FR2943056A1 - New N-(2-aza-bicyclo(2.2.1)-hex-1-yl)-aryl-methyl-heterobenzamide derivatives are glycine transporter 1 inhibitors useful to treat e.g. dementia, psychosis, schizophrenia, anxiety, panic attacks, and obsessive compulsive disorder - Google Patents

Abstract

N-(2-Aza-bicyclo[2.2.1]-hex-1-yl)-aryl-methyl-heterobenzamide derivatives (I) and their base or acid addition salts are new. N-(2-Aza-bicyclo[2.2.1]-hex-1-yl)-aryl-methyl-heterobenzamide derivatives of formula (I) and their base or acid addition salts are new. R : H, (1-6C) alkyl or (3-7C)-cycloalkyl optionally substituted by one or more groups comprising halo, (3-7C)-cycloalkyl, (1-6C)alkyl, (1-6C)alkoxy, or OH; R 1>a phenyl or naphthyl (both optionally substituted by one or more substituents of halo, 1-6C alkyl, 1-6C alkoxy, halo-1-6C-alkyl, hydroxy, halo-(1-6C)alkoxy, (1-6C)alkyl-thio, (1-6C)alkyl-SO, or (1-6C)alkyl-SO 2); Het : a heteroaryl group; and R 2>one or more substituents comprising H, halo, halo-(1-6C) alkyl, (1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)-cycloalkyl-(1-3C) alkyl, (1-6C) alkoxy, benzyl, (1-6C)alkyl-thio, (1-6C) alkyl-SO, or (1-6C) alkyl-SO 2. Independent claims are included for: (1) the preparation of (I); (2) C-(2-aza-bicyclo[2.1.1]hex-1-yl)-methylamine compounds of formula (II); and (3) heterocyclic ketone compounds of formula (III). Y 1>a leaving group or Cl. [Image] [Image] ACTIVITY : Nootropic; Neuroleptic; Neuroprotective; Cerebroprotective; Tranquilizer; Antidepressant; Antimanic; Antiaddictive; Antialcoholic; Endocrine-Gen.; Eating-Disorders-Gen.; Antimigraine; Analgesic; Hypnotic. MECHANISM OF ACTION : Glycine transporter 1 (glyt1) inhibitor. The ability of (I) to inhibit glyt1 was tested in SK-N-MC cells (human neuroepithelial cells). The result showed that N-[(2-aza-bicyclo[2.1.1]hex-1-yl)-phenylmethyl]-(3-chloro-4-trifluoromethyl)-pyridine-2-carboxamide exhibited an IC 50value of 0.11 mu M.

Description

N - [(2-AZA-BICYCLO [2.1.1] HEX-1-YL) -ARYL-METHYL] -HETEROBENZAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF

The present invention relates to N - [(2-aza-bicyclo [2.2.1] hex-1-yl) -aryl-methyl] -heterobenzamide derivatives, to their preparation and their therapeutic application, in the treatment or the prevention of diseases involving carriers of glycine GIyt1.

The compounds of the invention correspond to the general formula (I) NNOR (I) in which: - R represents a hydrogen atom or a group chosen from (C 1 -C 6) alkyl, (C 3 -C 7) - cycloalkyl or allyl, optionally substituted by one or more groups chosen independently of one another from halogen atoms, (C 3 -C 5) -cycloalkyl, (C 1 -C 6) alkyl groups, C6) alkoxy, hydroxy; - 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) alkoxy groups, halo- (C1-C6) alkyl, hydroxy, halo- (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C6-C6) alkyl-SO, (C, -C6) alkyl-SO2 ; Het represents a heteroaryl group; 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, benzyl, (C 1 -C 6) alkyl-thio, (C 1 -C 6) alkyl-SO, (C 1 - C6) alkyl-SO2; in the form of a base or an acid addition salt.

The compounds of formula (I) have an asymmetric carbon atom. They can therefore exist in the form of 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 that 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 term Ct-C, where t and z can take the values from 1 to 6, a carbon chain which may have from t to z carbon atoms, for example C1_C6 a carbon chain which may have from 1 to 6 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example, a C1-C6-alkyl 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; alkoxy, an -O-alkyl group; hydroxy, a group OH, an allyl, a group (CH2) -CH = CH2 alkyl-thio, a sulfur atom substituted with an alkyl group; halogen atom, fluorine, chlorine, bromine or iodine; halo-alkyl, an alkyl group of which one or more hydrogen atoms have been substituted with a halogen. By way of example, mention may be made of trifluoromethyl, trifluoroethyl and pentafluoroethyl groups; heteroaryl group, a 5- or 10-membered mono or bicyclic heteroaromatic group comprising from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. By way of example of a heteroaryl group, mention may be made of pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine groups. , indole, isoindole, benzimidazole, indazole, indolizine, benzofuran, isobenzofuran, benzothiophene, benzo [c] thiophen, pyrrolopyridine,

