MXPA06004271A - Derivatives of n-[heteroaryl(piperidine-2-yl)methyl]benzamide, preparation method thereof and application of same in therapeutics - Google Patents

Abstract

The invention relates to compounds having general formula (I), wherein:R1 represents H or an alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl, alkenyl, alkynyl group;R2 represents a pyridinyl, furanyl, thienyl, thiazolyl or oxazolyl group, said group being optionally substituted;and R3 represents H, one or more substituents selected from among the halogen atoms and the trifluoromethyl, alkyl, cycloalkyl, alkoxy, phenyl, cyano, acetyl, benzoyl, thioalkyl, alkylsulfonyl, carboxy or alcoxycarbonyl groups, or a group having general formula NR4R5 or SO2NR4R5 or CONR4R5 in which R4 and R5 each represent H or an alkyl group or, together with the nitrogen atom bearing same, form a pyrrolidine, piperidine or morpholine ring, said compound taking the form of a base, an acid addition salt, a hydrate or a solvate. The invention also relates to the use of the compound in therapeutics.

Description

DERIVATIVES OF? F- [HETEROARIL (PIPERIDIN-2-IL) ETHYL] BENZAM1DA, ITS PREPARATION AND ITS THERAPEUTIC APPLICATION The compounds of the invention correspond to the general formula (I) wherein: Rt represents a hydrogen atom, a linear or branched alkyl group (1 to 7 carbon atoms) optionally substituted with one or more fluorine atoms, a cycloalkyl group (3 to 7 carbon atoms), a cycloalkyl group (3 to 7 carbon atoms) -alkyl (1 to 3 carbon atoms), a phenyl-alkyl group (1 to 3 carbon atoms) optionally substituted with one or two methoxy groups, an alkenyl group (2 to 4 carbon atoms) carbon), or an alkynyl group (2 to 4 carbon atoms); R 2 represents a pyridinyl, furanyl, thienyl, thiazolyl or oxazolyl group, said group being optionally substituted with one or more substituents chosen from halogen atoms and the trifluoromethyl, linear or branched alkyl (1 to 6 carbon atoms) and alkoxy groups (1 to 6 carbon atoms); R3 represents a hydrogen atom, one or more substituents selected from halogen atoms and trifluoromethyl groups, linear or branched alkyl (1-6 carbon atoms), cycloalkyl (3 to 7 carbon atoms), alkoxy (1-6 carbon atoms) carbon), phenyl, cyano, acetyl, benzoyl, thioalkyl (1 to 6 carbon atoms), alkylsulfonyl (1 to 6 carbon atoms), carboxy or alkoxy (1 to 6 carbon atoms) carbonyl, a group of general formula NR4R5 or S02NR4R5 or CONR4R5 in which R4 and R5 each represent, independently of each other, a hydrogen atom or a linear or branched alkyl group (1 to 6 carbon atoms), or cycloalkyl (3 to 7 carbon atoms), or R4 and R5 with the nitrogen atom to which they are attached form a cycle of pyrrolidine, piperidine or morpholine. The compounds of the formula (I) can have one or more asymmetric carbon atoms. Therefore, they may exist in the form of threo or erythro enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention. The compounds of formula (I) may exist in the form of bases or acid addition salts. Such addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, for the purification or isolation of the compounds of formula (I), also form part of the invention. The compounds of general formula (I) can also exist in the form of hydrates or solvates, that is to say in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention. The compounds of the invention exhibit a particular activity as specific inhibitors of glycine transporters glytl and / or glyt2. The compounds of general formula (I), of threo or erythro configuration, in which Ri is other than a hydrogen atom, can be prepared by a process illustrated in the following scheme 1. Scheme 1 The coupling of a diamine of general formula (II) is carried out, in which R ^ and R2 are as defined above (with R, different from a hydrogen atom) with an activated acid or an acid chloride of general formula (I II) in which Y represents an activated OH group or a chlorine atom, and R3 is as defined above, using methods known to the person skilled in the art. The diamine of general formula (II) can be prepared by a process illustrated by the following scheme 2.

