MXPA06004270A - Derivatives of n-heterocyclylmethylbenzamides, preparation method thereof and application of same in therapeutics - Google Patents

Abstract

The invention relates to a compound having general formula (I), wherein:R represents a hydrogen atom or a vinyl group;n represents 0, 1 or 2;X represents a groups having formula CH or a nitrogen atom;R1 represents a phenyl or naphthyl group, or a cyclohexyl group, or a heteroaryl group;R2 represents a hydrogen atom, or one or more substituents selected from among the halogen atoms and the trifluoromethyl, alkyl, alkoxy, thienyl, phenyloxy, hydroxy, mercapto, thioalkyl, cyano groups or a group having general formula -NR4R5, SO2NR4R5, -SO2-alkyl, -SO2-phenyl, -CONR4R5, -COOR7, -CO-alkyl, -CO-phenyl, -NHCOR8, -NHSO2-alkyl, -NHSO2-phenyl and -NHSO2NR4R5 or a divalent group having formula -OCF2O-;and R4 and R5 each represent a hydrogen atom or an alkyl group or R4 and R5, together with the nitrogen atom bearing same, form a pyrrolidine, piperidine or morpholine ring. The invention also relates to the use of said compound in therapeutics.

Description

USE OF TRICICLIC COMPOUNDS AS GLYCINE TRANSPORTATION INHIBITORS The present invention aims at the derivatives of N-heterocyclicmethyl-benzamides, their preparation and their application in therapy. The compounds of the invention correspond to the general formula (I): wherein: R represents a hydrogen atom or a vinyl group; n represents 0 or 1 or 2 when R represents a hydrogen atom and n represents 1 when R represents a vinyl group; X represents a group of the formula CH or a nitrogen atom when R represents a hydrogen atom and X represents a group of the formula CH when R represents a vinyl group; Ri represents either a phenyl or naphthyl group optionally substituted by one or more substituents chosen from halogen atoms, straight or branched C C-C6 alkyl, hydroxy and C?-C6 alkoxy groups, the trifluoromethyl group, or a cyclohexyl group, or a heteroaryl group selected from the groups thienyl, pyridinyl, oxazolyl, furanyl, thiazolyl, quinoline and isoquinolinyl; R 2 represents either a hydrogen atom, or a plurality of substituents chosen from the halogen atoms and the trifluoromethyl, C?-C6 alkyl, C?-C6 alkoxy, thienyl, phenyloxy, hydroxy, mercapto, thio-C C-C6 alkyl groups , cyano or a group of general formula - N R4R5, SO2N R4R5, -SO2-C6-C6 alkyl, -SO2-phenyl, -CONR4R5, -COOR7, -CO-C6-C6 alkyl, -CO-phenyl, - NHCOR 8, -N HSO 2 -alkyl C? -C6, -N HSO 2 -phenyl and -N HSO 2 N R 4 R 5 or a group of formula -OCF 2 O- attached at positions 2 and 3 of the phenyl group; the C-i-Cß, alkoxy d-Cß, -SO 2 -alkyl, C-i-Cß, -CO-alkyl groups Ci-Cß and -N HS? 2-Ci-C? Alkyl being optionally substituted with one or more groups R3; the phenyl, -SO2-phenyl, -CO-phenyl and -N HSO2-phenyl groups optionally being substituted with a group R6; R 3 represents a halogen atom, a phenyl group, Ci-Cβ alkoxy, - N R 4 R 5; R4 and R5 represent, independently of one another, a hydrogen atom or a C-? -C6 alkyl group or R4 and R5 form, with the nitrogen atom supporting them, a pyrrolidinium cycle, a piperidinium cycle or a morpholinium cycle; Re represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxy group, a mercapto group, a C? -C6 alkyl group or C?? C6 alkoxy; R represents a hydrogen atom or a C 1 -C 6 alkyl group optionally substituted with one or more R 3 groups, or a phenyl group optionally substituted with a R 6 group; Rs represents a Ci-Cß alkyl group optionally substituted with one or more R3 groups, or a C-i-Ce alkoxy group, or a phenyl group optionally substituted with a R6 group. Among the compounds of the general formula (i), a certain number of subsets of preferred compounds are distinguished: Group 1: the threo-configuration compounds of the general formula (I) in which n represents 0 or 1; Group 2: the compounds of group 1 in which formula X represents a group of formula CH; Group 3: the compounds of group 2 in which formula R represents a hydrogen atom; Group 4: the compounds of group 3 whose formula n represents 1; Group 5: the compounds of group 4 in which formula R 1 represents an optionally substituted phenyl group. The compounds of formula (I) may comprise several asymmetric centers. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention. More particularly, the compounds of formula (I), in which R = H, can exist in the form of diastereomers threo ((1S, 2S) and (1R, 2?)) Or erythro ((1S, 2R) and (1 R, 2S.).) or of pure enantiomers or mixture of such isomers.

