MXPA06008041A - Aryloxyalkylcarbamate-type derivatives, preparation method thereof and use of same in therapeutics - Google Patents

Abstract

The invention relates to a compound having general formula (I), wherein:m represents 0, 1, 2 or 3;n represents 0, 1, 2 or 3;X represents an oxygen or sulphur atom or an SO or SO2 group;R1 and R2 represent, independently of each other, a hydrogen atom or a C1-3-alkyl group, or R1 and R2 together form a -(CH2)p- group, in which p represents an integer varying between 1 and 5, such that n + p is an integer varying between 2 and 5;R3 represents a hydrogen or fluorine atom or a hydroxy or methyl group;R4 represents a group having general formula CHR5CONHR6 in which R5 represents a hydrogen atom or a C1-6-alkyl group and R6 represents a hydrogen group or a C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkylene group;and Y represents a group that is selected, for example, from a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, said group being optionally substituted. Said compound takes the form of a base, an acid addition salt, a hydrate or a solvate. The invention also relates to the use of same in therapeutics

Description

DERIVATIVES OF TYPE ARI LOXIALQUILCARBAMATOS, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS The subject of the invention is aryloxyalkylcarbamate derivatives, their preparation and their application in therapy. The compounds of the invention correspond to the general formula (I): (I) in which: m represents 0, 1, 2 or 3; n represents 0, 1, 2 or 3; X represents an oxygen or sulfur atom or an SO or SO2 group; Ri and R2 represent, independently of each other, a hydrogen atom or an alkylC? -C3 group, or Ri and R2 together form a group - (CH2) P-, where p represents an integer ranging from 1 to 5; in such a way that, n + p, is an integer ranging from 2 to 5; R3 represents a hydrogen or fluorine atom or a hydroxy or methyl group; R represents a group of the general formula CHR5CONHR6 in which R5 represents a hydrogen atom or a C-6 alkyl group and Rβ represents a hydrogen atom or a C-6 alkyl, C3-7 cycloalkyl, cycloalkyl group -C3-7-C 1-6 -alkylene, Y represents: a group Yi selected, especially, from a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl , cinolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl; the group Y-i is optionally substituted by one or more substituents Y2, identical or different from each other, or by a group Y3; Y2 represents a halogen atom, a cyano, nitro, alkyl-C-i group. 8, C 1 -8-alkoxy, C 1 -8-thioalkyl, C 1-8-fluoroalkyl, C 1-8-fluoroalkoxy, C 1-8-fluorothioalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 3 -cycloalkyl 7-C1-8 alkylene, C3-7 cycloalkyl-C1-8 alkyloxy, hydroxy, NR7R8, NHCOR7, NHSO2R7, COR7, CO2R7, CON R7R8, SO2R7, SO2NR7R8, -O- (C1-3 alkylene) - O-, phenyloxy, phenylthio, phenylalkyloxy-d-Cs or phenylalkylthio-C? -C8; Y3 represents a group chosen, especially, from a phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; the group (s) Y3 can be replaced by one or several groups Y 2 identical or different from each other; R7 and R8 represent, independently of each other, a hydrogen atom or a C1-C6 alkyl group, or form with the nitrogen atom carrying them an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, piperazine, optionally substituted cycle by a C1-3 alkyl or benzyl group. Among the compounds of general formula (I), a first group of compounds is the group for which: Y represents: a group Y1 chosen, especially, from a phenyl, pyridinyl, pyrimidinyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, benzoxazolyl; the group Y 1 is optionally substituted by one or more substituents, more particularly by one or two substituents Y 2 identical or different from each other, or by a group Y 3; Y 2 represents a halogen atom, more particularly, a chlorine, a fluorine or a bromine, a cyano group, C 1-8 alkyl, more particularly, a methyl, isopropyl, butyl, tertbutyl or tetramethylbutyl, C 1 -8 alkoxy, more particularly, a methoxy, ethoxy or propoxy, fluoroalkyl-C? -8, more particularly, a trifluoromethyl, fluoroalkoxy-C1-8, more particularly, a trifluoromethoxy, phenyloxy, phenylalkylene-CT-Cs, more particularly, a phenyl- (1 , 1-dimethylmethylene); Y3 represents a phenyl group; Y3 can be replaced by one or more groups, more particularly, by one or two Y2 groups identical or different from each other. Among the compounds of the first group as defined above, a second group of compounds is the group for which: Y represents: a group Y-i chosen, especially, between a phenyl or a naphthyl; the group Y-1 is optionally substituted by one or several substituents, more particularly, by one or two substituents Y 2 identical or different from each other, or by a group Y 3; Y 2 represents a halogen atom, more particularly, a chlorine, a fluorine or a bromine, a cyano group, C 1-8 alkyl, more particularly, a methyl, isopropyl, butyl, tertbutyl or tetramethylbutyl, C 6 alkoxy, more particularly, a methoxy, ethoxy or propoxy, fluoroalkyl-ds, more particularly, a trifluoromethyl, fluoroalkoxy-C? -8, more particularly, a trifluoromethoxy, phenyloxy, ferylalkylene-Ci-Cs, more particularly, a phenyl- (1, 1-dimethylmethylene); Y3 represents a phenyl group; Y3 can be replaced by one or several groups, more particularly, by one or two groups Y2 identical or different from each other. Among the compounds of general formula (I), a third group of compounds is the group for which: m represents 0, 1, 2 or 3; and / or n represents 0, 1, 2 or 3; and / or R and R2 represent, independently of each other, a hydrogen atom or a C1 -3 alkyl group, or R- [and R2 together form a group - (CH2) P-, where p represents a whole integer that goes from 1 to 5 so that n + p is an integer ranging from 2 to 5; with the proviso that when R ^ and R2 represent, independently of each other, a hydrogen atom or a C1 -3 alkyl group, then m + n > 1 .