Scheme 2 The Weinreb amide of the formula (IV) is reacted, wherein BOC denotes a 1,1-dimethylethoxycarbonyl group, with the lithiated heterocycle of the general formula (V), wherein R 2 is as defined above, in an ether type solvent such as diethyl ether, between -90 ° C and -30 ° C; a ketone of the general formula (VI) is obtained which is reduced to a threo-configuration alcohol of the general formula (VII) with a reducing agent such as K-Selectride® or L-Selectride® (potassium or lithium tri-sec-butylborohydride), in an ether solvent such as tetrahydrofuran, between -78 ° C and room temperature.

The carbamate of the general formula (VII) can then be reduced to ? / - threo methylaminoalcohol of the general formula (VIII) by the action of a mixed hydride such as double lithium aluminum hydride, in an ether type solvent such as tetrahydrofuran, between room temperature and reflux temperature. The threo alcohol of the general formula (VI II) is then transformed in two stages into an intermediate diamine of the general formula (II) in which R represents a methyl group in the form of threo, or an erythro-threo mixture depending on the nature of the heterocycle in the following manner: first the alcohol functional group is transformed into a nucleofugic group, for example, a methanesulfonate group, by the action of methylsulfonyl chloride, in a chlorinated solvent such as dichloromethane, and in the presence of a base such as triethylamine, between 0 ° C and room temperature, and then the nucleophilic group is reacted with liquefied ammonia at -50 ° C, in an alcohol such as ethanol, in a closed medium, such as an autoclave, between -50 ° C and the room temperature. The carbamate of the general formula (VII) can also be deprotected by a strong base such as aqueous potash, in an alcohol such as methanol, to obtain the threo amino alcohol of the general formula (IX), then carry out a? / - alkylation by a halogenated derivative of the formula RZ, wherein R ^ is as defined above, but is different from a hydrogen atom, and Z represents a halogen atom, in the presence of a base such as potassium carbonate, in a polar solvent such as? , / V-dimethylformamide, between room temperature and 100 ° C. The alcohol of the general formula (X) thus obtained is then treated in the same manner as described for the alcohol of the general formula (VIII). The compounds of the general formula (I) in which R ^ represents a hydrogen atom can be prepared from a compound of the general formula (1) in which Ri represents: - an optionally substituted phenylmethyl group, deprotecting the nitrogen of the piperidine cycle, for example, with an oxidizing agent or with a Lewis acid, such as boron tribromide or by hydrogenolysis, - an alkenyl group, preferably allyl, deprotecting the nitrogen from the piperidine cycle, for example, with a complex of palladium 0, to obtain a compound of the general formula (I), in which -i represents a hydrogen atom. On the other hand, the chiral compounds of the general formula (1) corresponding to the enantiomers (1R, 2R) - (1S, 2S) - (1S, 2R) and (1R, 2S) of the different erythro / threo diastereomers, are they can be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) with chiral column, or by cleavage of the racemic amine of the general formula (II) using a chiral acid, such as tartaric acid, camphorsulfonic acid, dibenzoyl acid -tartaric, N-acetyl-leucine, by fractional recrystallization and preferably of a diastereomeric salt in an alcohol type solvent, or by enantioselective synthesis according to scheme 2 using a chiral Weinreb amide of the general formula (IV). The Weinreb amide of racemic or chiral formula (IV) can be prepared according to a method analogous to that described in Eur. J.

