FR2842805A1 - N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND APPLICATION THERAPEUTICS - Google Patents

Abstract

Compounds of general formula where R1 represents H or an alkyl, cycloalkylalkyl, phenylalkyl, alkenyl or alkynyl, X represents either H or one or more halogen atoms, alkyl or alkoxy, R2 represents H or one or more halogen atoms or alkoxy groups , or optionally substituted amino, R3 represents either an optionally substituted aminosulfonyl group, or a cyano group or a group of formula S-alkyl, or an alkylsulfonyl group, or a carboxy or alkoxycarbonyl group, or an optionally substituted carbamoyl group, or a group acetyl or benzoyl, either an alkyl, phenyl, thienyl or thianthenyl group. Therapeutic application.

Description

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Derivatives of N- [phenyl (piperidin-2-yl) methyl] benzamide, their preparation and their therapeutic application.

dans laquelle R1 représente soit un atome d'hydrogène, soit un groupe (C1-C7) alkyle linéaire ou ramifié éventuellement substitué par un ou plusieurs atomes de fluor, soit un groupe (C4-C7) cycloalkyle,

soit un groupe (C3-C) cycloalkyl (C1-C3) alkyle, soit un groupe phényl (Ci-C3) alkyle, soit un groupe (C2-C4) alcényle, soit un groupe (C2-C4) alcynyle, X représente un atome d'hydrogène ou un ou plusieurs substituants choisis parmi les atomes d'halogènes et les groupes trifluorométhyle, (C1-C4) alkyle linéaire ou ramifié et (C1-C4) alcoxy, R2 représente soit un atome d'hydrogène, soit un ou plusieurs substituants choisis parmi les atomes d'halogènes et les groupes (C1-C4)alcoxy, méthylènedioxy et amino de formule générale NR4R5 dans laquelle R4 et R5 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou un groupe (C1-C4)alkyle, ou forment, avec l'atome d'azote qui les porte, un cycle pyrrolidine, pipéridine, morpholine ou pipérazine, R3 représente un ou plusieurs substituants choisis parmi les suivants : soit un groupe de formule générale SO2NR6R7 dans laquelle R6 The compounds of the invention correspond to the general formula (I)

in which R1 represents either a hydrogen atom or a linear or branched (C1-C7) alkyl group optionally substituted by one or more fluorine atoms, or a (C4-C7) cycloalkyl group,

either a (C3-C) cycloalkyl (C1-C3) alkyl group, a phenyl (C1-C3) alkyl group, a (C2-C4) alkenyl group, or a (C2-C4) alkynyl group, X represents a hydrogen atom or one or more substituents selected from halogen atoms and trifluoromethyl, (C1-C4) alkyl linear or branched and (C1-C4) alkoxy, R2 represents either a hydrogen atom, or one or a plurality of substituents selected from halogen atoms and (C1-C4) alkoxy, methylenedioxy and amino groups of the general formula NR4R5 wherein R4 and R5 are each independently of one another hydrogen or group (C1-C4) alkyl, or form, with the nitrogen atom which carries them, a pyrrolidine, piperidine, morpholine or piperazine ring, R3 represents one or more substituents chosen from the following: either a group of general formula SO2NR6R7 in which R6

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(C1~C3) alcoxy (C1~C3) alkyle, (C1~C3) alkylaminocarbonyle, ou forment, avec l'atome d'azote qui les porte, un cycle pyrrolidine éventuellement substitué par un ou deux groupes méthyle, un cycle pipéridine ou un cycle morpholine, soit un groupe de formule générale S (C1-C3) alkyle,

soit un groupe (C1~C3) alkylsulfonyle, soit un groupe carboxy ou (C1~C3)alcoxycarbonyle, soit un groupe de formule générale CONR6R7 dans laquelle R6 et R7 sont tels que définis ci-dessus, soit un groupe acétyle ou benzoyle, soit un groupe cyano soit un groupe (C1-C4) alkyle, soit un groupe phényle substitué ou non par un ou plusieurs substituants choisis parmi les atomes d'halogène, les groupes (C1-C3) alcoxy, le groupe méthylthio, le groupe trifluorométhyle, le groupe trifluorométhoxy, le groupe cyano, les groupes (C1-C4) alkyles et le groupe phényle, soit un groupe thiényle, benzothiényle ou thianthrényle. and R7 represent, independently of each other, a hydrogen atom or a linear or branched or cyclic (C1-C4) alkyl group, (C1-C3) alkylamino (C1-C3) alkyl,

(C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkylaminocarbonyl, or form, with the nitrogen atom which carries them, a pyrrolidine ring optionally substituted by one or two methyl groups, a piperidine ring or a morpholine ring, ie a group of general formula S (C1-C3) alkyl,

either a (C 1 -C 3) alkylsulfonyl group, or a carboxy or (C 1 -C 3) alkoxycarbonyl group, or 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 is a (C1-C4) alkyl group or a phenyl group which may or may not be substituted by one or more substituents chosen from halogen atoms, (C1-C3) alkoxy groups, methylthio group and trifluoromethyl group, the trifluoromethoxy group, the cyano group, the (C1-C4) alkyl groups and the phenyl group, either a thienyl, benzothienyl or thiantenyl group.

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

Compounds of structure similar to that of the compounds of the invention are described in US Pat. No. 5,254,569 as analgesics, diuretics, anticonvulsants, anesthetics, sedatives, and cerebroprotectives, by a mechanism of action on opiate receptors. Other compounds of similar structure are described in patent application EP-0499995 as 5-HT3 antagonists useful in the treatment of psychotic disorders, neurological diseases, gastric symptoms, nausea and vomiting.

The compounds of the invention exhibit a particular activity as specific transporters inhibitors

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 glycine glytl and / or glyt2.

groupes (C1-Cç) alkyles, cyano, S (C-C3) alkyles, aryles ou hétéroaryles et R2 représentant un atome d'hydrogène ou d'halogène. Les composés préférés comme inhibiteurs du transporteur glyt2 sont de configuration (R,R), avec R3 représentant un groupe aminosulfonyle de formule générale SO2NR6R7 ou aminocarbonyle de formule générale CONR6R7 'et R2 représentant un ou plusieurs substituants choisis parmi les atomes d'halogènes et les groupes amino de formule générale NR4R5 - Les composés de formule générale (I) dans laquelle R1 est différent d'un atome d'hydrogène peuvent être préparés par un procédé illustré par le schéma 1 qui suit. Preferred compounds lacking opiate or 5-HT3 receptor activity as glyt1 transporter-specific inhibitors are of the (S, S) configuration with R3 representing one or more groups selected from the group consisting of

(C1-C6) alkyl, cyano, S (C-C3) alkyl, aryl or heteroaryl groups and R2 representing a hydrogen or halogen atom. The preferred compounds as inhibitors of the transporter glyt2 are of configuration (R, R), with R3 representing an aminosulfonyl group of general formula SO2NR6R7 or aminocarbonyl of general formula CONR6R7 'and R2 representing one or more substituents chosen from halogen atoms and amino groups of the general formula NR4R5 - The compounds of the general formula (I) in which R1 is other than a hydrogen atom can be prepared by a process illustrated in the following scheme 1.

On effectue un couplage d'une diamine de formule générale (II), dans laquelle X est tel que défini ci-dessus et R1 est différent d'un atome d'hydrogène, avec un acide activé ou un chlorure d'acide de formule générale (III) dans laquelle Y représente un groupe nucléofuge tel qu'un atome d'halogène et R2 et R3 sont tels que définis ci-dessus, en utilisant les méthodes connues de l'homme du métier. Diagram 1

Coupling of a diamine of general formula (II), wherein X is as defined above and R1 is different from a hydrogen atom, with an activated acid or an acid chloride of general formula (III) wherein Y represents a nucleofuge group such as a halogen atom and R2 and R3 are as defined above, using methods known to those skilled in the art.

The diamine of general formula (II) can be prepared by

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 a method illustrated by the following diagram 2.

On fait réagir l'amide de Weinreb de formule (IV) avec le dérivé de phényllithium de formule générale (V), dans laquelle X est tel que défini ci-dessus, dans un solvant éthéré tel que l'éther diéthylique, entre -30 C et la température ambiante ; on obtient une cétone de formule générale (VI)que l'on réduit en alcool de configuration thréo de formule générale (VII) par un agent réducteur tel que le K-Selectride ou le L-Selectride (tri-sec-butylborohydrure de potassium ou de lithium), dans un solvant éthéré tel que le tétrahydrofurane, entre -78 C et la température ambiante. Figure 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.degree. C and the ambient temperature; a ketone of general formula (VI) is obtained which is reduced in threo configuration alcohol of general formula (VII) by a reducing agent such as K-selectride or L-selectride (potassium tri-sec-butylborohydride or of lithium), in an ethereal solvent such as tetrahydrofuran, between -78 C and room temperature.

The carbamate of general formula (VII) can then be reduced to the threo N-methylaminoalcohol of general formula (VIII) by the action of a mixed hydride such as 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 converted into a threo diamine of general formula (II) in which R1 represents a methyl group in two.

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 steps: the alcohol function is first converted into a nucleofugal group, for example a methanesulfonate group by the action of methylsulfonyl chloride, in a chlorinated solvent such as dichloromethane, and in the presence of a base such as triethylamine, between 0 C and the ambient temperature, then the nucleofuge group is reacted with liquefied ammonia at -50 ° C., in an alcohol such as ethanol, in a closed medium 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 threo amino alcohol of general formula (IX), then proceed to an N -alkylation by means of a halogenated derivative of formula R1Z, in which R1 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, N-dimethylformamide, between ambient temperature and 100 ° C. The alcohol of general formula (X) thus obtained is then treated as described in connection with the alcohol of general formula (VIII).

