FR2941954A1 - N- (6-AZA-BICYCLO ° 3.2.1! OCT-1-YL) -ARYL-METHYL DERIVATIVES BENZAMIDE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

The present invention relates to N - [(6-aza-bicyclo [3.2.1] oct-1-yl) -aryl-methyl] -benzamide derivatives of general formula (I): - R represents an atom of hydrogen or a (C -C) alkyl, (C -C) -cycloalkyl group, optionally substituted by one or more fluorine, (C -C) -cycloalkyl, (C -C) alkenyl, phenyl, (C -C) alkoxy hydroxy; R represents a phenyl or naphthyl, optionally substituted by one or more halogen, (C 1 -C) alkyl, (C 1 -C 4) alkoxy, halo (C 1 -C) alkyl, NR R, (C 1 -C) alkyl-thio, (C -C) alkyl-SO, phenyl or heteroaryl,; R represents one or more hydrogen, halogen, halo- (C -C) alkyl, (C -C) alkyl, (C -C) cycloalkyl, (C -C) -cycloalkyl- (C -C) atoms; alkyl; R, R and R represent, independently of one another, a hydrogen atom or a (C 1 -C 4) alkyl group; R represents a (C -C) alkyl group; R and R may together form a ring selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine rings, optionally substituted by a (C 1 -C 4) alkyl group. Therapeutic use and synthesis method.

Description

The present invention relates to N - [(6-AZA-BICYCLO [3.2.1] OCT-1-YL) -ARYL-METHYL] -BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF 6-aza-bicyclo [3.2.1] oct-1-yl) aryl-methyl-benzamide, in their preparation and their therapeutic application in the treatment or prevention of diseases involving glycine carriers GIyt1.

The compounds of the invention have the general formula (I) wherein R represents a hydrogen atom or a group selected from (C 1 -C 5) alkyl, (C 3 -C 7) -cycloalkyl optionally substituted with one or more groups independently selected from fluorine, (C3-C7) -cycloalkyl, (C2-C4) alkenyl, phenyl, (C1-C6) alkoxy hydroxy; the phenyl group being optionally substituted by one or more alkoxy groups; - R, represents a phenyl or naphthyl group, optionally substituted by one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) groups; alkoxy, halo- (C 1 -C 6) alkyl, NR 4 R 5, NR 3 C (O) OR 4, NR 3 SO 2 R 4, NR 3 C (O) R 6, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkylethio, (C , -C6) alkyl-SO2, phenyl or heteroaryl, the phenyl group being optionally substituted by one or more substituents independently selected from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy groups , halo- (C 1 -C 6) alkyl, NR 4 R 5, NR 3 C (O) OR 4 NR 3 SO 2 R 4, NR 3 C (O) R 6, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-thio, (C, -C6) alkyl-SO2, the heteroaryl group being optionally substituted by one or more substituents independently selected from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C 1 - C6) alkyl, NR4R5; R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl groups, (C 3 -C 8) -Cycloalkyl- (C 1 -C 3) alkyl, (C 1 -C 6) alkoxy, NR 4 R 5, phenyl, heteroaryl, cyano, acetyl, (C 1 -C 6) thioalkyl, (C 1 -C 6) alkylsulfonyl carboxy or (C 1 -C 6) alkoxycarbonyl; the phenyl group being optionally substituted by one or more substituents independently selected from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C 1 -C 6) alkyl, NR 4 R 5 groups, NR 3 C (O) OR 4 NR 3 SO 2 R 4, NR 3 C (O) R 6, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-thio, (C 1 -C 6) alkyl-SO 2, the heteroaryl group optionally being substituted with one or more substituents independently selected from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C 1 -C 6) alkyl, NR 4 R 5; - R3, R4 and R5 represent independently of each other a hydrogen atom or a group (C, -C6) alkyl; - R6 represents a (C 1 -C 6) alkyl group; - R4 and R5 can form together, with the nitrogen atom which carries them, a ring selected from the azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine rings, optionally substituted by a (C1-C6) alkyl group ; - R3 and R4 can form together with the atoms that carry them, a 5- or 6-membered ring; - R3 and R6 can form together, with the atoms that carry them, a 5- or 6-membered ring; in the form of a base or an acid addition salt.

The compounds of formula (I) have 3 asymmetric carbon atoms. They can therefore exist in the form of diastereoisomers and enantiomers. These enantiomers, including racemic mixtures, form part of the invention. The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids which are useful, for example, for the purification or the isolation of the compounds of formula (I) also form part of the invention.

In the context of the invention, the following is understood to mean: ## STR2 ## where t and z may take the values from 1 to 6, a carbon chain that may have from t to z carbon atoms, for example C 1 -C 6 a carbon chain which may have from 1 to 6 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example, a C1-C6alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl; alkenyl, a linear or branched mono- or poly-unsaturated aliphatic group, for example comprising one or two ethylenic unsaturations, amino, an NH 2 alkoxy group, a ûO-alkyl group; acetyl, -C (O) -, cyano, -CN, -hydroxy, -OH, -thioalkyl, alkyl-substituted sulfur; halogen atom, fluorine, chlorine, bromine or iodine, haloalkyl, an alkyl group of which one or more hydrogen atoms have been substituted by a halogen. By way of example, there may be mentioned trifluoromethyl, trifluoroethyl, pentafluoroethyl, 20-heteroaryl, a 5- or 6-membered heteroaryl group comprising from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur. . As an example of a heteroaromatic group, there may be mentioned pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine groups. Among the compounds of general formula (I) which are the subject of the invention, a first group of compounds is constituted by the compounds for which R represents a hydrogen atom or a (C 1 -C 6) alkyl group; R 1, R 2, R 3, R 4 and R 5 being as defined above.