Med. Chem., 35, (2000), 979-988 and J. Med. Chem., 41, (1998), 591-601. The lithiated heterocycles of general formula (V) can be prepared according to methods known to the person skilled in the art and analogous to those described in JOC, 62, (1997), 5484-5496 and Tetrahedron Letters, 35, (1 994) , 3673-3674. Halogenated derivatives of formula R ^ are commercially available. Some acids and acid chlorides of the general formula (III) are commercially available, or when they are new they can be obtained according to methods analogous to those described in EP-0556672, US-3801636, and in J. Chem. Soc, (1927), 25, Chem. Pharm. Bull. , (1992), 1789-1792, Aust. J. Chem., (1984), 1938-1 950 and J. O. C, (1980), 527. The following examples illustrate the preparation of some compounds of the invention. Elemental microanalyses, IR and NMR spectra, and HPLC on a chiral column confirm the structures and enantiomeric purities of the obtained compounds. The numbers indicated in parentheses in the titles of the examples correspond to those of the 1st column in the table given below. In the names of the compounds the hyphen "-" is part of the word, and at the end of the line the hyphen "_" serves only to cut at the end of the line; it must be suppressed in the absence of a cut, and must not be replaced by a normal script or by a space. Example 1 (Compound No. 2) 2-Chloro-? / - [(1-methylpiperidin-2-yl) -3-thienylmethyl] -3-trifluoromethylbenzamide hydrochloride 1: 1. eleven . 2- (3-thienylcarbonyl) pipepdin-1-carboxy 1,1-dimethylethyl ester. In a 100-ml flask, under an argon atmosphere, they are introduced 1.8 g (10.8 mmol) of 3-bromothiophene in solution in 20 ml of anhydrous diethyl ether and the medium is cooled to -40 ° C. Then 4.8 ml (12 mmol) of a 2.5 M solution of butyl lithium in cyclohexane are slowly added and the mixture is left at this temperature for 2 h. Using a transfer needle, the lithiated heterocycle is added to a solution of 1.5 g (5.5 mmol) of 2- (α-methoxy-β-methylmethylcarbamoyl) piperidin-1-carboxylate 1,1-dimethylethyl ester in 50 ml of anhydrous diethyl ether cooled to -20 ° C and the mixture with stirring is allowed to return to room temperature for 2 h. After hydrolysis with a saturated aqueous solution of ammonium chloride, the aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue is purified by chromatography on a silica gel column eluting with a mixture of ethyl acetate and cyclohexane. 1.2 g of a compound in the form of a colorless oil is obtained which is used as it is in the next step. 1 .2. thirteen- [1,1-dimethylethyl] -hydroxy (3-thienyl) methyl] piperidin-1-carboxylate In a 250 ml flask, under an argon atmosphere, 1.2 g (4 mmoles) of 1,1-dimethylethyl 2- (3-thienylcarbonyl) -piperidin-1-carboxylate in 40 ml of anhydrous tetrahydrofuran, cool the solution to -78 ° C, add drop drop 12 ml (12 mmol) of a solution of L-Selectride® 1 M (lithium tri-sec-butylborohydride) in tetrahydrofuran and stir the mixture at -78 ° C for 5 h. It is slowly hydrolysed with 7 ml of water and 7 ml of an aqueous solution of 35% hydrogen peroxide, and the mixture is allowed to return to room temperature by stirring for 2 h. It is diluted with water and ethyl acetate, the phases are separated and the aqueous phase is extracted with ethyl acetate. After washing the combined organic phases, drying over sodium sulfate, filtration and evaporation, the residue is purified by chromatography on a silica gel column eluting with a mixture of ethyl acetate and cyclohexane. 1 g of product is obtained in the form of a colorless oil which is used as it is in the next step. 1.3. threo- (1-methyl-piperidin-2-yl) (3-thienyl) -methanol. Into a 50 ml 2-neck flask, under a nitrogen atmosphere, 0.63 g (16.6 mmol) of lithium aluminum hydride in 10 ml of anhydrous tetrahydrofuran are introduced, the mixture is heated to reflux, 1 g (3.3 g) is added. mmoles) of a solution of 1,3-dimethylethyl thio- [hydroxy (3-thienyl) methyl] -piperidine-1-carboxylate in 35 ml of tetrahydrofuran, and the mixture is refluxed for 2 h. It is cooled, hydrolyzed slowly with a 0.1 M potassium sodium sodium tartrate solution, and the mixture is left stirring overnight. The precipitate is filtered and clarified with tetrahydrofuran, and then the filtrate is concentrated under reduced pressure. 0.6 g of a colorless oily product are obtained. 1 .4. (1-methylpiperidin-2-yl) (3-thienyl) methanamine. Into a 50 ml flask, under a nitrogen atmosphere, 0.6 g (2.8 mmol) of threo- (1-methylpiperidin-2-yl) (3-thienyl) methanol and 0.4 ml (2.8 mmol) are introduced. triethylamine in 10 ml of anhydrous dichloromethane, the medium is cooled to 0 ° C, 0.22 ml (2.8 mmol) of methanesulfonyl chloride are added, the mixture is allowed to slowly return to room temperature for 1 h and concentrated under reduced pressure. In an autoclave provided with magnetic stirring and cooled to -50 ° C, liquefied ammonia is introduced, a solution of the crude methanesulfonate previously prepared in solution in 30 ml of absolute ethanol is added, the autoclave is closed and the stirring is maintained for 48 h . The mixture is transferred to a flask, concentrated to dryness, the residue is diluted with water and dichloromethane, the phases are separated and the aqueous phase is extracted with dichloromethane. After washing the combined organic phases, drying over magnesium sulfate, filtration and evaporation of the solvents, 0.5 g of amine is isolated in the form of an oily compound which is used as it is in the next step. fifteen. 2-Chloro -? / - [(1-methylpiperidin-2-yl) (3-thienyl) methyl] -3-trifluoromethylbenzamide hydrochloride 1: 1 0.25 g are introduced into a 50 ml flask. (1.17 mmol) of (1-methylpiperidin-2-yl) - (3-thienyl) metanamine and 0.26 ml (1.4 mmol) of triethylamine in solution in 20 ml of dichloromethane at 0 ° C. Then a solution of 0.34 g (1.4 mmol) of 2-chloro-3-trifluoromethylbenzoic acid chloride in 100 ml of dichloromethane is added and the mixture is left with stirring to return to room temperature 2 h. The mixture is treated with water, extracted several times with dichloromethane. After drying of the organic phases with water and then with an aqueous 1N sodium hydroxide solution, drying over magnesium sulfate, filtration and evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a silica gel column eluting with a mixture. of dichloromethane and methanol. 0.23 g of oily product is obtained which is isolated in the form of hydrochloride from a solution of 0.1 N hydrochloric acid in propan-2-ol. Finally, 0.1 g of hydrochloride is isolated in the form of a white solid composed of a mixture of threo / erythro diastereoisomers in an 83/17 ratio. Melting point: 124-126 ° C. Example 2 (Compound No. 6). Treo-2-chloro-3-methyI- / V - [(1-allylpiperidin-2-N) -3-pyridinylmethylbenzamide hydrochloride 1: 1. 2.1. 2- (3-pyridinylcarbonyl) piperidine-1-carboxylate 1,1-dimethylethyl ester In a 500 ml flask, under argon atmosphere, 14.5 g (91.8 mmoles) of 3-bromopyridine are introduced in solution in 100 ml of anhydrous diethyl ether and the medium is cooled to -78 ° C. Then 40.4 ml (100.9 mmol) of a solution of butyllithium 2.5 in cyclohexane are slowly added and the mixture is left at this temperature for 0.5 h.