Among the compounds of the third group as defined above, a fourth group of compounds is the group for which: m represents 0, 1, 2 or 3; and / or n represents 0, 1, 2 or 3; and / or R ^ and R2 together form a group - (CH2) P-, where p represents an integer ranging from 1 to 4 such that n + p equals 4. Among the compounds of general formula (I ), a fifth group of compounds is the group for which X represents an oxygen atom. Among the compounds of general formula (I), a sixth group of compounds is the group for which R3 represents a hydrogen atom. A seventh group consists of the compounds for which at the same time R, R2, R3, R, R5, Re, R7, s, X, Y, Yt, Y2, Y3, n and m are as defined in subgroups of compounds mentioned above. The compounds of general formula (I) may comprise one or more asymmetric carbons. These may exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention. The compounds of formula (I) can exist in the state of bases or of addition salts with acids. Said 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) are also part of the invention. The compounds of general formula (I) can be in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Said hydrates and solvates are also part of the invention. In the context of the invention, it is understood that: - Ct-Z where tyz can take values from 1 to 8, a carbon chain which may have, for example, carbon atoms, for example, C1 -3, a carbon chain which may have from 1 to 3 carbon atoms; -alkyl, a saturated, linear or branched aliphatic group; for example, a C3-alkyl group represents a straight or branched carbon chain of 1 to 3 carbon atoms, more particularly, a methyl, ethyl, propyl, 1-methylethyl; - alkylene, a linear or branched, saturated divalent alkyl group, for example, an alkylene-C1-3 group represents a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, more particularly, a methylene, ethylene, 1 - methylethylene, propylene, 1,1-dimethylmethylene; - cycloalkyl, a cyclic alkyl group, for example, a C3-5 cycloalkyl group represents a cyclic carbonic group of 3 to 5 carbon atoms, more particularly, a cyclopropyl, cyclobutyl, cyclopentyl; - alkenylene, a bivalent unsaturated 2-carbon aliphatic group, more particularly, an ethylene; - alkoxy, a linear or branched saturated aliphatic chain-O-alkyl group; - thioalkyl, a saturated or straight or branched aliphatic chain -S-alkyl group; - fluoroalkyl, an alkyl group in which one or several hydrogen atoms have been replaced by a fluorine atom; -fluoroalkoxy, an alkoxy group in which one or several hydrogen atoms have been replaced by a fluorine atom; - fluorothioalkyl, a thioalkyl group in which one or several hydrogen atoms have been replaced by a fluorine atom; -Halogen atom, a fluorine, a chlorine, a bromine or an iodine. The compounds of the invention can be prepared according to different methods, illustrated by means of the following schemes. In this way, a preparation method (scheme 1) consists of reacting an amine of general formula (II), in which: Y, X, R ^ R2, R3, m and n are as defined in the general formula (I), with a carbonate of general formula (III), in which: Z represents a hydrogen atom or a nitro group, R5 is as defined in the general formula (I) and R represents a methyl group or ethyl, in a solvent such as toluene or dichloroethane, at a temperature comprised between 0 and 80 ° C. The carbamatoesters of general formula (IV) obtained in this way are subsequently converted into compounds of general formula (I) by aminolysis, by means of an amine of general formula R6NH2, where R6 is as defined in the general formula (I ). The aminolysis reaction can be carried out in a solvent such as methanol or ethanol, or a mixture of solvents such as methanol and tetrahydrofuran.

Scheme 1 Another method (scheme 2) to obtain the compounds of general formula (I) in which R 2 represents more particularly a hydrogen atom, is to react a derivative of general formula (lia) in which W represents a hydroxyl group, mesylate, tosylate, or a chlorine, bromine or iodine atom, and in which: Y, X, Ri, R3, m, and n are as defined in general formula (I), with an oxazolidin- dione of general structure (V) in which R5 is as defined in general formula (I), to give the oxazolidinedione derivative of general structure (VI). In the case where W represents a hydroxyl group, the reaction can be carried out according to the conditions of Mitsunobu (Synthesis, 1 981, 1 -28), for example, by the action of diethyl azodicarboxylate or diisopropyl in the presence of triphenylphosphine. In the case where W represents a chlorine, bromine, or iodine atom, or a mesylate or tosylate group, the reaction can be carried out in the presence of a base such as 1, 1, 3,3-tetramethylguanidine, hydride of sodium or sodium terbutylate in a solvent such as tetrahydrofuran, acetonitrile or dimethylformamide, at a temperature between 0 ° C and the reflux temperature of the solvent. The oxazolidinedione derivative of the general formula (VI) obtained in this way is then converted into a compound of the general formula (I) by aminolysis, by means of an amine of the general formula R6NH2, where R6 is as defined in general formula (I) Scheme 2 Another variant (scheme 3) for obtaining the compounds of general formula (I) in which: X represents more particularly an oxygen atom, is to react an alcohol derivative of general formula (Vl la), (Vllb) or (Vl) lc) with a phenol derivative of general structure YOH in which Y is as defined in the general formula (I), for example, according to the reaction conditions of Mitsunobu (Synthesis, 1981, 1 -28) or modified (Tetrahedron Letters 1993, 34. 1639-1642), and the carbamate-ester (IVa) and oxazolidin-dione (Via) derivatives are then transformed into compounds of general formula (I) by aminolysis reaction, by means of a amine of general structure R6NH2, where R6 is as defined in the general formula (I) In the general formulas (Vlla), (Vl lb) and (Vl lc), the groups Ri, R2, R3, R5, Re , m, n, and R are as defined above.

Another variant (scheme 4) to obtain the compounds of general formula (I) in which Y represents more particularly, a group Y1-Y3 of the aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type, consists in making reacting an aryl halide derivative of general structure (Vlll), in which: U is a bromine or iodine atom and Y ^ X, R ^ R2, R3, R5, R6, n and m are as defined in the general formula (I), with an aryl- or heteroaryl boronic acid derivative of the formula Y3B (OH) 2, wherein Y3 is as defined in general formula (I), according to the reaction conditions of Suzuki (Chem. Rev. 1995, 95, 2457-2483) or with an aryl- or heteroaryl-tri-alkylstannane derivative of the formula Y 3 Sn (R ') 3, wherein Y 3 is as defined in the general formula ( I) and R 'is an alkyl-C? -4, according to the reaction conditions of Stille (Angew.Chem.Imt.Ed. 1 986, 25, 504-524).

