MXPA06004266A - Derivatives of n-[phenyl(pyrrolidine-2-yl)methyl]benzamide and n-[(azepan-2-yl)phenylmethyl]benzamide, preparation method thereof and application of same in therapeutics - Google Patents

Abstract

The invention relates to compounds having general formula (I), wherein:n represents the number 1 or 3;R1 represents either H or a cycloalkyl, cycloalkylalkyl, phenylalkyl, alkenyl, alkynyl group;X represents either H or one or more substituents selected from among halogen atoms and the trifluoromethyl, alkyl and alkoxy groups;and R2 represents H, or one or more substituents selected from among the halogen atoms and the trifluoromethyl, alkyl, alkoxy, cycloalkyl, phenyl, cyano, acetyl, benzoyl, S-alkyl, alkyl-sulfonyl, carboxy and alkoxycarbonyl groups, or a group having formula NR3R4, SO2NR3R4 or CONR3R4, in which R3 and R4 each represent H or an alkyl or cycloalkyl group or, together with the nitrogen atom, form a pyrrolidine, piperidine or morpholine ring. The invention also relates to the use of said compounds in therapeutics.

Description

DERIVATIVES OF N- [PHENYL (PYROLYLIDIN-2-IL) METHYL] BENZAMIDE AND / V - [(AZEPAN-2-IL) FENILMETIL] BENZAMIDA, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS The subject of the present invention is compounds that correspond to the general formula (I): wherein: n represents the number 1 or 3, Ri represents either a hydrogen atom, or an alkyl group d. C7 linear or branched, optionally substituted by one or more fluorine atoms, either a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl-C3 alkyl group, or a phenyl-C3 alkyl group, optionally substituted with one or two methoxy groups, either a C2-C4 alkenyl group, or a C2-C4 alkynyl group, X represents either a hydrogen atom, or one or more substituents chosen from the halogen atoms and the trifluoromethyl groups, alkyls d-C6 and d-C6 alkoxy, linear or branched, R 2 represents either a hydrogen atom, or one or more substituents chosen from halogen atoms, and trifluoromethyl, d-C 6 alkyls, d-C 6 alkoxy, linear or branched, C 3 -C 7 cycloalkyls, phenyl, cyano, acetyl groups, benzoyl, S-alkyls d-C6, (d ~ C6) alkylsulfonyls, carboxy and (d-C6) alkoxycarbonyls, or a group of general formula NR3R4, S02NR3R4 or CONR3R4, in which R3 and R4 represent each, independently of each other, a hydrogen atom or a linear or branched d-C6 alkyl group or cycloalkyl C3-C7, or form, with the nitrogen atom that supports them, a pyrrolidino, piperidino or morpholino cycle. The compounds of general formula (I) can exist in the form of racemes threo (1 R.2R; 1 S.2S) or erythro (1S, 2R; 1 R.2S) or in the form of enantiomers; they can exist in the state of free bases or addition salts to acids. Compounds of analogous structure to that of the compounds of the invention are described in patent US-5254569 as analgesics, diuretics, anticonvulsants, anesthetics, sedatives, cerebroprotectors, by a mechanism of action on opioid receptors. The compounds of the invention exhibit a particular activity as specific inhibitors of glycine transporters glytl and / or glyt2. The compounds of general formula (I) in which R ^ is different from a hydrogen atom can be prepared by a process illustrated by scheme I below.

Scheme 1 A coupling of a diamine of general formula (II) of relative configuration threose or erythro or in mixture is carried out, in which R-y and X are as defined above (with R ^ different from a hydrogen atom) with an activated acid or an acid chloride of the general formula (III) in which Y represents a nucleofugic group, such as a halogen atom and R2 is as defined above, using methods known to the person skilled in the art. The compounds of general formula (i) erythro or threo can be obtained pure according to all methods known to the person skilled in the art, for example by separation by high performance liquid chromatography. For n = 1 with Ri different from the hydrogen atom and X as defined above, the diamine of general formula (II), of relative configuration treo or erythro or in mixture, can be prepared by the procedure illustrated in scheme 2 way A. Ketone IV in which P represents Boc up to erythro / threo alcohol (X) can be reduced, the ratio of which depends on the nature of the hydride used according to the method described in J. Chem. Soc. Chem. Commun. , 1986, 412-413. The protective group is then removed according to a conventional method, in a mixture of dichloromethane and trifluoroacetic acid. In this way, the amino alcohol (XI) is obtained, on which it is then proceeded to one? -alkylation by means of a halogenated derivative of formula R-iZ, and of a base of the potassium carbonate type to give the functionalized aminoalcohol of general formula (XII). Finally in the classic Mitsunobu conditions, according to a method described in Bull. Soc. Chim. Belg. (106), 1997, 77-84 in the presence of hydrazoic acid and triphenylphosphine, the diamine of general formula (II) is obtained.

Scheme 2 (XH) For n = 1 with R ^ = CH3 and X as defined above, it is also possible to obtain the diamine of general formula (II), of relative configuration thre or erythro or in mixture, according to routes B and B 'of the Scheme 2 and according to scheme 3. In accordance with route B, the ketone (IV) is reacted wherein X is as defined above, with the benzylhydroxylamine hydrochloride at pyridine reflux to provide a mixture of oxime (V) which is deprotected with trifluoroacetic acid to obtain the free amine (VI). The methylation of pyrrolidine is conventionally effected at reflux of formaldehyde and formic acid to generate the compound (VII).

