to 5 mg / kg intraperitoneally or orally.

Study of the transport of glycine in the homogenate of mouse spinal cord.

The capture of [ ¹ C] glycine by the glyt2 transporter is studied in the homogenate of mouse spinal cord by measuring the radioactivity incorporated in the presence or absence of the compound to be studied.

After euthanasia of the animals (OFl Iffa Credo male mice weighing 20 to 25 g on the day of the experiment), the spinal cord from each animal is quickly removed, weighed and stored on ice. The samples are homogenized in a Krebs-HEPES ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) buffer, pH 7.4, at a rate of 25 ml / g of tissue. 50 μl of homogenate are pre-incubated for 10 min at 25 ° C in the presence of Krebs-HEPES buffer, pH 7.4 and of compound to be studied at different concentrations, or of 10 mM of glycine to determine the non-specific uptake. The [ ¹ C] glycine (specific activity = 112mCi / mmol) is then added for 10 min at 25 ° C to the final concentration of 10 μM. The reaction is stopped by vacuum filtration and the radioactivity is estimated by solid scintillation by counting on. a Microbeta Tri-lux ™ counter. The effectiveness of the compound is determined by the IC ₅₀ concentration capable of decreasing the specific glycine uptake by 50%, defined by the difference in radioactivity incorporated by the control batch and the batch which received the 10 mM glycine. The compounds of the invention in this test have an IC ₅₀ of the order of 0.001 to 10 μM.

Ex vivo study of the inhibitory activity of a compound on the capture of [ ¹⁴ C] glycine in the spinal homogenate of mice. Increasing doses of the test compound are administered orally (preparation by trituration of the test compound in a mortar, in a Tween / Methocel ™ solution at 0.5% in distilled water) or intraperitoneal (test compound dissolved in physiological saline, or triturated in a mortar, in a Tween / Methocel ™ solution at 0.5% in distilled water) to male OFl Iffa Credo mice of 20 to 25 g on the day of the experiment . The control group is treated by the vehicle. The doses in mg / kg, the route of administration, the treatment time and the euthanasia time are determined according to the compound to be studied. After euthanasia by decapitation of the animals at a given time after administration, the marrow is quickly removed, weighed and introduced into glass scintillation vials, stored in crushed ice or frozen at -80 ° C (in both cases the samples are kept for 1 day maximum). Each sample is homogenized in a Krebs-HEPES buffer at pH 7.4, at a rate of 25 ml / g of tissue. 50 μl of each homogenate are incubated for 10 min at room temperature in the presence of buffer. Non-specific catch is determined by adding

10 mM glycine to the control group.

The reaction is stopped by vacuum filtration and the radioactivity is estimated by solid scintillation by counting on a Microbeta Tri-lux ™ counter. An inhibitor of [ ¹ C] glycine uptake will decrease the amount of radioligand incorporated into each homogenate.

The activity of the compound is evaluated by its ED ₅₀ , an effective dose which inhibits 50% of the capture of [ ¹⁴ C] glycine compared to the control group. The best compounds of the invention have, in this test, a

ED ₅₀ from 1 to 20 mg / kg, intraperitoneally or orally.

The results of the tests carried out on the compounds of the invention of configuration (IS, 2S) and their threo racemates of configuration (1R, 2R; 1S, 2S) in the general formula (I) of which R ₂ represents one or more atoms of halogens or trifluoromethyl groups show that they are inhibitors of the glycine glytl transporter present in the brain, both in vitro and ex vivo.

These results suggest that the compounds of the invention can be used for the treatment of behavioral disorders associated with dementia, psychoses, in particular schizophrenia (deficit form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptics. , for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorder, for the treatment of various forms of depression, including psychotic depression, for the treatment of disorders due to abuse or alcohol withdrawal, sexual behavior disorders, eating disorders, and for the treatment of migraine. The results of the tests carried out on the compounds of the invention of configuration (1J, 2R) and their racemates of configuration (1R, 2R; IS, 2 S) in the general formula (I) of which R ₂ represents both an atom halogen and an amino group NR ₃ R ₄ show that they are inhibitors of the glycine transporter glyt2, present mainly in the spinal cord, and this in vitro and ex vivo.

These results suggest that the compounds of the invention can be used for the treatment of painful muscular contractures in rheumatology and in acute spinal pathology, for the treatment of spastic contractures of medullary or cerebral origin, for the symptomatic treatment of acute and subacute pains mild to moderate intensity, for the treatment of intense and / or chronic pain, neurogenic pain and rebellious pain, for the treatment of Parkinson's disease and parkinsonian symptoms of neurodegenerative origin or induced by neuroleptics, for the treatment generalized primary and secondary epilepsies, partial with simple or complex symptomatology, mixed forms and other epileptic syndromes in addition to another antiepileptic treatment, or as monotherapy, for the treatment of sleep apnea, and for neuroprotection. ^''

This is why the present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the base state or of a pharmaceutically acceptable salt or solvate, and as a mixture, as the case may be. if necessary, with suitable excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

The pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraoccular administration. Unit administration forms can be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches ("patch"), suppositories. For topical administration, ointments, lotions and eye drops can be considered.

Said unit forms are dosed to allow daily administration of 0.01 to 20 mg of active principle per kg of body weight, depending on the dosage form.