Among the compounds of general formula (I) which are subjects of the invention, a second group of compounds is constituted by compounds for which R represents a hydrogen atom or a methyl or ethyl group; R1, R2, R3, R4, R5 and R6 being as defined above. Among the compounds of general formula (I) which are subjects of the invention, a third group of compounds is constituted by the compounds for which R 1 represents a phenyl group, optionally substituted with one or more substituents chosen independently from one of the following groups: other of the halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, hydroxy; R, R2, R3, R4 and R5 being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a fourth group of compounds is constituted by the compounds for which R represents a phenyl group, optionally substituted with one or more substituents chosen independently of one another among the halogen atoms, methyl, ethyl, methoxy, hydroxy; R 1, R 2, R 3, R 4, R 5 and R 6 being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a fifth group of compounds is constituted by the compounds for which R 2 represents one or more substituents chosen from the hydrogen atom, the halogen atoms, the groups halo- (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-SO 2; R, R 1, R 3, R 4 and R 5 being as defined above.

Among the compounds of general formula (I) which are subjects of the invention, a sixth group of compounds is constituted by the compounds for which R 2 represents one or more substituents chosen from hydrogen, halogen atoms, groups trifluoromethyl, methyl, methoxy, ethanesulfonyl; R, R 1, R 3, R 4 and R 5 being as defined above.

Among the compounds of general formula (I) which are subjects of the invention, a seventh group of compounds is constituted by compounds for which: R represents a hydrogen atom or a methyl or ethyl group; R 1 represents a phenyl group, optionally substituted by one or more substituents chosen independently of one another from halogen atoms, methyl, ethyl, methoxy and hydroxy groups; R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, trifluoromethyl, methyl, methoxy, ethanesulfonyl groups; In the form of a base or an acid addition salt.

Among the compounds of general formula (I) which are subjects of the invention, mention may be made especially of the following compounds: N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - ( 2-methyl-3-trifluoromethyl) benzamide; N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-methoxy-2-methyl) -benzamide; N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenylmethyl] - (2,6-dichloro-3-trifluoromethyl) benzamide and its hydrochloride; N- [6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide and its hydrochloride; (+) - N - [(6-Azabicyclo [3.2.1] oct-5-yl) phenylmethyl] - (2-chloro-3-trifluoromethyl) benzamide and its hydrochloride; () N - [(6-Azabicyclo [3.2.1] oct-5-yl) phenylmethyl] - (2,6-dichloro-3-trifluoromethyl) benzamide and its hydrochloride; (-) - N - [(6-Azabicyclo [3.2.1] oct-5-yl) phenylmethyl] - (2-chloro-3-trifluoromethyl) benzamide and its hydrochloride; (+) - N - [(6-Azabicyclo [3.2.1] oct-5-yl) phenylmethyl] - (2,6-dichloro-3-trifluoromethyl) benzamide and its hydrochloride; N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (4-chloro-5-ethanesulfonyl-2-methoxy) -benzamide and its hydrochloride; N - [(6-Azabicyclo [3.2.1] oct-5-yl) phenylmethyl] - (2-chloro-5-trifluoromethyl) benzamide and its hydrochloride; N - [(6-Azabicyclo [3.2.1] oct-5-yl) phenylmethyl] - (2,6-dichloro) benzamide; N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-chloro-2-methyl) -benzamide; N - [(6-Azabicyclo [3.2.1] oct-5-yl) - (4-fluoro-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide; N - [(- 6-Aza-bicyclo [3.2.1] oct-5-yl) - (4-fluoro-phenyl) -methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide; N - [(- 6-Azabicyclo [3.2.1] oct-5-yl) - (3-methoxy-phenyl) -methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide; N - [(6-Azabicyclo [3.2.1] oct-5-yl- (3-methoxy-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide; N- [6-Aza] bicyclo [3.2.1] oct-5-yl- (3-hydroxy-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide N - [(6-Aza-bicyclo [3.2.1] oct 5-yl) - (3-hydroxy-phenyl) -methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide 6 N - [(6-Aza-bicyclo [3.2.1] oct-5- yl) -m-tolyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide and its hydrochloride; 2-Chloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5 N-[(6-Aza-bicyclo [3.2.1] oct-5-yl-m-tolyl-methyl] - (2,6-dichloro-N-phenyl-methyl] - (3-trifluoromethyl) -benzamide; 3-Trifluoromethyl) -benzamide, 2-chloro-N - [(6-methyl-6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide and N- [(6-Azabicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) methyl] - (2-chloro-3-trifluoromethyl) -benzamide hydrochloride and its hydrochloride; N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide and n n hydrochloride;

The compounds of the invention exhibit particular activity as inhibitors of GIyt1 glycine transporters, including an improved activity and safety profile.

The compounds of general formula (I) can be prepared by a process illustrated in Scheme 1 which follows. SCHEME 1 (I) (II) Coupling of a diamine of general formula (II) wherein R and R 1 are as defined above, in particular when R represents a hydrogen atom, an allyl or phenylmethyl group, with an activated acid or an acid chloride of general formula (III) in which Y represents an OH group; activated or a chlorine atom and R2 is as defined above, using the methods known to those skilled in the art.

The compounds of general formula (I) in which R represents a hydrogen atom may also be prepared from compounds of general formula (I) in which R represents: either a phenylmethyl group by deprotecting nitrogen by hydrogenolysis, or an alkenyl group, preferably allyl, deprotecting the nitrogen, for example by a complex of palladium zero according to methods known to those skilled in the art.