Finally, the hydrogenation catalyzed by palladium on carbon of this compound, in an alcohol solvent in the presence of aqueous hydrogen chloride, leads to the diamine of general formula (II). According to route B ', the ketone of general formula (IV) in which P represents C02Et and X can be reacted as defined above, with the benzylhydroxylamine hydrochloride at reflux of ethanol to provide a mixture of oximes (HIV) on which a palladium-catalyzed hydrogenation is carried out on carbon in an alcohol solvent in the presence of aqueous hydrochloric acid to provide the carbamate (IX). The reduction of the carbamate of the general formula (IX) by lithium aluminum double hydride at reflux of a solvent such as ether leads to the diamine of the general formula (11). According to scheme 3, the aminoalcohol (XIII) is transformed into nitride (XIV) under the classical conditions of Mitsunobu, according to a method described in J. Org. Chem., (64), 1999, 6106-61 1 1. The reduction of the carbamate nitride (XIV) by double lithium aluminum hydride at reflux of a solvent such as tetrahydrofuran leads to a mixture of diamines of general formula (II).

Scheme 3 The diamine of general formula (II) of threor or erythro relative configuration in which R ^ is different from a hydrogen atom and n = 3 can be prepared by a process illustrated in scheme 4 below.

Scheme 4 (XXII) (XX) (II, R1 = CH3) 25 (II, n = 3) The alpha-lithiation of the azepane of the general formula (XVI) is carried out in which Boc represents a 1,1-dimethylethoxycarbonyl group, by sec-butyl lithium in the presence of TMEDA (?.? /.? / '.' '-tetramethylethylenediamine) in an ether solvent such as diethyl ether at -78 ° C, to react the lithiumamine formed in situ on the benzaldehyde of general formula (XVII) according to a method described in J. Org. Chem., (58), 5, 1993, 1 1 09-1 1 1 7. A mixture of alcohol of general formula (XVIII) of erythro configuration and cyclic carbamate of general formula (XIX) of threo configuration is thus obtained. The carbamate of general formula (XVIII) of erythro configuration can then be reduced to erythro-methylaminoalcohol of general formula (XXII) by the action of a mixed hydride such as lithium aluminum double hydride, in an ethereal solvent such as tetrahydrofuran, between the ambient temperature and the reflux temperature. The erythro alcohol of general formula (XXII) is then transformed into the erythro intermediate of general formula (II) in which R1 represents a methyl group, in two stages: first, the alcohol function is transformed into a nucleophilic group, for example, a methanesulfonate group, by the action of mesyl chloride, in a chlorinated solvent such as dichloromethane, and in the presence of a base such as triethylamine, between 0 ° C and room temperature, and then the nucleophilic group is reacted with liquefied ammonia to - 50 ° C, in an alcohol such as ethanol, in a closed medium such as an autoclave, between -50 ° C and room temperature. The carbamate of the general formula (XVII I) of erythro configuration can also be deprotected by means of a strong base such as aqueous potassium hydroxide, in an alcohol such as methanol to obtain the corresponding aminoalcohol of the general formula (XI II). In the same hydrolysis conditions, the cyclic carbamate threo of the general formula (XIX) leads to the threo amino alcohol of the general formula (XX). Then, N-alkylation is carried out by means of a halogenated derivative of formula RZ, in which R ^ is as defined above, but different from a hydrogen atom, and Z represents a halogen atom, in the presence from a base such as potassium carbonate, in a polar solvent such as? /,? / - dimethylformamide, between room temperature and 100 ° C to lead to the alkylated derivative of general formula (XXI). The latter is then treated as described with respect to the alcohol of general formula (XXII). The compounds of the general formula (I), in which R represents a hydrogen atom, can be prepared from a compound of the general formula (I) in which R ^ represents either an optionally substituted phenylmethyl group and deprotecting the nitrogen of the piperidine cycle, for example by an oxidizing agent or by a Lewis acid such as boron tribromide, or by hydrogenolysis or an alkenyl group, preferably allyl, followed by a deprotection by a Pd ° complex to obtain a compound of the formula general (I) in which Ri represents a hydrogen atom. In addition, the chiral compounds of the general formula (I) can be obtained either by separating the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column, either from the obtained chiral amine or by splitting of the racemic amine of the general formula (II) by use of a chiral acid, such as tartaric acid, camphorsulfonic acid, dibenzoyltartaric acid,? acetyl-leucine, by fractional recrystallization and preferably of a diastereomeric salt in an alcohol type solvent, or by chiral synthesis according to the B 'or A pathway from the ketone of the general formula (IV) chiral of scheme 2, also from the chiral alcohol of general formula (XIII) of scheme 3. The ketone of the general formula (IV) racemic can be prepared according to a method described in Tetrahedron Lett., (38) (5), 1997, 783-786; Tetrahedron, (59), 2003, 1083-1094. In a chiral series, the ketone of the general formula (IV) or the chiral alcohols of the general formulas (X) or (XIII) can be prepared according to a method described in the international patent application WO03004468 and in J. Chem. Soc. Perkin Trans I, 1987, 1465-1471. The perhydroazepine of the general formula (XVI) can be prepared according to a method described in J. Org. Chem., (58), 5, 1 993, 1 1 09-1 1 17; The following examples illustrate the preparation of some compounds of the invention. The elementary microanalyses, and the I.R. and R.M.N. and HPLC on a chiral column confirm the structures and enantiomeric purities of the obtained compounds.