Another process variant, illustrated by Scheme 3 which follows, may be used in the case where R 1 represents a methyl group and X represents a hydrogen atom.

The pyridine oxime of formula (XI) is quaternarized, 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 as than ethanol and 1N hydrochloric acid. The diamine of general formula (II) in which R1 represents a methyl group and X represents a hydrogen atom in the form of a mixture of the two 9/1 threo / erythro diastereoisomers are obtained.

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On peut la salifier, par exemple avec de l'acide oxalique, puis purifier par recristallisation de l'oxalate formé dans un mélange d'alcool et d'un solvant éthéré tel que le méthanol et l'éther diéthylique, pour obtenir le diastéréoisomère thréo (1R,2R ; 1S,2S) pur. Figure 3

It can be salified, for example with oxalic acid, and 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 (1R, 2R, 1S, 2S) pure.

The compounds of general formula (I) in which R 1 represents a hydrogen atom may be prepared by a process illustrated in Scheme 4 which follows.

A partir de l'amine de formule générale (XIII), dans laquelle X est tel que défini ci-dessus, on effectue un couplage avec un acide activé ou un chlorure d'acide, tel que décrit cidessus, de formule générale (III), selon des méthodes connues de l'homme du métier, pour obtenir le composé de formule générale (XIV). Finalement on effectue une hydrogénation de ce dernier, par exemple par l'hydrogène en présence d'un Figure 4

Starting from the amine of general formula (XIII), in which X is as defined above, a 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, a hydrogenation of the latter is carried out, for example by hydrogen in the presence of a

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 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) wherein R1 represents a hydrogen atom.

The amines of general formula (XIII) can be prepared according to a method to that described in Chem. Pharm. Bull.

(1984), 35, 12, 4893-4906 and in Synthesis (1976), 593-595.

Finally, to obtain chiral compounds, corresponding to the (1R, 2R) or (1S, 2S) enantiomers of the threo diastereoisomer, the final products of general formula (I) can be separated by high performance liquid chromatography (HPLC). chiral column, or perform the resolution of the racemic amine of general formula (II) by using a chiral acid, such as tartaric acid, camphorsulfonic acid, dibenzoyltartric acid or, preferably, N- acetylleucine, by the fractional and preferential recrystallization of a diastereoisomeric salt in an alcohol-type solvent, or enantioselective synthesis according to scheme 2, using a chiral Weinreb amide of general formula (IV).

The Weinreb amide of formula (IV) racemic or chiral can be prepared according to a method similar to that described in Eur. J. Med. Chem. (2000), 35, 799-988 and J. Med. Chem.

(1998), 41, 591-601. The phenyllithic compound of general formula (V) wherein 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 general formula (XI) may be prepared according to an analogous method to that described in patent application EP-0366006. Finally, the amine of general formula (XIII) may 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) where Y

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 represents a non-commercially available OH group may be prepared according to various methods known to those skilled in the art; a first approach consists of the synthesis of sulfonamide derivatives. Some of these are described in 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.

The metachlorosulfonyl acids can be obtained according to a method analogous to those described in J. Chem. Soc.

(C), (1968), 13, and in US-2273444, DE-19929076, EP-0556674, by heating the acid in chlorosulfonic acid at 140 ° C for 1 to 2 days.

Chlorosulphonylation in ortho or para position can be carried out from a diazonium salt according to a method analogous to that described in patent US-3663615, with 4-amino-3-chlorobenzoic acid, by bubbling with sulfur in the presence of cupric salt, in a solvent such as acetic acid, cold, on the corresponding diazonium salt.

The sulfonamides are obtained by reacting the chlorosulfonyl derivatives in the presence of an excess of amine in a solvent such as tetrahydrofuran, at room temperature or under reflux.

The secondary sulfonamides may be methylated according to a method analogous to that described in patent BE-620741, using dimethylsulfate in the presence of a base such as concentrated sodium hydroxide, 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 of the synthesis of sulfoxide derivatives of benzoic acids. Some of them are described in 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

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 halogenated derivative with alkylsulfonyl chloride in the presence of copper.

Biphenyl type benzoic acid derivatives can be synthesized by Suzuki coupling, by heating the benzoic acid derivative substituted on the phenyl ring by an iodine atom in the presence of a boronic acid, a base such as 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), and J. Labeled Compd.

Radiopharm., (1997), 39 (6), 501-508.

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

Esters or amides can also be introduced by direct carbonylation with a strong base para acid, under the conditions described in Tetrahedron Lett., (2000), 41, 317-3160.

Deprotonation of the aromatic nucleus by a strong base such as Schlosser base (butyllithium / potassium tert-butylate, in a solvent such as tetrahydrofuran, at low temperature, followed by the addition of an electrophile of the alkylchloroformate or chloride type alkylcarbamoyl leads to the 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, a palladiumtetrakis triphenylphosphine type catalyst in a tetrahydrofuran-type solvent, according to a method similar to that described in FIG. Org. Chem. (1967) 62.25, 8634-8639.

The following examples illustrate the preparation of

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 some compounds of the invention. Elemental microanalyses and I.R. and R.M.N. spectra and chiral column HPLC confirm the structures and enantiometric 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 compound names, the dash "-" is part of the word, and the dash "~" is only used for the cut at the end of the line; it must be deleted in the absence of a cut, and must not be replaced by a normal dash or a space.

Example 1 (Compound N 25).

amino]sulfonyl]-N-[(1-méthylpipéridin-2-yl)phénylméthyl]benz- amide 1:1. Threo-3-bromo-4 - [[(cyclopropyl) (methyl) - hydrochloride

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

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

1. 1.1. 3-bromo-4-chlorosulfonylbenzoic acid.

In a three-necked 500 ml flask, 35 g (0.162 mol) of 4-amino-3-bromobenzoic acid (J.Med Chem (2000), 43, 21.3820-3823) are placed in 82 ml of acid. 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 mol) 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 minutes.

On the other hand, in a three-necked flask of 1 1 is placed 164 ml of acetic acid, the medium is cooled to 0 C and sulfur dioxide is bubbled to saturation.

To this solution was added 21.8 g (0.162 mol) of copper chloride in 41 ml of water. At 0 ° C., the solution of the diazonium salt is slowly added and left at 0 ° C. for 2 hours.

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.

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1. 1.2. 3-Bromo-4 - [[(cyclopropyl) amino] sulfonyl] benzoic acid.

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

After evaporation of the tetrahydrofuran under reduced pressure, the residue is taken up in dichloromethane and the mixture is acidified with 1N hydrochloric acid.

3,27 g d'acide 3-bromo-4-[[(cyclopropyl)amino]sulfonl]- benzoïque. After filtration of the precipitate formed and drying, we obtain

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] sulphonyl] benzoic acid.

In a 100 ml flask, 2 g (6.3 mmol) of 3-bromo-4 - [[(cyclopropyl) amino] sulphonyl] benzoic acid are placed in solution in 12 ml of methanol and 1.8 ml of concentrated sodium hydroxide solution. 1.78 ml (18.8 mmol) of dimethyl sulfate are added and the mixture is heated at 55 ° C. for 30 minutes.

3.6 ml of sodium hydroxide and 1.78 ml of dimethyl sulphate are added so that the mixture remains basic, and it is left at 55 ° C. for 2 hours.

After evaporation of the solvents 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.

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

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

1. 2.1. Threo- [hydroxy (phenyl) methyl] piperidine-1-carboxylic acid 1,1-dimethylethyl ester.

In a 250-ml flask under an argon atmosphere, 2.0 g (6.9 mmol) of 2-benzoylpiperidine-1-carboxylic acid 1,1-dimethylethyl ester in 30 ml of ether are introduced.

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 anhydrous diethyl, 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 and maintained stirring 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 come to room temperature with stirring for 2 hours.

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 sulphate 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-phenyl (piperidin-2-yl) methanol.

In a 250 ml flask is placed a solution of 2.0 g (6.9 mmol) of 1,1-dimethylethyl threo- [hydroxy (phenyl) methyl] piperidine-1 carboxylate in 40 ml of methanol, a solution is added. aqueous potassium hydroxide prepared from 2 g of potassium hydroxide pellets and 20 ml of water, and the mixture is refluxed for 2 hours.

The mixture 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 sulphate, filtration and evaporation of the solvent under reduced pressure, 1 g of white solid is obtained.

Melting point: 172-174 ° C.

1. 2.3. Threo- (1-methylpiperidin-2-yl) phenylmethanol.

In a 100 ml flask a solution of 1 g (5.2 mmol) of threo-phenyl (piperidin-2-yl) methanol in 30 ml of anhydrous N, N-dimethylformamide is added, 0.32 ml (5 ml) is added. 2 mmol) of iodomethane and 0.8 g (5.8 mmol) of potassium carbonate, and the mixture is heated at 80 ° C. for 2 hours.

It is cooled to room temperature, hydrolyzed by

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 addition of water and extracted several times with ethyl acetate. After washing the combined organic phases with water and saturated aqueous sodium chloride solution, drying over magnesium sulfate, filtering and evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with with a mixture of dichloromethane and methanol. 0.8 g of oily compound is obtained.

1. 2.4. Threo- (1-methylpiperidin-2-yl) phenylmethanamine.