A solution of 10 g (36.7 mmoles) of 2 - (? / - methoxy-? / - methylcarbamoyl) piperidine-1-carboxylate 1,1-dimethylethyl ester in 50 ml anhydrous diethyl ether cooled to -78 is added. ° C and the mixture is left at this temperature for 2 hours with stirring and then 12 hours at room temperature. After hydrolysis with a saturated aqueous solution of ammonium chloride, the aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue is purified by chromatography on a silica gel column eluting with a mixture of ethyl acetate and cyclohexane. 5.5 g of a compound in the form of a colorless oil is obtained which is used as it is in the next step. 2.2. threo- [hydroxy (3-pyridinyl) methyl] piperidine-1-carboxylate 1,1-dimethylethyl. Into a 500 ml flask under an argon atmosphere, 5.4 g (18.6 mmol) of 1,1-dimethylethyl 2- (3-pyridinylcarbonyl) -piperidine-1-carboxylate in 220 ml of anhydrous tetrahydrofuran are introduced. cooling to -78 ° C, 55.8 ml (55.8 mmol) of a 1 M solution of L-Selectride® (lithium tri-sec-butylborohydride) in tetrahydrofuran are added dropwise, and the mixture is stirred at -78 ° C. for 3 h. It is slowly hydrolysed with 67 ml of water and 67 ml of an aqueous solution of 35% hydrogen peroxide, and the mixture is allowed to return to room temperature with stirring for 2 h.

