MXPA06009623A - Derivatives of alkylpiperazine- and alkylhomopiperazine- carboxylates, preparation method thereof and use of same as faah enzyme inhibitors - Google Patents

Abstract

The invention relates to a compound having general formula (I), wherein:n=1 or 2;p represents an integer varying between 1 and 7;A is selected from one or more X, Y and/or Z groups;X=optionally-substituted methylene;Y=C2-alkenylene, optionally substituted, or C2-alkynylene;Z=C3-7-cycloalkyl;G=single bond, O, S, SO, SO2, C=O or CH(OH);R1 represents an aryl- or heteroaryl-type group;and R2 represents a hydrogen atom or a C1-6-alkyl group;R3 represents a hydrogen atom or a C1-6-alkyl, C3-7--cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl group, said compound taking the form of a base, an acid addition salt, a hydrate or a solvate. The invention also relates to the use thereof as FAAH enzyme inhibitors for the treatment of pain, inflammation, neurodegenerative diseases, etc.

Description

FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO, In ce qui coi. eme les codes a deux lettres et autres abrévia- 'SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, lions, are referenced aux "Notes explicatives relative aux codes et GQ, GW, ML, MR, JSTE, SN, TD, TG). abréviations "figurant au début de chaqué ordinaire de la Gazette du PCT Publiee: - avec rapport de recherche internationale - avant l'expiration du délai prévu pour la modification des revendications, sera republiée si des modifications sont re- ques DERIVATIVES OF ALQUILPIPERAZIN AND ALQUILHOMOPIPERAZ1N- CARBOXILATOS, ITS PREPARATION AND ITS APPLICATION AS INHIBITORS OF THE ENZYME FAAH The invention relates to alkylpiperazine- and alkylhomopiperazinecarboxylate derivatives, their preparation and their application in therapy. There are already known derivatives of phenylalkylcarbamates, of dioxane-2-alkylcarbamates and of 1-piperazin- and 1-homopiperazine-carboxylates, described respectively in WO2004 / 067498A, WO2004 / 020430A and PCT / FR2004 / 00328, inhibitors of the enzyme FAAH (by its initials in English: Fatty Acid Amido Hydrolase, amido-hydrolase of fatty acids). There is still a need to find and develop products inhibiting the FAAH enzyme. The compounds of the invention respond to this objective. The compounds of the invention correspond to the general formula (I): (l) wherein: n represents an integer equal to 1 or 2; p represents an integer ranging from 1 to 7; A is selected from one or more groups X, Y and / or Z; X represents a methylene group optionally substituted by one or two C? _6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-3 alkylene groups; Y represents either a C2 alkenylene group optionally substituted with one or two C6_6 alkylene groups, C3-7 cycloalkyl or C3-7 cycloalkyl C3_3 alkylene; or a C2 alkynylene group; Z represents a group of formula: or represents an integer ranging from 1 to 5; r and s represent integers and are defined so that r + s is a number ranging from 1 to 5; G represents a single bond, an oxygen or sulfur atom or a SO, SO2, C = O or CH (OH) group; R-i represents a group R4 optionally substituted with one or more groups R5 and / or R6; R represents a group selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthalenyl, diphenylmethyl, quinolinyl. , tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indanyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl , pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl or isothiazolopyridinyl; R 5 represents a halogen atom or a cyano group, nitro, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, C 1-6 thioalkyl, C 1-6 fluoroalkyl, C 1-4 