Scheme 4 Compounds of general formulas (I I), (l ia), (lll), (V), (Vl la), (Vl lb), (Vl lc), (Vl ll) and the phenol derivatives of general structure YOH, when their mode of preparation is not described, are commercially available or described in the literature, or, they can be prepared according to methods that are described there or that are known to man by trade. Amines of general formula R6NH2 are commercially available. The following examples illustrate the preparation of some compounds of the invention. These examples are not limiting and only illustrate the invention. The microanalyses, the spectra I. R. and R. M. N. and / or LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) confirm the structures and purities of the obtained compounds. PF (° C) represents the melting point in degrees Celsius. The numbers indicated in parentheses in the titles of the examples correspond to those in the first column of the table presented below. The ICPA nomenclature (Union Internationaie de Chimie Puré et Appliquée-WJPAC in English (International Union of Chemistry Pure and Applied) has been used for the naming of the compounds in the following examples. For example, for the biphenyl group, the following numbering has been respected: Example 1 (compound n ° 1). { 2 - [(4-chlorophenyl) oxy] ethyl} 1 - (methylamino) -2-oxoetyl carbamate eleven . [(Phenyloxycarbonyl) oxy] ethyl acetate It is added slowly, at room temperature, to a solution of 25 g (240 mmol) of ethyl glycolate and 55 ml (31 5 mmol) of diisopropylethylamine in 500 ml of toluene, 32 ml (256 mmol) of phenyl chloroformate. Stirring is maintained at room temperature for 2 hours. The formed salt is separated, and the filtrate is concentrated under reduced pressure. 53.7 g of oily product are obtained, which is used as such in the next step. 1 .2. . { [( {2 - [(4-Chlorophenyl) oxy] ethyl} amino) carbonyl] oxy} ethyl acetate A solution of 0.6 g (3.5 mmol) of [(4-chlorophenyl) oxy] ethylamine (Chim. Ther. 973, 8, 259-270) is heated at 60 ° C overnight. of 1.3 g (5.8 mmol) of ethyl [(phenyloxycarbonyl) oxy] acetate, prepared in step 1 .1. , in 30 ml of toluene. It is evaporated to dryness, and the product is purified by chromatography on silica gel; Elution is carried out by means of a 30/70 mixture of ethyl acetate and cyclohexane. 0.7 g of oily product containing -1.0% of cyclized product oxazolidin-dione are obtained, used as such in the next step. 1 .3. . { 2 - [(4-Chlorophenyl) oxy] ethyl} 2- (methylamino) -2-oxoethyl carbamate 3.5 ml (7 mmol) of a 2M methylamine solution in tetrahydrofuran are added to a solution of 0.7 g (2.3 mmol) of. { [( {2 - [(4-chlorophenyl) oxy] ethyl} amino) carbonyl] oxy} ethyl acetate, prepared in stage 1 .2. , in 5 ml of methanol. It is left to react overnight at room temperature. Dry evaporate, and wash the residual solid by means of hexane, then diisopropyl ether to obtain 0.59 g of product in powder form. Melting point (° C): 147-149 LC-MS: M + H = 287. 1 H-NMR (DMSO) d (ppm): 7.75 (m, 1 H), 7.40 (m, 1 H ), 7.25 (d, 2H), 6.95 (d, 2H), 4.35 (s, 2H), 3.95 (t, 2H), 3.35 (m, 2H), 2.60 (d, 3H). Example 2 (compound No. 1 1) (2 - amino-2-oxoethyl 2 - [(4-cyanophenyl) oxy] ethyl) carbamate 2.1. 3- (2-hydroxyethyl) -l, 3-oxazolidin-2,4-dione A solution of 3 ml (39.6 mmol) of methyl glycolate in 25 ml of tetrahydrofuran is added dropwise over 2 hours to a solution of 49 ml (95 mmol) of phosgene 1.9M in toluene, diluted in 50 ml of tetrahydrofuran and cooled by means of an ice bath. Subsequently, it is stirred at room temperature for 16 hours, and evaporated dry. Co-evaporate 4 times with 30 ml of dichloromethane. The residue is taken up in 40 ml of acetonitrile and added dropwise in 1 hour to a solution of 3.4 ml (59.4 mmol) of ethanolamine and 30 ml (178 mmol) of diisopropylethylamine in a mixture. 50/1 0 acetonitrile and dichloromethane cooled by means of an ice bath. It is then stirred at room temperature for 16 hours. It is filtered on Celite, evaporated to dryness, and the product is purified by chromatography on silica gel; elution is carried out by means of a 70/30 mixture, then 80/20 ethyl acetate and n-hexane, to obtain 4.9 g of product as a white solid. 2.2. (2 - [(4-Cyanophenyl) oxy] ethyl) carbamic acid 2-amino-2-oxoethyl 0.61 ml (1.35 mmol) of a 2.2M solution of diethylazodicarboxylate in toluene is added dropwise, to a solution of 0.13 g (0.88 mmol) of 3- (2-hydroxyethyl) -1,3-oxazolidin-2,4-dione, prepared in step 2.1. , of 0.35 g (1.35 mmol) of triphenylphosphine and of 0.1 g (0.89 mmol) of 4-hydroxybenzonitrile in 2 ml of benzene cooled by means of an ice bath. Then, the reaction mixture was stirred at room temperature for 16 hours. Dry evaporate, and purify the product by chromatography on silica gel; elution is carried out by means of a 99/1 mixture, then 98/2 dichloromethane and ethyl acetate. The product is recovered in 1.5 ml of a 7M ammonia solution (10.5 mmol) in methanol. It is stirred for one hour. The precipitate is filtered, and washed with ethyl acetate to obtain 0.035 g of white solid. Melting point (° C): 204-206. LC-MS: M + H = 264. 1 H-NMR (DMSO) d (ppm): 7.55 (d, 2H), 7.05 (m, 1 H), 6.90-6, 80 (m + d, 4H), 4.35 (s, 25), 4.05 (t, 2H), 3.45 (m, 2H).

Example 3 (compound n ° 58) [2-amino-2-oxoethyl 4- (1-naphthalenyloxy) butyl] carbamate 3. 1 . 3- [4- (l-Naphthalenyloxy] butyl) -1,3-oxazolidin-2,4-dione It is added dropwise to a solution of 3.1 g (11.1 mmol) of 1 - [(4-bromobutyl) oxy] naphthalene (Eur. J. Med. Chem. 1 997, 32, 175-179) and of 1.35 g (13.3 mmol) of 1,3-oxazolidin-2,4- dione (J. Med. Chem. 1991, 34 1 542-1 543) in 30 ml of tetrahydrofuran, a solution of 2.55 g (22.2 mmol) of 1,1-3,3-tetramethylguanidine in 30 ml. of tetrahydrofuran. Heat to reflux for 8 hours. Add 0.28 g (2.7 mmol) of 1, 3-oxazolidin-2,4-dione and 0.32 g (2.7 mmol) of 1,1-3,3-tetramethylguanidine, and stir in the water. heat to reflux for 4 more hours. The reaction mixture was cooled by means of an ice bath and 1 00 ml of ethyl acetate was added, then 50 ml of 1 M aqueous hydrochloric acid. Decanting, the aqueous phase was extracted by means of 2 x 80 ml of acetate of ethyl. The organic phases are then washed with 80 ml of water, then 80 ml of a saturated aqueous solution of sodium chloride. It is dried over sodium sulfate, then evaporated to dryness. The product is purified by chromatography on silica gel; Elution is carried out by means of an 80/20 mixture of cyclohexane and ethyl acetate, to obtain 2.0 g of product used as such in the next step. 3. 2. [2-Amino-2-oxoethyl] [4- (1-naphthalenyloxy] butyl] carbamic acid 1.50 g (5.0 mmol) of 3- [4- (1-naphthalenyloxy] butyl] -1.3 is dissolved. -oxazolidin-2,4-dione, prepared in step 3.1, in a mixture of 10 ml of tetrahydrofuran and 28 ml of a solution of 7 N ammonia (200 mmol) in methanol, is allowed to react overnight at room temperature The product is then purified by chromatography on silica gel, followed by elution with a 97/3 mixture of dichloromethane and methanol.