The compounds of formula (I) can exist in the state of bases or acid addition salts. Such addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, for the purification or isolation of the compounds of the formula (I) also form part of the invention. The compounds of the general formula (I) can also exist in the form of hydrates or solvates, ie in the form of combinations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention. The compounds of the invention have a particular activity as specific inhibitors of glycine transporters glytl and / or glyt2. The compounds of general formula (I) can be prepared by a process illustrated in scheme 1 below. Scheme 1 (I) According to scheme 1, a coupling of a diamine of the general formula (II) is carried out, wherein n, X, R and Ri are as defined above, with an activated acid or a chloride of acid of the general formula (III) in which Y represents a nucleofugic group, such as a halogen atom, and R2 is as defined above, using the methods known to the person skilled in the art. The diamines of the general formula (II), in which R = H and n, X and Ri are as defined above, can be prepared by a process illustrated in scheme 2 below. Scheme 2 (IV) (V) The ketone of the general formula (IV) is reacted, wherein n, X and Ri are as defined above, with the benzyloxyhydroxylamine hydrochloride, at reflux of pyridine, to obtain the oxime of the general formula (V ). The two Z and £ forms of the oxime can be separated according to methods known to the person skilled in the art such as chromatography on a silica gel column. The oxime (V) preferably in the form of hydrochloride Z is then reduced to reflux of tetrahydrofuran with double aluminum hydroxide and lithium to provide the diamine of the general formula (I I) mostly threo. By reduction of the form of the oxime of the general formula (V), a mixture of diamine (I I) is obtained in the form of two diastereoisomers (thre / erythro). The erythro and threo diastereoisomers can be separated according to methods known to the person skilled in the art such as chromatography on a column of silica gel. Another variant preparation of the diamines of the general formula (II), in which R and Ri are as defined above, n is equal to 1 and X is a CH, is illustrated in scheme 3 below. Scheme 3 The alcohols of the general formula (VI) are transformed into amines by a Mitsunobu reaction according to the method described in Bull. Soc. Chim.Belg. (106), 1997, 77-84 and in Tetrahedron: Asymmetry, (6), 1995, 1699-1702. In addition, the chiral compounds of the general formula (I), which correspond to the enantiomers (1 R.2R) or (1S, 2S) of the threo diastereomer and to the enantiomers (1S, 2R) or (1R, 2S) of the Erythro diastereoisomer can also be obtained by separating the racemic compounds by high-performance liquid chromatography (H PLC) on a chiral column, either from the chiral amine obtained either by splitting the racemic amine of the formula (II), by use of a chiral acid, such as tartaric acid, camphorsulfonic acid, dibenzoyl-tartaric acid,? / -acetyleucine, by fractional recrystallization and preferably of a diastereomeric salt in an alcohol type solvent, or by a synthesis enantioselective from an erythro or threo chiral alcohol using a procedure analogous to that described in scheme 3. The chiral alcohols can be obtained by a method analogous to that described in Tetrahedron, (55), 1999,2795-281 0. In the case where R represents a vinyl group and R represents a quinoline group, the diamine of the general formula (II) can be prepared according to scheme 3 using corresponding commercial chiral alcohols. The ketone of the general formula (IV) racemic can be prepared either by deprotonation of an activated complex of cyclic bridged amines and reaction with an electrophile, such as an ester or an amide of einreb, according to a method analogous to that described in Chem. Commun., 1999, 1927-1928, either by reaction of an organometallic on the ethyl ester of 2-quinuclidipic acid, according to a method analogous to that described in J. Med. Chem., 1980, 180-184, or by oxidation of the corresponding alcohol obtained by different methods analogous to those described in J. Org. Chem., 50, 1985, 29-31 and Chem. Co m. , 1999, 1927-929 with oxidants known to the person skilled in the art such as manganese dioxide or the oxalyl chloride-dimethylsulfoxide system.

The alcohols of the general formula (VI) can also be obtained by reduction of corresponding ketones of the general formula (IV) under conditions known to the person skilled in the art. Acids and acid chlorides of the general formula (I I I) are commercially available or are prepared by analogy with methods known to the person skilled in the art. For example, 4-amino-3-chloro-5-trifluoromethylbenzoic acid can be prepared by chlorination of 4-amino-5-trifluoromethylbenzoic acid with sulfuryl chloride in a chlorinated solvent such as chloroform, according to a method analogous to that described in Arzneim. Forsch., 34, 1 1 a, (1984), 1668-1679. The 2,6-dichloro-3-trifluoromethylbenzoic acid can be prepared by methods analogous to those described in US 3, 823, 134. The benzoic acids derived from sulfonamides can be prepared by methods analogous to those described in US Pat. described DE-2436263, BE-620741, DE-1 158957, US-31 12337, G B-915259, US-3203987, DE-642758, EP-68700, FR-2396757, D E-2734270, and in J. Pharm.