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 hyphen "-" is part of the word, and the hyphen "_" is only useful for the cut at the end of the line; It must be eliminated in the absence of a cut and should not be replaced by a normal script or by a space. Example 1 (Compound No. 1) Threo-2-chloro-β / - [(1-methylpyrrolidin-2-yl) phenylmethyl] -3-trifluoromethylbenzamide hydrochloride 1: 1. eleven . 2 - [[(Benzyloxy) imino] (phenyl) methyl] pyrrolidin-1-tert-butylcarboxylate. In a 1000 ml round bottom flask equipped with magnetic stirring, 8.8 g (31.36 mmol) of 2-benzoylpyrrolidin-1-butyl-butylcarboxylate and 5.6 g (35.1 5 mmol) of benzylhydroxylamine hydrochloride were introduced into the flask. solution in 100 ml of absolute ethanol and 35 ml of 1 M sodium hydroxide and heated to reflux for 16 h. After evaporation to dryness of the reaction medium under reduced pressure, the residue was diluted in water and dichloromethane, the aqueous phase was separated, and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporation of the solvent under reduced pressure, the residue was purified by chromatography on a column of silica gel, eluting with a mixture of ethyl acetate and cyclohexane. This gave 8 g of product in the form of an oil. 1 .2. Phenyl (pyrrolidin-2-yl) methanone O-benzyl oxime In a 500 ml round bottom flask equipped with magnetic stirring, 8 g (20 mmol) 2 - [[(benzyloxy) imino] (phenyl) -methyl] were introduced. pyrrolidin-1-re-butylcarboxylate in solution in 400 ml of a mixture of 30% trifluoroacetic acid in dichloromethane and stirred 4 h at room temperature. After evaporation to dryness of the reaction medium under reduced pressure, the residue was diluted in ammonia and dichloromethane, the aqueous phase was separated, and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporation of the solvent under reduced pressure, the residue was purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 4 g of product were obtained. 1.3 (1-methylpyrrolidin-2-yl) (phenyl) methanone O-benzyl oxime. Into a 50 ml round bottom flask equipped with magnetic stirring, 1.2 g (4.28 mmol) of phenyl (pyrrolidin-2-yl) methanone O-benzyl oxime were introduced into 4 ml of a mixture (1/1). of formic acid and 37% aqueous formaldehyde and heated to reflux for 16 h. After evaporation to dryness of the reaction medium under reduced pressure, the residue was diluted in ammonia and dichloromethane, the aqueous phase was separated, and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporating the solvent under reduced pressure, the residue was purified by chromatography on a column of silica gel eluting with a mixture of dichloromethane and methanol. 1.05 g of product were obtained. 5 1 .4 [(1-methylpyrrolidin-2-yl) phenyl) methyl] amine.

In a Parr reactor under a nitrogen atmosphere, 0.05 g (3.56 mmol) of (1-methylpyrrolidin-2-y) (phenol) methanone O-benzyl oxime in solution in a mixture of 20 ml of ethanol and 1 ml were placed. 0 ml of 1 N hydrochloric acid in the presence of a 10% palladium-on-carbon spatula tip. The reagents were placed under a hydrogen atmosphere and stirred for 8 h. After filtration of the catalyst and evaporation of the filtrate under reduced pressure, the residue was diluted in ammonia and dichloromethane, the aqueous phase was separated, and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporating the solvent under reduced pressure, 0.54 g of product was obtained in the form of an oil which was used crude in the next step. 1.5 Hydrochloride of threo-2-chloro-? - [(1-methylpyrrolidin-2-yl) phenylimethyl] -3-trifluoromethylbenzamide 1: 1. In a 1 00 ml round bottom flask, under a nitrogen atmosphere, 0.54 g (2.84 mmol) of [(1-methylpyrrolidin-2-yl) phenyl) methyl] amine and 0.41 g of potassium carbonate in solution in 7 ml of dichloromethane at 0 ° C were placed. A solution of 0.72 g (2.97 mmol) of 2-chloro-3-trifluoromethylbenzoic acid chloride in solution in 3 mL of dichloromethane was added and left at room temperature for 16 h. The reaction mixture was diluted in water and dichloromethane, the aqueous phase was separated, and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporating the solvent under reduced pressure, the residue was purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. Thus, 10 mg of threo-2-chloro-β / - [(1-methylpyrrolidin-2-yl) phenyl methyl] -3-trifluoromethylbenzamide was isolated. The latter was dissolved in some my propan-2-ol, were added 6 ml of a 0.1 N solution of hydrochloric acid in propan-2-ol, and the mixture was concentrated under reduced pressure in order to reduce the volume of the solvent. After trituration, 0.1 g of hydrochloride was finally isolated in the form of a solid. Melting point: 96-1 10 DC Example 2 (compound No. 2) Threo-4-amino-3,5-dichloro -? / - [(1-methylpyrrolidin-2-yl) phenylmethylbenzamide 1: 1 hydrochloride. In a 100 ml round bottom flask equipped with magnetic stirring, 0.975 g (4.73 mmol) of 4-amino-3,5-dichlorobenzoic acid, 0.639 g (4.73 mmol) of hydroxybenzotriazole 0.906 g (4.73 mmol) of hydrochloride were added. 1 - [3- (dimethylamine) propyl] -3-ethylcarbodiimide in solution in 50 ml of dichloromethane. It was left 30 min. at room temperature and 0.9 g (4.73 mmol) of [(1-methylpyrrolidin-2-yl) phenyl) methyl] amine was added in solution in 20 ml of dichloromethane and left at room temperature overnight. After hydrolysis with water and dilution with dichloromethane, the aqueous phase was separated and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporation of the solvent under reduced pressure, the residue was purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.19 g of oily product was obtained. The latter was dissolved in a few ml of propan-2-ol, 20 ml of a 0.1 N solution of hydrogen chloride in propan-2-ol was added, and the mixture was concentrated under reduced pressure in order to reduce the volume of the solvent. After trituration, 0.1 9 g of hydrochloride was finally isolated in the form of a solid. Melting point: 155-273 DC Example 3 (Compound No. 3). Treo- - [(1-Iylpyrrolidin-2-yl) phenyl-methyl] -2-chloro-3-triflu or romethyl benza mida eleven . 3.1. Erythro-2- [hydroxy (phenylmethyl] pyrrolidin-1-ferrobutylcarboxylate.