To prepare tablets, a pharmaceutical carrier is added to the active principle, micronized or not, which can be composed of diluents, such as, for example, lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders, (polyvinylpyrrolidone, hydroxy_propylmethylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulfate can also be added.

The production techniques can be direct compression, dry granulation, wet granulation or hot melting. The tablets can be plain, coated, for example with sucrose, or coated with various polymers or other suitable materials. They can be designed to allow rapid, delayed or prolonged release of the active principle using polymer matrices or specific polymers used in the coating.

To prepare capsules, the active principle is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot fusion), liquids or semi-solids.

The capsules can be hard or soft, film-coated or not, so as to have rapid, prolonged or delayed activity (for example for an enteric form). A composition in the form of a syrup or elixir or for administration in the form of drops may contain the active principle together with a sweetener, preferably calorie-free, methylparaben or propylparaben as an antiseptic, a flavoring agent and a coloring agent.

The powders and granules dispersible in water can contain the active principle in admixture with dispersing agents or wetting agents, or dispersing agents such as polyvmylpyrrolidone, as well as with sweeteners and flavor correcting agents.

Suppositories prepared with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols, are used for rectal administration.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used.

The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives, or else with a polymer matrix or with a cyclodextrin (transdermal patches, sustained-release forms).

The topical compositions according to the invention comprise a medium compatible with the skin. They may be in particular in the form of aqueous, alcoholic or hydroalcoholic solutions, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or gel, microemulsions, d aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These dosage forms are prepared according to the usual methods of the fields considered. Finally, the pharmaceutical compositions according to the invention may contain, beside one compound of general formula (I), other active principles which may be ^useful in the treatment of disorders and diseases indicated above.

Claims

claims

1. Compound, in the form of a pure optical isomer (1R, 2R) or (1S, 2S) or in the form of a threo diastereoisomer {1R, 2R; 1S, 2S), corresponding to the general formula (I)

in which

R _x represents either a hydrogen atom, or a (Ci-C- linear or branched alkyl group optionally substituted by one or more fluorine atoms, or a (C ₄ -C ₇ ) cycloalkyl group, or a (C ₃ -C ₇ ) cycloalkyl (C _x -C ₃ ) alkyl, either a phenyl (C _x -C ₃ ) alkyl group, or a (C ₂ -C ₄ ) alkenyl group, or a (C ₂ -C ₄ ) alkynyl group , X represents a hydrogen atom or one or more substituents chosen from halogen atoms and trifluoromethyl groups, (C- _L -C _J ) linear or branched alkyl and (C ^ C ^ alkoxy,

R ₂ represents either a hydrogen atom or one or more substituents chosen from halogen atoms and (C ₁ -C ₄ ) alkoxy, methylenedioxy and amino groups of general formula NR ₄ R ₅ in which R ₄ and R ₅ each represent, independently of one another, a hydrogen atom or a (C _x -C ₄ ) alkyl group, or form, with the nitrogen atom which carries them, a pyrrolidine, piperidine ring, morpholine or piperazine,

R ₃ represents one or more substituents chosen from the following: o or a group of general formula S0 ₂ NR ₆ R ₇ in which R ₆ and R ₇ each represent, independently of one another, a hydrogen atom or a (C ₁ -C ₄ ) linear alkyl group or branched or cyclic, (C ^ C ^ alkylamino (Ci ^) alkyl, (C _X _C ₃ ) alkoxy (0 ^ 0 ₃ ) alkyl, (C ₁ _C ₃ ) alkylaminocarbonyl, or form, with the nitrogen atom which carry them, a pyrrolidine ring optionally substituted by one or two methyl groups, a piperidine ring or a morpholine ring, either a group of general formula S (C ^ C ^ alkyl, or a (C ₁ _C ₃ ) alkylsulfonyl group, or a carboxy group or (C _X _C ₃ ) alkoxycarbonyl, ie a group of general formula CONR ₆ R ₇ in which R ₆ and

R ₇ are as defined above, either an acetyl or benzoyl group, a cyano group, a linear or branched (C _x -C ₄ ) alkyl group, or a cyclo (C ₅ -C ₆ ) alkyl group or cyclo (C ₅ -C ₆ ) alkenyl, either a phenyl group substituted or not by one or more substituents chosen from halogen atoms, (C _X _C ₃ ) alkoxy groups, methylthio group, trifluoromethyl group, the trifluoromethoxy group, the cyano group, the (C ₁ -C ₄ ) alkyl groups and the phenyl group, either a thienyl, benzothienyl or thianthenyl group, in the base state or as an addition salt with an acid.

2. Compound according to Claim 1, characterized in that it has the configuration 1S, 2S and in that R ₃ represents one or more substituents chosen from the groups

(C _! -C ₄ ) alkyls, cyano, S (C _α _C ₃ ) alkyls, optionally substituted phenyls, thienyl or thianthrenyl and R ₂ represents a hydrogen or halogen atom.

3. Compound according to claim 1, characterized in that it is of configuration 1R, 2R and in that R ₃ represents an aminosulfonyl group of general formula S0 ₂ NR ₆ R ₇ or aminocarbonyl of general formula CONR ₆ R ₇ and R ₂ represents one or more substituents chosen from halogen atoms and amino groups of general formula NR ₄ R ₅ .

4. Medicament, characterized in that it consists of a compound according to one of claims 1 to 3.

5. Pharmaceutical composition characterized in that it contains a compound according to one of claims 1 to 3, associated with an excipient.