The compounds of general formula (I) in which R is different from the hydrogen atom may also be prepared from compounds of general formula (I) in which R represents a hydrogen atom or by alkylation with a hydrogen atom. RX type halide or mesylate, in which R is as defined above and X is mesylate or halogen, in the presence of a mineral base, for example potassium carbonate in acetonitrile, or by an Eschweiler-type reaction - Clarke or by a reductive amination with a suitable aldehyde or ketone according to methods known to those skilled in the art, or with a suitable epoxy derivative, according to the methods known to those skilled in the art.

The compounds of general formula (I) in which the group R 1 is a phenyl group substituted by a hydroxyl may be obtained from the corresponding compound of general formula (I) substituted by a methoxy, using the methods known to man of career. The diamine of general formula (II) can be prepared by the methods illustrated by Schemes 2 for amine (IIa) and (IIb) and 3 for amine (IIc) which follow.

Scheme 2 (IVa) SCHEME 3 (IVc) According to Scheme 2, the nitrile of formula (IVa) is reacted with the lithiated aromatic of general formula (V), wherein R, is as defined above in an ethereal solvent such as tetrahydrofuran or ether, at low temperature, for example at -70 ° C. An imine is thus obtained which is in particular reduced diastereoselectively with a reducing agent such as sodium borohydride, in a protic solvent such as methanol to give the amine of general formula (IIa). The amine (IIa) can be debenzylated by hydrogenation in the presence of palladium catalyst to provide the deprotected amine (IIb) (Scheme 2). According to Scheme 3, the nitrile of formula (IVc) may also be reacted with the lithiated aromatic compound of general formula (V) in which R 1 is as defined above in an ethereal solvent such as tetrahydrofuran. or ether, at low temperature for example at -70 ° C. An imine is thus obtained which is reduced with a reducing agent such as sodium borohydride in a protic solvent such as methanol to give the amine of general formula (IIc) (Scheme 3).

Moreover, the chiral compounds of general formula (I) can be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column, or by separation by chromatography on silica gel of the chiral diastereoisomers of the amine of formula general (IIa) then debenzylation, as described in Scheme 2.

The nitrile of formula (IVa) is prepared according to a method described in Tetrahedron: Asymmetry, 2006 (17), 252-258 and the nitrile of formula (IVc) is synthesized according to this same reference, using allylamine. The lithiated aryls of general formula (V) can be prepared according to methods known to those skilled in the art.

Acids and acid chlorides of general formula (III) are commercially available or prepared by analogy with methods known to those skilled in the art

The following examples illustrate the preparation of some compounds of the invention. In these examples: Elemental microanalyses, I.R. and R.M.N. and chiral column HPLC confirm the structures and enantiomeric purities of the compounds obtained, - For NMR descriptions, "m" means multiplet, "s" singlet, "t" triplet, "d" doublet, 10 "q" quadruplet, dxd means double doublet, txt means triple triplet, dxt double triplet, etc. - The numbers indicated in parentheses in the titles of the examples correspond to those of the 1st column of the table given below, - "decomp." means "decomposition", 15 - The Roman numerals in parenthesis correspond to the corresponding general formulas which are indicated in the synthesis diagrams, - The nomenclature used is the nomenclature following the IUPAC (International Union of Pure and Applied Chemistry) recommendations.

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 No. 3): N - [(6-Azabicyclo [3.2.1] oct-5-yl) -25-phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) hydrochloride benzamide (1: 1).

1.1 Phenyl- [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1] oct-5-yl-methylamine (III). In a 100 ml three-necked solution under argon, 1 g of 6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1] octane-5-carbonitrile (IVa) (4, 16 mmol) at -70 ° C. in 35 ml of anhydrous tetrahydrofuran. 7.4 ml of a 1.13M solution (cyclohexane / ether) of phenyl lithium (8.32 mmol) are added dropwise. It is left for 2 hours and a half at -70 ° C. and then hydrolyzed at -20 ° C. with 15 ml of water. After extraction, the organic phase is concentrated under reduced pressure and the residue is taken up in 20 ml of methanol. 0.79 g of sodium borohydride (20.8 mmol) are added in portions. The reaction medium is left stirring overnight at room temperature. After evaporation under reduced pressure, the residue is taken up in 50 ml of ether and 50 ml of water. The medium is acidified with a 1N hydrochloric acid solution and then extracted. The aqueous phase is basified with ammonia and then reextracted twice with 50 ml of dichloromethane. The organic phases are combined, dried over sodium sulfate, filtered and evaporated under reduced pressure. There is thus obtained 1.5 g of an oil which is purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol. 1.15 g of phenyl- [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1] oct-5-yl] -methylamine (IIa) are thus obtained, a mixture of 2 chiral diastereoisomers, in the form of an oil. 1.2 (6-Aza-bicyclo [3.2.2] oct-5-yl) -phenyl-methylamine (IIb).

In a Parr flask, 4 g of compound of formula (IIa) (12.5 mmol) are placed in 80 ml of methanol in the presence of a tip of 20% palladium hydroxide spatula, under 4 atmospheres. hydrogen at room temperature for 6 hours. After filtration of the catalyst and evaporation of the filtrate under reduced pressure, the residue is taken up in 10 ml of dichloromethane and 20 ml of aqueous ammonia. After extraction, the organic phase is washed in a saturated solution of sodium chloride, dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. There is thus obtained 1 g of (6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methylamine of formula (IIb) in the form of an oil which can be used crude in the next step.

An analytical sample is obtained by salification of the base with a solution of 2N hydrochloric ether and then trituration in ether.