In a 100 ml flask, under argon atmosphere, 0.8 g (3.65 mmol) of threo- (1-methylpiperidin-2-yl) phenylmethanol and 0.48 ml (3.65 mmol) of triethylamine are introduced into the mixture. 20 ml of anhydrous dichloromethane, the mixture is cooled to 0 ° C., 0.28 ml (3.63 mmol) of methanesulfonyl chloride are 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 previously prepared methanesulphonate dissolved in 10 ml of absolute ethanol is added, the autoclave is closed and stirring is maintained. for 48 hours.

The mixture is transferred to a flask, concentrated under reduced pressure and the residue is purified by column chromatography on 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.

(méthyl)amino]sulfonyl]-N-[(1-méthylpipéridin-2-yl)- phénylméthyl]benzamide 1 :1. 1. 3. Threo-3-bromo-4 - [[(cyclopropyl) hydrochloride -

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

3-bromo-4-[[(cyclopropyl)(méthyl)amino]sulfonyl]benzoïque, de 350 mg (1,82 mmoles) de chlorhydrate de 1-(diméthylaminopropyl)-3-éthylcarbodiimide, de 250 mg (1,82 mmoles) d'hydroxybenzotriazole dans 20 ml de dichlorométhane agitée pendant 10 min,on ajoute une solution de 372 mg (1,82 To a solution of 610 mg (1.82 mmol) of acid

3-bromo-4 - [[(cyclopropyl) (methyl) amino] sulfonyl] benzoic, 350 mg (1.82 mmol) of 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 250 mg (1.82 mmol) ) of hydroxybenzotriazole in 20 ml of dichloromethane stirred for 10 min, a solution of 372 mg (1.82

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 mmol) of threo- (1-methylpiperidin-2-yl) phenylmethanamine in 5 ml of dichloromethane, and the mixture is stirred overnight.

It is hydrolyzed with water and 1N sodium hydroxide and 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 column chromatography on 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 0.1 N hydrochloric acid solution in propan-2-ol, and then concentrating the mixture under reduced pressure.

[[(cyclopropyl)(méthyl)amino]sulfonyl]-N-[(1-méthylpipéridin- 2-yl)phénylméthyl]benzamide 1 :1. After trituration with isopropyl ether, 219 mg of threo-3-bromo-4- hydrochloride are finally isolated.

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

Melting point: 163-165 ° C.

Example 2 (Compound N 29).

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

2. 1. 3-Bromo-4 - [[[(ethylamino) carbonyl] amino] sulfonyl] benzoic acid.

1 g (3.4 mmol) of methyl 4- (aminosulfonyl) -3-bromobenzoate dissolved in 15 ml of tetrahydrofuran are placed in a Schlenk tube in the presence of 0.45 g (3.4 mmol) of carbonate. of potassium and 0.27 ml (3.4 mmol) of ethyl isocyanate, and the mixture was refluxed overnight.

The solvent is evaporated 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, and then ethyl acetate and methanol.

0.9 g of 3-bromo-4 - [[[(ethylamino) carbonyl] amino] sulfonyl] benzoic acid are obtained in the form of a white solid.

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1]-N-[(1-méthylpipéridin-2-yl)phénylméthyl]benzamide. 2. 2. Threo-3-bromo-4 - [[[(ethylamino) carbonyl] amino] sulfony

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

(1,82 mmoles) de thréo-(1-méthylpipéridin-2-yl)phényl~ méthanamine, on obtient 482 mg d'un solide correspondant au produit de couplage. In the same manner 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) 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 250 mg (1.82 mmol) hydroxybenzotriazole and 371 mg

(1.82 mmol) of threo- (1-methylpiperidin-2-yl) phenyl-methanamine gives 482 mg of a solid corresponding to the coupling product.

Melting point: 215-220C.

Example 3 (Compound N 134).

2-Chloro-6-fluoro-3-methyl-N - [(1S) - [(2S) - [(1-methylpiperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1.

3. (2S) -2-benzoylpiperidine-1-carboxylate
1,1-dimethylethyl.

In a 500 ml flask, under a nitrogen atmosphere, 11.8 g (43.3 mmol) of (2S) -2- (N-methoxy-N-methylcarbamoyl) piperidine-1-carboxylic acid 1,1-dimethylethyl ester are introduced. 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 70/30 mixture are added dropwise. 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 off and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue is purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane.

4.55 g of solid product is obtained.

Melting point: 123-125 C.

 [[alpha]] D25 = -25.4 (c = 2.22, CH2Cl2) ee = 97.2%.

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3.2. (1S)-2-[(2S)-hydroxy(phényl)méthyl]pipéridine-1- carboxylate de 1,1-diméthyléthyle.

3.2. (1S) -2 - [(2S) -hydroxy (phenyl) methyl] piperidine-1-carboxylic acid 1,1-dimethylethyl ester.

In a 500 ml flask, under a nitrogen atmosphere, 4.68 g (16.2 mmol) of 1,1-dimethylethyl (S) -2-benzoylpiperidine-1-carboxylate are introduced into 170 ml of anhydrous tetrahydrofuran, the solution is cooled to -78 ° C., 48.5 ml (48.5 mmol) of a 1M solution of L-selectride (lithium tri-sec-butylborohydride) in tetrahydrofuran are added dropwise, and The mixture is stirred at room temperature for 5 hours.

It is slowly hydrolyzed with 34 ml of water and 34 ml of a 35% aqueous solution of hydrogen peroxide, and the mixture is allowed to come to room temperature with stirring for 2 hours.

It is diluted with water and ethyl acetate, the aqueous phase is separated off and 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.

[[alpha]] D25 = + 63.75 (c = 0.8, CH2Cl2) ee = 97.8%.

3.3. (1S) - [(2S) - (1-methylpiperidin-2-yl] phenylmethanol.

d'une solution de ( 1S) -2- [ ( 2 S) -hydroxy (phényl ) méthyl ] ~ pipéridine-1-carboxylate de 1,1-diméthyléthyle dans 35 ml de tétrahydrofurane et on maintient le mélange au reflux pendant 3,5 h. In a 200 ml bicol, under a nitrogen atmosphere, 2.96 g (78.1 mmol) of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran are introduced, the mixture is heated to reflux, add 4.49 g (15.4 mmol)

of a solution of (1S) -2- [(2 S) -hydroxy (phenyl) methyl] -piperidine-1-carboxylic acid 1,1-dimethylethyl ester in 35 ml of tetrahydrofuran and the mixture is maintained under reflux for 3, 5 h.

It is cooled, slowly hydrolyzed with a 0.1M solution of potassium sodium tartrate and the mixture is left stirring overnight.

It is filtered and the precipitate is rinsed with tetrahydrofuran and the filtrate is concentrated under reduced pressure.

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3.4. (1S)-[(2S)-(1-méthylpipéridin-2-yl)]phényl- méthanamine. 2.95 g of a colorless oily product are obtained.

3.4. (1S) - [(2S) - (1-methylpiperidin-2-yl)] phenylmethanamine.

introduit 2,95 g (14,4 mmoles) de ( 1 S) - [ ( 2S) - ( 1-méthyl~ pipéridin-2-yl)]phénylméthanol et 2 ml (14,4 mmoles) de triéthylamine dans 70 ml de dichlorométhane anhydre, on refroidit le milieu à 0 C, on ajoute 1,1 ml (14,4 mmoles) de chlorure de méthane sulfonyle, on laisse le mélange revenir lentement à température ambiante pendant 2 h et on le concentre sous pression réduite. In a 250 ml flask, under a nitrogen atmosphere, one

2.95 g (14.4 mmol) of (1S) - [(2S) - (1-methyl-piperidin-2-yl)] phenylmethanol and 2 ml (14.4 mmol) of triethylamine are introduced into 70 ml of anhydrous dichloromethane, the medium is cooled to 0 ° C., 1.1 ml (14.4 mmol) of methanesulphonyl chloride are added, the mixture is allowed to slowly return to room temperature for 2 hours and it is concentrated under reduced pressure.

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

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

N- [ ( 1 S) - [ ( 2 S) [ ( 1-méthylpipéridin-2-yl ) ] phényl- méthyl]benzamide 1 :1. 3. 5. 2-Chloro-6-fluoro-3-methylhydrochloride

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

(1S)-[(2S)-(1-méthylpipéridin-2-yl)]phénylméthanamine en solution dans 10 ml de dichlorométhane, 0,3 ml de triéthylamine et 0,49 g de chlorure d'acide 2-chloro- 6-fluoro-3-méthylbenzoïque, et on agite le mélange pendant 12 h. In a 100 ml flask was placed 0.48 g (2 mmol) of

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

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 column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol.

700 mg of oily product corresponding to the coupling product is obtained.

The hydrochloride is prepared by dissolving it in a few

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 ml of propan-2-ol, adding 20 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, 700 mg of hydrochloride are finally isolated.

Melting point: 164-166 ° C.

 [[alpha]] D25 = + 51.5 (c = 0.506, CH30H).

Example 4 (Compound N 42).

Threo-4-chloro-3 - [(dimethylamino) sulfonyl] N - [(piperidin-2-yl) phenylmethyl] benzamide hydrochloride 1: 1.

4. 1. 4-chloro-3 - [(dimethylamino) sulfonyl] -
N- [phenyl (pyridin-2-yl) methyl] benzamide.

To a solution of 2.9 g of 4-chloro-3 - [(dimethylamino) 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) of 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The mixture is left for 15 minutes at room temperature, then 2 g (10.85 mmol) of phenyl (pyridin-2-yl) methanamine are added and the mixture is stirred at room temperature for 6 hours.

The mixture is hydrolyzed with 1N sodium hydroxide and extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure.

We obtain 3 g of compound which is used as such in the next step.