Pharmacol. (1962), 14, 679-685. The metachlorosulfonipidated acids can be obtained according to a method analogous to those described in J. Chem. Soc. (C), (1968), 13, and in the patents US-2273444, DE-19929076, and EP-0556674. Chlorosulfonylation in the 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. chlorosulfonylated derivatives in the presence of an excess of amine in a solvent such as tetrahydrofuran, at room temperature or reflux Secondary sulfonamides can be methylated according to a method analogous to that described in the patent BE-620741. 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 Certain sulfoxide derivatives of benzoic acids are described in DE-2056912, DE-2901 17 0 and US-3953476, or can be obtained by methods analogous to those described in patents BE-872585 and J. Org. Chem. ((1991), 56 (1), 4976- 4977. The benzoic acid derivatives of the general formula (III), wherein R 2 represents a branched alkyl group can be prepared according to methods analogous to those described in US Pat. No. 4,879,426 and Syn. Lett. (1 996), 473-474 and J. Med. Chem. (2001), 44, 1085-1098. The benzoic acid derivatives of the biphenyl type can be prepared according to known methods. by the person skilled in the art Finally, the benzylated carbonyl acids can be synthesized according to methods analogous to those described in US-37254 7 and GB-913100 and in Chem. Pharm. Bull., (1988), 36 (9). ), 3462-3467 and J. Labelled Compd. Radiopharm., (1997), 39 (6), 501- 508. Esters or amides can be introduced by direct carbonilac on with a strong para base of the acid, under the conditions described in Tetrahedron Lett., (2000), 41, 3157-3160. Finally the cyano derivatives of benzoic acids are obtained by heating and a halogenated benzoic acid or ester in the presence of potassium cyanide, of a catalyst of the paladiotetrakistriphenylphosphine type in a solvent of the tetrahydrofuran type, according to a method analogous to that described in J. Org. Chem. (1 967) 62, 25, 8634-8639. Other acids and acid chlorides of the general formula (II I) can be obtained according to methods analogous to those described in the patents EP-0556672, US-3801636, and in J. Chem. Soc., (1927), 25, Chem. Pharm. Bull. , (1992), 1789-1792, Aust. J. Chem., (1984), 1938-1950 and J. O. C, (1980), 527. The following examples illustrate the preparation of some compounds of the invention. The elementary microanalyses, and the spectra of I. R. and R.M .N. and PLC H 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 should be deleted in the absence of a cut, and should not be replaced by a normal script or by a space. Example 1 (Compound No. 3) Threo-2-chloro-γ / - hydrochloride. { ? i-azabicyclo [2.2.2] oct-2-yl) phenylmethyl] -3-trifluoromethylbenzamide 1: 1 .1. Hydrochloride of (Z) -1-azabiciclof2.2.2. "Loct-2-yl (phenyl) methanone O-benzyl oxime.