In a 250 ml three-necked flask equipped with magnetic stirring, under a nitrogen atmosphere, 3 g (10.89 mmol) of fer-butyl 2-benzoylpyrrolidin-1-carboxylate were placed in solution in 10 ml of tetrahydrofuran at -70. ° C. 29 mL (43.58 mmol) of a 1.5 M diisobutylaluminum hydride solution in toluene was added dropwise. It was left for 2 hours at -70 ° C and allowed to rise to -20 ° C. It was then hydrolyzed with caution with 50 ml of methanol. After evaporation of the reaction mixture under reduced pressure, the residue was diluted with 1N hydrochloric acid and dichloromethane, the aqueous phase was separated, and extracted with dichloromethane. After washing of the combined organic phases, drying over sodium sulfate and evaporation of the solvent under reduced pressure, 2.8 g of a mixture containing mostly the diastereoisomer erythro-2- [hydroxy (phenylmethyl) pyrrolidine-1-carboxylate) were obtained. -butyl which was used crude in the next step 3.2 Erythro-phenyl (pyrrolidin-2-yl) methanol trifluoroacetate In a 250 ml round bottom flask equipped with magnetic stirring, 5 g (21 g) were placed (21 g. .99 mmoles) of erythro-2- [hydroxy (phenylmethyl] -pyrrolidin-1-ferrobutylcarboxylate in solution in a mixture of 75 ml of dichloromethane and 30 ml of trifluoroacetic acid and the mixture was stirred. The reaction medium was evaporated under reduced pressure to obtain 5 g of a mixture containing erythro-phenyl (pyrrolidin-2-yl) methanol trifluoroacetate which was used in the next step. (1-alkylpyrrolidinyl-2-yl) phenyl) meta nol. In a 250 ml round bottom flask equipped with magnetic stirring, 5 g (17.16 mmoles) of erythro-phenyl (pyrrolidin-2-yl) methanol trifluoroacetate, 5.9 g (43 mmol) of carbonate were placed. of potassium and 1.8 ml (20.6 mmoles) of allyl bromide in solution in 50 ml of acetonitrile, and stirred at room temperature for 16 h. After evaporation to dryness of the reaction medium under reduced pressure, the residue was diluted in ammonia and dichloromethane, the aqueous phase was separated and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporation of the solvent under reduced pressure, the residue was purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol.