It is recrystallized from ethyl acetate, then washed with diethyl ether to obtain 0.73 g of product as a white solid. Melting point (° C): 80-82. LC-MS: M + H = 317. RMN-H: (CDCU) d (ppm): 8.25 (dd, 1H), 7.80 (dd, 1H), 7.55-7.30 (m, 4H), 6.80 (d, 1H), 6.00 (m, 1H), 5.65 (m, 1H), 5.05 (m, 1H), 4.65 (s, 2H) , 4.20 (t, 2H), 3.35 (m, 2H), 2.00 (m, 2H), 1.90 (m, 2H). Example 4 (compound no. 85) 4 - [(4'-Fluoro-4-biphenyl) oxy] -1-piperidinecarboxylate 2- (methylamino) -2-oxoethyl 4. 1. 4 - [(4-Bromophenyl) oxy] -1-piperidinecarboxylate 1,1-dimethylethyl. They are added to a solution of 2.01 g (10 mmol) of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. in 20 ml of dimethylformamide, 7 g (40 mmol) of 1-bromo-4-fluorobenzene and 2.5 g (50 mmol) of 50% sodium hydride in mineral oil. The mixture is stirred at 1000 ° C for 3 hours, then evaporated to dryness. The residue is taken up in 50 ml of ice water and extracted with dichloromethane. The organic extracts are evaporated dry to obtain 3.5 g of an oily product used as such in the next step. 4.2. 4 - [(4-Bromophen-yl) oxy] piperidine are added to a solution of 3.5 g (9.83 mmol) of 4 - [(4-bromophenyl) oxy] -1-piperidinecarboxylic acid 1,1-dimethylethyl ester, prepared in stage 4.1. , in 20 ml of dichloromethane, 10 ml of trifluoroacetic acid, and the solution is stirred at room temperature for 1 hour. It is evaporated to dryness, then the residue is recovered by means of 30 ml of toluene which evaporates again dry. Subsequently, the residue is washed with pentane, then recovered in a mixture of 60 ml of dichloromethane and 20 ml of 4N aqueous ammonia solution. It is stirred vigorously for 1 5 minutes, then the organic phase is decanted, dried over sodium sulfate, and evaporated dry to obtain 2.7 g of product in the form of oil, used as such in the next step. 4.2. 4 - [(4-Bromophenyl) oxy] -1-piperidinecarboxylic acid 2- (ethyloxy) -2-oxoethyl) 2.7 g (7.58 mmol) of 4 - [(4-bromo phenyl) oxy] piperidine are mixed. , prepared in stage 4.2. , and 1.70 g (7.6 mmol) of. { [(phenyloxy) carbonyl] oxy} Ethyl acetate, prepared according to Example 1.1, in 40 ml of toluene, and the solution is heated at 50 ° C. for 20 hours.After cooling, it is evaporated to dryness, and the product is purified by chromatography on Silica gel; Elution is carried out by means of a 40/60 mixture of ethyl acetate and cyclohexane. It is then triturated in diisopropyl ether to obtain 2.9 g of product in powder form. Melting point (C °): 87-88. 4.3. 4 - [(4-Bromophenyl) oxy] -1-piperidinecarboxylic acid 2- (methylamino) -2-oxoethyl ester. 2.9 g are stirred at room temperature for 20 hours. (7.5 mmol) of 2- (ethyloxy) -2-oxoethyl 4 - [(4-bromophenyl) oxy] -1-piperidinecarboxylate, prepared in step 4.3. , dissolved in 10 ml of a 33% ethanolic solution of methylamine. After evaporation, the product is purified by chromatography on silica gel and the elution is carried out with ethyl acetate to obtain 0.8 g of product in the form of gum, used as such in the next step. 4.5. 4 - [(4'-Fluoro-4-biphenyl) oxy] -1-piperidinecarboxylic acid 2- (methylamino) -2-oxoethyl. It is placed in a glass tube with a lid of 0.1 g (0.27 mol) of 4 - 2- (Methylamino) -2-oxoethyl [(4-bromophenyl) oxy] -1-piperidinecarboxylate, prepared in step 4.4. , 0.01 g of titanium ester (triphenylphosphine) palladium (0) and 0.057 g (0.4 mmol) of 4-fluorophenylboronic acid. 4 ml of toluene, 2 ml of a 2N aqueous solution of sodium carbonate and 0.5 ml of ethanol are added. Heat at 80 ° C under stirring for 2 hours. After cooling, 1 ml of water and 2 ml of toluene are added. The organic phase is extracted and the product is purified by chromatography on silica gel; The elution is carried out by means of a 95/5 mixture of dichloromethane and methanol. The product is redissolved in 1 ml of ethanol, then re-precipitated by the addition of 2 ml of water to obtain 0.031 g of product in powder form. Melting point (° C): 1 17-1 1 9. LC-MS: M + H 387. 1 H-NMR (CDCl 3) d (ppm): 7.70 (dd, 2H); 7.65 (d, 2H); 7.30 (dd, 2H); 7.20 (d, 2H); 6.25 (broad s, 1 H), 4.80 (s + m, 3H); 4.00-3.70 (m, 4H); 3.05 (d, 3H); 2.25-2.00 (m, 4H). Example 5 (compound n ° 120) 4-. { [(4-Bromophenyl) oxy] methyl) -1-piperidinecarboxylate 2- (methylamino) -2-oxoethyl . 1 . 4-. { [(4-Bromophenyl) oxy] methyl} -1,1-dimethylethyl-1,1-piperidinecarboxylate The procedure is as described in Example 4.1. Starting from 2.5 g (1 1, 6 mmol) of 4- (hydroxymethyl) -1-piperidinecarboxylate of 1,1-dimethylethyl and of 8. 13 g (46.4 mmol) of 1-bromo-4-fluorobenzene , 5.75 g of crude product are obtained in the form of an oil. . 2. 4-. { [(4-Bromophenyl) oxy] methyl} piperidine The procedure is as described in Example 4.2. From 5.75 g of 4-. { [(4-bromophenyl) oxy] methyl} 1, 1-dimethylethyl 1,3-piperidinecarboxylate, prepared in step 5.1, 3 g of product are obtained in the form of an oil. 5.3. 4-. { [(4-Bromophenyl) oxy] methyl} 2- (Ethyloxy) -2-oxoethyl-1-piperidinecarboxylate The procedure is as described in Example 4.3. From 1.6 g (5.9 mmol) of 4-. { [(4-bromophenyl) oxy] methyl} piperidine, prepared in step 5.2, and 1.32 g (5.9 mmol) of . { [(phenyloxy) carbonyl] oxy} ethyl acetate, prepared according to example 1.1, the product is obtained in the form of an oil. 5.4. 4-. { [(4-Bromophenyl) oxy] methyl} 2- (Methylamino) -2-oxoethyl-1-piperidinecarboxylate The procedure is as described in Example 4.4. From 4-. { [(4-bromophenyl) oxy] methyl} 2- (Ethyloxy) -2-oxoethyl -1-piperidinecarboxylate, prepared in step 5.3, 1.1 g of product are obtained in powder form. Melting point (° C): 163-165. LC-MS: M + H = 386. 1 H-NMR (CDCl 3) d (ppm): 7.35 (d, 2 H); 6.75 (d, 2H); 6.05 (broad s, 1H); 4.70-4.50 (m, 2H); 4.30-4.10 (m, 2H); 3.80 (d, 2H); 3.00 -2.75 (m, 2H); 2.85 (d, 3H); 2.10-1.80 (m, 3H); 1.45-1.20 (m, 2H). Example 6 (compound no. 154) 4-. { [(4 '- (Trifluoromethyl) -4-biphenyl) oxy] methyl) -1-piperidinecarboxylic acid 2- (methylamino) -2-oxoethyl ester The procedure is as described in example 4.5. From 0.1 g (0.26 mmol) of 4-. { [(4-bromophenyl) oxy] meth} -1- 2- (Methylamino) -2-oxoethyl piperidinecarboxylate, prepared according to Example 5, and 0.074 g (0.389 mmol) of 4-trifluoromethylphenylboronic acid, 0.049 g of product are obtained in powder form. Melting point (° C): 197-199. LC-MS: M + H = 451. 