35 imidazopyridine, pyrazolopyridine, triazolopyridine, tetrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine, triazolopyrimidine, tetrazolopyrimidine, pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine, pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine, triazolopyridazine, tetrazolopyridazine, pyrrolotriazine, imidazotriazine, pyrazolotriazine, triazolotriazine, tetrazolotriazine, furopyridine , furopyrimidine, furopyrazine, furopyridazine, furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyrazine, oxazolopyridazine, oxazolotriazine, isoxazolopyridine, isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine, isoxazolotriazine, oxadiazolopyridine, oxadiazolopyrimidine, oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine, benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine, thienopyrimidine, thienopyrazine thienopyridazine, thienotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine, thiazolotriazine, isothiazolopyridine, isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine, isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine, thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine, benzothiazole, benzoisothiazole, benzothiadiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline, naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine, pyrimidopyridazine, pyrimidotriazine, pyrazinopyrazine, pyrazinopyridazine, pyrazinotriazine, pyridazinopyridazine, pyridazinotriazine.

Among the compounds of general formula (I) that are the subject of the invention, a first group of compounds consists of the compounds for which - R represents a hydrogen atom or an allyl group; - 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; Het represents an indole, thiophene or pyridine group; R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo- (C 1 -C 6) alkyl, benzyl, (C 1 -C 6) alkyl-thio 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 notably be made of the following compounds: N - [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl- methyl] - (4,5-dibromo) -thiophene-2-carboxamide; N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide; N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2,5-dichloro) -thiophene-3-carboxamide; (+) - N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide, and its hydrochloride; (-) - N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide, and its hydrochloride; N - [(2-Azabicyclo [2.1.1] hex-1-yl) - (4-fluoro-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide; N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] -2-methylsulfanyl-nicotinamide; N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide; N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (1-benzyl) -1H-indole-4-carboxamide; N - [(2-Azabicyclo [2.1.1] hex-1-yl) -naphthalen-2-ylmethyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride; N - [(2-Azabicyclo [2.1.1] hex-1-yl) -naphthalen-2-ylmethyl] -2-methylsulfanylnicotinamide and its hydrochloride; N - [(2-Azabicyclo [2.1.1] hex-1-yl) - (3-methoxy-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride; N - [(2-Azabicyclo [2.1.1] hex-1-yl) - (3-methoxy-phenyl) methyl] -2-methylsulfanylnicotinamide, and its hydrochloride; N - [(2-Azabicyclo [2.1.1] hex-1-yl) -m-tolyl-methyl] -2-methylsulfanyl-nicotinamide, and its hydrochloride; N - [(2-Azabicyclo [2.1.1] hex-1-yl) - (3-trifluoromethyl-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride; N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -m-tolyl-methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride; (+) - N - [(2-Alyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide; (-) - N - [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide;

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 by Scheme 1 which follows

Scheme 1 (II) Coupling of a diamine of general formula (II), wherein R and R, are as defined above, especially when R represents a hydrogen atom or an allyl group, with an activated acid, for example via a mixed anhydride or an acid chloride of the general formula (III) in which Y represents a leaving group derived for example from benzotriazole, acylurea or a halogen atom and R2 is such that defined above, using the methods known to those skilled in the art. The compounds of the general formula (I) in which R represents hydrogen can also be prepared from compounds of the general formula (I) in which R represents: - a protective group which can be deprotected by hydrogenolysis, or an allyl group, by deprotecting the nitrogen, for example by a complex of palladium zero, according to the methods known to those skilled in the art.

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

The compounds of the general formula (I) in which the R 1 group is a phenyl group substituted by a hydroxy can be obtained from the corresponding compound of the general formula (I) substituted by a methoxy, using the methods known to man of the job. The diamine of general formula (II) can be prepared by methods illustrated by Schemes 2 for amine (IIa) and 3 for amine (IIb) and (IIc) which follow: SCHEME 2 (V) The ester (IV) is converted to amide (V) by heating the trimethylaluminum complex and the appropriate amine, such as morpholine, under the reflux of a solvent such as toluene. The amine (V) may be deprotected using a phenyllithium type lithian in a solvent such as tetrahydrofuran at low temperature, for example at -70 ° C. N-allylation is then carried out using allyl bromide in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile at room temperature, to obtain compound (VII). The morpholinic amide of formula (VIl) is reacted with the lithiated aromatic compound of general formula (VIII), in which R 1 is as defined above, in an ethereal solvent such as ether or tetrahydrofuran, at low temperature. temperature. A ketone of general formula (IX) is thus obtained which is reacted with the hydrochloride of O-benzylhydroxylamine, under reflux of pyridine, to obtain a mixture of oxime Z / E of general formula (X). The oxime (X) is then reduced at reflux of the ether with the double hydride of aluminum and lithium, to provide the diamine of general formula (IIa).