fluoroalkoxy, C 1-6 fluorothioalkyl, NR 7 R 8, NR 7 COR 8, NR7CO2R8, NR7SO2R8, COR7, CO2R7, WITH R7R8, SO2R7, SO2N R7R8 or -O- (C1-3 alkylene) -O; R6 represents a phenyl, phenyloxy, benzyloxy, naphthalenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl group; the R6 group (s) being optionally substituted with one or more R5 groups identical or different from one another; R7 and R8 represent, independently of each other, a hydrogen atom or a C1-C6 alkyl group, or form with the atom (s) that contain them a cycle chosen from an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine cycle or piperazine, this cycle being optionally substituted with a C-? 6 alkyl or benzyl group; R2 represents a hydrogen atom or a C-? 6 alkyl group; R3 represents a hydrogen atom or a C1-6 alkyl group, C3-7 cycloalkyl or C3-7 cycloalkyl-C-? -3 alkyl. In the context of the invention, the compounds of general formula (I) / / can therefore comprise several A groups identical or different from each other. Among the compounds of general formula (I), a first sub-group of compounds consists of compounds for which: n represents an integer equal to 1 or 2; p represents an integer ranging from 1 to 7; A is chosen from one or more groups X and / or Y; X represents a methylene group optionally substituted with one or two C1-6 alkyl groups, more particularly methyl; Y represents either a C2 alkenylene group or a C2 alkynylene group; G represents a single bond, an oxygen atom or a C = O group; Ri represents a group R4 optionally substituted with one or more groups R5 and / or R6; R represents a group chosen from a phenyl, naphthalenyl, diphenylmethyl, quinolinyl, indolyl, pyrazolyl, isoxazolyl, pyrimidinyl or thiazolyl; R5 represents a halogen atom, more particularly chlorine, fluorine, bromine or iodine, or a cyano group, C6-6 alkyl, more particularly a methyl, an isopropyl or a ter-butyl, C1-6alkoxy, more particularly a methoxy, C1-6 fluoroalkyl, more particularly a trifluoromethyl, fluoroalkoxy C-? -6, more particularly a trifluoromethyl, or -O- (C1-3 alkylene) -O, more particularly an -OCH2O-; R6 represents a phenyl, naphthalenyl or benzyloxy group; R2 represents a hydrogen atom or a C-? 6 alkyl group; R3 represents a hydrogen atom or a C? -6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-3 alkyl group. Among the compounds of general formula (I), a second sub-group of compounds consists of compounds for which: n represents an integer equal to 1; p represents an integer ranging from 1 to 4; A is chosen from one or more groups X and / or Y; X represents a methylene group optionally substituted with one or two C1-6 alkyl groups, more particularly methyl; Y represents a C2 alkynylene group; G represents a single bond or an oxygen atom; R represents a group R optionally substituted with one or more groups R5 and / or R6; R4 represents a group chosen from a phenyl, naphthalenyl or isoxazolyl; R5 represents a halogen atom, more particularly chlorine or fluorine, a cyano group, C-uß alkoxy, more particularly a methoxy or C1-6 fluoroalkyl, more particularly a trifluoromethyl; R6 represents a phenyl group; R 2 represents a hydrogen atom or a C 1-7 alkyl group; R3 represents a hydrogen atom or a C C? _6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-3 alkyl group. Among the compounds of general formula (I), a third sub-group of compounds consists of compounds for which: n, p, A, X, Y, Z, o, r, s, G, R1? R, R5, R8, 7 and Rs are as defined in general formula (I) or in subgroups such as defined above; R2 represents a hydrogen atom; R 3 represents a hydrogen atom, a C-6 alkyl group, more particularly a methyl, C 3-7 