1 H-NMR (DMSO) d (ppm): 7.85-7.65 (m, 7H), 7.05 (d, 2H), 4.35 (s, 2H ), 4.05 (broad d, 2H), 3.90 (d, 2H), 2.85 (m, 2H), 2.60 (d, 3H), 2.00 (m, 1H), 1.80 (broad d, 2H), 1.35-1.10 (m, 2H) Example 7 (compound no. 137) 4 - [(1-Naphthalenyloxy) methyl) -1-piperidinecarboxylate of 2-amino-2-oxoethyl 7. 1 4 - 1,1-dimethylethyl [(1-naphthalenyloxy) methyl] -1-piperidinecarboxylate. It is added dropwise to a solution of 5.0 g (23.2 mmol) of 4- (hydroxymethyl) -1. 1,1-dimethylethylpiperidin carboxylate, 4.3 g (29.8 mmol) of 1-naphthalenol and 7.82 g (29.8 mmol) of triphenylphosphine in 120 ml of tetrahydrofuran, cooled under nitrogen by means of a bath of ice, a solution of 6.03 g (29.8 mmol) of diisopropyl azodicarboxylate. The reaction mixture is allowed to return to room temperature, and stirring is maintained overnight. Add 2 ml of methanol, then evaporate dry. The residue is taken up in 200 ml of dichloromethane and washed, in turn, with a 10% aqueous solution of potassium hydrogensulfate, with water and with an aqueous solution of 1 M sodium hydroxide. It is dried over sodium sulphate and evaporated. dry. The product is purified by chromatography on silica gel; Elution is carried out by means of an 80/20, then 70/30 and 50/50 mixture of cyclohexane and dichloromethane, to obtain 7.96 g of product in the form of oil, which solidifies. Melting point (° C): 97-1 00. 7.2. 4 - [(1-Naphthalenyloxy) methyl] piperidine A solution of 7.96 g (29.1 mmol) of 4 - [(1-naphthalenyloxy) methyl] -1-piperidinecarboxylate of the same is heated at 60 ° C for 6 hours. 1,1-dimethylethyl, prepared in step 7.1. , in 120 ml of methanol and 28 ml of 35% aqueous hydrochloric acid. It is cooled to room temperature and evaporated to dryness, then coevaporated twice with ethanol. The solid residue is washed with diethyl ether, then dried under vacuum in the presence of phosphorus pentoxide, to obtain 3.1 g of white solid. The solid is taken up in 80 ml of water and an aqueous solution of 30% sodium hydroxide is added until basic pH is reached, then it is extracted twice with 1 50 ml of diethyl ether. The extracts are dried over sodium sulfate and concentrated dry to obtain 2.75 g of oily product used as is in the next step. 7.3. 4 - 2- (Ethyloxy) -2-oxoethyl [2- (ethylamino) -methyl] -1-piperidinecarboxylate. It is heated at 50 ° C overnight, a solution of 2.75 g (11.4 mmol) of 4 - [(1-naphthalenyloxy) methyl] piperidine, prepared in step 7.2. and 2.56 g (11.4 mmol) of [(Phenyloxycarbonyl) oxy] ethyl acetate, prepared according to Example 1.1, in 80 ml of toluene. The mixture is evaporated to dryness, the residue is recovered by means of a mixture of water, dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate. The organic phase is decanted, dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel; Elution is carried out by means of a 50/50 mixture of cyclohexane and dichloromethane, then with dichloromethane and with a 95/5 mixture of dichloromethane and ethyl acetate. 2.05 g of product are obtained in the form of oil, used as such in the next step. 7.4. 4 - [(1-Naphthalenyloxy) methyl-1-piperidinecarboxylate 2-amino-2-oxoethyl) 1.0 g (2.69 mmol) of 4- (1-naphthalenyloxy) methyl] -1- is dissolved 2- (ethyloxy) -2-oxoethyl piperidinecarboxylate, prepared in step 7.3., in 12 ml of a 7N ammonia solution (84 mmol) in methanol. It is left to react at room temperature for 3 days. Dry evaporate and purify by chromatography on silica gel; elution is carried out by means of a 90/10, then 80/20, 70/30 and 50/50 mixture of dichloromethane and ethyl acetate, then with a 95/5 mixture of ethyl acetate and methanol. It is then recrystallized from ethyl acetate to obtain 0.77 g of product. Melting point (° C): 135-136. LC-MS: M + H = 343. 1 H NMR (DMSO) d (ppm): 8.15 (dd, 1H), 7.80 (dd, 1H), 7.50-7.30 (m, 4H ), 7.30 (m, 1H), 7.15 (m, 1H), 6.95 (d, 1H), 4.35 (s, 2H), 4.15-4.00 (m + d, 4H), 4.90 (m, 2H), 2.10 (m, 1H), 1.90 (d, 2H), 1.45-1.25 (m, 2H). Example 8 (compound No. 148) 4 - [(7-Quinolinyloxy) metM] -1-piperidinecarboxylic acid 2-amino-2-oxoethyl 8. 1- 2- (Methyloxy) -2-oxoethyl 4- (hydroxymethyl) -1-piperidinecarboxylate The procedure is as described in Example 2.1., using 6.84 g (59.4 mmol) of 4- (hydroxymethyl) piperidine, in place of ethanolamine, to obtain 7.85 g of product as a colorless oil. 8.2. 4 - [(7-Quinolinyloxy) methyl] -1-piperidinecarboxylic acid 2-amino-2-oxoethyl 0.26 g (1.03 mmol) of 1,1 '- (azodicarbonyl) dipiperidine (ADDP) are added to a solution 0.16 g (0.69 mmol) of 2- (methyloxy) -2-oxoethyl 4- (hydroxymethyl) -l-piperidinecarboxylate, prepared in step 8.1., 0.26 ml (1.03 mmol) of tri-n-butylphosphine and 0.13 g (0.90 mmol) of 7-hydroxyquinoline in 2.5 ml of benzene cooled by means of an ice bath. The mixture is stirred for minutes at 0 ° C, then at room temperature for 16 hours. Filter over Celite and rinse with diethyl ether. The filtrates are evaporated dry and purified by chromatography on silica gel.; elution is carried out by means of a 70/30 mixture of ethyl acetate and n-hexane. The product obtained is dissolved in 3 ml (21 mmol) of a 7M ammonia solution in methanol. It is stirred for 3 hours, then it is evaporated dry. The product is purified by chromatography on silica gel; The elution is carried out by means of a 90/10 mixture of ethyl acetate and ethanol and recrystallized from ethyl acetate to obtain 0.115 g of product as a white solid. Melting point (° C): 137-139. LC-MS: M + H = 344. RMN-1H (CDCl 3) d (ppm): 7.80 (dd, 1H), 8.05 (dd, 1H), 7.70 (d, 1H), 7.40 (d, 1H), 7.30-7.15 (m, 2H), 6.05 (m, 1H), 5.65 (m, 1H), 4.60 (s, 2H), 4 , 25 (m, 2H), 4.00 (d, 2H), 2.90 (m, 2H), 2.10 (m, 1H), 1.95 (d, 2H), 1.50-1, 30 (m, 2H). Example 9 (compound no. 168) 4-. { 2 - [(4-Bromophenyl) oxy] ethyl} 2- (methylamino) -2-oxoethyl -1-piperidinecarboxylate Or in X0YCH * 9. 1. 4- { 2 - [(4-Bromophenyl) oxy] ethyl} 1,1-Dimethylethyl -1-piperidinecarboxylate The procedure is as described in Example 4.1. Starting from 1.93 g (8.4 mmol) of 1,1-dimethylethyl 4- (2-hydroxyethyl) -1-piperidinecarboxylate and 5.88 g (33.6 mmol) of 1-bromo-4- fluorobenzene, 4.1 g of crude product are obtained in the form of an oil. 9.2. 4-. { 2 - [(4-Bromophenyl) oxy] ethyl} piperidine The procedure is as described in Example 4.2. From 4-. { 2 - [(4-Bromophenyl) oxy] ethyl} 1,1-dimethylethyl 1,1-piperidinecarboxylate, prepared in step 9.1, 1.79 g of product is obtained in powder form. Melting point (° C): 100-102. 9.3. 