According to Scheme 3, a nitrile of formula (XI) is reacted with the lithiated aromatic compound of general formula (VIII), in which R 1 is as defined above, in an ethereal solvent such as tetrahydrofuran or ether, at low temperature, for example - 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 (IIb). The amine (IIb) can be debenzylated by hydrogenation in the presence of palladium catalyst to provide deprotected amine (IIc).

Moreover, the chiral compounds of general formula (I) corresponding to the S or R enantiomers can be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column, or could be obtained by resolution of the racemic amine. of general formula (II) using a chiral acid, such as dibenzoyl-tartaric acid or by fractional and preferential recrystallization of a diastereoisomeric salt. The ester of formula (IV) is prepared according to a method described in J. Org. Chem., 2003, 9348-9355. The nitrile of formula (XI) is prepared according to a method described in Tetrahedron: Asymmetry, 2006 (17), 252-258. The lithiated derivatives of general formula (VIII) may 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, "q" quadruplet, dxd means double doublet, txt means triple triplet, dxt double triplet, etc. The numbers indicated in parentheses in the titles of examples 25 correspond to those in the 1st column of the table given below, "decomp." means "decomposition", - For compounds in salt form, the numbers in parentheses indicate the ratio (acid: base); - "ee" means enantiomeric excess; 30 - The Roman numerals in parenthesis correspond to the corresponding 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 names of the compounds, the -dash - "-" • is part of the word, and the hyphen "_" 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. 1): N - [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethyl] - (4,5-dibromo) -thiophene-2-carboxamide .

1.1 (2-Benzoyl-2-aza-bicyclofl.2.1-hex-1-yl) -morpholin-4-yl-methanone In a three-necked 500 ml under argon, 10 ml of morpholine (115 mmol) are added dropwise to a solution of 29 ml of 2N trimethylaluminum (58 mmol) in 200 ml of dry toluene and heated at 60 ° C for 15 minutes. A solution of 20 g of 2-benzoyl-2-azabicyclo [2.1.1] hexane-1-carboxylic acid ethyl ester (77.1 mmol) in 190 ml of anhydrous toluene is canulated in the reaction medium, which is then heated overnight to reflux.

After cooling, it is hydrolyzed carefully with 60 ml of water with stirring. The precipitate formed is filtered through Celite then rinsed with dichloromethane. The filtrate is evaporated under reduced pressure. The residue obtained is triturated in ether. 18.35 g of 2-benzoyl-2-aza-bicyclo [2. 1.1] hex-1-yl) -morpholin-4-yl-methanone as a dark beige solid. 1H NMR (400MHz, DMSO-d6) δ ppm 7.69 (d, J = 8Hz, 2H), 7.56-7.45 (m, 3H), 3.76 (d, J = 7.7 Hz, 1H), 3.64-3.26 (m, 9H), 2.73 (t, J = 2.7 Hz, 1H), 2.10 (m, 2H), 1.97 (m, 1H). ), 1.52 (m, 1H). Mp 176-177 ° C 1.2. (2-Azabicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone. In a three-necked 1 L under argon, 10 g of 2-benzoyl-2-azabicyclo [2. 1.1] hex-1-yl) -morpholin-4-yl-methanone (compound obtained according to step 1.1) (33.3 mmol) in 400 ml of anhydrous tetrahydrofuran at -70 ° C. 50 ml of 0.8 M phenyl lithium (cyclohexane / ether) (40 mmol) are added dropwise and the resulting solution is stirred for 1 hour at -70 ° C. It is hydrolyzed with 100 ml of water and allowed to rise to room temperature. After extraction, the organic phase is concentrated and the residue is taken up in ether. This ether phase is poured into the previously acidified aqueous phase. After extraction, the aqueous phase is basified with ammonia and then extracted with dichloromethane (3 × 200 ml). The organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure. 5.2 g of (2-aza-bicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone are thus obtained in the form of a dark beige solid. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 3.71 (m, 2H), 3.55 (m, 4H), 3.44 (m, 2H), 2.87 (s, 2H), 2 , 69 (widened, 1H), 2.60 (t, J = 2.9 Hz, 1H), 1.84 (m, 2H), 1.43 (m, 2H). Mp 97.5-98 ° C

1.3. (2-Allyl-2-aza-bicyclo [2.1.11hex-1-yl) -morpholin-4-yl-methanone. In a 500 ml flask, 7.4 g of (2-aza-bicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone (compound obtained according to step 1.2) ( 37.7 mmol) in 100 ml of acetonitrile and 10.4 g of potassium carbonate (75.4 mmol). To this suspension is added dropwise a solution of 3.9 ml of allyl bromide (45.2 mmol). The reaction medium is stirred overnight at ambient temperature and then concentrated under reduced pressure. The residue is solubilized in 100 ml of dichloromethane. The organic phase is washed with water, dried over sodium sulphate, filtered and then evaporated under reduced pressure. 8.9 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -morpholin-4-ylmethanone are thus obtained in the form of an oil.