In a 100 ml round bottom flask equipped with magnetic stirring, 2.2 g (9.35 mmoles) of 1-azabicyclo [2.2.2.] Oct-2-yl (phenyl) methanone was introduced. { Chem. Commun., 1999, 1927-1928) and 3 g (18.69 mmoles) of benzyloxyhydroxylamine hydrochloride in 50 ml of pyridine, and the mixture was heated at reflux for 20 h. After evaporation of the solvents under reduced pressure, the residue was diluted with water and chloroform, the aqueous phase was separated, and extracted with chloroform. 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 chloroform and methanol. 0.5 g of a fraction corresponding to the (£) -1-azabicynic [2.2.2.] Oct-2-yl (phenyl) methanone O-benzyl oxime and 2.25 g of another fraction corresponding to the hydrochloride of (Z) - 1 were obtained. -azabicyclo [2.2.2.] oct-2-yl (phenyl) methanone O-benzyl oxime. PF 195- 197 ° C. 1.2. treo-f 1-azabiciclor2.2.2. loct-2-yl (phenyl) metfell In a 250-ml three-necked flask fitted with magnetic stirring, under a nitrogen atmosphere, 1.3 g (34.32 mmol) of aluminum and lithium double hydride suspended in 10 ml were placed. of tetrahydrofuran, 2.2 g (6.16 mmol) of (Z) -1-azabicyclo [2.2.2.] oct-2-yl (phenyl) methanone O-benzyl oxime hydrochloride was added in portions and heated to reflux for 2 h. After cooling, the solution was hydrolyzed at 0 ° C successively with 1.3 ml of water, then 1.3 ml of 15% aqueous sodium hydroxide and 3.9 ml of water. The heterogeneous mixture was filtered over celite®, the filtrate was concentrated under reduced pressure, then the residue was diluted with 1 N hydrochloric acid and chloroform. The organic phase was separated and the aqueous phase was basified with ammonia. It was extracted twice with chloroform. After washing the combined organic phases, drying over sodium sulphate and evaporation of the solvent under reduced pressure, 1.25 g of threo- [1-azabicyclo [2.2.2.] Oct-2-yl (phenyl) methyl was obtained. ] amine in the form of an oil that crystallizes and which was used as such in the next step. Melting point: 120 - 140 ° C 1 .3. Threo-2-chloro -? / - r (1-azab-cyclo [2.2.2"loct-2-yl) phenyl hydrochloride methylp-3-trifluoromethylbenzamide 1: 1. Into a 100 ml round bottom flask equipped with magnetic stirring, 0.51 g (2.12 mmol) of 2-chloro-3-trifluoromethylbenzoic acid chloride in solution in 5 ml of chloroform was placed in the presence of 0.29 g (2.12 mmol). ) of potassium carbonate at 0 ° C and a solution of 0.42 g (1.93 mmoles) of threo- [1-azabicyclo] or [2.2.2.] oct-2-yl (phenyl) methyl] amine was poured into solution in 5 ml of chloroform and the mixture was stirred at room temperature for 6 h. After hydrolysis with water and dilution with chloroform, the aqueous phase was separated and extracted with chloroform. 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 chloroform and methanol. 0.18 g of oily product were obtained. The latter was dissolved in a few ml of propan-2-ol, 6 ml of a 0.1 N solution of hydrochloric acid in propan-2-oi was added, and the mixture was concentrated under reduced pressure in order to reduce the volume of the solvent . After grinding, 0.15 g of hydrochloride in the form of a solid was finally isolated. Melting point: 257-262 ° C Example 2 (Compound No. 4) Threo-2,6-dichloro -? / - [(1-azabicyclo [2.2.2] oct-2-yl) phenylmethyl] -3 hydrochloride -trifluoromethylbenzamide 1: 1. Into a 100 ml round-bottomed flask equipped with magnetic stirring, 0.36 g (1.38 mmol) of 2,6-dichloro-3-trifluoromethylbenzoic acid, 0.187 g (1.38 mmol) of hydroxybenzotriazole, 0.264 g were introduced ( 1.3 mmol) of 1 - [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride in solution in 7 ml of chloroform and the mixture was stirred at room temperature for 30 min. 0.3 g (1.38 mmol) of threo- [1-azabicic! O- [2.2.2.Joct-2-yl (phenyl) methyl] amine in solution in 5 ml of chloroform was added and stirred at room temperature for one night. After hydrolysis with water and dilution in chloroform, the aqueous phase was separated, and extracted with chloroform. 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 chloroform and methanol. 0.37 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 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, 0.35 g of hydrochloride was finally isolated in the form of a solid. Melting point: 270-273 ° C Example 3 (Compound No. 14). 2-Chloro-N- (8a, 9S-cinconan-9-yl) -3-trifluoromethylbenzamide hydrochloride 2: 1. 3.1. 8a, 9S-cinconan-9-amine 0.74 g (2.5 mmol) of 8a, 9R-cinconan-9-oI (cinchonidine) were introduced into a 1 00 ml three-necked flask equipped with magnetic stirring under a nitrogen atmosphere. and 0.79 g (3 mmol) of triphenylphosphine in suspension in 15 ml of tetrahydrofuran, and 3.5 ml of a 0.9 M solution in benzene (3 mmoles) of hydrazoic acid were added. To this solution was added, dropwise, a solution of 0.55 ml (2.75 mmol) of diisopropylcarbodiimide in 1.5 ml of tetrahydrofuran and heated at 40 ° C for 16 h. 0.65 g (2.5 mmol) of triphenylphosphine was added and stirred for 30 min, 0.5 ml of water was added and the stirring was resumed 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 evaporating the solvent under reduced pressure, 0.97 g of an orange oil containing the 8, 9S-cinconan-9-amine that was used crude in the next step. 3.2. 2-Chloro-N- (8a, 9S-cinconan-9-yl) 3-trifluoromethyl-benzamide hydrochloride, 2: 1. According to the method described in example 1.3, starting from 0.97 g (3.3 mmoles) of 8, 9S-cinconan-9-amine, 0.84 g (3.4 mmoles) of 2-cioro-3-trifluoromethylbenzoic acid hydrochloride and 0.5 g (3.63 mmol) of potassium carbonate gave 0.360 g of oil which was dissolved in 30 ml of 1N hydrochloric acid. The aqueous phase was extracted with chloroform, then the solvent was evaporated under reduced pressure. 0.26 g of hydrochloride were thus obtained in the form of a white solid Melting point: 185-205 ° C; [a] D25 = -5.4 (c = 0.986, MeOH). EXAMPLE 4 (Compound No. 17) 2-6-Dichloro-β / - [(1 S) - [(2S) (1-azabicyclo) hydrochloride [2.2.2] oct-2-yl) phenylmethyl] -3- (trifluoromethyl) benzamide 1: 1 4. 1 D (tartrate) of (1S) -r (2S) -1-azabicyclo2.2.2.1oct-2-yl (phenol) metip-amine. 9.4 g (43.45 mmol) of threo- [1-azabicyclo [2.2.2.] Oct-2-yl (phenyl) methyl] amine was dissolved in 150 ml of ethanol. A solution of 6.52 g (43.45 mmoles) of D-tartaric acid in solution was poured into 200 ml of ethanol. After evaporation of the solvent under reduced pressure, the residue was placed in 500 ml of a solution of ethanol and water (9/1) then heated to solution. After 3 successive recrystallizations, 5.39 g of (1S) - [(2S) -1-azabicyclo [2.2.2.] Oct-2-yl (phenyl) methyl] amine D-tartrate were obtained.