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 of methanol and 20 ml of 1N hydrochloric acid in the presence of 0.05 g of platinum oxide, and hydrogenation is carried out for 6 hours.

The catalyst is filtered off, the filtrate is concentrated to dryness and the residue is taken up in dichloromethane.

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 and the solution is treated with ammonia. The organic phase is separated, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure.

The residue is purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol.

Two fractions are obtained: the least polar (320 mg) and the most polar (325 mg) corresponding to the threo diastereoisomer.

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 is finally isolated.

Melting point: 232-236 C.

Example 5 (Compound N 59).

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

5. 1. 4-Chloro-3- (ethylsulfonyl) benzoic acid.

In a 250 ml three-necked flask under a nitrogen atmosphere, 2.52 g (40 mmol) of copper are placed in 12 ml of anhydrous N, N-dimethylformamide, the suspension is cooled to 0.degree. drop, 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.

A solution of 5 g (18 mmol) of 4-chloro-3-iodobenzoic acid (J. Chem.

Soc. (1925), 25) in 56 ml of anhydrous N, N-dimethylformamide, allowed to warm to room temperature and the mixture was heated at 50 ° C overnight.

The solvent is evaporated under reduced pressure and the residue is taken up with hydrochloric acid. A precipitate forms which is collected by filtration and dried under reduced pressure. It is purified by chromatography on silica gel, eluting with a mixture of dichloromethane and

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 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- (Benzyloxyiminophenylmethyl) -1-methylpyridinium trifluoromethanesulfonate.

To a suspension of 35 g (120 mmol) of 0-benzyloxime phenyl (pyridin-2-yl) methanone in 200 ml of diethyl ether is added, dropwise and at 0 C, 17.4 ml (120 mmol) of methyl trifluoromethanesulfonate 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 is used as it is in the next step.

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

14.8 g (31.89 mmol) of 2- (benzyloxyiminophenylmethyl) -1-methylpyridinium trifluoromethanesulfonate and 0.74 g of platinum oxide in 50 ml of ethanol are placed in a Parr vial. 1N hydrochloric acid and hydrogenation for 5 h.

The ethanol is evaporated under reduced pressure, the residue is extracted with dichloromethane, the aqueous phase is separated off, an aqueous ammonia solution is added and the mixture is extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 6.7 g of oily product comprising 10% erythro diastereoisomer are obtained.

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 of methanol, and the salt obtained is purified by recrystallization from a mixture of methanol and methanol. diethyl ether.

Finally, 4.7 g of diastereo [(1-methylpiperidin-2-yl) phenylmethyl] threo isomer is isolated.

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Melting point: 156-159 C.

[(1-méthylpipéridin-2-yl)phënylméthyl]benzamide 1:1. 5. 3. Threo-4-chloro-3-ethylsulfonyl-N-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, 350 mg (1.82 mmol) of 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, 413 mg of hydrochloride are finally isolated.

Melting point: 231-233C.

Example 6 (Compound N 117).

Threo-4-chloro-3- (thien-2-yl) -N - [(1-methylpiperidin-2-yl) phenylmethyl] benzamide hydrochloride 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 and 1.9 g (14.8 mmol) are introduced into a 100 ml flask. of 2-thiopheneboronic acid and 1.24 g (1.3 mmol) of tris (dibenzylideneacetone) dipalladium in 40 ml of N, N-dimethylformamide, and the mixture is heated at 70 ° C. for 24 hours.

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 are saponified under standard conditions to obtain the acid in the form of a white solid.

Melting point: 200-202 C.

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6. 2. Threo-4-chloro-3- (thien-2-yl) - N - [(1-methylpiperidin-2-yl) phenylmethyl] benzamide hydrochloride
1: 1.

As described in Example 1.3, starting from 412 mg (1.82 mmol) of 4-chloro-3- (thien-2-yl) 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, gets an oil 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, 413 mg of hydrochloride are finally isolated.

Melting point: 156-158 C.

Example 7 (Compound N 67).

N-[(1-méthylpipéridin-2-yl)phénylméthyl]benzamide 1:1. Threo-2-chloro-5- (methoxycarbonyl) hydrochloride

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

7. 1. 2-Chloro-5- (methoxycarbonyl) benzoic acid.

In a 250 ml flask is placed 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. of palladiumbis (triphenylphosphine) in 56 ml of methanol and 28 ml of N, N-dimethylformamide. The flask is purged with carbon monoxide, placed under a carbon monoxide atmosphere and heated at 60 ° C. for 24 hours.

The solvents are evaporated under reduced pressure, the residue is taken up in water and dichloromethane, the organic phase is separated off, dried over sodium sulphate, 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

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 platinum oxide spatula tip, and hydrogenation under pressure is carried out for 4 hours.

The catalyst is filtered off, rinsed with dichloromethane, the filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on 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, 350 mg (1.82 mmol) of 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 N 70).

N-[(1-méthylpipéridin-2-yl)phénylméthyl]benzamide 1:1. Threo-4- (aminocarbonyl) -3,5-dichlorohydrochloride

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

8. 1. 4- (Aminocarbonyl) -3,5-dichlorobenzoic acid.

0.79 g (2.377 mmoles) of methyl 3,5-dichloro-4-iodobenzoate (Chem Ber. (1941), 74, 807-821), 0.17 g (2.61 g) are placed in a Schlenk tube. mmol) of potassium cyanide, 0.045 g (0.237 mmol) of copper iodide and 0.137 g (0.119 mmol) of palladium tetrakistriphenylphosphine in 5 ml of degassed tetrahydrofuran, and the mixture is heated at 80 ° C. for 4 hours.

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The solvent is evaporated under reduced pressure, the residue is taken up with water and dichloromethane, the organic phase is separated off, 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.

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

The solvent is evaporated 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.

N-[(1-méthylpipéridin-2-yl)phénylméthyl]benzamide 1:1. 8. 2. Threo-4- (aminocarbonyl) -3,5-dichlorohydrochloride

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

As described in Example 1.3, starting from 393 mg (1.82 mmol) of 4- (aminocarbonyl) -3,5-dichlorobenzoic acid, 350 mg (1.82 mmol) of 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, 86 mg of hydrochloride is finally isolated.

Melting point: 297-299 ° C.

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Example 9 (Compound N 73).

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

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

9. 1. 3,5-Dichloro-4- (morpholin-4-ylcarbonyl) benzoic acid.

In a three-necked state under a nitrogen atmosphere, potassium tert-butoxide (940 mg, 8.37 mmol) is placed in 15 ml of anhydrous tetrahydrofuran at -76 ° C., the mixture is stirred for 30 minutes and added dropwise. 400 mg (2.09 mmol) of 3,5-dichlorobenzoic acid dissolved in 5 ml of anhydrous tetrahydrofuran is added dropwise, 5.3 ml (8.37 mmol) of n-butyllithium 1.6M in hexane, and stirring continued at -76 C for 1 h.

0.55 ml (4.7 mmol) of morpholinylcarbonyl chloride are added dropwise, the temperature is allowed to return to ambient temperature and 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 evaporated under reduced pressure. The residue is purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol.

We obtain 428 mg of crude acid which is used as it is in the next step.

carbonyl)-N-[(1-méthylpipéridin-2-yl)phénylméthyl]- benzamide 1:1. 9. 2. Threo-3,5-dichloro-4- (morpholin-4-yl) hydrochloride

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

To a solution of 428 mg (1.4 mmol) of 3,5-dichloro-4- (morpholin-4-ylcarbonyl) benzoic acid, 270 mg (1.4 mmol) of 1- (dimethylaminopropyl) hydrochloride. 3-ethylcarbodiimide, 190 mg (1.4 mmol) of hydroxybenzotriazole in 20 ml of dichloromethane stirred for 10 min, is added a solution of 290 mg (1.4 mmol) of threo- (1-methylpiperidin-2-yl) ) phenylmethanamine in 5 ml of dichloromethane, and the mixture is stirred overnight.

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The mixture is hydrolysed with 1 N water and sodium hydroxide and extracted with dichloromethane, the organic phase is separated off, washed with water, dried over sodium sulphate, filtered and concentrated. under reduced pressure. The residue is purified by column chromatography on 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: 210-220C.

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

In the "R2" column, "C6H5" is phenyl, "C6H4 is monosubstituted phenyl, and" C6H3 "is disubstituted phenyl, substituents and their positions are indicated.

In the "R2" and "R3" columns, "pyrrolid" refers to a pyrrolidin-1-yl group.

In the "R3" column, "cC3H5" refers to a cyclopropyl group, "morphol" refers to a morpholin-1-yl group, "piperid" refers to a piperidin-1-yl group.

In the "Salt" column, "-" refers to a compound in the base state, "HCl" refers to a hydrochloride and "tfa" refers to a trifluoroacetate.

In the "stereo" column, "S, S; R, R" denotes the mixture of diastereoisomers 1S, 2S, 1R, 2R, S, S denotes the isomer 1S, 2S and R, R denotes the isomer 1R, 2R .

The rotatory power of compound N 134 is +51.5 (c = 0.806, CH 3 OH) and the rotatory power of compound N 135 is -9.71 (c = 0.515, CH 3 OH).