Mp = 215-225 ° C 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (m, 4H), 7.76 (m, 2H), 7.56 -7.43 (m, 4H) ), 5.09 (brs, 1H), 3.49 (m, 1H), 3.11 (m, 1H), 2.72 (m, 1H), 2.19 (m, 1H), 1, 87 (m, 1H), 1.83 ± 1.17 (m, 8H).

1.3 N - [(6-Azabicyclo [3.2.1-tert-5-yl] -phenyl-methyl-2- (2,6-dichloro-3-trifluoromethyl) -benzamide Hydrochloride (1: 1). In a 25 ml flask were placed 240 mg of (2,6-dichloro-3-trifluoromethyl) -benzoic acid (0.92 mmol), 124 mg of hydroxybenzotriazole (0.92 mmol), 180 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.92 mmol) dissolved in 5 ml of dichloromethane and the mixture is stirred at room temperature for 15 minutes. 200 mg (0.92 mmol) of (6-azabicyclo [3.2.1] oct-5-yl) -phenyl-methylamine of formula (IIb) in solution in 5 ml of dichloromethane are added and the mixture is stirred at room temperature for one hour. night. The reaction medium is then diluted with 10 ml of dichloromethane and then washed successively with water (5 ml), with 1N sodium hydroxide solution (5 ml) and with saturated sodium chloride solution (5 ml). The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. In this way 180 mg of N - [(6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide is obtained, which is salified in the form of of hydrochloride by solubilization of the base in dichloromethane, addition of an excess of 1N hydrochloric acid in ether and concentration under reduced pressure. Mp = 249.5-250.5 ° C 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (m, 1H), 9.66 (d, J = 9Hz, 1H), 8.86 ( m, 1H), 8.01 (m, 1H), 7.84 (m, 1H), 7.69 (m, 2H), 7.50 (m, 2H), 7.42 (m, 1H). , 5.79 (d, J = 9.1Hz, 1H), 3.57 (m, 1H), 3.16 (m, 1H), 2.69 (m, 1H), 2.16-1, 84 (m, 3H), 1.77-138 (m, 5H). Example 2 (Compound No. 8): (+) - N - [(6-Azabicyclo [3.2.1] oct-5-yl) -25-phenylmethyl] - (2,6-dichloro-3) hydrochloride trifluoromethyl) benzamide (1: 1).

2.1. First diastereoisomer of phenyl - [6 - ((R) -1-phenyl-ethyl) -6-azabicyclo [3.2.1-oct-5-yl-methylamine (IIa)

The two diastereoisomers (IIa) can be separated by separation on silica gel with a mixture of dichloromethane and methanol as eluent. The least polar compound is phenyl- [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1] oct-5-yl] -methylamine (IIa).

1H NMR (400MHz, DMSO-d6) δ ppm 7.47 (m, 4H), 7.39 -7.17 (m, 6H), 4.26 (s, 1H), 4.23 (m, 1H), 3.17 (m, 1H), 3.56 (d, J = 8.7 Hz, 1H), 2.28 (m, 1H), 2.07 (m, 1H), 2.00 (m, 1H), m, 2H), 1.65 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.28-0.86 (m, 6H) 2.2. (+) (6-Azabicyclo [3.2.11oct-5-yl] -phenyl-methylamine (IIb1)) enantiomer This compound is obtained according to Example 1.2 starting from the compound of formula (IIa1). A compound of formula (IIbl) in base form.

Mp = 84-85 ° C ee = 100% [δ] 20 ° C CHCl3 = +55.2 c = 0.80g / 100 ml 1 H NMR (400 MHz, CDCl3) δ ppm 7.29 7.13 (m, 5H) ), 3.72 (s, 1H), 3.01 (m, J = 5.4 Hz and 10 Hz, 1H), 2.87 (m, J = 10 Hz and 1 Hz, 1H), 2.25 (m, 1H), 1.83 (m, 1H), 1.70 (m, 3H), 1.58 (m, 1H), 1.52-1.39 (m, 2H), 1.31 1.08 (m, 4H).

2.3 (+) - N - (6-Azabicyclo [3.2.1-tert-5-yl] -phenyl-methyl-2- (2,6-dichloro-3-trifluoromethyl) -benzamide hydrochloride (1: 1). This compound is obtained according to Example 1.3 starting from the compound of formula (IIb1). An analytical sample is obtained in hydrochloride form by solubilization of the base in dichloromethane, addition of an excess of 1 N hydrochloric acid in ether and concentration under reduced pressure.

Mp: 241-242 ° C 25 ee: 95% [D] 20 ° C MeOH = + 30.7 c = 0.75 g / 100 ml

1H NMR (400MHz, DMSO-d6) δ ppm 9.62 (d, J = 8.9Hz, 1H), 9.42 (m, 1H), 8.84 (m, 1H), 7.97. (m, 1H), 7.80 (m, 1H), 7.59 (m, 2H), 7.46 (m, 2H), 7.39 (m, 1H), 5.70 (broad d, J = 9Hz, 1H), 3.49 (m, 1H), 3.13 (m, 1H), 2.65 (m, 1H), 2.11-1.20 (m, 9H)

Example 3 (Compound No. 6): (-) - N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2,6-dichloro-3-) hydrochloride trifluoromethyl) benzamide (1: 1). 3.1 Second diastereoisomer of phenyl-6- (1R) -1-phenyl-ethyl) -6-azabicyclo [3.2.11oct-5-yl-methylamine (IIa2) The 2 diastereoisomers (IIa) can be separated by separation on silica gel with a mixture of dichloromethane and methanol as eluent. The most polar compound is phenyl-C- [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1] oct-5-yl] methylamine (IIa 2). 1H NMR (400MHz, DMSO-d6) δ ppm 7.46 (m, 2H), 7.34 (m, 2H), 7.29-7.14 (m, 6H), 4.23 (q, J = 6); , 8Hz, 1H), 3.56 (m, 1H), 3.21 (m, 1H), 3.06 (m, 1H), 2.26 (m, 1H), 2.19 (m, 2H). ), 1.75 -1.16 (m, 10H), 0.89 (m, 2H).