Melting point: 125-135 ° C. [α] D 25 = -46.1 (c = 0.616; MeOH). 4.2. 2.6-dichloro -? / - r (1 S) -r (2S) (1-azabiciclof2.2.2loct-2-yl) phenylmethyl-3- (trifluoromethyl) benzamide hydrochloride 1: 1 In a round bottom flask 100 ml gifted with magnetic stirring, 3.33 g (12.02 mmoies) of 2,6-dichloro-3- (trifluoromethyl) benzoic acid chloride in solution in 30 ml of chloroform were placed in the presence of 1.82 g (13.22 mmoles) of potassium carbonate at 0 ° C and a solution of 2.6 g (12.02 mmol) of (1 S) - [(2S) -1-azabicyclo [2.2.2.] oct-2-yl (pheny1) methyl] amine was poured. (obtained by basification of the salt described in 4.1 after extraction) in solution in 40 ml of chloroform and the mixture was stirred at room temperature for 6 h. After hydrolysis with water and dilution with chloroform, the aqueous phase was separated and extracted with chloroform. After washing the combined organic phases, drying over sodium sulphate and evaporation of the solvent under reduced pressureThe residue was purified by chromatography on a column of silica gel, eluting with a mixture of chloroform and methanol. 5.4 g of oily product were obtained. The latter was dissolved in a few ml of chloroform, 600 ml of an ether solution saturated with hydrochloric acid was added and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate. This gave 4.7 g of 2,6-dichloro -? / - [(1 S) - [(2S) (1-azabicyclo [2.2.2] oct-2-it) phenylmethyl] -3- (trifluoromethyl) hydrochloride. Benzamide Melting point: 264-268 ° C [a] D25 = +61 .1 c = 0.32, MeOH. MeOH) Example 5 (Compound NT26) Threo hydrochloride? / - [1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methyl] -2,6-dichloro-3- (trifluoromethyl) benzamide 1: 1 . 5.1 1 -azabicycloi2.2.21oct-2-yl (4-fluorofenyl) methanol. In a 100 ml three-necked flask under argon, 1.1 g (10 mmol) of quinuclidine were placed in 40 ml of dry tetrahydrofuran at 0 ° C. 1.33 ml (10.5 mmol) of boron trifluoride complex was added dropwise and stirred 30 min. at 0 ° C (solution A). In parallel, in a 250 ml three-necked flask under argon, 2.47 g (22 mmol) of dry potassium tert-butylate were placed in 60 ml of dry tetrahydrofuran. It was cooled to -70 ° C and 22 ml of a solution 1 of sec-butyllithium in the cyclohexane / hexane mixture (22 mmol) was dropped dropwise keeping the temperature below -60 ° C (solution B). After the end of the addition, solution A was channeled into solution B keeping the temperature around -70 ° C. The stirring was stopped at 2 h. Into a 50 ml three-necked flask under argon, 2.36 g (22 mmol) of 4-fluorobenzaldehyde distilled in solution were placed in 20 ml of tetrahydrofuran at -70 ° C. Solution B was channeled maintaining the temperature towards -70 ° C. The resulting solution was left for 30 min. at -70 ° C and allowed to rise to -20 ° C. It was then hydrolyzed with a 10% hydrochloric acid solution. It was extracted with ether, then the aqueous phase was resumed and basified with ammonia. It was extracted with chloroform, then the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel eluting with a mixture of chloroform and methanol. This gave 0.53 g of 1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) -methanol in the form of a yellowish solid. Melting point: 69-70 ° C. 5.2 1 -azabiciclof2.2.21oct-2-yl (4-fluorophenyl) methanone. In a 250 ml three-necked flask under argon were placed 1.3 ml of dimethylsulfoxide in 40 ml of tetrahydrofuran at -70 ° C, 0.9 ml of oxalyl chloride (1.1 mmol) was added dropwise and left stirring for 30 min. at this temperature. A solution of 1 g (4.6 mmoles) of 1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methanol in 40 ml of tetrahydrofuran was added dropwise. After 30 min. , 4 ml (27.6 mmoles) of triethylamine was added at -70 ° C. The reaction mixture was then stirred at -70 ° C, 30 min. at 0 ° C, then 1 h at room temperature. The mixture was poured into a solution of ammonia, then extracted several times with chloroform. The organic phases were dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column eluting with a mixture of chloroform and methanol. This gave 1 g of 1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methanone. Melting point: 68-69 ° C. 5.3 ("Z) 1-azabfcichlor2.2.2 oct-il (4-fluorophenyl) -methanone O-benzyloxyamine hydrochloride, according to the operating procedure described in Example 1 .1, starting from 1. 17 g (5 mmol) of ketone gave 1.4 g of (Z) -1-azabicyclo [2.2.2] oct-il (4-phlorophenyl) methanone O-benzyl oxime hydrochloride after trituration in ether of the residue obtained after of the reaction treatment Melting point: 202-203 ° C 5.4 Treo 1 -azabicichlor2.2.21oct-il (4-fluorophenyl) methanamine According to the operating procedure described in 1.2, from 1. 47 g (4.54 mmol) of (Z) -1-azabicyclo [2.2.2] oct-il (4-fluorophenyl) methanone O-benzyl oxime hydrochloride gave 1 g of 1-azabicyclo [2.2.2] oct-il ( 4-f! Uorophenyl) methanamine threo (diastereoisomeric excess, = 90%) 5.5 Hydrochloride of? / - r (S) -l 2 S) - 1 -azabicichlor.2.2.21oct-2-yl (4-fluorofenyl) ) methyp-2,6-dichloro-3- (trifluoromethylDbenzamide 1: 1). According to the operating procedure described in 1.3, from 0.39 g (1 .6) 6 mmoles) of threo 1-azabicyclo [2.2.2] oct-il (4-fluorophenyl) methanamine, 0.5 g (1.83 mmoles) of 2,6-dichloro-3-trifluoromethylbenzoic acid chloride, 0.25 g (1. 83 mmol) of potassium carbonate, after purification by chromatography, 0.79 g of threo? / - [1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methyl] -2.6- were obtained dichloro-3- (trifluoromethyl) benzamide in the form of an oil which is converted to a salt with a solution of gaseous hydrochloric acid in ethyl ether. Melting point: 290-291 ° C. The other compounds were obtained following the methods described in Examples 1, 2 and 5 from other functionalized aldehydes. Table 1 below illustrates the chemical structures of some compounds of the invention.