cycloalkyl, more particularly a cyclopropyl, or C 3-7 cycloalkyl C 1-3 alkyl, more particularly a -CH 2 cyclopropyl. Among the compounds of the general formula (I), mention may be made of the following compounds: 2- (methylamino) -2-oxoethyl -4- (2-biphenyl-3-ylethyl) piperazine-1-carboxylate, -4- 2- (Methylamino) -2-oxoethyl, 2- (1-naphthyl) ethyl] piperazine-1-carboxylate 2- (methylamino) 2- (methylamino) 2- (methylamino) -2-biphenyl-4-ylethyl-piperazin-2-carboxylate -2-oxoethyl, -4-. { 2- [3- (4-chlorophen i I) isoxazol-5-yl] ethyl} piperazin-1-2- (methylamino) -2-oxoethyl carboxylate, -4-. { 2- [5- (4-chlorophenyl) isoxazol-3-yl] ethyl} 2- (Methylamino) -2-oxoethyl piperazin-1-carboxylate, 2- (methylamino) -2-oxoethyl, 4- (3-biphenyl-3-ylpropyl) piperazine-1-carboxylate, -4- (3- b ife ni l-4-i I prop i I) pipe razin-1-2- (methylamino) -2-oxoethyl carboxylate, -4- (3-biphenyl-3-yl-1,1-dimethylpropyl) piperazine- 1-2- (methylamino) -2-oxoethyl carboxylate, 2- (methylamino) -2-oxoethyl, 4- [3- (3'-chlorobiphenyl-3-yl) -propyl] piperazin-1-carboxylate, - 4- (3- (4'-chloro-biphenyl-3-yl) -propyl] -piperazin-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [3- (3'-m ethoxybifen i-3 -Il) -propyl] piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [3- (4'-methoxybiphenyl-3-yl) -propyl] piperazine-1-carboxylate 2- (methylamino) -2-oxoethyl, -4- [3- (3'-chlorobiphenyl-4-yl) -propyl] piperazin-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [3- ( 4'-chloro-biphen-l-4-yl) -propyl] piperazine-1-carboxylate 2- (methylamino) -2-oxoethyl, -4- [3- (2-naphthyl) propyl] piperazine-1-carboxylate of 2- (methylamino) -2-oxoethyl, -4-. { 3- [5- (4-cl or rofen i I) isoxazol-3-yl] propyl} piperazin-1-2- (methylamino) -2-oxoethyl carboxylate, -4-. { 3- [3- (4-clo rofen i I) isoxazol-5-yl] propyl} 2- (Methylamino) -2-oxoethyl piperazine-1-carboxylate, -4- [4- (3-chlorophen-I) butyl] piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [4- (4-Clo rofen-yl) butyl] -piperazin-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4-. { 4- [3 '- (trifluoromethyl) phenyl] butyl} 2- (Methylamino) -2-oxoethyl -1-p -perazin-1-carboxylate, -4-. { 4- [4 '- (trifluoromethyl) phenyl] butyl} -1-Piperazin-1-carboxylate of 2- (methyloxy) -2-oxoethyl, -4-. { 4- [4- (trifluoromethyl) phen i I] but-3-in-1 -i l} 2- (Methylamino) -2-oxoethyl piperazin-1-carboxylate, -4- [5- (3-chlorophen I) pe nt-4-in-1-l] piperazin-1-carboxylate 2- (Methylamino) -2-oxoethyl, -4- [5- (2,4-d-chlorophenyl) pe nt-4-n-1-yl] piperazin-1-carboxylate of 2- (methylamino) - 2-Oxoethyl, -4- [5- (2,5-dichlorophenyl) pent-4-yn-1-yl] -piperazin-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [5 - (3,4-Dichlorophenyl) pent-4-yn-1-yl] piperazin-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [5- (3-chloro-4-f-Iorofen i) pen t-4-in-1 -yl] piperazin-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [3- (2-chlorophenoxy) propyl] piperazine-1-carboxylate of 2 - (Methylamino) -2-oxoethyl, -4- [3- (3-chlorophenoxy) propyl] piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [3- (4-chlorophenoxy) propyl] ] 2- (Methylamino) -2-oxoethyl piperazine-1-carboxylate, 2- (methylamino) -2-oxoethyl, -4- [3- (2,3-dichlorophenoxy) propyl] piperazine-1-carboxylate, -4 - [3- (2,4-dichlorophenoxy) propyl] piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl, -4- [3- (2 , 2- (methylamino) -2-oxoethyl, 4- [3- (2,6-dichlorophenoxy) propyl] piperazine-1-carboxylic acid 2- (methylamino) -carboxylate, 5-dichlorophenoxy) propyl] piperazine-1-carboxylate 2-oxoethyl, and 2- (methylamino) -2-oxoethyl-4- [3- (3,5-dichlorophenoxy) propyl] piperazin-1-carboxylate. The compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They can exist in the form of enantiomers or diastereoisomers. The compounds of. General formula (I) can also exist in the form of cis (Z) or trans (E) stereoisomers. These stereoisomers, enantiomers and diastereomers, 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 the salts of other acids use for example, for the purification or isolation of the compounds of formula (I) also form part of the invention. The compounds of the general formula (I) can be present in the form of hydrates or solvates, that is to say in the form of combinations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention. In the context of the invention, it is meant by: Ct-Z where tyz can have the values from 1 to 7, a carbon chain which may have from carbon atoms, for example, C1 -3 a carbon chain which may have 1 to 3 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example, a C-α-6 alkyl group represents a carbon chain of 1 to 6 carbon atoms, straight or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl; alkylene, a linear or branched, saturated divalent alkyl group, for example a C al-C al3 alkylene group, represents a divalent carbon chain of 1 to 3 carbon atoms, straight or branched, more particularly a methylene, ethylene, 1-methylethylene or propylene; cycloalkyl, a cyclic alkyl group, for example, a C3-7 cycloalkyl group represents a cyclic carbonic group of 3 to 7 carbon atoms, more particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; C2 alkenylene, a divalent unsaturated, 2-carbon aliphatic group, more particularly an ethylene, C2-alkynylene, a -C = C- group; alkoxy, a linear or branched saturated aliphatic chain-O-alkyl group; thioalkyl, a group -S-alkyla of saturated, linear or branched aliphatic chain; 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 more hydrogen atoms have been replaced by a fluorine atom; halogen atom, a fluorine atom, chlorine, bromine or iodine. The compounds of the invention can be prepared according to different methods illustrated by the following schemes. Thus, according to a first method (scheme 1) the compounds of general formula (I) can be prepared by reacting an amine of general formula (IV), in which Ri, G, A, p and n are as defined in general formula (I), with a carbonate of general formula (I 1 la) in which V represents a hydrogen atom or a nitro group, R 2 is as defined in the general formula (I) and R represents a methyl or ethyl group. The carbamate ester of the general formula (II) obtained in this way is then converted into a compound of the general formula (I), by aminolysis by an amine of the general formula R3N H2 in which R3 is as defined in general formula (I). The aminolysis reaction can be carried out in a solvent such as methanol or ethanol, or in a mixture of solvents such as methanol and tetrahydrofuran. Scheme 1 (IV) (II) Another method (scheme 2) for obtaining the compounds of general formula (I) is to react a piperazine or homopiperazine derivative of the general formula (Vi 1) in which PG represents a protective group, such as a tert-butyloxycarbonyl (Boc), with a carbonate of general formula (11 lb) in which V represents a hydrogen atom or a nitro group and R2 and R3 are as defined in the general formula (I), and then deprotect the compound resulting, for example in the presence of a solution of hydrochloric acid in a solvent, such as isopropanol. The carbamate-amide of general formula (V) thus obtained is then transformed into the compound of general formula (I), by reaction with a derivative of general formula (VI) in which Ri, G, p and A are as they have defined