3.2 (-) - (6-Azabicyclo [3.2.1-tert-5-yl] -phenyl-methylamine (IIb 2) enantiomer This compound is obtained according to Example 1.2 starting from the compound of formula (IIa 2). Compound of formula (IIb2) in base form

Mp = 82.5-83.5 ° C ee = 93% [δ] 20 ° C CHCl3 = -18.3 ° c = 0.58 g / 100 ml 1 H NMR (400 MHz, CDCl3) δ ppm 7.29 -7 , 13 (m, 5H), 3.72 (s, 1H), 3.02 (m, J = 5.4 Hz and 10 Hz, 1H), 2.88 (m, J = 10 Hz and 1 Hz, 1H), 2.25 (m, 1H), 1.83 (m, 1H), 1.70 (m, 3H), 1.59 (m, 1H), 1.52-1.39 (m, 1H), m.p. 2H), 1.33-1.08 (m, 4H).

3.3 (-) - N - (6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl-(2,6-dichloro-3-trifluoromethyl) -benzamide hydrochloride (1: 1). This compound is obtained according to example 1.3 starting from the compound of formula (IIb2). Mp: 192-193 ° C. ee = 92% [ao] 20 ° C. MeOH = -40.5 ° c = 0.194 g / 100 ml 1H NMR (400MHz, DMSO-d6) δ ppm 9.61 (d, J = 8.6Hz, 1H), 9.54 (m, 1H), 8.83 (m, 1H), 7.97. (m, J = 8.8 Hz, 1H), 7.79 (m, 1H), 7.60 (m, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.38 (m, 1H), (m, 1H), 5.71 (d, J = 8.5 Hz, 1H), 3.49 (m, 1H), 3.13 (m, 1H), 2.65 (m, 1H), 2 11-1.78 (m, 3H), 1.71-1.22 (m, 6H).

Example 4 (Compound No. 20): 2-Chloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) -35-phenylmethyl] - (3-trifluoromethyl) - In a 25 ml flask, 0.17 g of N - [(6-aza-bicyclo [3.2.1] oct-5-yl) -phenylmethyl] - (2-chloro-3-trifluoromethyl) - is placed in a 25 ml flask. benzamide (0.40 mmol) and 0.084 g of potassium carbonate (0.60 mmol) in 4 ml of acetonitrile, to which 50 μl of iodoethane (0.60 mmol) are added.

The reaction medium is stirred overnight at room temperature, then 3 hours at 50 ° C and then concentrated under reduced pressure. The residue is then diluted with 10 ml of dichloromethane and washed with water (5 ml). After extraction, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. There is thus obtained 158 mg of an oil which is purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol. 84 mg of 2-chloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide are thus obtained in the form of powder.

MP: 160-162 ° C 1H NMR (400MHz, DMSO-d6) ppm 8.60 (d, J = 7.7Hz, 1H), 7.92 (m, 1H), 7.63 (m, 2H) ), 7.43-7.21 (m, 5H), 4.93 (d, J = 7.7 Hz, 1H), 3.41 (m, 1H), 2.82 (m, 1H), 2.62 -2.39 (m, 2H), 2.20 (m, 2H), 1.72 (m, 1H), 1.53-0.84 (m, 9H).

Example 5 (Compound No. 22): 2-Chloro-N - [(6-methyl-6-azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) hydrochloride benzamide (1: 1).

In a 25 ml flask, 0.127 g of N - [(6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide is placed ( 0.30 mmol) and 1 ml of formaldehyde in 2 ml of formic acid. The reaction mixture is heated at 100 ° C overnight. After cooling, the medium is hydrolysed, basified to pH 9 with ammonia and then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. There is thus obtained 113 mg of an oil which is salified in hydrochloride form by solubilization of the base in dichloromethane, addition of an excess of 1 N hydrochloric acid in ether and concentration under reduced pressure.

Mp: 186-188 ° C NMRH (400 MHz, DMSO-d6) δ ppm 10.20 (m, 1H), 9.34 (d, J = 9.8 Hz, 1H), 8.06 (m.p. , J = 7.7 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.68 (m, 3H), 7.53 -7.38 (m, 3H), 5.74 (d, J = 9.8 Hz, 1H), 4.16 (m, 1H), 3.10 (m, 1H), 2.73 - 2.50 (m, 4H), 2.40 (m, 1H), 2.10 -1.38 (m, 7H). Example 6 (Compound No. 23): N - [(6-Azabicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2-chloro-3-) hydrochloride trifluoromethyl) benzamide (1: 1).

6.1. 6-Allyl-6-aza-bicyclo [3.2.1] octane-5-carbonitrile (1Vc). In a sealed 5 ml tube under argon, 0.5 g of 3-chloromethylcyclohexanone (3.4 mmol), 3 ml of anhydrous methanol, 0.93 ml of acetone cyanohydrin (10.2 mmol) and 0.5 g of acetone are added. 26 ml of allylamine (3.4 mmol). The reaction mixture is heated for 3 days at 100 ° C. After cooling, the reaction medium is poured into 10 ml of 1N aqueous sodium hydroxide solution. After two extractions with dichloromethane, the combined organic phases are washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with a mixture of petroleum ether and ethyl acetate. There is thus obtained 426 mg of 6-allyl-6-azabicyclo [3.2.1] octane-5-carbonitrile (IVc) as an oil.