In the column "R", -CH = CH2 designates a vinyl group, in the column "RT C6H5 designates a phenyl group and 4-C9H6N designates a quinoIein-4-yl group In the column" Salt ", - designates a compound in the base state, "HCl" designates a hydrochloride and "tfa" denotes a trifluoroacetate Compounds 14, 19 to 23, 24 of the table are presented in the form of hydrochloride or dihydrochloride (see table) solvated with a or several water molecules Compounds 15 and 16 of the table form a pair of enantiomers that are separated by preparative PLC H using a CH I RALCEL® AD 20 μm column and as a solvent an isohexane / propan-2-ol 95/5 mixture , same for compounds 17 and 18. Table 2 gives the physical properties, melting points and rotary powers of the compounds in the table, "(d)" indicates a melting point with decomposition.

Table 1 (i) Table2: 10 15 20 10 15 20 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 human glytl trans-carrier. The capture of [14C] glycine was studied in SK-N-MC cells (human neuro-epithelial cells) expressing the native human glytl transporter for the measurement of the radioactivity incorporated in the presence or absence of the compound to be tested. The cells were cultured in monolayers for 48 h in plaques pretreated with 0 fibronectin., 02%. On the day of the experiment, the culture medium was removed and the cells were washed with a Krebs-H EPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanol-phonic acid) at pH 7.4. After 10 min. preincubation at 37 ° C in the presence of either buffer (control lot), either compound to be tested at different concentrations or 10 mM glycine (determination of the non-specific capture), then 10 μM of [14 C] glycine ( 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-H EPES buffer at pH 7.4. The radioactivity incorporated by the cells was then estimated after adding 100 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 Cl 5_, concentration of the compound that decreases the glycine-specific capture by 50%, defined by the difference in radioactivity incorporated by the control lot and the batch that has received the glycine at 10 mM. The most active compounds of the invention, in this test, had a Cl5o of the order of 0.001 to 10 μM. The individual results of some compounds were as follows (IC 50 in μM): Compound No. 3 0.017 Compound H '° 4 0.004 Compound No. 14 0.07 Compound N9 17 0.001 Compound No. 26 0.07 Ex vivo study of the inhibitory activity of a compound Increasing doses of compound to be studied were administered orally (preparation by grinding the molecule to be tested in a mortar in 0.5% Tween / Methocel ™ solution in distilled water) or intraperitoneally (solution of the molecule to be tested in physiological saline) or preparation by grinding in a mortar in a 0.5% Tween / Methocel ™ solution in water, depending on the solubility of the molecule) in OF1 Iffa Credo male mice of 20 to 25 g on the day of the experiment. The control group was treated with the vehicle. The doses in mg / kg, the route of administration and the treatment time were determined depending on the molecule to be studied. After euthanasia by decapitation of the animals at a given time after administration, the cerebral cortex of each animal was quickly placed on ice, weighed and kept at 4 ° C or frozen at -80 ° C (in both cases). cases the samples were kept 1 day maximum). Each sample was homogenized in a Krebs-HEPES buffer at pH 7.4 at a rate of 10 ml / g of tissue. 20 μl of each homogenate was incubated for 10 min. at room temperature in the presence of 10 mM L-alanine and buffer. The non-specific capture was determined by the addition of 10 mM glycine to the control group. The reaction was stopped by vacuum filtration and retained radioactivity was estimated by solid scintillation by counting on Microbeta Tri-lux ™ counter. An inhibitor of the capture of [f C] glycine will decrease the amount of radioligand incorporated in each homogenate. The activity of the compound was evaluated by its ED 50, a dose that inhibits 50% of the capture of [14 C] glycine with respect to the control group. The most potent compounds of the invention, in this assay, had an ED5_ of 0.1 to 5 mg / kg intraperitoneally or orally. Study of the transport of glycine in the mouse spinal cord homogenate. The capture of [14C] glycine by the glyt2 transporter was studied in the mouse spinal cord homogenate by the measurement of radioactivity incorporated in the presence or absence of the compound to be studied. After euthanasia of the animals (OF1 Iffa Credo male mice weighing 20 to 25 g on the day of the experiment), the spinal cord of each animal was quickly removed, weighed and kept on ice. The samples were homogenized in a Krebs-H EPES buffer ([4- (2-hydroxyethi)? Iperazine-1-ethansulfonic 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 the compound to be studied at different concentrations, or 1 0 mM glycine to determine the non-specific capture. The [4C] g (icine (specific activity = 1 12rnC / rnmoles) was then added for 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 consistent scintillation by counting on a Microbeta Tri-lux ™ counter The efficacy of the compound was determined by the concentration CI5o capable of decreasing by 50% the specific capture of glycine, defined by the difference of radioactivity incorporated by the control lot and the batch which has received the glycine at 10 mM The most active compounds of the invention, in this test, had a Cl5_ of the order of 0.02 to 10 μM.The Cl5o of compound No. 17 was 0.69 μM The results of the tests carried out on the compounds of the invention of the general formula (I) showed that they are the inhibitors of glycine transporters glytl, present mainly in the brain, and glycine transporters glyt2, present mainly in the spinal cord. The compounds according to the invention can be used for the preparation of medicaments, in particular of inhibitors of the glycine transporters glytl and / or glyt2. Thus, according to another of its aspects, the invention relates to medicaments comprising a compound of the formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid, or also a hydrate or a solvate of the compound of the formula (I) The compounds of the invention can be used mainly for the treatment of behavioral disorders associated with dementia, of psychoses, in particular of schizophrenia (deficient form and productive form) and of acute or chronic extrapyramidal symptoms induced by neuroleptics, for the treatment of various forms of anxiety, of panic attacks, of phobias, of obsessive compulsive disorders, for the treatment of different forms of depression, including psychotic depression, for the treatment of disorders due to abuse or abstinence from alcohol , 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 neuroleptics, for the treatment of generalized primary and secondary epilepsies, partial with simple or complex symptomatology, of mixed forms and other epileptic syndromes as a complement to another antiepileptic treatment, or in monotherapy, for the treatment of sleep apnea, and for neuroprotection. 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 basic or salt or pharmaceutically acceptable salt state, and in a mixture, if necessary, with one or more suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

The pharmaceutical compositions according to the invention can thus be 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. By way of example, a unit form of administration of a compound according to the invention in the form of a tablet can comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg H idroxypropyl methylcellulose 2.25 mg Magnesium Stearate 3.0 mg 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 galenic form. There may be particular cases in which the highest or lowest dosages are appropriate; such doses are not outside the scope of the invention. In accordance with standard practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight and the response of said patient. The present invention, according to another of its aspects, also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a of its pharmaceutically acceptable salts or hydrates or solvates.