1H NMR (400MHz, DMSO-d6) δ ppm 5.85 (m, 1H), 5.24 (m, 1H), 5.09 (m, 1H), 3.78 (t extended, J = 4. , 7 Hz, 2H), 3.54 (m, 4H), 3.44 (m, 2H), 3.05 (broadened d, J = 5.7 Hz, 2H), 2.69 (extended s, 2H ), 2.56 (t extended, J = 3 Hz, 1H), 1.83 (m, 2H), 1.68 (m, 2H).

1.4 (2-AIlvl-2-aza-bicylo [2.1.11hex-1-yl] -phenylmethanone. In a 250 ml three-necked flask under argon, 3.2 g of (2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone (compound obtained according to US Pat. Step 3) (13.5 mmol) in 70 ml of tetrahydrofuran at -70 ° C. 16.2 ml of 1M phenyllithium (cyclohexane / ether) are added dropwise and the mixture is left for 1 hour at -70 ° C. After hydrolysis with 20 ml of water, allowed to warm to room temperature. After evaporation of the solvent under reduced pressure, the residue is taken up in ethyl acetate. After extraction, the organic phase is 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 petroleum ether and ethyl acetate. There is thus obtained 2 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methanone as an oil.

1H NMR (400MHz, DMSO-d6) δ ppm 8.28 (m, 2H), 7.64 (txt, J = 7.3 and 1.4Hz, 1H), 7.52 (m, 2H), 5.73 (m, 1H), 5.20 (m, J = 17 and 2 Hz, 1H), 5 (m, J = 10 and 2 Hz, 1H), 2.99 (dxt, J = 5.6 and 1.5 Hz, 2H), 2.86 (s, 2H), 2.70 (t, J = 2.9 Hz, 1H), 1.99-1.85 (m, 4H). 1.5. (2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methanone O-benzyl-oxime. 0.8 g of 2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethanone (compound according to step 1.4) are placed in a 50 ml flask (3.7 mmol). ) in 12 ml of pyridine and then 0.91 g of O-benzylhydroxylamine hydrochloride (7.4 mmol) are added. The reaction medium is heated overnight under reflux and then concentrated under reduced pressure. The residue is taken up in basified water with ammonia and then extracted 3 times with dichloromethane. The organic phases are combined, washed in saturated sodium chloride solution and then dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. 1.2 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethanone O-benzyl-oxime are thus obtained in the form of an oil.

1H NMR (400MHz, DMSO-d6) δ ppm 7.49-7.45 (m, 2H), 7.42-7.26 (m, 8H), 5.76 (m, 1H), 5, 17 (m, J = 17 Hz and 1.7 Hz, 1H), 5.09 (s, 1H), 5.03 (m, 1H), 3.06 (dxt, J = 5.9 Hz and 1, 4 Hz, 2H), 2.66 (s extended, 2H), 2.62 (t extended, J = 3 Hz, 2H), 1.79 (m, 2H), 1.63 (m, 2H). 1.6 (2-Allyl-2-aza-bicyclohexyl) -hex-1-yl) -phenyl-methylamine. In a three-necked 50 ml under nitrogen, place 0.32 g of lithium aluminum hydride (8.4 mmol) in 15 ml of ether. A solution of 0.7 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethanone O-benzyl-oxime (compound according to step 1.5) is then added ( 2.1 mmol) in 3 ml of ether and then heated at 40 ° C for 3 hours. After cooling, the reaction medium is hydrolysed at 0 ° C. with 1.4 ml of a 0.1 M aqueous solution of sodium tartrate of potassium and potassium overnight. After filtration of the reaction medium, the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. 0.3 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine are thus obtained in the form of an oil.

1 H NMR (400 MHz, DMSO-d 6) δ ppm 7.36-7.15 (m, 51-1), 5.87 (m, 1H), 5.23 (m, 1H), 5.06 ( m, 1H), 4.14 (s, 1H), 3.36 (m, J = 13.5 and 5.5 Hz, 1H), 3.06 (m, J = 13.5 and 6.4 Hz , 1H), 2.76 (extended d, J = 8 Hz, 1H), 2.43 (m, 2H), 1.78 (extended s, 2H), 1.39-1.21 (m, 3H) 1.08 (m, 1H).