It is diluted with water and ethyl acetate, the phases are separated and the aqueous phase is extracted with ethyl acetate. After washing the combined organic phases, drying over sodium sulfate, filtration and evaporation, the residue is purified by chromatography on a silica gel column eluting with a mixture of ethyl acetate and cyclohexane. 4.13 g of product are obtained in the form of a colorless oil which is used as it is in the next step. 2.3. threo-3-pyridinyl (2-piperidin-2-yl) methanol. A solution of 0.5 g (1.71 mmol) of threo- [hydroxy (3-priridinyl) methyl] -piperidine-1-carboxylate 1,1-dimethylethyl ester in 6 ml of ethanol is placed in a 50 ml flask. add an aqueous solution of potash prepared from 0.5 g of potash in lentils and 3 ml of water, and the mixture is heated at reflux for 2 h. The mixture is cooled, the solvent is evaporated under reduced pressure, water is added and the mixture is extracted several times with dichloromethane. After washing the combined organic phases, drying over magnesium sulfate, filtering and evaporating the solvent under reduced pressure, 0.3 g of white solid is obtained which is used as it is in the next step. 2.4. threo-1-allyl-piperidin-2-yl (3-pyridinyl) methanol. Into a 50 ml flask equipped with magnetic stirring and argon circulation, 0.3 g (1.56 mmol) of threo-3-pyridinyl (2-piperidin-2-yl) methanol and 10 ml of acetonitrile are introduced. To the obtained suspension, 0.32 g of potassium carbonate and 0.17 ml (1.2 eq) of allyl bromide are then added. The agitation of the suspension is maintained for 6 h at 25 ° C. 10 ml of water and 10 ml of ethyl acetate are added, the aqueous phase is decanted and extracted three times with 10 ml of ethyl acetate, the combined organic phases are washed with 50 ml of water and then 500 ml of a solution saturated with sodium chloride. Dry over sodium sulfate, filter and remove the solvents under reduced pressure. 0.22 g of yellow oil are obtained, which is purified by chromatography on silica gel (120 g column and elution gradient from 2% to 10% methanol in dichloromethane in 30 min). 0.10 g is isolated as a yellow oil. 2.5. threo- (1-allyl-piperidin-2-yl) (3-pyridinyl) methylamine. Into a 50 ml flask, under a nitrogen atmosphere, 0.71 g (3.05 mmol) of threo-1-allyl-piperidin-2-yl (3-pyridinyl) methanol and 0.43 ml (3.05 mmol) of triethylamine are introduced in 15 ml. of anhydrous dichloromethane, the medium is cooled to 0 ° C, 0.23 ml (3.05 mmol) of methanesulfonyl chloride are added, the mixture is allowed to slowly return to room temperature for 1 h and concentrated under reduced pressure.

In an autoclave provided with magnetic stirring and cooled to -50 ° C, liquefied ammonia is introduced, a solution of the crude methanesulfonate previously prepared in solution in 30 ml of absolute ethanol is added, the autoclave is closed and the stirring is maintained for 48 h . The mixture is transferred to a flask, concentrated to dryness, the residue is diluted with water and dichloromethane, the phases are separated and the aqueous phase is extracted with dichloromethane. After washing the combined organic phases, drying over magnesium sulfate, filtration and evaporation, 0.57 g of amine is isolated in the form of an oily compound which is used as it is in the next step. 2.6. Threo-2-chloro-3-methyl-? / - [(1-allyl-piperidin-2-yl) -3-pyridinylmethylbenzamide hydrochloride 1: 1. 50 ml of dichloromethane, 0.22 g (1.28 mmol) of 2,3-dichlorobenzoic acid, 0.25 g (1.29 mmol) of 1- [3- (dimethylamino) hydrochloride are successively introduced into a 50 ml flask. propy!] - 3-ethylcarbodiimide and 0.17 g (1.29 mmol) of hydroxybenzotriazole and the mixture is stirred at room temperature for 1 h. 0.3 g (1.29 mmoles) of threo- (1-allyl-piperidin-2-yl) - (3-pyridinyl) methylamine in solution in 4 ml of dichloromethane are added and stirring is continued for 15 h. The mixture is treated with water, extracted several times with dichloromethane. After washing the organic phases with water and then with an aqueous 1N sodium hydroxide solution, drying over magnesium sulfate, filtration and evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a silica gel column eluting with a mixture. of dichloromethane and methanol. 0.15 g of oily product is obtained which is isolated in the form of hydrochloride from a solution of 0.1 N hydrochloric acid in propan-2-ol. Finally, 0.10 g of hydrochloride is isolated as a white solid. Melting point: 149-151 ° C. The following table illustrates the chemical structures and physical properties of some compounds of the invention. In the column "Salt", "-" indicates a compound in the form of a base and "HCI" indicates a hydrochloride.