Thus, 1.1 g of a mixture containing erythro- (1-allylpyrrolidinyl-2-yl) phenyl) methanol was obtained. 3.4. Erythro - [(1-alkylpyrrolidinyl-2-yl) phenyl) methyl] amine. In a 1 00 ml three-necked flask equipped with magnetic stirring under a nitrogen atmosphere, 1.1 g (5.06 mmol) of erythro-1 - (allyl pyrrolidinyl-2-yl) phenyl) methanol and 1.6 g (6.07 g) were placed. mmoles) of triphenylphosphine in solution in 15 ml of tetrahydrofuran. 6 ml of a 1 M solution in benzene (6 mmoles) of hydrazoic acid was added. To this solution was added, dropwise, a solution of 1.09 ml (0.56 mmoles) of diisopropylcarbodiimide in 10 ml of tetrahydrofuran. The mixture was heated at 40 ° C for 16 h, then 1.3 g (5.06 mmol) of triphenylphosphine was added, the mixture was stirred for 30 min, then 0.6 ml of water was added and stirring was continued for 6 h. It was hydrolyzed with 1 N hydrochloric acid and diluted with chloroform. The aqueous phase was basified with ammonia and extracted several times with chloroform. After washing the combined organic phases, drying over sodium sulphate and evaporation of the solvent under reduced pressure. 1 g of an orange oil containing threo - [(1-allylpyrrolidinyl-2-yl) phenyl) methyl] amine was obtained which was used crude in the next step. 3.5 Treo-V - [(1-allylpyrrolidin-2-yl) phenyl-methyl] -2-chloro-3-trifluoro-methylbenzamide According to the procedure described in Example 1 .5, starting from 1 g (4.62) mmoles) of threo [(1-alkylpyridin-2-yl) phenyl) methyl] amine, 1.13 g (4.62 mmol) of 2-chloro-3-trifluoromethylbenzoic acid chloride and 0.64 g (4.62 mmol) of potassium carbonate , 20 mg of an oil that crystallized was obtained. Melting point: 17-123 ° C. EXAMPLE 4 (Compound No. 4) 3- (Aminosulfonyl) -4-chloro -? / - [(S) - [(2S) -1-methy1-pyrrolidin-2-yl] hydrochloride ( phenyl) methyl] benzamide 1: 1. 4.1. 2 - [(Benzyloxy) imino] phenylmethylpyrrolidin-1-ethylcarboxylate. In a 100 ml round bottom flask equipped with magnetic stirring, 1.36 g (5.5 mmol) of ethyl 2-benzoylpyrrolidin-1-carboxylate in 30 ml of ethanol was added and 1.75 g was added ( 0.96 mmole) of benzylhydroxylamine hydrochloride and the mixture was heated under reflux for 12 h. After evaporation of the solvent under reduced pressure, the residue was taken up in ethyl acetate and the organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. 1.95 g of a yellow oil was obtained which was purified by chromatography on a column of silica gel eluting with a mixture of ethyl acetate and cyclohexane. 1.56 g of product were obtained. 4.2 (S) -2 - [(S) -amino (phenyl) methyl] pyrrolidin-1-ethylcarboxylate and ethyl [phenyl (-pyrrolidin-2-yl) methyl] carbamate. In a Parr reactor of 250 ml, 1.56 g (4.43 mmol) of ethyl [(benzyloxy) imino] phenylmethylpyrrolidin-1-carboxylate were introduced into 40 ml of ethanol and 8 ml of acid. 1 N hydrochloric acid, 0.15 g of palladium on carbon at 10% was added and the mixture was placed under a hydrogen atmosphere for 7 h. After filtration of the catalyst and evaporation of the filtrate under reduced pressure, the residue was diluted in ammonia and dichloromethane, the aqueous phase was separated, and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporating the solvent under reduced pressure, 1 g of a mixture containing (S) -2 - [(S) -amino (phenyl) methyl] pyrrolidin- was obtained. 1-ethyl carboxylate and ethyl [phenyl (-pyridinidin-2-yl) methyl] carbamate, which were used crude in the next step. 4.3 [(S) - [(2S) - (1-methylpyrrolidin-2-yl)] phenyl) methyl] amine. In a 100 ml round bottom flask equipped with magnetic stirring, under a nitrogen atmosphere, 1 g (4 mmol) of the mixture containing (S) -2 - [(S) -amino (phenyl) methyl] pyrrolidin was introduced. Ethyl-1-carboxylate and ethyl [phenyl (pyrrolidin-2-yl) methyl] carbamate in 20 ml of anhydrous ether at 0 ° C. 0.8 g (21 mmol) of lithium aluminum double hydride was added in portions and heated to reflux for 5 h. After cooling, it was treated successively with 0.8 ml of water, 0.8 ml of 15% sodium hydroxide and 2.4 ml of water. After filtration over Celite®, the filtrate was concentrated under reduced pressure. The obtained residue (0.7g) was purified by chromatography on a column of silica gel eluting with a mixture of dichloromethane of methanol and ammonia. 0.12 g of product were obtained as a yellow oil. 4.4 3- (Aminosulfonyl) -4-chloro -? / - [(S) - [(2S) -1-methylpyrrolidin-2-yl] (phenyl) methyl] benzamide hydrochloride 1: 1. According to the operating mode described in example 2, starting from 0.12 g (0.63 mmol) of [(S) - [(2S) - (1-methylpyrrolidin-2-yl)] phenyl) methyl] amine, 0.12 g ( 0.63 mmol) of 1- (3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, 0.085 g (0.63 mmol) of hydroxybenzotriazole and 0.14 g (0.63 mmol) of 4-chloro-3-sulfonylbenzoic acid were obtained after for treatment and purification by chromatography on silica gel with a gradient of dichloromethane and methanol, 0.12 g of 3- (aminosulfonyl) -4-chloro -? / - [(S) - [(2S) -1-methylpyrrolidin -2-yl] (phenyl) methyl] benzamide. The latter was dissolved in a few ml of propan-2-ol, 20 ml of a 0.1 N solution of hydrogen chloride in propan-2-ol was added, and the mixture was concentrated under reduced pressure in order to reduce the volume of the solvent. After trituration, 0.09 g of hydrochloride was finally isolated in the form of a white solid. Melting point: 165-273 ° C. Example 5 (Compound No. 5) Erythro-4-amino-3-chloro-? / - f1-methylpyridin-lidinyl-2-yl] (phenyl) methyl hydrochloride] -5 - (trifluoromethyl) benzamide 1: 1 5.1 Erythro- [azido (phenyl) methyl] pyrrolidin-1-ethylcarboxylate. In a 500 ml three-necked flask equipped with magnetic stirring under an argon atmosphere, 2.9 g (11.6 mmol) of threo- [hydroxy (phenyl) methyl] pyrrolidin-1-ethylcarboxylate in solution was placed in 150 ml. tetrahydrofuran at 0 ° C. 4.57 g (17.4 mmoles) of triphenylphosphine and 35 mmoles of a solution of hydrazoic acid in toluene were added. 2.74 ml (17.4 mmol) of ethyl azidodicarboxylate was added dropwise and the mixture was stirred for 24 h. 1N sodium hydroxide was added and the taken-over mixture was taken up in ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. 10 g of a residue was obtained which was purified by chromatography on silica gel with a gradient of cyclohexane and ethyl acetate. There was thus obtained 1.17 g of erythro- [azido (phenyl) methyl] pyrrolidin-1-ethylcarboxylate. 5.2 Erythro - [(1-methylpyrrolidin-2-yl) phenyl) methyl] amine. In a 100 ml three-necked flask equipped with magnetic stirring under argon, 0.8 g (21.32 mmol) of lithium aluminum hydride in 25 ml of tetrahydrofuran was placed and a solution of 1.17 g (4.26 g) was added. mmoles) of erythro [azido (phenyl) methyl] pyrrolidin-1-ethylcarboxylate in 10 ml of tetrahydrofuran and the mixture was heated at 70 ° C for 2 h. After cooling, it was treated successively with 0.8 ml of water, 0.8 ml of 15% sodium hydroxide and 2.4 ml of water. After filtration over Celite®, the filtrate was evaporated under reduced pressure and the residue was purified by chromatography on silica gel with a mixture of dichloromethane, methanol and ammonia. 0.16 g of erythro - [(1-methylpyrrolidin-2-yl) phenyl) methyl] amine were thus obtained and 0. 1 5 g of [methylphenyl (pyrrolidinyl-2-yl) methyl] amine. 5.3 erythro-4-amino-3-cycloo -? - [1-methyl-pyrrolidinyl-2-yl] (phenyl) -methyl] -5- (trifluoromethyl) -benzamide hydrochloride 1: 1 According to the mode described in Example 2, starting with 0.073 g (0.38 mmol) of erythro (1-methylpyrrolidin-2-yl)] phenyl) methyl] amine, 0.074 g (0.38 mmol) of hydrochloride of 1- [3- (dimethylammono) propyl] -3-ethylcarbodimamide, 0.052 g (0.38 mmol) of hydroxybenzotriazole and 0.092 g (0.63 mmol) of 4-amino-3-chloro-5-trifluoromethylbenzoic acid, obtained after treatment and purification by chromatography on silica gel with a gradient of dichloromethane and methanol, 0.089 g of erythro-4-amino-3-chloro -? / - [1-methylpyrrolidinyl-2-yl] (phenyl) methyl] -5- (trifluoromethyl) benzamide. The latter was dissolved in a few ml of propan-2-ol, 20 ml of a 0.1 N solution of hydrogen chloride in propan-2-ol was added, and the mixture was concentrated under reduced pressure in order to reduce the volume of the solvent. After trituration, 0.07 g of hydrochloride was isolated in the form of a white solid. Melting point: 130-273 ° C Example 6 (Compound No. 6) 3- (Aminosulfonyl) -4-chloro -? / - [(R) - [(2S) -1-methylpyrrolidin-2-yl] hydrochloride] (phenyl) methyl] benzamide 1: 1. Using the synthesis method of Example 5 starting from the chiral threo amino (2S) -2- [2- (S) -hydroxy (pheny1) methyl] pyrrolidin-1-carboxylate amino acid, 0.12 g of hydrochloride of 3- ( aminosulfonyl) -4-chloro -? / - [(R) - [(2S) -1-methylpyrrolidin-2-yl] (phenyl) methyl] benzamide 1: 1. Melting point: 190-273 ° C Example 7 (Compound No. 7) ^ Erythro-2-chlorohydrochloride? - [(R) - [(2S) -1-methylazepan-2-yl] (phenyl) methyl] -3- (trifluoromethyl) benzamide 1: 1 7.1 2- [Hydroxy (phenyl) methyl] azepane-1-carboxylate of fer-butyl. In a 250 ml three-neck flask equipped with magnetic stirring under an argon atmosphere, 5 g (25.09 mmol) of fer-butyl azepane-1-carboxylate and 3.8 ml (25.09 mmol) of tetramethylenediamine in solution were placed in 30 ml. of anhydrous ether at -75 ° C. 21 ml (27.60 mmoles) of 1.3 M sec-butyllithium in cyclohexane were added dropwise. The temperature was allowed to rise to -50 ° C in 3 h (solution TO). In a 250 ml round bottom flask equipped with magnetic stirring under an argon atmosphere, 3.8 ml (37.63 mmol) of benzaldehyde were placed in 10 ml of anhydrous ether (solution B). The 2 solutions were cooled to -75 ° C and solution A was introduced into solution B controlling the temperature. After the end of the addition, it was allowed to rise to room temperature and left stirring overnight. After hydrolysis with a saturated solution of ammonium chloride, the aqueous phase was 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 was purified (1.0 g) by chromatography on a column of silica gel, eluting with a mixture of ethyl acetate and cyclohexane. There were thus obtained 2 g of fer-butyl 2- [hydroxy (phenyl) methyl] azepan-1-carboxylate. 7.2 (1-methylazepan-2-yl) phenyl) methanol.