4-. { 2 - [(4-Bromophenyl) oxy] ethyl} 2- (Ethyloxy) 2-oxoethyl -1-piperidinecarboxylate The procedure is as described in Example 4.3. From 1.76 g (6.19 mmol) of 4-. { 2 - [(4-Bromophenyl) oxy] ethyl} piperidine, prepared in step 9.2, and 1.39 g (6.19 mmol) of. { [(phenyloxy) carbonyl] oxy} ethyl acetate, prepared according to example 1.1, 1.4 g of product is obtained in the form of an oil. 9.4. 4-. { 2 - [(4-Bromophenyl) oxy] ethyl} 2- (Methylamino) -2-oxoethyl-1-piperidinecarboxylate The procedure is as described in Example 4.4. From 1.3 g (3.14 mmol) of 4-. { 2 - [(4-Bromophenyl) oxy] ethyl} -1- 2- (ethyloxy) -2-oxoethyl piperidinecarboxylate, prepared in step 9.3, 0.95 g of product are obtained in powder form. Melting point (° C): 101-103. LC-MS: M + H = 400. 1 H-NMR (CDCl 3) d (ppm): 7.55 (d, 2 H); 7.00 (d, 2H); 6.25 (broad s, NH); 4.90-4.70 (m, 2H), 4.50-4.25 (m, 2H), 4.20 (t, 2H); 3.20-2.90 (m, 2H); 3.10 (d, 3H); 2.05-1.90 (m, 5H); 1.55-1.30 (m, 2H). Example 10 (compound no. 186) 4-. { 2 - [(4'-Chloro-4-biphenyl) oxy] ethyl} 2- (methylamino) -2-oxoetheyl-1-piperidinecarboxylate The procedure is as described in example 4.5. From 0.1 g (0.25 mmol) of 4-. { 2 - [(4-Bromophenyl) oxy] ethyl} 2- (Methylamino) -2-oxoethyl -1-piperidinecarboxylate, prepared according to Example 9, and 0.177 g (0.75 mmol) of 4-chlorophenylboronic acid, 0.087 g of product are obtained in powder form. Melting point (° C): 104-106. LC-MS: M + H = 431. 1 H NMR (CDCl 3) d (ppm): 7.70-7.50 (m, 6H); 7.10 (d, 2H); 6.20 (broad s, NH); 4.85-4.60 (m, 2H); 4.45-4.15 (m, 2H); 4.20 (t, 2H); 3.15- 2.95 (m, 2H); 3.05 (d, 3H); 2.10-1.85 (m, 5H), 1.50-1.25 (m, 2H) Example 11 (compound No. 183) 4- [2- (7-lsoquinolinyloxy) ethyl] -1-piperidinecarbamate 2-amino-2-oxoethyl 11. 1. 2- (Methyloxy) -2-oxoethyl 4- (2-Hydroxyethyl) -1-p -peridincarboxylate The procedure is as described in Example 2.1, using 7.6 g (59.4 mmol). ) of 4- (2-hydroxyethyl) piperidine, in place of ethanolamine, to obtain 7.1 g of product as a colorless oil. 11.2. 4- [2- (7-lsoquinolinyloxy) ethyl] -1-piperidincarbamate 2-amino-2-oxoethyl The procedure is as described in Example 8.2., From 0.46 g (1.84 mmol) of ADDP, 0.30 g (1.24 mmol) of 2- (methyloxy) -2-oxoethyl 4- (2-hydroxyethyl) -1-piperidinecarboxylate, prepared in step 11.1., of 0.46 ml of tri-n-butylphosphine and 0.26 g (1.84 mmol) of 7-hydroxyisoquinoline in 4 ml of benzene. The product is purified by chromatography on silica gel and the elution is carried out with ethyl acetate, then with a 95/5 mixture of ethyl acetate and ethanol to obtain 0.25 g of product as a white solid. Melting point (° C): 179-181. LC-MS: M + H = 358. NMR: 1H (CDCl 3) d (ppm): 9.15 (s, 1H), 8.45 (d, 1H), 7.60 (d, 1H), 7, 35 (dd, 1H), 7.20 (d, 1H), 6.05 (m, 1H), 5.75 (m, 1H), 4.60 (s, 2H), 4.20 (t, 4H) ), 2.90 (m, 2H), 1.90-1.70 (m, 5H), 1.40-1.20 (m, 2H). Example 12 (compound no. 83) 3 - [(1-Naphthalen i loxi) meti I] -1-pyrrole id icarboxylate 2-amino-2-oxoethyl 12. 1. 3 - [(1-Naphthalenyloxy) methyl] -1-pyrrolidinecarboxylate of 1, 1-dimethylethyl is added, dropwise, to a solution of 1.0 g (4.9 mmol) of 3- (hydroxymethyl) -1-pyrrolidincarboxylate 1,1-dimethylethyl ester (described in WO 0066557), 0.95 g (6.4 mmol) of 1-naphthalenol and 1.4 g (6.9 mmol) of tri-n-butylphosphine in 40 ml of toluene and 20 ml of tetrahydrofuran, cooled under nitrogen medium of an ice bath, a solution of 1.74 g (6.9 mmol) of ADDP. The reaction mixture is allowed to return to room temperature, and stirring is maintained for 24 hours. The mixture is filtered and the precipitate is rinsed with toluene. It evaporates dry. The residue is taken up in dichloromethane and washed with an aqueous solution of 1 M sodium hydroxide. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column and the elution is carried out with dichloromethane, then with a 98/2 mixture of dichloromethane and methanol, to obtain 0.80 g of product as a colorless oil. 12.2. 3 - [(1-Naphthalenyloxy) methyl] pyrrolidine A solution of 0.42 g (1.28 mmol) of 3 - [(1-naphthalenyloxy) methyl] -1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester is stirred for 6 hours. , prepared in step 12. 1. , in 10 ml of 1,4-dioxane and 6 ml of a 2N aqueous hydrochloric acid solution. It is evaporated to dryness, then coevaporated twice with toluene. The solid residue is washed with diethyl ether. The solid is recovered with dichloromethane, and a concentrated solution of ammonia is added until basic pH is reached. Filter Whatman PTFE cartridge and concentrate the organic phase to obtain 0.21 g of oily product used as it is in the next step. 12.3. 3 - [(1-N-tatalenyloxy) methyl] -1-pyrrolidinecarboxylate 2- (ethyloxy) -2-oxoethyl) A solution of sodium chloride is heated at 60 ° C overnight. 0.20 g (0.88 mmol) of 3 - [(1-naphthalenyloxy) methyl] pyrrolidine, prepared in step 12.2. and 0.35 g (1.5 mmol) of [(phenyloxycarbonyl) oxy) ethyl acetate, prepared according to Example 1.1, in 6 ml of toluene. Dry evaporate and recover the residue by means of a mixture of water, dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate. The organic phase is decanted, dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatograon a silica gel column and the elution is carried out with dichloromethane, then with a 99/1 mixture of dichloromethane and methanol. 0.24 g of product are obtained in the form of oil, used as such in the next step. 12.4. 3 - [2-amino-2-oxoethyl] 2- [(1-naphthalenyloxy) methyl] -1-pyrrolidinecarboxylate 0.24 g (0.67 mmol) of 3 - [(1-naphthalenyloxy) methyl] -1-pyrrolidinecarboxylate are dissolved from 2- (ethyloxy) -2-oxoethyl, prepared in step 12.3. , in 15 ml of a 7N ammonia solution (105 mmol) in methanol. Stir in a capped tube at room temperature for 3 days. Dry evaporate and purify the residue by chromatograon a silica gel column; elution is carried out by means of a mixture 97/3, then 94/6 dichloromethane and methanol. The solid obtained is triturated in diethyl ether and filtered to obtain 0.15 g of product. Melting point (° C): 161-163. LC-MS: M + H = 329. 1 H-NMR (DMSO) d (ppm): 8, 15 (m, 1 H), 7.75 (m, 1 H), 7.50-7.30 (m) m, 4H), 7, 10-6.90 (s, 2H), 6.80 (m, 1 H), 4.40 (s, 2H), 4.20-4.05 (m, 2H), 3.90-3.30 (m, 4H), 2.90-2.70 (m, 1 H), 2.30-2, 10 (m, 1H), 2.05-1, 85 (m, 1 HOUR). The following table illustrates the chemical structures and ical properties of some compounds according to the invention.