1.7 Nf (2-Allyl-2-aza-bicyclof2.1.11hex-1-yl) -phenyl-methyl-(4,5-dibromo) -thiophene-2-carboxamide In a 250-ml flask, 1.75 is placed. g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) phenyl-methylamine (compound according to step 1.6) (7.66 mmol) in 30 ml of dichloromethane at 0 ° C in the presence of 2.1 g of potassium carbonate (15.3 mmol). A solution of 2.8 g of (4,5-dibromo) -thiophene-2-carboxylic acid chloride (9.2 mmol) in 20 ml of dichloromethane is added and the mixture is stirred overnight at room temperature. The reaction medium is then diluted with 100 ml of dichloromethane and then washed successively with water (50 ml), 1N sodium hydroxide (50 ml) and in a saturated solution of sodium chloride (50 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 ammoniacal methanol. There is thus obtained 3.2 g of N - [(2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2 carboxamide. 1 H NMR (400 MHz, CDCl 3) δ ppm 7.40-7.08 (m, 7H), 5.79 (m, 1H), 5.18 (m, 1H), 5.06 (m, 1H) , 4.98 (m, 1H), 3.36 (m, 1H), 3.07 (m, 1H), 2.87 (m, 1H), 2.54 (m, 1H), 2.46 (m, 1H), m, 1H), 1.55-1.22 (m, 4H).

Mp = 59-60 ° C

Example 2 (Compound No. 2): N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide.

7.5 ml of palladium tetrakis (triphenylphospine) (0.004 mmol) and 0.19 g of N, N-dimethylbarbituric acid (1.2 mmol) in solution are placed in a 10 ml flask under argon with a condenser. in 2 ml of dichloromethane. The reaction medium is heated to 40 ° C., then 0.2 g of N - [(2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4 5-dibromo) -thiophene-2-carboxamide (Compound 1) (0.4 mmol) in 2 ml of dichloromethane, and further heating for 2 hours at 40 ° C. 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 sulphate, 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 70 mg of N - [(2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide in powder form.

1H NMR (400MHz, DMSO-d6) δ ppm 8.69 (d, J = 8.8Hz, 1H), 8.15 (s, 1H), 7.39 (m, 2H), 7.33 ( m, 2H), 7.26 (m, 1H), 5.29 (d, J = 7.8 Hz, 1H), 2.79 (s, 2H), 2.63 (m, J = 2.8; Hz, 1H), 1.62 (m, 2H), 1.15 (m, 2H). Mp = 189-190 ° C Example 3 (Compound No. 17): (+) - N - [(2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethyl] - (4) , 5-dibromo) -thiophene-2-carboxamide.

This compound is obtained by preparative HPLC separation of N - [(2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2 carboxamide (compound no. 1) using a CHIRALpake AD 2011m column and as solvent an 80/20 acetonitrile / propan-2-ol mixture. 1H NMR (400MHz, DMSO-d6) δ ppm 8.65 (m, 1H), 8.15 (s, 1H), 7.4-7.2 (m, 5H), 5.75 (m, 1H), 5.40 (m, 1H), 5.30 (m, 1H), 5.02 (m, 1H), 3.20 (m, 2H), 2.70 (m, 1H), 2, 60-2.50 (m, 2H), 1.58 (m, 1H), 1.4 (m, 3H). ee = 99.7% [δ] 20 ° C MeOH = + 39.2 ° c = 0.475 g / 100 ml

Example 4 (Compound No. 4): (+) - N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene Hydrochloride -2-carboxamide (1: 1). This compound is obtained according to the method described in Example 2, starting from the compound No. 17 described in Example 3, after salification in hydrochloride form by solubilization of the base in ether, addition of an excess of 1N hydrochloric acid in ether and then concentration under reduced pressure .1H NMR (400MHz, DMSO-d6) δ ppm 9.77 (m, 1H), 9.55 (d, J = 8.9 Hz) , 1H), 8.93 (m, 1H), 8.46 (s, 1H), 7.56-7.38 (m, 5H), 5.70 (d, J = 9.2 Hz, 1H) , 3.30 (m, 2H), 2.84 (m, 1H), 2.10 (m, 1H), 1.87 (m, 1H), 1.66 (m, 2H). Mp = 211-213 ° C ee = 99.7% [aa0] 20 ° c MeOH = + 35.5 ° c = 1.02 g / 100 ml

Example 5 (Compound No. 18): (-) - N - ((2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethyl] - (4,5-dibromo) -th iophène-2-carboxamide.

The compound is obtained by preparative HPLC separation of N - [(2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2- carboxamide (compound no. 1) using a CHIRALpak AD 20 m column and as solvent an 80/20 acetonitrile / propan-2-ol mixture.