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Board

NO x Pl R2 R3 Stéréo seul F (oc) M ! y R 1 4-Cl - 3-S0,-(H,)( (CC3H5) ;-R: 1Cl- 126-128 ---##H"" CH3 ~" 4-C1 3-SO,N(CH,)(cC,H,) S,S;,RHC1 126-128 2 H CH3 4-C1 3-So2N (CH3) S,S;R,R HCl 148-152 31 H CH3 2-C1 5-So2NCH (CH3) I S, S; R, R, HC1 205-206,5 4. H CH3 4-C1, 6-N (CH3) 3-SOzN (CH3) S, S; R, R HC1 251-253 5' H CH3 2-Cl 5-SOzNH (cC3H5) S, S; R, R HCl 214-216 6J H CH3 4-Cl 3-SO2NHCH(CH3)2 S, S; R, R HC1 226-227 7' H CH3 4-CI 3-SO2N(CH3)CH(CH3)2 | S, S; 2?, i? HCl ! 157-158

NO x Pl R2 R3 Stereo only F (oc) M! R 1 4 -Cl-3-S0, - (H,) ((CC 3 H 5); -R: 1Cl-126-128 --- ## H "" CH 3 - "4-Cl 3 -SO, N (CH 3) , (cC, H) S, S;, RHCI 126-128 2H CH3 4 -Cl3-SO2N (CH3) S, S; R, R HCl 148-152 31H CH3 2-Cl 5 -SSO2NCH ( CH3) IS, S; R, R, HCl 205-206.5 4. H CH3 4-Cl, 6-N (CH3) 3-SOzN (CH3) S, S; R, R HCl 251-253 5 'H CH3 2-Cl 5-SOzNH (cC3H5) S, S; R, R HCl 214-216 6J H CH3 4-Cl3-SO2NHCH (CH3) 2 S, S; R, R HCl 226-227 7 'H CH3 4 -CI 3 -SO 2 N (CH 3) CH (CH 3) 2 S, S; 2H, HCl 157-158

<tb> 8 <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3-SO2-pyrrolid <SEP> S, <SEP> S <SEP>;<SEP> R, <SEP> R <SEP> HCl <SEP> 145-150
<Tb>

9' H CH3 1 2-C1 ! 5-SO,N (CH3) S, S; R, R HCl 134-140 10 H CH3 2-Cl ! 5-SO,NHCH3 Bzz HCl j >250 1111 H CH3 4-CI 3-SOzNH~(cC3H) ~ j S, S; R, RI HC1 208-210

9 'H CH3 1 2-C1! 5-SO, N (CH 3) S, S; R, R HCl 134-140 CH3 2 -Cl! 5-SO, NHCH 3 B z HCl; 250 1111 H CH 3 4 -Cl 3-SO 2 NH 4 (cC 3 H) S, S; R, RI HC1 208-210

<Desc / Clms Page number 28>

0 x..-..- - ...- RI -..- - R2 ~ R3 ~~ ..-- stéréo - Sel -'- .~E (C2.~- 12 H CH3 4-Cl 3-SO2N(CH2CH2OCH3)2 S, S; R, R HCl M+H=539

0 x ..-..- - ...- RI -..- - R2 ~ R3 ~~ ..-- stereo - Sel -'-. ~ E (C2. ~ - 12 H CH3 4-Cl 3- SO 2 N (CH 2 CH 2 OCH 3) 2 S, S, R, R HCl M + H = 539

<tb> 13 <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3-SO2NHCH3 <SEP> S, <SEP> S <SEP>;<SEP> R, <SEP> R <SEP> - <SEP> 69-70
<tb> 14 <SEP> 2-F <SEP> CH3 <SEP> 4-Cl <SEP> 3-SO2NH2 <SEP> S, <SEP> S <SEP>;<SEP> R, <SEP> R <SEP> - <SEP> 269-271
<Tb>

151 H (CH2)2CH3 4-Cl 3-So2N (CH3) S,S;R,R HCI 243-244,5 i6i H CH3 4-Cl 3-S0zNHCHzcC3Hs S, S; R, R HCl 200-202 17 ' H CH3 4-Cl 3-SO2- [2, 5- (CH ) 3 2-pyrrolid] S, S; R, R HCl 140-148 18 H CH3 4-Cl 3-SO2-morphol S,S;R,R - 156-160 19 H CH3 4-Cl 3-S02NHCONHCHzCH3 S, S; R, R HCl 210-214 20' CH3 4-Cl 3-S0zN(CH3)CH2CH2N(CH3)z S,S;R,R 2HCl M+H=508 21 H CH3 4-Cl 3-S02N (CH)) CHzCH (CH3) S,S;R,R HCl 112-120 22 rH3 2-C1 5-S0zN(CH3)CH(CH3)z j S, S; R, R HCl j 175-177 23 H CH3 2-CI 5-S0zN(CH)) (cC3Hs) S, S; R, Ri HCl 220-222 24 C"3 3-Br 4-S0zNH (cC3Hs) S, S; R, RI HC1 ; 197-199 25: H i CH3 3-Br 4-SO2N(CH3)(CC3H5) S, S; R, R HCl 163-165 26 H i CH3 2,4-Clz 5-S0zNHz I S, S; R, R HC11 280-282 CH) 3-S0zNHz S,S;R,R 75-78 I CH3 4-Cl 3-SOZNHZ S, S; R, R! 1 - 138-140 29 H H CH j 3-Br 4-S0)NHCONHCHzCH-j S,S;R,R\ - j 215-220 30 CH3 3-C1 ~ 4-SOZ-piperid- - S, 5; , 1 , HC1 ; 250-252

H (CH 2) 2 CH 3 Cl-3-SO 2 N (CH 3) S, S; R, R HCl 243-244.5; CH 3 4 -Cl 3 -SO 2 NHCH 2 cC 3 H 5 S, S; R, R HCl 200-202; 17H-CH 3 Cl-3-SO 2 - [2,5-CH] 3 2-pyrrolid] S, S; R, R HCl 140-148 18 H CH3 4-Cl 3 -SO2-morphol S, S; R, R-156-160 19 H CH3 4-Cl3-SO2NHCONHCH2CH3S; R, R HCl 210-214 20 'CH3 4 -Cl3-SO2N (CH3) CH2CH2N (CH3) z S, S; R, R 2HCl M + H = 508 21H CH3 4-Cl3-SO2N (CH)) CH 2 CH (CH 3) S, S; R, R HCl 112-120; R H 3 2 -Cl 5 -SO 2 N (CH 3) CH (CH 3) n; S, S; R, R HCl 175-177 23 H CH3 2 -Cl 5-SO0N (CH)) (cC3Hs) S, S; R, RI HCl 220-222 24 C3-3-Br4-S0zNH (cC3H5) S, S, R, R1HCl, 197-199: CH3 3-Br4-SO2N (CH3) (CC3H5) S ## STR2 ## 4-Cl 3 -SOZNH 2 S, S; R, R! 1 - 138-140 29 HH CH 3 -Br 4 -S0) NHCONHCH 2 CH 2 S, S; R, R 3 - C1-4-SO2-piperid-S5; 1HCl; 250-252;

<Desc / Clms Page number 29>

N X R1 RZ R3 ~ ~ Stéréo Sel F ( C) 31 CH3 "~" 3-Cl ~ 4-SOZN (CH3) S, S; R, R HCl 218-220 32 H CH3 3-Cl 4-SO2-pyrrolid S, S; R, R Hic1 206-208 33; H CH3 3-Br 4-SOZN (CH3)2 S, S; R, R HCl 208-210 341 H CH3 3-Cl 4-S02-morphol S, S; R, R HC1 242-244 35 H CH3 3-Br 4-SO2-pyrrolid Bzz Hic1 140-142 361 H CH3 3-Cl, 5-pyrrolid 4-SO2-pyrrolid S, S; R, R HCl 179-192 37! H CH3 3,5-Cl2 4-So2NH2 Bzz Hic1 227-234 38 H CH3 3,5-Cl2 4-SO2-pyrrolid S, S; R, R HC1 160-167 39, H CH (CH3) 4-C1 3-SON (CH3) S, S; R, R HCl , 250-260 4 0 H ( CHZ ) jCH3 ; 4-C1 3-SO z N ( CH s ) 5,5; Cl 210-212 41, H CHZCH3 4-Cl 3-SOZN (CH3) Bzz HCl 127-128 42' H H 4-C1 3-So2N (CH3) S, S; R, R HC1 232-236 43: 3-OCH3 i CH3 4-Cl 3-SO2NH2 S, S; R, RÎ i - 138-140 44 j 2-OCH3 CH3 4-Cl 3-SOZNHZ 5,5; - ! 158-160 45 4-CH3 CH3 4-C1 3-S02NH, S, S; R, R - 188-190 46; 4-OCH3 CH, 4-Cl 3-SO2NH2 5;, - 178-180 471 2-CF3 CH3 4-C1 3-SONH2 5,5; - j 196-197 48 2-Cl CH3 4-C1 3-So2NH2 5,5;, - ; 171-172 49, 2, 4- (CH3) : CH3 4-Cl ~ ~ ~~ 3-SOZN (CH3) 5,5;: - 193