Into a 100 ml two-necked flask under a nitrogen atmosphere, provided with magnetic stirring and provided with a refrigerant, was suspended in 10 ml of tetrahydrofuran 1.2 g (32.74 mmoles) of lithium double hydride and aluminum. A solution of 2 g (6.55 mmoles) of 2- [hydroxy (phenyl) methyl] azepan-1-fer-butylcarboxylate in 10 ml of tetrahydrofuran was added dropwise and heated to reflux for 5 h. After cooling, 5.5 ml of a 0.1 M solution of double potassium tartrate and sodium were added and stirred overnight at room temperature. After filtration of the insoluble under reduced pressure and rinsing with tetrahydrofuran, the filtrate was concentrated under reduced pressure. 1.36 g of an oil was obtained which was purified by chromatography on a column of silica gel, eluting with a dichloromethane mixture., methanol and ammonia. 0.95 g of (1-methylazepan-2-yl) phenyl) -methanol was obtained. 7.3 [(1 -MetiIazepan-2-yl) phenyl) methyl] amine. In a 100 ml round bottom flask under nitrogen atmosphere equipped with magnetic stirring were placed 0.95 g (4.33 mmol) of (1-methylazepan-2-yl) phenyl) methanol, 0.6 ml (4.33 mmol) of triethylamine in solution in 20 ml of dichloromethane at 0 ° C. 0.34 ml of mesyl chloride was added and stirred at room temperature for 3 h. After evaporation of the solvents under reduced pressure, the residue was taken up in 20 ml of ethanol and a solution of liquefied ammonia was added in an autoclave cooled to -50 ° C. The autoclave was closed and allowed to stir at room temperature for 48 h. The reaction mixture was diluted in water and dichloromethane. The aqueous phase was extracted 3 times with dichloromethane. After washing the combined organic phases, drying over sodium sulphate and evaporating the solvent under reduced pressure, 1.7 g of [(1-methylazepan-2-yl) phenyl) methyl] amine was obtained as an oil which used gross in the next stage. 7.4 Erythro-2-chloro -? / - (1-methylazepan-2-yl) (phenyl) methyl] -3- (trifluoromethyl) benzamide hydrochloride 1: 1. According to the operating procedure described in Example 2, starting from 1.7 g (7.79 mmol) of [(1-methylazepan-2-yl) phenyI) methyl] amine, 1.49 g (7.79 mmol) of hydrochloride of 1 - [3- (dimethylamino) propyl] -3-ethylcarbodiimide, 1.05 g (7.79 mmoles) of hydroxybenzotriazole and 1.74 g (7.79 mmoles) of 2-chloro-3-trifluorobenzoic acid were obtained after treatment and purification by chromatography on silica gel 0.8 g of erythro-2-chloro -? / - (1-methylazepan-2-yl) (phenyl) methyl] -3- (trifluoromethyl) benzamide. The latter was dissolved in a few ml of propan-2-oI, 20 ml of a 0.1 N solution of hydrochloric acid in propan-2-ol was added, and the mixture was concentrated under reduced pressure in order to reduce the volume of the solvent . After trituration, 0.48 g of hydrochloride was finally isolated in the form of a solid. Melting point: 124-273 ° C Table 1 below illustrates the chemical structures and melting points of some compounds of the invention. In the column "Salt", - designates a compound in the base state, "HCl", designates a hydrochloride and "tfa", designates a trifluoroacetate. Compound 7 exists as a mixture of erythro (7.5) and treo (2.5). t t H (l or Ul Table 1 r co t t H o o The compounds of the invention were subjected to a series of pharmacological tests that have shown their interest as substances with therapeutic activities. Study of glycine transport in SK-N-MC cells expressing the native glvtl human transporter. The capture of [14C] glycine in the SK-N-MC cells (human neuro-epithelial cells) expressing the native human glytl transporter is studied by measuring the incorporated radioactivity in the presence or absence of the compound to be tested. The cells are cultured in monolayer for 48 h in plaques pretreated with 0.02% fibronectin. On the day of the experiment, the culture medium is removed and the cells are washed with a Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazin-1-ethanesulfonic acid) at pH 7.4. After 10 min. of preincubation at 37 ° C in the presence of either buffer (control lot), either of compound to be tested at different concentrations or of 10 mM glycine (determination of non-specific capture), then 10 μM of [14 C] glycine was added (specific activity 1 12 mCi / mmoles). Incubation continued for 10 min. at 37 ° C, and the reaction was stopped with 2 washes with a Krebs-HEPES buffer at pH 7.4. The radioactivity incorporated by the cells was then estimated after adding 1 00 μl of scintillating liquid and stirring for 1 h.