1H NMR (400MHz, DMSO-d6) δ ppm 8.65 (m, 1H), 8.15 (s, 1H), 7.4-7.2 (m, 5H), 5.75 (m, 1H), 5.40 (m, 1H), 5.30 (m, 1H), 5.02 (m, 1H), 3.20 (m, 2H), 2.70 (m, 1H), 2, 60-2.50 (m, 2H), 1.58 (m, 1H), 1.4 (m, 3H). ee = 100% [CD] 20 ° C MeOH = -36.4 ° c = 0.45 g / 100 ml Example 6 (Compound No. 5): (-) - N - [(2-aza-bicyclohydrochloride) [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide (1: 1).

This compound is obtained according to the method described in Example 2, starting from the compound No. 18 described according to Example 5, after salification in hydrochloride form by solubilization of the base in ether, addition of an excess of 1 N hydrochloric acid in ether and then concentration under reduced pressure. 1H NMR (400MHz, DMSO-d6) δ ppm 9.52 (d, J = 9.2Hz, 1H), 8.42 (s, 1H), 7.50-7.34 (m, 5H) , 5.66 (d, J = 8.9 Hz, 1H), 3.25 (m, 2H), 2.80 (m, 1H), 2.07 (m, 1H), 1.83 (m.p. , 1H), 1.62 (m, 2H). Mp = 227-228 ° C ee = 100% [δ] 20 ° C MeOH = -36.2 ° c = 1.02 g / 100 ml Example 7 (Compound No. 7): N - [(2-Aza) Bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-methylsulfanyl) -nicotinamide.

7.1 (2-Benzyl-2-aza-bicyclo [2.1.11hex-1-yl] -phenyl-methylamine.

In a three-necked 500 ml under argon, 3 g of 2-benzyl-2-azabicyclo [2.1.1] hexane-1-carbonitrile (XI) (15.1 mmol) are placed at -70 ° C. in 100 ml of tetrahydrofuran. anhydrous. 37.8 ml of a 0.8 M solution (cyclohexane / ether) of phenyl lithium (30.2 mmol) are added dropwise. The mixture is stirred for 2 hours at -70 ° C. and then hydrolyzed at -20 ° C. with 30 ml of water. After extraction, the organic phase is concentrated and the residue is taken up in 40 ml of methanol. 2.8 g of sodium borohydride (75 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 100 ml of ether and 100 ml of water. The medium is acidified with a 1N hydrochloric acid solution, and then the ether phase is extracted. The aqueous phase is basified with ammonia and then reextracted twice with 100 ml of dichloromethane. The organic phases are combined, then dried over sodium sulphate, filtered and evaporated under reduced pressure. 4.15 g of (2-benzyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine (II b) are thus obtained in the form of an oil which crystallizes in the cold. 1 H NMR (200 MHz, CDCl 3) δ ppm 7.6-7.3 (m, 5H), 4.4 (s, 1H), 4.2 (d, J = 16Hz, 1H), 3.6 ( d, J = 16Hz, 1H), 3.0 (d, J = 9Hz, 1H), 2.6 (m, 1H), 2.4 (d, J = 9Hz, 1H), 1, 8 (widened, 2H), 1.6-1.2 (m, 4H). Mp 63.5-64 ° C.

An analytical sample is obtained in hydrochloride form by solubilization of the base in ether, addition of an excess of 1N hydrochloric acid in ether and concentration under reduced pressure. Mp = 140-142 ° C

7.2 (2-Aza-bicyclof2.1.11hex-1-yl) -phenyl-methylamine 0.43 g of (2-benzyl) -propan under 4 atmospheres of hydrogen at 40 ° C for 3 hours were placed in a Parr-vial 2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine (1.54 mmol) in 20 ml of ethanol and 5 ml of 1 N hydrochloric acid in the presence of a spatula tip. palladium on carbon at 10%. After filtration of the catalyst and concentration of the filtrate under reduced pressure, the residue is taken up in 30 ml of dichloromethane and 30 ml of water basified with ammonia. After extraction, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. 0.24 g of (2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methylamine are thus obtained in the form of a yellow oil which solidifies in the cold and which is used as such in the next step. Mp = 46.5-47 ° C. An analytical sample is obtained in hydrochloride form by solubilization of the base in ether, addition of an excess of 1N hydrochloric acid in ether, and then concentration under reduced pressure. 1H NMR (400MHz, DMSO-d6) δ ppm 10.12-8.71 (m, 4H), 7.46-7.35 (m, 6H), 4.83 (m, 1H), 3, (M, 2H), 2.72 (m, 1H), 2.10 (m, 1H), 1.89 (m, 1H), 1.57 (t extended, J = 9.3 Hz, 1H). , 1.36 (t extended, J = 9.3 Hz, 1H). Mp 220-223 ° C decomp.