NX R1 RZ R3 ~ ~ Stereo Salt F (C) 31 CH3 "~" 3-Cl ~ 4-SOZN (CH3) S, S; R, R HCl 218-220 32 H CH 3 Cl-4-SO 2 -pyrrolid S, S; R, R HicI 206-208 33; CH 3 -Br 4-SOZN (CH 3) 2 S, S; R, R HCl 208-210 CH3 3 -Cl4-SO2-morphol S, S; R, R 2 CH 1 Cl 2 -Br 4-SO 2 -pyrrolid Bzz Hic 1- 140-142 361 H CH3 3-Cl, 5-pyrrolido-4-SO2-pyrrolid S, S; R, R HCl 179-192 37! H CH3 3,5-Cl2 4 -S0NH2 Bzz Hic1 227-234 38 H CH3 3,5-Cl2 4-SO2-pyrrolid S, S; R, R HCl 160-167 39, H CH (CH 3) 4-Cl 3 -SH (CH 3) S, S; R, R HCl, 250-260 ° H (CHZ); 4-Cl 3 -SO z N (CH s) 5.5; Cl 210-212 41, CHZCH3 4 -Cl3-SOZN (CH3) Bzz HCl 127-128 42 'HH4-Cl3-SO2N (CH3) S, S; R, R HCl 232-236 43: 3-OCH3 CH3 4 -Cl3-SO2NH2 S, S; R, R = 138-140; CH 2 OCH 3 CH 3 4 -Cl 3 -SO 2 ZH 5 5.5; -! 158-160 45 4-CH3 CH3 4-C1 3-SO2NH, S, S; R, R - 188-19046; 4-OCH 3 CH, 4-Cl 3 -SO 2 NH 2 5 ;, 178-180 471 2-CF 3 CH 3 4 -Cl 3 -SHHH 5,5; 196-197 48 2-Cl CH3 4 -Cl3 -S02NH2,5,5 ;, -; 171-172 49, 2-4 (CH3): CH3 4-Cl ~~~ 3-SOZN (CH3) 5.5 ;: - 193

<Desc / Clms Page number 30>

N 0 x P, R2 Pl Stéréo Sel F ( C) 50 2-CH , 4-OCH3 ! CH3 4-C1 3-SOzN (CH3) S, S; R, R1 Hic1 160-165 511 2, 6- (CH3) : CH3 4-C1 3-SO2NH2 S, 5; R, R 225-226 52'i 2-CH2CH3 i CH3 4-Cl 3-S02NH2 S, S; R, R tfa 236-238 53; H i CH,C,H, 4-Cl i 3-SO2NH2 1 5,5; R, R! - 87-88 54, 2-1 i CH3 4-Cl 3-SOzNH2 S, Si R, RI - 204-206

## EQU1 ## CH3 4-C1 3-SOzN (CH3) S, S; R, RI Hic1 160-165 511 2, 6- (CH3): CH3 4-Cl3-SO2NH2 S, 5; R, R 225-226; 52'i 2-CH 2 CH 3 CH 3 4 -Cl 3 -SO 2 NH 2 S, S; R, R tfa 236-238 53; CH, C, H, 4-Cl-3-SO2NH2 1 5.5; R, R! 87-88 54, 2-1 CH3 4 -Cl3-SOzNH2 S, Si R, RI-204-206

<tb> 55 <SEP> 3-Ci <SEP> CH3 <SEP> 4-Cl <SEP> 3-SO2NH2 <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> - <SEP> 188-189
<Tb>

561 2-CH3 CH3 4-ci 3-SO z NH2 5,sur - 193-195 57 H CH3 3,4-cil2 5-So2NH, S, S; R, R HCl 352-354 z H 1 CH3 li 2, 3- (OCH3) 5-So2NHCH3 S, S; R, R - 209-210

561 2-CH 3 CH 3 4 -Cl 3 -SO 2 NH 2 5, over-193-195 57 H CH 3 3,4-cil 2 5 -SSO 2 NH, S, S; R, R HCl 352-354; HCl 3 CH 2, 3- (OCH 3) 5 -SO 2 NHCH 3 S, S; R, R - 209-210

<tb> 59 '<SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3-SO2CH2CH3 <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> HCl <SEP> 231-233
<tb> 60 <SEP> H <SEP> CH3 <SEP> 4-Cl, <SEP> 2-OCH3 <SEP> 5-SO2CH2CH3 <SEP> S, <SEP> S <SEP>;<SEP> R, <SEQ> R <SEP> HCl <SEP> 251-252
<Tb>

61 H CH3 2-C1 i 5-So2CH3 S, S; R, RI - 166-167 62 H 1 CH3 2-ci 1 4-sotch3 S,S;R,R HC1 277-278 63 H : CH3 2-C1 1 5-SCH3 S, S; R, R HCl 232-234 64 H : CH3 4-C1 i 3-Co2CH3 S, S; R, R HCl 153-156 65 H ! CH3 4-Cl 3-CON (CH 3) 1 S, S; R,.R Hic1 180-182 66' H si CH3 4-ci | 3-CO?H S,SiR,R, HCl\ 278-280 67 H CH3 2-Cl 5-CO,CH, , S, Si R, R HC1 j 228-230 68 H Chez i 2,5-Cl2 I 4-CO2CH3 \s,S;R,R\ HC1 ; 218-221

CH3 2-C1 5-SO2CH3 S, S; R, RI-166-167 62 H 1 CH3 2-C 1-4 -sotch3 S, S; R, R H 277-278 H: CH3 2-C1 1 -CH3 S, S; R, R HCl 232-234 H: CH3 4-Cl 3-Co 2 CH 3 S, S; R, R HCl 153-156 65H! CH3 4-Cl 3-CON (CH 3) 1 S, S; R, .R Hic1 180-182 66 'H if CH3 4-ci | 3-CO? HS, SiR, R, HCl? 278-280? H? CH? 2-Cl? -CO, CH, S, Si R, R HCl, 228-230, 68 H In 2,5-Cl? -CO 2 CH 3 S, S; R, R 1 HCl; 218-221

<Desc / Clms Page number 31>

####
<Tb>

69, H CH3 3,5-Cl, 4-Co2CH2CH3 S, S; R, R HCl 118-120 70 H CH3 3, 5-clo 4-CONH2 I S, S; R, R HCl 297-299 71i H CH3 3, 5-C12 4-CO-pyrrolid S, S; R, Rj HCl 240-250

69, H 3 CH 3 3,5-Cl, 4-Co 2 CH 2 CH 3 S, S; R, R HCl 118-120; 70H CH3; 3,5-clo 4-CONH2 IS, S; R, R, HCl 297-299; CH 3 3, 5-Cl 2 4-CO-pyrrolid S, S; R, RI HCl 240-250

<tb> 72. <SEP> H <SEP> CH3 <SEP> 3,5-Cl2 <SEP> 4-CO-piperid <SEP> S, <SEP> S <SEP>;<SEP> R, <SEP> R <SEP> HCl <SEP> 200-205
<Tb>

7 3 H CH3 3,5-Cl, 4-CO-morphol S, S; R, R HCl 210-220 7 4 H CH3 3,5-Cl, 4-CON (CH3) S,S;R,R HCl 197-204

CH 3 3,5-Cl, 4-CO-morphol S, S; R, R HCl 210-220 7 4 H CH3 3,5-Cl, 4-CON (CH3) S, S; R, R HCl 197-204

<tb> 75 <SEP> H <SEP> CH3 <SEP> 2-Cl <SEP> 3-CN <SEP> S, <SE> S <SEP>;<SEP> R, <SEP> R <SEP> HCl <SEP> 148-150
<tb> 76 <SEP> H <SEP> CH3 <SEP> H <SEP> 3-CN <SEP> S, <SE> S <SEP>;<SEP> R, <SEQ> R <SEP> HCl <SEP> 72-74
<Tb>

#'. H CH3 2-C1 1 5-CN S, S; R, R HCl 284-285

# '. CH3 2-C1 1 5-CN S, S; R, R HCl 284-285

<tb> 78 <SEP> H <SEP> CH3 <SEP> H <SEP> 4-COCH3 <SEP> S, <SE> S <SEP>;<SEP> R, <SEP> R <SEP> - <SEP> 156-157
<Tb>

79 H CH3 H 3-COC6H S,S; ,RJHC1: 110-111 80' H CH3 4-Br i 3-CH3 S, S; R, Rj Î - 126-128 CH3 3-Br 4-CH3 S, S; R, R - 136-137 82 H CH3 H 3-CH ,S,, HC1 97-99 8 3 H CH 3-F 4-CH3 S,S;R,RI - 123-124 84 ; H CH3 ! 3-OCH3 4-CH3 I S, S; R, RÎ - 108-109 85 H CH5 1 H ' 3, 4- (CH3) I S. S; R. R; - 117-118 g6, CH, 'ici 4-Br 2-CH3 S, S; R, R' - 123-124 8 7 ; H CH3 3, 5- (OCH3) li 4-CH, i S, 5: R, R\ HC1 ' 138-140

79 H CH3H3-COC6H S, S; , RJHCI: 110-111 80% CH3 4 -Bri3-CH3 S, S; R, R12 - 126-128 CH3 3-Br4-CH3 S, S; R, R - 136-137 82 H CH3 H 3 -CH, S, HCl 97-998 3 H CH3-F4-CH3 S, S; R, RI-123-124 84; H CH3! 3-OCH3 4-CH3 IS, S; R, R - 108-109 85 H CH5 1 H '3, 4- (CH3) I S. S; R. R; 117-118 g, CH 4, here, 4-Br 2 -CH 3 S, S; R, R '- 123-124 8 7; CH 3, 5- (OCH 3) 4-CH, S, 5: R, R 'HCl 138-140

<Desc / Clms Page number 32>

)##################"R"Stéréo Sel ( C) N : Stéréo Sel 1 1 .

) ################## "R" Stereo Salt (C) N: Stereo Salt 1 1.