The count was performed on Microbeta Tri-lux ™ counter. The efficacy of the compound was determined by the Cl50, concentration of the compound that decreases the glycine-specific capture by 50%, defined by the difference of radioactivity incorporated by the control lot and the batch that has received the glycine at 10 mM. The compounds of the invention, in this test, had an Cl 50 of the order of 0.01 to 10 μM. Study of the transport of glycine in the mouse spinal cord homogenate The capture of [14C] glycine by the glyt2 transporter in mouse spinal cord homogenate is studied by measuring the incorporated radioactivity in the presence or absence of the compound to study. After euthanasia of the animals (male OF1 Iffa mice Credo weighing 20 to 25 g on the day of the experiment), the spinal cord of each animal is quickly taken, weighed and stored on ice. The samples were homogenized in a Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethane sulfonic acid), pH 7.4, at a rate of 25 ml / g of tissue. 50 μl of homogenate was preincubated for 10 min. at 25 ° C in the presence of Krebs-HEPES buffer, pH 7.4 and compound to be studied at different concentrations, or 10 mM glycine to determine the non-specific capture. The [14 C] glycine (specific activity = 12mCi / mmol) was then added over 10 min. at 25 ° C to the final concentration of 10 μM. The reaction was stopped by vacuum filtration and the radioactivity was estimated by scintillation by counting in a Microbeta Tri-lux ™ counter. The efficacy of the compound was determined by the Cl50 capable of diminishing by 50% the specific capture of glycine, defined by the difference of radioactivity incorporated by the control lot and the batch that has received the glycine at 10 mM. The compounds of the invention, in this test, had an Cl 50 of the order of 0.1 to 10 μM. The results of the tests carried out on the compounds of the invention showed that they are inhibitors of the glycine transporter glytl present in the brain and glyt2 present in the marrow. These results suggest that the compounds of the invention can be used for the treatment of behavioral disorders associated with dementia, of psychosis, in particular of schizophrenia (deficient form and productive form) and of acute or chronic extrapyramidal symptoms induced by neurolepsies, for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders, for the treatment of different forms of depression, including psychotic depression, for the treatment of disorders due to alcohol abuse or abstinence, of sexual behavior disorders, of eating disorders, and for the treatment of migraine. In addition, the compounds of the invention can be used for the treatment of painful muscular contractures in rheumatology and acute rickets, for the treatment of spastic contractures of medullary or cerebral origin, for the symptomatic treatment of acute and subacute pains of light to moderate intensity , for the treatment of intense and / or chronic pains, neurogenic pains and rebel pains, for the treatment of Parkinson's disease and parkinsonian symptoms of neurodegenerative origin or induced by neurolepsies, for the treatment of generalized primary and secondary epilepsies, partial of simple or complex symptomatology, of mixed forms and other epileptic syndromes as a complement of another antiepileptic treatment, or in monotherapy, for the treatment of sleep apnea, and for neuroprotection. This is why the present invention also aims at pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the base or salt or pharmaceutically acceptable solvate state, and in a mixture, if necessary. , with suitable excipients. Said excipients are chosen according to the desired pharmaceutical form and mode of administration. The pharmaceutical compositions according to the invention can thus be used for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular administration. The 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 may be considered. Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active principle per kg of body weight, according to the galenic form.