in the general formula (X) and W represents a chlorine, bromine or iodine atom or a mesylate or tosylate group. The N-alkylation reaction can be carried out in a solvent, such as acetonitrile or toluene, in the presence of a base, such as potassium carbonate or diisopropylethylamine. Scheme 2 The compounds of general formula (I), (II) and (IV), in which R ^ represents a group of the aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type, can also be prepared by reaction of the compounds of general formula (I), (II) or (IV) corresponding, for which R2 is substituted with a chlorine, bromine, iodine or with a triflate group in the position in which the R6 group must be introduced, with a derivative of aryl-or heteroaryl-boronic acid following the reaction conditions of Suzuki. { Chem. Rev. 1 995, 95, 2457-2483) or with an aryl-or heteroaryl-alkylatannane derivative following the Stille reaction conditions. { Angew. Chem. Int. Ed. 1 986, 25, 504-524). The carbonates of general formula (I 1 la) and (1 1 lb) can be prepared according to any method described in the literature, for example by reaction of an alcohol of the respective general formula HOCH R2COOR, in which R represents a methyl or ethyl group , or HOCH R2CON H R3, wherein R3 is as defined in general formula (I), with phenyl chloroformate or 4-nitrophenyl, in the presence of a base such as triethylamine or diisopropylethylamine. The compounds of general formula (IV), (VI) and (Vi l) as well as the amines of general formula R3N H2, when their mode of preparation is not described, are commercially available or are described in the literature or can be prepared according to different methods described in the literature or known to the person skilled in the art. The invention, according to another of its aspects, also aims at the compounds of formula (I I) and (V). These compounds are useful as synthesis intermediates of the compounds of formula (I). The following examples illustrate the preparation of some compounds of the invention. These examples are not limiting and only serve to illustrate the invention. The microanalyses, the spectra of I. R. and R.M. N. and / or the LC-MS analyzes (Liquid Chromatography coupled with Mass Spectrometry) 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 following table. Example 1 (Compound No. 85) fraps-4- (3-phenylprop-2-en-1-yl) piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester 1 . 1 . frat? s-4- (3-phenylprop-2-en-1-yl) piperazin-1-carboxylate 2- (ethoxy) -2-oxoethyl A solution of 1.40 g is heated at 80 ° C overnight. (6.93 mmoles) of trans-1 -cinamylpiperazine and 1.74 g (7.76 mmoles) of. { [(phenyloxy) carbonyl] oxy} ethyl acetate (J. Med. Chem., 1 999, 42, 277-290) in 15 ml of toluene. It is evaporated to dryness and taken up in 50 ml of ethyl acetate. Wash 20 ml of water and 1 x 10 ml of a saturated aqueous solution of sodium chloride twice. Dry over sodium sulfate and evaporate to dryness. The residue is purified by chromatography on silica gel eluting with a 50/50 mixture of cyclohexane and ethyl acetate and then with ethyl acetate to obtain 0., 814 g of product in the form of a pale yellow oil. 1 .2. fra / 7s-4- (3-phenylprop-2-en-1-yl) piperazin-1-carboxylate 2- (methylamino) -2-oxoethyl 0.8 g (2.4 mmol) of tat7s- are dissolved 4- (3-Phen'lprop-2-en-1-yl) piperazine-1-carboxylic acid 2- (ethoxy) -2-oxoethyl ester, obtained in step 1. 1, in 10 ml of a 2M solution of methylamine (20 mmol) in methanol. It is left to react for one and a half hours at room temperature and then evaporated to dryness. The residue is purified by chromatography on silica gel eluting first with ethyl acetate and then with a 90/10 mixture of ethyl acetate and methanol. 