Claims (2)

CLAIMS 1. A compound that responds to the general formula (I): wherein: R represents a hydrogen atom or a vinyl group; n represents 0 or 1 or 2 when R represents a hydrogen atom and n represents 1 when R represents a vinyl group; X represents a group of formula CH or a nitrogen atom when R represents a hydrogen atom and X represents a group of formula CH when R represents a vinyl group; Ri represents either a phenyl or naphthyl group optionally substituted with one or more substituents chosen from halogen atoms, C1-Cß alkyl, hydroxy and straight or branched C?-C6 alkoxy groups, the trifluoromethyl group, or a cyclohexyl group, or a heteroaryl group selected from the groups thienyl, pyridinyl, oxazolyl, furanyl, thiazolyl, quinoleinyl and isoquinolinyl; R 2 represents either a hydrogen atom, or a plurality of substituents selected from halogen atoms and trifluoromethyl, Ci-Cß alkyl, C alco-C alco alkoxy, thienyl, phenyloxy, hydroxy, mercapto, Ci-Cß thioalkyl, cyano or a group of the general formula) - R4RS, SO2NR4R5, -S? 2-alkyI-Ce, -SO2-phenyl, -CONR4R5, -COOR7, -CO-C? -C6 alkyl, -CO-phenyl, - N HCOR? - N HSO2-C-C6 alkyl, -N HSO2-phenyl and -NHSO2N R4R5 or a group of the formula -OCF2O- attached at positions 2 and 3 of the phenyl group; the alkyl d-Ce, C 1 -C 6 alkoxy-SO 2-C 1 -C 6 alkyl, -CO-C 6 alkyl and -N HS 0 2 -alkyl d-C 6 groups optionally substituted with one or more R 3 groups; the phenyl, -SO2-phenyl, -CO-phenyl and -NHSO2-phenyl groups optionally being substituted with a group R6; R3 represents a halogen atom, a phenyl group, d-C6 alkoxy, -NR4R5; R4 and R5 represent, independently of one another, a hydrogen atom or a d-Cß alkyl group or R4 and R5 form with the nitrogen atom supporting them a pyrrolidinium cycle, a piperidinium cycle or a morpholinium cycle; R6 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxy group, a mercapto group, a d-Cß alkyl group or d-Ce alkoxy; R7 represents a hydrogen atom or a d-C6 alkyl group optionally substituted with one or more R3 groups, or a phenyl group optionally substituted with a group Re; Rs represents a Ci-Ce alkyl group optionally substituted with one or more R3 groups, or a C6-C6 alkoxy group, or a pheiio group optionally substituted with a group Re, in the free base or addition salt state of a acid, hydrate or solvate. 2. A compound according to claim 1, characterized in that it has a threo configuration. 3. A compound according to any of claims 1 and 2, characterized in that n represents 0 or 1. 4. A compound according to claim 3, characterized in that X represents a group of the formula CH. 5. A compound according to claim 4, characterized in that R represents a hydrogen atom. 6. A compound according to claim 5, characterized in that n represents 1. 7. A compound according to claim 6, characterized in that Ri represents an optionally substituted phenyl group. 8.. A medicament characterized in that it consists of a compound according to one of claims 1 to 7. 9. A pharmaceutical composition characterized in that it comprises a compound according to one of claims 1 to 7, as well as at least one pharmaceutically acceptable excipient. 10. A use of a compound of the formula (i) according to one of claims 1 to 7, for the preparation of a medicament for the treatment of behavioral disorders associated with dementia, psychoses, various forms from anxiety, to panic attacks, to phobias, to obsessive-compulsive disorders, to different forms of depression, to disorders due to alcohol abuse or abstinence, to sexual behavior disorders, to eating disorders of food and migraine.

1. Use of a compound of the formula (I) according to one of claims 1 to 7, for the preparation of a medicament intended for the treatment of contractures, pain, Parkinson's disease and symptoms parkinsonians, epilepsies, mixed forms and other epileptic syndromes as a complement to another antiepileptic treatment, or monotherapy, of sleep apnea, and for neuroprotection. SUMMARY A compound of the general formula (I) in which R represents a hydrogen atom, or a vinyl group; n represents 0 or 1 or 2; X represents a group of the formula CH or a nitrogen atom; Ri represents either a phenyl or naphthyl group, either a cyclohexyl group, or a heteroaryl group; R 2 represents either a hydrogen atom, or a plurality of substituents chosen from the halogen atoms and the trifluoromethyl, alkyl, alkoxy, thienyl, phenyloxy, hydroxy, mercapto, thioalkyl, cyano groups or a group of the general formula -N R 4 R 5, S 0 2 N R4R5, -SO2-alkyl, -S02-phenyl, -CONR4R5, -COOR7j -CO-alkyl, -CO-phenyl, -NHCORs, -NHSO2-alkyl, -NHSO2-phenyl and -N HSO2N R4R5 or a group of the formula -OCF2O-; R4 and R5 each represent a hydrogen atom or an alkyl group or R4 and Rs form with the nitrogen atom that supports a pyrrolidine, piperidine or morpholine cycle. The compounds of the formula (I) have a particular activity as specific inhibitors of the glytl and / or glyt2 transporters.