7.3 Nf (2-Azabicyclof 2.1.11hex-1-yl) -phenyl-methyl-2- (2-methylsulfanyl) -nicotinamide In a 25 ml flask was placed 0.22 g of (2-methylsulfanyl) acid. Nicotinic acid (1.27 mmol), 0.17 g of hydroxybenzotriazole (1.27 mmol), 0.25 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.27 mmol) ) in solution in 2 ml of dichloromethane and the mixture is stirred at room temperature for 15 minutes. 0.2 g (1.0 mmol) of (2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethylamine in solution in 2 ml of dichloromethane are added and the mixture is stirred at room temperature for a period of 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 ammoniacal methanol. There is thus obtained 63 mg of N - [(2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-methylsulfanyl) -nicotinamide in powder form. Mp = 141-143 ° C 1 H NMR (400 MHz, DMSO-d6) ppm 8.79 (d, J = 8.5 Hz, 1H), 8.55 (dxd, J = 5 Hz and 1.7 Hz) , 1H), 7.76 (dxd, J = 7.5 Hz and 1.8 Hz, 1H), 7.43-7.18 (m, 6H), 5.30 (d, J = 8.6 Hz , 1H), 2.77 (m, 2H), 2.63 (m, 1H), 2.45 (s, 3H), 1.70 (m, 1H), 1.64 (m, 1H), 1H. , 14 (m, 2H). The other compounds described in Table 1 are obtained according to the methods described in Examples 1 to 7 from appropriate lithiens.

The following Table 1 illustrates the chemical structures of some compounds of the invention. In the column: - "Salts": - denotes a compound in the basic state, "HCI" means a hydrochloride, the number in parenthesis indicates the ratio (acid: base), - The compounds of the table are in the form of hydrochloride solvated with one or more water molecules, in columns R, R, and R2: - Cl is chlorine, Br is bromine, - CH3 is methyl, - OCH3 is methoxy, 20 - Ph is phenyl, - CF3 signifies 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] 20 ° C gives 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 "m / z" column informs the molecular ion (M + H +) or (M +) observed by analysis of the products by mass spectrometry, ie by LC -MS (Liquid Chromatography coupled to Mass Spectroscopy) carried out on an Agilent LC-MSD5 Trap device in ESI positive mode, or by direct introduction by MS (Mass Spectroscopy) on an Autospec M (EBE) device using the DCINH3 technique or using the electronic impact technique on a Waters GCT type device.

TABLE 1 ## STR4 ## Stereochemistry salts 1 allyl Ph 4,5-Br 2 -thiophen-2-yl racemic 2H Ph 4, 5-Br 2 -thiophen-2-yl racemic 3H Ph 2,5-Cl 2 -thiophen 3-yl racemic 4H-4,5-Br-thiophen-2-yl chiral dextrorotatory HCl (1: 1) H Ph-4,5-br-2-thiophen-2-yl HCl chiral levorotatory (1: 1) H Racemic 4-F-Ph-3-Cl-4-CF 3 -pyridin-2-yl H Ph 2 -CH 3 -pyridin-3-yl racemic H Ph 3 -Cl-4-CF 3 -pyridin-2-yl racemic H Ph 1 -benzyl-indol-4-yl-racemic H naphth-2-yl 3-Cl-4-CF3-pyridin-2-yl racemic HCl (1: 1) 11 H naphth-2-yl 2 -CH 3 -pyridin-3 Racemic 1H (1: 1) 12 H 3 -OCH 3 Ph 3 -Cl-4-CF 3 -pyridin-2-yl racemic HCl (1: 1) 13H 3 -OCH 3 -Ph 2 -CH 3 -, pyridine 3-yl racemic HCl (1: 1) 14 H 3 -CH3-Ph 2 -CHS-pyridin-3-yl racemic HCl (1: 1) H 3 -CF 3 -Ph 3 -Cl-4-CF 3 -pyridin-2 1H-racemic 1H (1: 1) 16H 3 -CH3-Ph 3 -Cl-4-CF3-pyridin-2-yl racemic HCl (1: 1) 17 allyl Ph 4,5-Br2-thiophen-2-yl chiral dextrorotatory 18 allyl Ph 4,5-Br 2 -thiophen-2-yl chiral levorotatory TABLE 2 No. PF ° C [ad 20 ° C ° LCMS MH + 1 59-60 NA 495 2 189-190 NA 455 3 135-136 NA 367 4 211-213 +35.5 (MeOH) c = 1.02 g / 100 ml 455 227-228 -36.2 (MeOH) c = 1.02g / 100ml 455 6 183.5-184.5 NA 414 7 141-143 NA 340 8 153-154 NA 396 9 140-143 NA 422 199-200 NA 446 11 162-163 NA 390 12 119 , 5-120.5 NA 426 13 146-147 NA 370 14 195-196 NA 354 110-120 NA 464 16 150.5-151.5 NA 410 17 NA +39.2 (MeOH) c = 0.475g / 100 ml 495 18 NA -36.4 (MeOH) c = 0.457g / 100 ml The compounds of the invention were subjected to a series of pharmacological tests which demonstrated their interest as substances with therapeutic activities.