Table (i) The compounds of the invention have been subjected to pharmacological tests that have allowed to determine their inhibitory effect of the FAAH enzyme (Fatty Acid Amido Hydrolase). The inhibitory activity has been evidenced in a radioenzymatic test based on the measurement of the hydrolysis product (ethanolamine [1 -3H]) of anandamide [ethanolamine 1 -3H] by the FAAH (Life Sciences (1995), 56, 1999- 2005 and Journal of Pharmacology and Experimented Therapeutics (1 997), 283. 729-734). In this way, brains are extracted from mice (minus the cerebellum) and stored at -80 ° C. The membrane homogenates are prepared extemporaneously by homogenizing the tissues with Polytron in a 10 mM Tris-HCl buffer (pH 8.0) containing 150 mM NaCl and 1 mM EDTA. Subsequently, the enzymatic reaction is treated by means of 70 μl of buffer containing bovine serum albumin without fatty acids (1 mg / ml). The compounds tested in different concentrations, anandamide [ethanolamine 1 -3H] (specific activity of 15-20 Ci / mmol) diluted in 1 μM of cold anandamide and the membrane preparation (400 μg of tissue frozen by proof). After 15 minutes at 25 ° C, the enzymatic reaction is stopped by the addition of 140 μL of chloroform / methanol (2: 1). The mixture is stirred 10 minutes, then centrifuged for 1 5 minutes at 3500g. An aliquot (30 μL) of the aqueous phase containing ethanolamine [1 -3H] is counted by liquid scintigra Under these conditions, the most active compounds in the The present invention has Cl50 (concentration that inhibits 50% the control enzymatic activity of FAAH) comprised between 0.001 and 1 μM. For example, compound No. 58 in the table shows an Cl50 of 0.047 μM. Therefore, it arises in this way that the compounds according to the invention have an inhibitory activity of the FAAH enzyme. The in vivo activity of the compounds of the invention has been evaluated in an analgesia test. In this way, the intraperitoneal (i.p.) administration of PBQ (phenylbenzoquinone, 2 mg / kg in a 0.9% sodium chloride solution containing 5% ethanol) in OF1 male mice from 25 to 30 g, causes abdominal stretching, on average 30 twists or contractions during the period of 5 to 15 minutes after the injection. The tested compounds are orally administered in suspension in 0.5% Tween 80, 60 minutes or 120 minutes before administration of PBQ. Under these conditions, the most powerful compounds of the invention reduce by 35 to 70% the number of stretches induced by the PBQ, in a range of doses comprised between 1 and 30 mg / kg. For example, compound No. 58 of the table reduces by 51% the number of stretches induced by the PBQ, in a dose of 1 mg / kg at 2 hours. The FAAH enzyme (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyzes the hydrolysis of the endogenous derivatives of amides and esters of different fatty acids such as N-arachidonoylethanolamine (anandamide), the? / - palmitoylethanolamine, the? / -oleoylethanolamine, the oleamide or the 2-arachidonoylglycerol. These derivatives exert different pharmacological activities interacting, among others, with the cannabinoid and vanilloid receptors. The compounds of the invention block this degradation pathway and increase the tissue percentage of these endogenous substances. These can be used for this purpose in the prevention and treatment of pathologies in which endogenous cannabinoids and / or any other substrate metabolized by the FAAH enzyme are involved. Mention may be made, for example, of the following diseases and conditions: pain, especially acute or chronic pains of the neurogenic type: migraine, neuropathic pain including the forms associated with the herpes virus and diabetes; Acute or chronic pains associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease, irritable bowel syndrome; acute or chronic peripheral pains; the vertigos; the vomiting; nausea, particularly those that are the result of chemotherapy; disorders of eating behavior, in particular anorexia and cachexia of various natures; neurological and psychiatric pathologies: tremors, dyskinesias, dystonia, spasticity, compulsive and obsessive behaviors, Tourette syndrome, any form of depression and anxiety of any nature and origin, mood disorders, psychosis; Acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, chorea Huntington, injuries related to cerebral ischemia and to injuries of the skull and spinal cord; epilepsy; sleep disorders that include sleep apnea; cardiovascular diseases, in particular, hypertension, cardiac arrhythmias, arteriosclerosis, cardiac crisis, cardiac ischemia; renal ischemia; cancers: benign skin tumors, papillomas and brain tumors, prostate tumors, brain tumors (glioblastomas, medulla-epitheliomas, medulloblastomas, neuroblastomas, tumors of embryonic origin, astrocytomas, astroblastomas, ependinomas, oligodendrogliomas, plexus tumor, neuroepitheliomas, epiphysis tumor, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanomas, schwannomas); disorders of the immune system, especially autoimmune diseases: psoriasis, lupus erythematosus, connective tissue diseases or connective diseases, Sjogrens syndrome, ankylosing spondyloarthritis, undifferentiated spondyloarthritis, Behcet's disease, hemolytic autoimmune anemias, sclerosis in plaques, lateral sclerosis amyotrophic, amyloidosis, rejection of grafts, diseases that affect the plasmocytic line; allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; infectious parasitic, viral or bacterial diseases: AIDS, meningitis, inflammatory diseases, especially joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease, irritable bowel syndrome, osteoporosis, eye conditions: ocular hypertension, glaucoma; lung conditions: respiratory diseases, bronchospasm, cough, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema; gastrointestinal diseases: irritable bowel syndrome, inflammatory bowel disorders, ulcers, diarrhea; urinary incontinence and bladder inflammation. The use of the compounds according to the formula (I), in a basic state, of addition salt with a pharmaceutically acceptable acid, hydrate or solvate, for the preparation of a medicament for treating the aforementioned pathologies, forms an integral part of the invention. The invention also relates to medicaments comprising a compound of formula (I), or an addition salt with an acid, or else a pharmaceutically acceptable hydrate or solvate of the compound of formula (I). These drugs find their use in therapy, especially in the treatment of the aforementioned pathologies. According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as an active principle, at least one compound of formula (I). These pharmaceutical compositions contain an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt, or a hydrate, or solvate of said compound, and optionally, one or more pharmaceutically acceptable excipients.