Table 25 The compounds of the invention have been subjected to a series of pharmacological tests that have shown their interest as substances with therapeutic activities. Study of the transport of glycine in SK-N-MC cells expressing the natural human transporter qlvtl. The capture of [14C] glycine in SK-N-MC cells (human neuroepithelial cells) expressing the natural human glytl transporter is studied by measuring the incorporated radioactivity in the presence or absence of the compound to be tested. The cells are cultured in monolayer for 48 h in plaques previously treated with 0.02% fibronectin. 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 of preincubation at 37 ° C in the presence of buffer (control group), of the compound to be tested with different concentrations, or 10 mM glycine (determination of non-specific capture), [14 C] glycine is added 10 μM (specific activity 1 12 mCi / mmoles). Incubation is continued for 10 min at 37 ° C, and the reaction is stopped by 2 washes with Krebs-HEPES buffer at pH 7.4. The radioactivity incorporated by the cells is then calculated after adding 100 μl of scintillation fluid and shaking for 1 h. The count is carried out with a Microbeta Tri-lux ™ counter. The efficacy of the compound is determined by the IC5o, concentration of the compound that decreases 50% the specific capture of glycine, defined by the difference of radioactivity incorporated by the control lot and the batch that has received the 10 mM glycine. The most active compounds of the invention have in this test an Cl50 of the order of 0.001 to 1 μM. Study of glycine transport in mouse spinal cord homogenate. The capture of [14C] glycine by the glyt2 transporter in mouse spinal cord homogenate is studied, by measuring the "incorporated radioactivity in the presence or absence of the compound to be studied." After performing the euthanasia on the animals (Iffa Credo OF1 male mice weighing 20 to 25 g on the day of the experiment), The spinal cord of each animal is quickly weighed and stored on ice.The samples are homogenized in a buffer of Krebs-HEPES ([4- (2-hydroxyethyl) piperazine-1-ethane sulfonic acid), pH 7.4, at the rate of 25 ml / g of tissue Pre-incubate 50 μl of homogenate for 10 min at 25 ° C in the presence of Krebs-HEPES buffer, pH 7.4 and the compound to be studied at different concentrations, or 10 mM glycine to determine the non-specific capture, then add [1 C] glycine (specific activity = 12 mCi / mmoles) for 10 min at 25 ° C, with a final concentration of 10 μM, the reaction is stopped by vacuum filtration and the radioactivity by solid scintillation by counting in a Micro counter beta Tri-lux ™.