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

[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. Counting is performed on a Microbeta Tri-IuxTM 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 an IC 50 of the order of 0.01 to 10 μM.

Table 3 gives some examples of IC 50 results for compounds according to the invention. TABLE 3 Compound IC50 (pM) 3 0.46 8 0.11 9 0.35 The results of the in vitro tests carried out on the chiral compounds of the invention and their racemates according to general formula (I) show that they are inhibitory. of glycine transporter glyt1 present in the brain. 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, especially 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, disorders of sexual behavior, eating disorders, migraine; pain ; sleep disorders.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular inhibitory drugs of the glycine transporter glyt1. Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid.

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 of a pharmaceutically acceptable salt, and in a mixture, where appropriate, with suitable excipients. .

Said excipients are selected 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, it is possible to envisage 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, such as, for example, lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders, is added to the active ingredient, micronized or not, ( polyvinylpyrrolidone, 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. It can be designed to allow rapid, delayed or sustained release of the active ingredient through specific polymer matrices or 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 composition in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably an acaloric, methylparaben or propylparaben as an antiseptic, a flavoring agent and a dye.

The 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 medium compatible with the skin. They may be in the form of, in particular, aqueous, alcoholic or aqueous-alcoholic solutions, 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 unit dosage form 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 the active ingredient administered per day may be in the range of 0.1 to 15 mg / kg, in one or more taken. 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 dosage appropriate to 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 25

Claims (19)

REVENDICATIONS1. Compound of general formula (I) (I) in which: R represents a hydrogen atom or a group chosen from (C 1 -C 6) alkyl, (C 3 -C 7) -cycloalkyl or allyl groups, optionally substituted with a or more groups independently selected from halogen, (C 3 -C 7) -cycloalkyl, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, hydroxy; - 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, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-thio, (C 1 -C 6) alkyl-SO, (C 1 -C 6) alkyl -SO2; Het represents a heteroaryl group; 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 5) - cycloalkyl- (C 1 -C 3) alkyl, (C 1 -C 6) alkoxy, benzyl, (C 1 -C 6) alkyl-thio, (C 1 -C 6) alkyl-SO, (C, -C6) alkyl-SO2; 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 an allyl group; R 1 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) alkoxy groups, halo- (C 1 -C 6) alkyl, - Het represents an indole, thiophene or pyridine group; R2 represents one or more substituents chosen from the hydrogen atom, the halogen atoms, the halo- (C 1 -C 6) alkyl, benzyl, (C 1 -C 6) alkyl-thio groups; in the form of a base or an acid addition salt. 3. 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 a leaving group or a chlorine atom and Het and R2 are defined according to claim 1. 4. Compounds of formula (II) in which R and RI are defined according to claim 1. 5. Compounds of formula (III) Y O wherein Het and R2 are defined according to claim 1 and Y represents a leaving group or a halogen atom. 6. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 2, or a salt of addition of this compound to a pharmaceutically acceptable acid. 7. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. (II) R NH2 8. Use of a compound of formula (I) according to any one of claims 1 to 2 for the preparation of a medicament for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases; to madness. 9. Use of a compound of formula (I) according to any one of claims 1 to 2 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. 10. Use of a compound of formula (I) according to any one of claims 1 to 2 for the preparation of a medicament for the treatment of various forms of anxiety, panic attacks, phobias, obsessive disorders compulsive. 11. Use of a compound of formula (I) according to any one of claims 1 to 2 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. 12. Use of a compound of formula (I) according to any one of claims 1 to 2 for the preparation of a medicament for the treatment of pain. 13. Use of a compound of formula (I) according to any one of claims 1 to 2 for the preparation of a medicament for the treatment of sleep disorders. 14. A compound according to any one of claims 1 to 2 for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases; to madness. 15. Compound according to any one of claims 1 to 2, for the treatment of psychoses, schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics. 16. A compound according to any one of claims 1 to 2 for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders. 17. A compound according to any one of claims 1 to 2 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. 18. A compound according to any one of claims 1 to 2 for the treatment of pain. 19. A compound according to any one of claims 1 to 2 for the treatment of sleep disorders.