Said excipients are chosen according to the desired pharmaceutical form and administration mode, among the usual excipients which are known to the man by trade. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active principle of formula (I) above, or its salt, solvate or eventual hydrate, can be administered in unitary administration form, mixed with usual excipients, animals and humans for the prophylaxis or treatment of the disorders or diseases mentioned above. Suitable unit dosage forms comprise oral forms such as tablets, soft or hard gelatin capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal, inhalation, subcutaneous, intramuscular or intravenous administration forms and forms of rectal administration or vaginal. For topical application, the compounds according to the invention can be used in creams, ointments or lotions. 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 Starch corn 5.0 mg Hydroxypropylmethylcellulose 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 also pertain to the invention. In accordance with standard practice, the appropriate dosage for each patient will be determined by the physician according to the mode of administration, the weight and the response of said patient. The invention, according to another of its aspects, also relates to a method for treating the above-mentioned pathologies comprising the administration of an effective dose of a compound according to the invention, of one of its addition salts with an acid pharmaceutically acceptable, a solvate or a hydrate of said compound.

Claims (12)

1. CLAIMS 1. Compound that corresponds to the formula (I): (i) wherein: m represents 0, 1, 2 or 3; n represents 0, 1, 2 or 3; X represents an oxygen or sulfur atom or an SO or SO2 group; R and R2 represent, independently of each other, a hydrogen atom or a C1 -3 alkyl group, or R, and R2 together form a group - (CH2) P-, where p represents an integer ranging from 1 to 5 in such a way that, n + p, is an integer ranging from 2 to 5; R3 represents a hydrogen or fluorine atom or a hydroxy or methyl group; R4 represents a group of general formula CHR5CONHR6 in which: R 5 represents a hydrogen atom or a C 1-6 alkyl group and R 6 represents a hydrogen atom or a C 1-6 alkyl, C 3 cycloalkyl group. , C3-7-cycloalkyl-C1-6 alkylene; Y represents: a group Yi selected, especially, from a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzlsoxazolyl, benzotlazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl; the group Y- is optionally substituted by one or more substituents Y2, identical or different from each other, or by a group Y3; Y2 represents a halogen atom, a cyano, nitro, alkyl-C-i group. 8, C 1 -C 8 alkoxy, C 1 -8 thioalkyl, C 1-8 fluoroalkyl, C 8 fluoroalkoxy, C 1-8 fluorothioalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 3-7 cycloalkyl -alkylene-C1 -8, cycloalkyl-C3- -alkyloxy-C1-8, hydroxy, NR7R8, NHCOR7, NHSO2R7, COR7, CO2R7, CONR7R8, SO2R7, SO2NR7R8, -O- (C1-3-alkylene) -O-, phenyloxy, phenylthio, phenylalkylene-C? -C8, phenylalkyloxy-C? -C8 or phenylalkylthio-C? -C8; Y3 represents a group chosen, especially, from a phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; the group (s) Y3 can be replaced by one or more groups Y2 identical or different from each other; R7 and R8 represent, independently of each other, a hydrogen atom or an alkyl-C-, 6 group, or form with the nitrogen atom carrying them an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, piperazine, optionally substituted by a C-3-alkyl or benzyl group; in the base state, of addition salt with an acid, hydrate or solvate.
2. 2. Compound of formula (I) according to claim 1, characterized in that: Y represents: a group Y-i chosen, especially, between a phenyl, pyridinyl, pyrimidinyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, benzoxazolyl; the group Y-i is optionally substituted by one or more substituents Y 2 identical or different from each other, or by a group Y 3; Y2 represents a halogen atom, more particularly, a cyano group, C1-8 alkyl, C1-8 alkoxy, fluoroalkyl-C-, 8, fluoroalkoxy-C1-8, phenyloxy, phenylalkylene-Ci-Ca; Y2 represents a phenyl group; Y3 can be replaced by one or more groups Y2 identical or different from each other; in the base state, of addition salt with an acid, hydrate or solvate.
3. 3. Compound of formula (I) according to claim 1 or 2, characterized in that: Y represents: a group Y-chosen, especially, between a phenyl or a naphthyl; the group Yi is optionally substituted by one or more substituents Y2 identical or different from each other, or by a group Y3; Y 2 represents a halogen atom, a cyano group, C 1 -C 8 -alkyl, C 1-8 alkoxy, C 1 -8 fluoroalkyl, C 1 -8 fluoroalkoxy, phenyloxy, C 1 -C 8 phenylalkylene; Y3 represents a phenyl group; Y3 can be replaced by one or more groups Y2 identical or different from each other; in the base state, of addition salt with an acid, hydrate or solvate.
4. 4. Compound of formula (I) according to any of claims 1 to 3, characterized in that: m represents 0, 1, 2 or 3; and / or n represents 0, 1, 2 or 3; and / or Ri and R2 represent, independently of each other, a hydrogen atom or a C1 -3 alkyl group, or R, and R2 together form a group - (CH2) P-, where p represents an integer ranging from 1 to 5 so that n + p is an integer ranging from 2 to 5; with the proviso that when R1 and R2 represent, independently of each other, a hydrogen atom or a C1-3 alkyl group, then m + n > 1; in the base state, of addition salt with an acid, hydrate or solvate.
5. 5. Compound of formula (I) according to any of claims 1 to 4, characterized in that: m represents 0, 1, 2 or 3; and / or n represents 0, 1, 2 or 3; and / or R-i and R2 together form a group - (CH2) P-, where p represents an integer ranging from 1 to 4 such that n + p equals 4; in the base state, of addition salt with an acid, hydrate or solvate.
6. 6. Compound of formula (I) according to any of claims 1 to 5, characterized in that X represents an oxygen atom; in the base state, of addition salt with an acid, hydrate or solvate.
7. 7. Compound of formula (1) according to any of claims 1 to 6, characterized in that R3 represents a hydrogen atom; in the base state, of addition salt with an acid, hydrate or solvate.
8. 8. Process for preparing a compound of formula (I) according to any of claims 1 to 7, comprising the step of transforming a compound of formula (IV), wherein: Y, X, R1 (R2, R3, R5, m and n are as defined according to any of claims 1 to 7, and R represents a methyl or ethyl group, by aminolysis by means of a amine of formula R6NH2, wherein R6 is as defined in formula (I) according to claim 1.
9. 9. Pharmaceutical composition containing at least one compound of formula (I) according to any one of claims 1 to 7, in pharmaceutically acceptable salt, hydrate or solvate base state, and optionally one or more pharmaceutically acceptable excipients 10.
10. Compound of formula (I) according to any of claims 1 to 7, in the state of pharmaceutically acceptable base, salt, hydrate or solvate for use as a medicament 1.
11. Use of a compound of formula (I) according to any of claims 1 to 7, in the salt base state, hydrate or solvate pharmaceutically acceptable, for the preparation of a medicament intended to prevent or treat a pathology in which the endogenous cannabinoids and / or any other substrate metabolized by the FAAH enzyme are involved.
12. 12. Use of a compound of formula (I) according to any of claims 1 to 7, in a pharmaceutically acceptable salt, hydrate or base solvate, for the preparation of a medicament intended to prevent or treat acute or chronic pain, dizziness, vomiting, nausea, eating disorders, neurological and psychiatric disorders, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancers, disorders of the immune system, allergic diseases, infectious parasitic, viral or bacterial diseases, inflammatory diseases, osteoporosis, eye diseases, lung diseases, gastrointestinal diseases or urinary incontinence.