1 H NMR (400 MHz, DMSO-d 6) δ ppm 8.60 (d, J = 7.7 Hz, 1H), 7.92 (m, 1H), 7.63 (m, 2H), 7.43. -7.21 (m, 5H), 4.93 (d, J = 7.7 Hz, 1H), 3.41 (m, 1H), 2.82 (m, 1H), 2.62-2.39; (m, 2H), 2.20 (m, 2H), 1.72 (m, 1H), 1.53 -0.84 (m, 9H).

6.2. (6-Allyl-6-aza-bicyclo (3.2.1) oct-5-yl) - (3-bromo-phenyl) methylamine (IIc).

The compound is obtained according to the method described in Example 1.1, starting from 1 g of 6-allyl-6-aza-bicyclo [3.2.1] octane-5-carbonitrile (1Vc), 2.5 equivalents of 3-bromophenyl lithium and 5 equivalents of sodium borohydride. After purification by column chromatography on silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol, 260 mg of an oil containing 140 mg of (6-allyl-6-aza-bicyclo [3.2.1] oct- 5-yl) - (3-bromo-phenyl) -methylamine (IIc) (0.42 mmol) used as in the next step. 6.3 Nf (6-Allyl-6-aza-bicyclof3.2.1 joct- 5-yl) - (3-bromo-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide.

In a 25 ml flask, 260 mg of (6-allyl-6-aza-bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methylamine (IIc) are placed (0.42 mmol) in 8 ml of dichloromethane at 0 ° C in the presence of 118 mg of potassium carbonate (0.78 mmol). 189 mg of (2-chloro-3-trifluoro) -benzoic acid acid chloride (0.78 mmol) are then added. The reaction medium is stirred overnight at room temperature. After hydrolysis and extraction, the organic phase is washed with 1N sodium hydroxide, dried over sodium sulfate, filtered and concentrated under reduced pressure. After purification by column chromatography on silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol, 146 mg of N - [(6-allyl-6-aza-bicyclo [3.2.1] oct-5-yl are obtained. ) - (3-bromo-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide as an oil.

1 H NMR (400 MHz, DMSO-d 6) δ ppm 8.68 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.63 (m). , 2H), 7.58 (m, 1H), 7.44 (m, 1H), 7.40 (m, 1H), 7.28 (d, J = 7.8 Hz, 1H), 5.81 (m, 1H), 5.22 (m, 1H), 5.00 (m, 1H), 4.97 (d, J = 7.7 Hz, 1H), 3.53 (m, 1H), 3 , 34 (m, 1H), 3.07 (m, 1H), 2.37 (m, 1H), 2.18 (m, 1H), 1.77 (m, 1H), 1.54-0, 77 (m, 7H). 6.4 N- (6-Azabicyclo [3.2.1-tert-5-yl] - (3-bromo-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide hydrochloride.

In a sealed tube under argon, 19 mg of palladium tetrakis (triphenylphosphine) (0.02 mmol) and 0.078 g of N, N-dimethylbarbituric acid (0.5 mmol) in solution in 3 ml of dichloromethane are placed. The reaction medium is heated to 40 ° C. before adding 0.09 g of N - [(6-allyl-6-azabicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl ] - (2-chloro-3-trifluoromethyl) benzamide (0.17 mmol) in 3 ml of dichloromethane. The mixture is heated for 2 hours at 40.degree. After cooling, it is diluted with 10 ml of dichloromethane and then hydrolyzed with 5 ml of sodium carbonate solution. The organic phase is separated and washed twice with 5 ml of 1N hydrochloric acid. The aqueous phases are combined and then basified with aqueous ammonia at pH 9 and then extracted twice with 25 ml of dichloromethane. The organic phases are dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with a mixture of dichloromethane and ammoniaal methanol. 62 mg of N - [(6-aza-bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide are thus obtained. is salified in hydrochloride form by solubilization of the base in dichloromethane, addition of an excess of 1 N hydrochloric acid in ether, concentration under reduced pressure, trituration in ether and filtration.

Mp: 250.5-251.5 ° C NMRH (400 MHz, DMSO-d6) δ ppm 9.62 (m, 1H), 9.45 (d, J = 9.2 Hz, 1H), 8 , 94 (m, 1H), 7.97 (dxd, J = 8 and 1.5 Hz, 1H), 7.91 (m, 1H) 7.77 (dxd, J = 7.8 and 1.4 Hz, 1H), 7.67 (t, J = 7.6 Hz, 2H), 7.59 (m, J = 8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H); , 5.74 (d, J = 9.1 Hz, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 2.64 (m, 1H), 2.08 (m, 1H) 1.94 (m, 1H), 1.80 (m, 1H), 1.72-1.40 (m, 5H).

The other compounds listed in Table 1 are obtained according to the methods described in Examples 1 to 6, from suitable lithiens or alkylating agents.

Table 1 which follows illustrates the chemical structures of some compounds of the invention.