881H CH3 4-Cl 3 -CH3 5.5, - 137.5-138 89! CH3 2-C1 5-CH3 S, S; R, R - 217, CH 2 Cl, 6-F 5-CH 2 S; R -, 149

<tb> 91 <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 2-CH3 <SEP> S, <SEP>S;<SEP> R, <SEQ> R <SEP> HCl <SEP> 228
<Tb>

92 ; H CH3 3-F 2-CH3 S, S; R, R HCl 52 93! H CH3 3-Cl 2-CH3 S, S; R, RI - 250 9,! H CH3 5-Ci 2-CH3 S, S; R, R HCl 263-264 95; H CH3 H 2, 3- (CH3) S, S; R, R HCl 263 96 H CH3 2-Cl 3-CH3 S, S; R, R; HCl 365 97 H CH3 5-F 2-CH, 5,5; HCl 260

92; CH3 3-F 2 -CH3 S, S; R, R HCl 52 93! CH3 3-Cl 2 -CH3 S, S; R, RI - 250 9 ,! CH 3 5 -Cl 2 -CH 3 S, S; R, R HCl 263-264 95; CH 3 H 2, 3- (CH 3) S, S; R, R HCl 263 96 H CH3 2-Cl 3 -CH3 S, S; R, R; HCl 365 97 H CH3 5-F 2 -CH, 5.5; HCl 260

<tb> 98 <SEP> H <SEP> CH3 <SEP> H <SEP> 2-CH3 <SE> S, <SE>S;<SEP> R, <SEQ> R <SEP> HCl <SEP> 252
<Tb>

99! H II CH3 H 2, 5- (CH3) S, S; R, R HCl 251

99! CH 3 H 2, 5- (CH 3) S, S; R, R HCl 251

<tb> 100 <SEP> H <SEP> CH3 <SEP> H <SEP> 2,4- <SEP> (CH3) 2 <SEP> S, <SEP>S;<SEP> R, <SEQ> R <SEP> HCl <SEP> 246
<tb> 101 <SEP> H <SEP> CH3 <SEP> 4 -Br <SEP> 2- <SEP> (CH2) 2CH3 <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> HCl <SEP> 172-174
<tb> 102 <SEP> H <SEP> CH3 <SEP> 2-Cl, <SEP> 6-F <SEP> 3-CH3 <SEP> S, <SEP> S <SEP>;<SEP> R, <SEP> R <SEP> HCl <SEP> 149-150
<Tb>

103; H CH3 3,5-Cl.. 4-C6H, S,S;.,. HCl 163-165 104' H CH3 4-Cl 3- (4-F-C6H4) 5,5; tfa ; 176

103; CH3 3,5-Cl, 4-C6H, S, S; HCl 163-165; CH3 4 -Cl 3- (4-F-C6H4) 5.5; tfa; 176

<tb> 105, <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3- <SEP> (thianthren-1-yl) <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> tfa <SEP> 146.5
<tb> 1061 <SEP> H <SEP> CH3 <SEP> 4-ci <SEP> 3-C6H5 <SEP> S, <SEP>S;<SEP> R, <SE> R <SEP> tfa <SEP>, <SEP> 147
<Tb>

<Desc / Clms Page number 33>

X , R1 R , R3 Stéréo Sel F ( C)

X, R1 R, R3 Stereo Salt F (C)

<tb> 107 <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3- <SEP> (4-OCF3-C6H4) <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> tfa <SEP> 169.5
<tb> 108 <SEP> H <SEP> CH3 <SEP> 4-CI <SEP> 3- <SEP> (3-F-4-C6H5-C6H3) <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> tfa <SEP> 129
<Tb>

109', H CH3 4-Cl ! 3- ( 3-Cl-4-F-C6H3) S, S; R, R) tfa 145

109 ', H CH3 4-Cl! 3- (3-Cl-4-F-C6H3) S, S; R, R) tfa 145

<tb> 110 <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3- [3,5- (CF3) 2-C6H3] <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> - <SEP> 115
<tb> 111 <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3- <SEP> (benzo [b] thien-3-yl] <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> tfa <SEP> 132
<tb> 112 <SEP> H <SEP> CH3 <SEP> 2-C1 <SEP> 3- (benzo [b] thien-3-yl) <SEP> S, S; R, R <SEP> HCl <SEP > 215-216
## STR3 # SEP> 5-276, <SEP> 5 <SEP>
<tb> 114 <SEP> H <SEP> CH3 <SEP> 2-C1 <SEP> 5- (thien-3-yl) <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> HCl <SEP> 292
<tb> 115, <SEP> H <SEP> CH3 <SEP> 3-C1 <SEP> 4- <SEP> (thien-2-yl) <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> HCl <SEP> 210-215
<tb> 116 <SEP> H <SEP> CH3 <SEP> 4-CI <SEP> 3- <SEP> (thien-3-yl) <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> HCl <SEP> 138-140
<tb> 117 <SEP> H <SEP> HC3 <SEP> 4-Cl <SEP> 3- <SEP> (thien-2-yl) <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> HCl <SEP> 156-158
<tb> 118 <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3- (3-CF3-C6H4) <SEP> S, <SEP>S;<SEP> R <SEP> R <SEP> HCl <SEP> 151
<Tb>

119', H 1 CH3 4-Cl 3- ( 4-OCHZCH3-C6H ) I i S, S; R, R' HCl 182 120 H î CH 4-CI j 3-(3-Cl-C6H4) 1 S,S;R,R HCl 164 121 H CH3 4-Cl 3- ( 4-SCH3-C6H4 ) 5,5;,! HC1 212

119 ', H 1 CH 3 Cl-3- (4-OCH 2 CH 3 -C 6 H), S, S; R, R 'HCl, CH 2 Cl 2 CH 3 Cl 3 (C 1 -C 6 H 4) 1 S, S; R, R HCl 164 121 H CH 3 Cl-3- (4-SCH 3 -C 6 H 4) 5, 5;,! HC1 212

<tb> 122 <SEP> H <SEP> CH3 <SEP> 4-ci <SEP> 3- (4-CF3-C6H4) <SEP> S, <SEP>S;<SEP> R, <SEQ> R <SEP> HCl <SEP> 167
<tb> 123 <SEP> H <SEP> CH3 <SEP> 4-CI <SEP> 3- (4-CH3-C6H4) <SEP> S, <SEP>S;<SEP> R, <SEP> R <SEP> HCl <SEP> 268
<tb> 124 <SEP> H <SEP> CH3 <SEP> 4-CI <SEP> 3- (4-CH3CH3-C6H4) <SEP> S, <SEP>S;<SEP> R, <SEQ> R <SEP> HCl <SEP> 218
<Tb>

125, H CH3 4-CI 3- ( 2-C1-CHQ ) S,S;R,R: 1 HCl , 217

125, CH3 4- (3- (2-C1-CH)) S, S; R, R: 1 HCl, 217

<Desc / Clms Page number 34>

<tb> N <SEP> X <SEP> R1 <SEP> R2 <SEP> R3 <SEP> Stereo <SEP> Salt <SEP> F <SEP>(<SEP> C) <SEP>
## STR2 ## SEP> 221
<tb> 127 <SEP> H <SEP> CH3 <SEP> 4-Cl <SEP> 3- <SEP> (3-OCH3-C6H4 <SEP> S, <SEP>S;<SE> R, <SEP> R <SEP> HCl <SEP> 182
<Tb>

128! H CH3 4-Cl ' 3- ( 4-CN-C6H4 ) S, S; 2?,* HC1 216 1291 H CH3 4-Cl i 3- (2, 3-C12-C6H3) S, S; R, R HC1 294 130 H CH3 4-Cl 1 3- ( 3, 4-C1z-C6H3) S,S;R,R HC1 239 1311 H CH3 4-Cl 3- (4-C6H,-C6H4) S, S; R, R HCl 235 132 H CH, 4-Cl 3- (3-C1, 6-OCH3-C6H3) S,S;R,R Hic1 179 1'. H ! CH3 4-Cl 3- (2, 4-C12-C6H3) S, S; R, R HCl 292 134 H , CH3 l 2-Cl, 6-F 3-CH3 1S,2S j HC1: 164-166 135 H CH3 j 4-Cl 3-S0NH2 Î 1R, 2R i HC1 281-287 136 H CH3 ', 4-C1 1 3-S02N (CH3) 1R 2R ' tfa 85-86 137 ; H li CH3 li 4-C1 l 3-S02N (CH,) 1S, 2S HCl 140-150 1381 H 1 CH3 4-Cl ! 3-SO2NH2 15,25 t 1 - : 135-137 139 H CH3 3-C1 4-C02CH3 5,5; R, R HC1 170-171 140 H CH, H 3-SO2CH3 5,5; R, Ri - 92-95 141 H CH3 H i 3- [ 3, 4- (OCH3) -C6H] S,S;R,R HCl 233

128! CH3 4-Cl '3- (4-CN-C6H4) S, S; Embedded image 2 - (2, 3-C12-C6H3) S, S; R, R HCl 294 130 H CH3 4-Cl 1 3- (3,4-C₁-C6HH) S, S; R, R HCl 239 1311 H CH3 4-Cl 3- (4-C6H, -C6H4) S, S; R, R HCl 235 132 H CH, 4-Cl 3- (3-Cl, 6-OCH3-C6H3) S, S; R, R H19171 '. H! CH3 4- (3- (2,4-C12-C6H3) S, S; R, R HCl 292.134H, CH3 1-2G, 6-F3-CH3 1S, 2SHCl: 164-166; 135H CH3; 4-Cl3-S0NH2; 1R, 2R1HCl; 281-287; 136H CH3 ', 4-C1 1 3-SO2N (CH3) 1R 2R' tfa 85-86137; ## STR2 ## 3-SO2NH2 15.25 t 1 -: 135-137 139 H CH3 3-C1 4-CO2CH3 5.5; R, R HCl 170-171 140 H CH, H 3 -SO 2 CH 3 5.5; R, R ', R', R, R, HCl 233, R3, R3 (OCH3) -C6H]

<Desc / Clms Page number 35>

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

Study of glycine transport in SK-N-MC cells expressing the native glytl human transporter.