The efficacy of the compound is determined by the Cl50 concentration capable of decreasing 50% the specific capture of glycine, defined by the difference of radioactivity incorporated by the control lot and the batch that has received 10 mM glycine. The most active compounds of the invention have, in this test, an Cl50 of less than 1 μM. Thus, it appears that the compounds according to the invention are specific inhibitors of the glycine transporters glytl and / or giyt2. Therefore, the compounds according to the invention can be used to prepare medicaments, in particular drugs inhibitors of the glycine transporters glytl and / or giyt2. Thus, according to another of its aspects, the invention relates to medicaments comprising a compound of the formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid, or also a hydrate or a solvate of the composed of the formula (I). The compounds of the invention can be used in particular for the treatment of behavioral disorders associated with dementia, psychosis, in particular schizophrenia (deficient form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptics, for the treatment of different forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders, for the treatment of different forms of depression, including psychotic depression, for the treatment of disorders due to alcohol abuse or abstinence, disorders of sexual behavior, disorders of food, and for the treatment of migraine. They can also be used for the treatment of painful muscular contractures in rheumatology and in acute spinal pathology, for the treatment of spastic contractures of medullary or cerebral origin, for the symptomatic treatment of acute and subacute pains of mild to moderate intensity, for treatment of intense and / or chronic pain, neurogenic pains and rebel pains, for the treatment of Parkinson's disease and parkinsonian symptoms of neurodegenerative origin or induced by neuroleptics, for the treatment of generalized primary and secondary epilepsies, partial of simple or complex symptomatology , of mixed forms and other epileptic syndromes as a complement of another antiepileptic treatment, or in monotherapy, for the treatment of sleep apnea, and for neuroprotection. The present invention also aims at pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in pharmaceutically acceptable base or salt or solvate form, and if appropriate, as a mixture with one or more suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration. The pharmaceutical compositions according to the invention can therefore be used for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intracranial, intranasal, transdermal, rectal, infraocular administration. The unit administration forms can be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal seals ("patch"), suppositories. For topical administration, ointments, lotions and eye drops may be considered. By way of example, a unit form of administration of a compound according to the invention in the form of a tablet can comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium Stearate 3.0 mg Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the galenic form. There may be particular cases in which higher or lower doses are appropriate; and such doses are not outside the scope of the invention. In accordance with standard practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight and the response of said patient. The present invention, according to another of its aspects, also relates to a method for treating the pathologies indicated above, comprising the administration to a patient, of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.

Claims (5)

1. CLAIMS 1. A compound that responds to the general formula (I): where: R? represents a hydrogen atom, a linear or branched alkyl group (1 to 7 carbon atoms) optionally substituted with one or more fluorine atoms, a cycloalkyl group (3 to 7 carbon atoms), a cycloalkyl group (3 to 7 atoms) carbon) alkyl (1 to 3 carbon atoms), a phenyl-alkyl group (1 to 3 carbon atoms) optionally substituted with one or two methoxy groups, an alkenyl group (2 to 4 carbon atoms) or an alkynyl group (2 to 4 carbon atoms); R 2 represents a pyridinyl, furanyl, thienyl, thiazolyl or oxazolyl group, said group being optionally substituted with one or more substituents chosen from halogen atoms and the trifluoromethyl, linear or branched alkyl (1 to 6 carbon atoms) and alkoxy groups (1 to 6 carbon atoms); R3 represents a hydrogen atom, one or more substituents selected from halogen atoms and trifluoromethyl groups, linear or branched alkyl (1-6 carbon atoms), cycloalkyl (3 to 7 carbon atoms), alkoxy (1-6 carbon atoms) carbon), phenyl, cyano, acetyl, benzoyl, thioalkyl (1 to 6 carbon atoms), alkylsulfonyl (1 to 6 carbon atoms), carboxy or alkoxy (1 to 6 carbon atoms) carbonyl, a group of general formula NR4R5 or S02NR4R5 or CONR4R5 in which R4 and R5 each represent, independently of each other, a hydrogen atom or a linear or branched alkyl group (1 to 6 carbon atoms), or cycloalkyl (3 to 7 carbon atoms), or R4 and R5 with the nitrogen atom to which they are attached form a cycle of pyrrolidine, piperidine or morpholine; in the form of a free base or addition salt to an acid, hydrate or solvate.
2. 2. A medicament characterized in that it comprises a compound according to claim 1, or an addition salt of this compound to a pharmaceutically acceptable acid, or also a hydrate or a solvate of the compound of formula (I).
3. 3. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient.
4. 4. The use of a compound of formula (I) according to claim 1, for the preparation of a medicament for the treatment of behavioral disorders associated with dementia, psychosis, various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders, different forms of depression, disorders due to alcohol abuse and abstinence, sexual behavior disorders, eating and migraine disorders.
5. 5. The use of a compound of formula (I) according to claim 1, for the preparation of a medicament intended for the treatment of contractures, pain, Parkinson's disease and parkinsonian symptoms, epilepsies, mixed forms and of other epileptic syndromes as a complement of another antiepileptic or monotherapy treatment, of sleep apnea, and for neuroprotection.