In the column: - "Salts" - means a compound in the basic state, "HCI" means a hydrochloride, the parenthesis indicates the ratio (acid: base), - The compounds of the table are in the form of hydrochloride solvated with one or more molecules of water, in the columns R, R, and R2: - - Cl means chlorine, - CH3 means methyl, - NH2 means amino, - OCH3 means methoxy, - Ph means phenyl, - SO2C2H5 means ethanesulfonyl, - CF3 means trifluoromethyl, - in column R2, the number in front of the substituents indicates the position in the general formula (I), Table 2 gives the physical properties, melting points and rotational potency of the compounds of Table 1 In Table 2: Column [aD] C informs the result of analysis of the rotatory power of the compounds of the table at the wavelength of 589 nM and the temperature of 20 ° C. The solvent indicated in parentheses corresponds to the solvent used to measure the rotary power in degrees and the letter c indicates the solvent concentration in g / 100 ml. NA means that the measurement of the rotatory power is not applicable, the column "m / z" informs the molecular ion (M + H +) or (M +) observed by product analysis by mass spectrometry, or by LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) performed on an Agilent LC-MSD Trap device in ESI positive mode, either by direct introduction by MS (Mass Spectroscopy) on an Autospec M (EBE) device using the DCINH3 technique or by using the electronic impact technique on a Waters GCT type device.

TABLE 1 R2 ## STR1 ## Stereochemistry salts 1H Ph 2 -CH3,3-CF3 - Diastereoisomer 1, racemic 2H Ph 2 -CH3,3-OCH3 - Diastereoisomer 1, racemic 3H Ph 2,6 (Cl) 2 , 3-CF3 HCI Diastereoisomer 1, (1: 1) racemic 4H Ph 1 HCl Diastereoisomer 1, 2-Cl, 3-CF3 (1: 1) racemic H Ph 2 -Cl, 3-CF3 Chiral HCI dextrorotatory (1: 1) 6 H Ph 2,6- (Cl) 2,3-CF3 HCl Chiral levorotatory (1: 1) 7H Ph 2 -Cl, 3-CF3 HCl Chiral levorotatory (1: 1) 8H Ph 2,6- (C1) 2,3-CF3 HCI O Dextrorotatory chiral 1 9 H Ph 2 -OCH3,4-Cl, 5-SO2C2H5 HCl Diastereoisomer 1, (1: 1) racemic H Ph 2 -Cl, 5-CF3 HCl Diastereoisomer 1, (1: 1) Racemic 11H Ph 2,6- (Cl) 2 Diastereoisomer 1, - racemic 12H Ph 2 -CH3,3-Cl - Diastereoisomer 1, racemic 13H 4-F-Ph 2 -Cl, 3- CF3 Diastereoisomer 1, Racemic 14H 4-F-Ph 2,6- (Cl) 2,3-CF3 - Racemic diastereoisomer 15 H 3 -OCH3- 2,6- (Cl) 2,3-CF3-Diastereoisomer 1, Racemic pH 16H 3-OCH3-2-Cl, 3-CF3 - Diastereoisomer 1, racemic Ph 17 H 3 -OH-Ph 2-Cl-CFO Dia 1 stereoisomer 1, - racemic 18 H 3 -OH-Ph 2,6- (Cl) 2,3-CF3 Diastereoisomer 1, racemic 19 H 3 -CH3-Ph 2-Cl-CF3 HCl Diastereoisomer (1: 1) racemic C2H5 Ph 2 -Cl, 3-CF3 Racemic diastereoisomer 21 H 3 -CH3-Ph 2,6- (Cl) 2,3-CF3 Racemic diastereoisomer 22 CH3 Ph 2-Cl-CF3 HC Diastereoisomer (1: 1) 1 Racemic 23 H 3-Br-Ph 2-Cl-CFH 3 HCl Diastereoisomer 1, (1: 1) Racemic 24 H 3 -Br-Ph 2,6- (Cl) 2,3-CF3 HCl Diastereoisomer (1: 1) racemic TABLE 2 N ° F ° C [aD ~ 20 ° C ° LCMS MH + 1 58, 5-59, 5 NA 403 2 233-234 NA 365 3 249.5-250.5 NA 457 4 260-262 NA 423 265.5-266.5 32.0 (MeOH, c = 0.66 g / 100 ml) 423 6 192-193 -40.5 (MeOH, c = 0.196 g / 100 ml) 457 7 266.5-267.5 -26.4 (MeOH, c = 0.73 g / 100 ml) 423 8 457 241-242 30.7 (MeOH, c = 0.75 g / 100 ml) 9 185-187 NA 477 10 188-190 NA 423 11 172 -174 NA 389 12 132-134 NA 369 13 244-246 NA 441 14 188-190 NA 475 15 208-210 NA 487 16 67-69 NA 453 17 180-182 NA 439 18 208-210 NA 473 19 257-259 NA 437 20 160-162 NA 451 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 glyt1 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 min preincubation at 37 ° C in the presence of either buffer (control group) or test compound at different concentrations or 10 mM glycine (non-specific uptake determination), 10 μM [14 C] glycine ( specific activity 112 mCi / mmol) are then added. Incubation is continued for 10 min at 37 ° C, and the reaction is stopped by 2 washes with Krebs-HEPES buffer pH 7.4. The radioactivity incorporated by the cells is then estimated after adding 100 μl of liquid scintillant and stirring for 1 h. The 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 C150 of the order of 0.001 to 10 NM. Table 3 shows some examples of IC50 results for compounds according to the invention.

TABLE 3 Compound IC50 (pM) 4 0.020 11 0, 90 17 0, 045 The results of the tests carried out on the chiral compounds of the invention and their racemates in the general formula (I) of which R2 represents one or more halogen atoms or trifluoromethyl groups show that they are inhibitors of glycine transporter glyt1 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 cognitive and / or behavioral disorders associated with neurodegenerative diseases, dementia; for the treatment of psychoses, in particular schizophrenia (deficient form and productive form), 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 bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, migraine; pain ; sleep disorders.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular glycine transporter glyt1 inhibitory drugs.