[14C] glycine uptake is studied in SK-N-MC (human neuroepithelial cells) cells expressing the native human glytl transporter by measuring the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured in monolayer for 48 h in 0.02% fibronectin pretreated plates.

On the day of the experiment, the culture medium is removed and the cells are washed with Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4.

After 10 minutes of preincubation at 37 ° C. in the presence of either buffer (control lot) or test compound at different concentrations or 10 mM glycine (non-specific capture determination), 10 M [14C] glycine (activity specific 112 mCi / mmol) are then added. The incubation is continued 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 l of liquid scintillant and stirring for 1 h. The count is performed on a Microbeta Tri-luxTM counter. The effectiveness of the compound is determined by the IC50 concentration of the compound which decreases by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control group and the batch which received glycine at 10 mM.

The compounds of the invention, in this test, have a CI, 0 of the order of 0.001 to 10 M.

Ex vivo study of the inhibitory activity of a compound on the uptake of [14C] qlycine in mouse cortical homo-menate.

* Increasing doses of the test compound are administered orally (preparation by trituration of the test molecule in a mortar in a Tween / MethocelTM solution).

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 0.5% in distilled water) or intraperitoneally (dissolution of the test molecule in physiological saline or prepation by trituration in a mortar in a 0.5% solution of Tween / methocel in water, according to the solubility of the molecule) in male OF1 Iffa Crédo 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 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 rapidly removed on ice, weighed and stored at 4 ° C or frozen at -80 ° C. (in both cases the samples are kept for 1 day. maximum). Each sample is homogenized in Krebs-HEPES buffer pH 7.4 at 10 ml / g of tissue. 20 l 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 addition of 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.

An inhibitor of [14 C] glycine uptake will decrease the amount of radioligand incorporated in each homogenate.

The activity of the compound is evaluated by its ED50, a dose which inhibits 50% of [14 C] glycine uptake compared to the control group.

The most potent compounds of the invention in this test have an ED50 of 0.1 to 5 mg / kg intraperitoneally or orally.

Study of glycine transport in mouse spinal cord homogenate.

[14C] glycine uptake by the glyt2 transporter is studied in mouse spinal cord homogenate by measurement of radioactivity incorporated in the presence or absence of test compound.

After euthanasia of the animals (male OF1 Iffa Crédo mice weighing 20 to 25 g on the day of the experiment), the spinal cord

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 each animal is quickly removed, weighed and stored on ice. The samples are homogenized in Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid), pH 7.4, at 25 ml / g of tissue.

50 μl of homogenate are preincubated for 10 min at 25 ° C. in the presence of Krebs-HEPES buffer, pH 7.4 and of the compound to be studied at different concentrations, or of 10 mM glycine to determine the non-specific capture. [14C] 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 by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control group and the batch which received 10 mM glycine.

The compounds of the invention in this test have an IC50 of the order of 0.001 to 10 μM.

Ex vivo study of the inhibitory activity of a compound on the capture of [14C] qlycine in mouse spinal homogenate.

Increasing doses of the test compound are administered orally (preparation by trituration of the test compound in a mortar, in a 0.5% solution of Tween / MethocelTM in distilled water) or intraperitoneally (dissolved test compound). in physiological saline, or triturated in a mortar, in a solution of 0.5% Tween / Methocel ™ in distilled water) to male OF1 Iffa Crédo 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 as well as 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 marrows are removed rapidly, weighed and introduced into glass scintillation vials, stored in crushed ice or frozen at -80 ° C (in both cases). samples are

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 kept 1 day maximum). Each sample is homogenized in Krebs-HEPES buffer at pH 7.4 at 25 ml / g of tissue. 50 l of each homogenate are incubated for 10 min at room temperature in the presence of buffer.

Nonspecific uptake is determined by addition of 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 [14 C] glycine uptake will decrease the amount of radioligand incorporated in each homogenate.

The activity of the compound is evaluated by its ED50, an effective dose which inhibits 50% of [14 C] glycine uptake compared to the control group.

The best compounds of the invention have, in this test, an ED50 of 1 to 20 mg / kg, intraperitoneally or orally.

The results of the tests carried out on the compounds of the invention of configuration (1S, 2S) and their threo racemates of configuration (lR, 2R; 1S, 2S) in the general formula (I) of which R2 represents one or more atoms of halogens or trifluoromethyl groups show that they are inhibitors of glycine transporter glytl present in the brain, and this 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 (deficient 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 disorders, 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.

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The results of the tests carried out on the compounds of the invention of configuration (1R, 2R) and their configuration racemates (1R, 2R, 1S, 2S) in the general formula (I) of which R2 represents both an atom of halogen and an NR3R4 amino group show that they are inhibitors of the glycine transporter glyt2, mainly present 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 muscle contractures in rheumatology and acute spinal pathology, for the treatment of spastic contractures of medullary or cerebral origin, for the symptomatic treatment of acute and subacute pain. mild to moderate, for the treatment of severe and / or chronic pain, neurogenic pain and rebel pain, for the treatment of Parkinson's disease and Parkinson's symptoms of neurodegenerative or neuroleptic origin, for treatment primary and secondary generalized 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.

Therefore, the subject of the present invention is also pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a base or of a pharmaceutically acceptable salt or solvate, and in a mixture, where appropriate. with appropriate 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, intraocular administration.

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The unit dosage forms may be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches, suppositories. For topical administration we can consider ointments, lotions and eye drops.

Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the dosage form.

In order to prepare tablets, a pharmaceutical carrier which may be composed of diluents, for example lactose, microcrystalline cellulose or starch, and formulation adjuvants such as binders (polyvinylpyrrolidone), is added to the active ingredient, which may or may not be micronized. , 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 sulphate may also be added.

The production techniques can be direct compression, dry granulation, wet granulation or hot melt.

The tablets may be bare, sugar-coated, for example with sucrose, or coated with various polymers or other suitable materials. It can be designed to allow rapid, delayed or sustained release of the active ingredient through polymer matrices or specific polymers used in the coating.

To prepare capsules the active ingredient is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot melting), liquids or semisolids.

The capsules may be hard or soft, film-coated or not, so as to have a rapid, prolonged or delayed activity (for example for an enteric form).

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A composition in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.

Water-dispersible powders and granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and taste-correcting agents.

For rectal administration, suppositories prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols, are used.

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 ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives, or 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 the form of aqueous, alcoholic or aqueous-alcoholic solutions, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or gel, microemulsions, aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered.

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Finally, the pharmaceutical compositions according to the invention may contain, besides a compound of general formula (I), other active ingredients which may be useful in the treatment of the disorders and diseases indicated above.

Claims (5)

 in which R 1 represents either a hydrogen atom or a linear or branched (C 1 -C 7) alkyl group optionally substituted with one or more fluorine atoms, a (C 4 -C 7) cycloalkyl group or a (C 3 -C 7) group ) cycloalkyl (C1-C3) alkyl, either a phenyl (C1-C3) alkyl group, a (C2-C4) alkenyl group, or a (C2-C4) alkynyl group, X represents a hydrogen atom or a a plurality of substituents chosen from halogen atoms and trifluoromethyl, (C1-C4) linear or branched alkyl and (C1-C4) alkoxy groups, R2 represents either a hydrogen atom or one or more substituents selected from the group consisting of halogens and the (C1-C4) alkoxy, methylenedioxy and amino groups of the general formula NR4R5 wherein R4 and R5 each independently represent a hydrogen atom or a (C1-C4) alkyl group , or form, with the nitrogen atom which carries them, a pyrrolidine, piperidine, morpholine or piperazine ring, R3 represents one or more substituents selected from the following:

 1. Compound, as pure (1R, 2R) or (1S, 2S) optical isomer or as threo (1R, 2R, 1S, 2S) diastereoisomer, having the general formula (I) <Desc / Clms Page number 44>  (C1-C3) alkoxy (C1-C3) alkyl, (C1-C3) alkylaminocarbonyl, or form, with the nitrogen atom which carries 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 (C1-C3) alkyl, a (C1-C3) alkylsulfonyl group, a carboxy or (C1-C3) alkoxycarbonyl group, or a group of general formula CONR6R7 in which R6 and R7 are as defined above, either an acetyl or benzoyl group, a cyano group or a (C1-C4) alkyl group, or a phenyl group substituted or not by one or more substituents chosen from the atoms of halogen, the (C1-C3) alkoxy groups, the methylthio group, the trifluoromethyl group, the trifluoromethoxy group, the cyano group, the (C1-C4) alkyl groups and the phenyl group, or a thienyl, benzothienyl or thianthrenyl group, base state or acid addition salt.

 or a group of general formula S02NR6R7 in which R6 and R7 each independently represent a hydrogen atom or a linear or branched or cyclic (C1-C3) alkyl (C1-C4) alkyl group, (C1-C3) alkylamino (C1-C3) alkyl, 2. Compound according to claim 1, characterized in that it is of configuration 1S, 2S and in that R3 represents one or more substituents chosen from the groups (C1-C4) alkyls, cyano, S (C1-C3) alkyls. , optionally substituted phenyls, thienyl or thianthrenyl and R2 represents a hydrogen or halogen atom. 3. Compound according to claim 1, characterized in that it is of configuration 1R, 2R and R3 represents an aminosulphonyl group of general formula SO2NR6R7 or aminocarbonyl of general formula CONR6R7 and R2 represents one or more substituents chosen from among the atoms halogens and amino groups of the general formula NR4R5. 4. Drug characterized in that it consists of a compound <Desc / Clms Page number 45>  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.