To prepare tablets, a pharmaceutical carrier, which may be composed of diluents, such as lactose, microcrystalline cellulose, starch, and formulation adjuvants as binders, (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), is added to prepare tablets, whether micronized or not. fluence 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. Embodiment techniques can be direct compression, dry granulation, wet granulation or hot melt. The tablets may be bare, wrapped as dragees, for example by sucrose, or coated with various polymers or other appropriate materials. They can be designed to allow a rapid, delayed or prolonged release of the active principle thanks to polymer matrices or to specific polymers used in the coating. To prepare capsules, the active ingredient is mixed with dry pharmaceutical vehicles (simple mixture, dry or wet granulation, or hot melt), liquid or semi-solid. The capsules can be hard or soft, film or not, so as to have a rapid, prolonged or delayed activity (for example for an enteric form). A composition in the form of syrup or elixir or for administration in the form of drops may contain the active principle together with a sweetener, preferably a caloric sweetener, methylparaben or propylparaben as an antiseptic, a flavoring agent and a dye. Powders and granules dispersible in water may contain the active ingredient mixed with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, also with sweeteners or taste correction agents. For rectal administration, suppositories prepared with binders that melt 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 dispersants 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 with a polymeric matrix or with a cyclodextrin (transdermal patches, prolonged release forms). The topical compositions according to the invention comprise a medium compatible with the skin. They can be present mainly in the form of aqueous, alcoholic or hydroalcoholic solutions, of gels, of water-in-oil or oil-in-water emulsions which have the appearance of a cream or a gel, of micro-emulsions, of aerosols, or also in form of vesicular dispersions containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered.

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

Claims (10)

1 . Compound that corresponds to the general formula (I): wherein: n represents the number 1 or 3, Ri represents either a hydrogen atom, or a linear or branched d-C7 alkyl group optionally substituted with one or more fluorine atoms, either a C3-C7 cycloalkyl group, or a group (C3-C7) cycloalkyl-d-C3 alkyl, either a phenyl-C1-C3 alkyl group optionally substituted with one or two methoxy groups, either a C2-C4 alkenyl group, or a C2-C4 alkynyl group, X represents a hydrogen atom or one or more substituents selected from the halogen atoms and the trifluoromethyl groups, dC6 alkyls and dC6 alkoxy linear or branched, R2 represents either a hydrogen atom, or one or more substituents selected from the group consisting of halogen atoms, and the trifluoromethyl groups, d-C6 alkyls, d-C6 alkoxy, linear or branched, C3-C7 cycloalkyls phenyl, cyano, acetyl, benzoyl, S-alkyls dC6, (d ~ C.) alkyl Lsulfonyl, carboxy and (d-CeJalkoxycarbonyl), or a group of general formula NR3R4 , S02NR3R4 or CONR3R4, in which R3 and R4 each represent, independently of each other, a hydrogen atom or a linear or branched d-C6 alkyl group or C3-C7 cycloalkyl, or form, with the nitrogen atom that it supports them, a pyrrolidinium, piperidinium or morpholinium cycle, in the base state or addition salt to an acid.

2. Compound according to claim 1, characterized in that it is of relative configuration treo (1 S.2S; 1R, 2R).

3. Compound according to claim 1, characterized in that it is of configuration (1 S.2S).

4. Compound according to claim 1, characterized in that it is of configuration (1 R, 2R and

5. Compound according to claim 1, characterized in that it is of relative erythro configuration (1 S.2R; 1R, 2S). Compound according to claim 1, characterized in that it is of configuration (1 R, 2S) 7. Compound according to claim 1, characterized in that it is of configuration (1 S.2R) 8. Drug, characterized in that it consists of A compound according to any of claims 1 to 5. 9. Pharmaceutical composition, characterized in that it contains a compound according to any of claims 1 to 5, associated with an excipient 10. Use of a compound according to claim 1, for the preparation of a medicament for the treatment of behavioral disorders associated with dementia, of psychosis, of various forms of anxiety, of panic attacks, of phobias, of Obsessive-compulsive disorders, of different forms of depression, of disorders due to abuse or abstinence from alcohol, of disorders of sexual behavior, of disorders of food intake and of migraine. eleven . Use of a compound according to claim 1, for the preparation of a medicament for the treatment of contractures, pain, Parkinson's disease and parkinsonian symptoms, epilepsies, mixed forms and other epileptic syndromes as a complement of another antiepileptic treatment, or in monotherapy, of sleep apnea and for neuroprotection.