Thus, according to another of its aspects, the invention relates to medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or a hydrate or a solvate of the compound of formula (I).

The present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a base or a pharmaceutically acceptable salt or solvate, and in a mixture, where appropriate, with suitable excipients.

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

The pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular administration.

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.

To prepare tablets, a pharmaceutical carrier which may be composed of diluents, for example lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders (polyvinylpyrrolidone), is added to the active ingredient, which may or may not be micronized. , hydroxypropyl methylcellulose, 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. They can be designed to allow rapid, delayed or sustained release of the active ingredient by means of 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), liquid or semi-solid. 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).

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

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 as microcapsules, optionally with one or more carriers 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 skin compatible medium. They may be in particular in the form of aqueous solutions, alcoholic or aqueous-alcoholic, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or a 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.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg Orally, the dose of active principle administered per day may be as high as 0.1 to 20 mg / kg, in one or more doses . There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual 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 of treatment of 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. 10

Claims (20)

CLAIMS1.Compound of general formula (I) R2 in which: - R represents a hydrogen atom or a group selected from the group (C, -C6) alkyl, (C3-C) - cycloalkyl, optionally substituted with one or a plurality of groups independently selected from fluorine, (C 3 -C 4) cycloalkyl, (C 2 -C 4) alkenyl, phenyl, (C 1 -C 6) alkoxy, hydroxy; the phenyl group being optionally substituted by one or more alkoxy groups; - R, represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy groups; , halo- (C 1 -C 6) alkyl, NR 4 R 5, NR 3 C (O) OR 4, NR 3 SO 2 R 4, NR 3 C (O) R 6, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-thio, ( C 1 -C 6) alkyl-SO 2, phenyl or heteroaryl, the phenyl group being optionally substituted with one or more substituents chosen independently from among the halogen atoms, the (C 1 -C 6) alkyl and (C 1 -C 6) alkoxy groups , halo- (C 1 -C 6) alkyl, NR 4 R 5, NR 3 C (O) OR 4 NR 3 SO 2 R 4, NR 3 C (O) R 6, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-thio, (C , -C6) alkyl-SO2, the heteroaryl group being optionally substituted by one or more substituents independently selected from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C, -C6) alkyl, NR4R5; R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl groups, (C 3 -C 8) -Cycloalkyl- (C 1 -C 3) alkyl, (C 1 -C 6) alkoxy, NR 4 R 5, phenyl, heteroaryl, cyano, acetyl, (C 1 -C 6) thioalkyl, (C 1 -C 6) alkylsulfonyl carboxy or (C 1 -C 6) alkoxycarbonyl; the phenyl group being optionally substituted by one or more substituents independently selected from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C 1 -C 6) alkyl, NR 4 R 5 groups, NR 3 C (O) OR 4 NR 3 SO 2 R 4, NR 3 C (O) R 6, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-thio, (C 1 -C 6) alkyl-SO 2, the heteroaryl group being optionally substituted by one or more substituents independently selected from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C 1 -C 6) alkyl, NR 4 R 5, - R 3, R 4 and R 5 represent independently of one another a hydrogen atom or a (C 1 -C 6) alkyl group; - R6 represents a (C 1 -C 6) alkyl group; - - R4 and R5 can form together, with the nitrogen atom which carries them, a ring selected from the azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine rings, optionally substituted by a (C, -C6) group; ) alkyl; - R3 and R4 can form together with the atoms that carry them, a 5- or 6-membered ring; - R3 and R6 can form together, with the atoms that carry them, a 5- or 6-membered ring; in the form of a base or an acid addition salt. 2. Compound of general formula (I) according to claim 1, characterized in that R represents a hydrogen atom, or a (C 1 -C 6) -alkyl group. 3. Compound of general formula (I) according to claim 1 or 2, characterized in that R, represents a phenyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, hydroxy groups. 4. Compound of general formula (I) according to any one of claims 1 to 3, characterized in that R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halogen groups ( C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy. (C 1 -C 6) alkyl-SO 2. 5. Compound of general formula (I) according to any one of claims 1 to 4, characterized in that: - R represents a hydrogen atom or a methyl group, ethyl; - R, represents a phenyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, methyl, ethyl, methoxy, hydroxy; R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, trifluoromethyl, methyl, methoxy, ethanesulfonyl groups; In the basic state or as an acid addition salt. 6. Process for the preparation of a compound of general formula (I) according to claim 1, characterized in that a compound of general formula (II) in which R and R are as defined according to claim 1, reacts with a compound of general formula (III) YO wherein Y represents an activated OH group or a chlorine atom and R2 is as defined according to claim 1. 7. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 5, or a salt of addition of this compound to a pharmaceutically acceptable acid. 8, Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 9. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases; to madness. 10. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of psychoses, schizophrenia (deficient form and productive form), acute extrapyramidal symptoms or chronic induced by neuroleptics. 11. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for treatment for the treatment of various forms of anxiety, panic attacks, phobias, obsessive compulsive disorder. 28 12. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, migraine. 13. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of pain. 14. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of sleep disorders. 15. A compound according to any one of claims 1 to 5 for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases; to madness. 16. Compound according to any one of claims 1 to 5, for the treatment of psychoses, schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics. 17. A compound according to any one of claims 1 to 5 for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders. 18. A compound according to any one of claims 1 to 5 for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, disorders of sexual behavior, eating disorders, migraine. 19. A compound according to any one of claims 1 to 5 for the treatment of pain. 20. A compound according to any one of claims 1 to 5 for the treatment of sleep disorders.