0.548 g of white powder are obtained. Fusion Point (° C): 109-111. LC-MS: M + H = 318. 1 H NMR (DMSO-d 6): d (ppm): 7.80 (broad s, 1H); 7.50 -7.15 (m, 5H); 6.55 (d, 1H); 6.25 (td, 1H); 4.40 (s, 2H); 3.40 (m, 4H); 3.10 (d, 2H); 2.60 (d, 3H); 2.40 (m, 4H). Example 2 (compound No. 99) 4-. { 3- [3- (trifluoromethyl) phenyl] prop-2-yn-1-yl} -1, 4-diazepane-1-carboxylate of 2-amino-2-oxoethyl 2. 1. 4- { 3- [3- (trifluoromethyl) phenyl] prop-2-yn-1-yl} -1,4-diazepane-1-carbaldehyde A mixture of 1.28 g (10 mmol) of 1,4-diazepam-1-carbaldehyde and 0.33 g (11 mmol) of para-formaldehyde is heated at 80 ° C. in 13 ml of dioxane until obtaining a homogeneous solution. 1.70 g (10 mmol) of 3-trifluoromethylphenylacetylene in solution are added in 7 ml of dioxane and 1.81 g (10 mmol) of copper diacetate. It is heated at 80 ° C for 4 hours. It is cooled to room temperature and diluted with 75 ml of ethyl acetate. The organic phase is washed with 25 ml of a 30% ammonia solution and then with a saturated aqueous solution of sodium chloride. Dry over sodium sulfate and evaporate to dryness. The remainder is purified by chromatography on silica gel eluting with a 98/2 / 0.2 mixture, then 96/4 / 0.4 and 94/6 / 0.6 dichloromethane, methanol and 30% ammonia to obtain , 67 g of product in the form of a yellow oil. 2.2. 4-. { 3- [3- (trifluoromethyl) phenyl] prop-2-yn-1-yl} -1, 4-diazepam 2.63 g (8.48 mmol) of 4- are dissolved. { 3- [3- (Trifluoromethyl) phenyl] prop-2-yn-1-yl} -1,4-diazepane-1 -carbaldehyde, obtained in step 2.1, in 7.5 ml of methanol. 3.5 ml of an aqueous solution of sodium hydroxide (30 mmoles) at 35% are added and the mixture is refluxed for 3 hours. It is cooled to room temperature. It is diluted with 20 ml of water and 75 ml of dichloromethane. Decant and then extract the aqueous phase with 2 times 25 ml of dichloromethane. The organic phases are washed with 25 ml of water and then with 25 ml of a saturated aqueous solution of sodium chloride. It is dried over sodium sulphate and evaporated to dryness to obtain 2.25 g of the product in the form of a red oil, which is used as such in the next step. 2.3. 4-. { 3- [3- (trifluoromethyl) phenyl] prop-2-yn-1-yl} -1, 4-diazepane-1-carboxylic acid 2- (ethyloxy) -2-oxoethyl ester A solution of 2.25 g (7.95 mmoles) of 4- is heated at 60 ° C overnight. { 3- [3- (trifluoromethyl) phenyl] prop-2-n-1-yl} -1, 4-diazepam, obtained in step 2.2, and 2.68 g (1 1, 9 mmoles) of. { [(phenyloxy) carbonyl] oxy} ethyl acetate in 10 ml of toluene. 5 g of silica are added and evaporated to dryness. The residue is purified by chromatography on silica gel eluting with a 60/40 mixture and then 40/60 of cyclohexane and ethyl acetate and then with ethyl acetate to obtain 2.42 g of the product as an orange oil. 2.4. 4-. { 3- [3- (trifluoromethyl) phenyl] prop-2-yn-1-yl} -1, 4-diazepane-1-carboxylic acid 2-amino-2-oxoethyl. 0.77 g (1.87 mmol) of 4- are dissolved. { 3- [3- (trifluoromethyl) phenyl] prop-2-yn-1-yl} -1, 4-diazepane-1-carboxylic acid 2- (ethyloxy) -2-oxoethyl ester, obtained in step 2.3, in 14 μl of a 7M solution of ammonia (98 mmol) in methanol. It is left to react overnight at room temperature and then 2 g of silica are added and evaporated to dryness. The residue is purified by chromatography on silica gel eluting with a mixture 97/3/0, 3, then 95/5 / 0.5 and 93/7 / 0.7 dichloromethane, methanol and 30% ammonia. It is then recrystallized from a mixture of ethyl acetate and diisopropyl ether to obtain 0.57 g of white crystals. Melting Point (° C): 1 02-1 04. LC-MS: M + H = 384. 1 H NMR (CDCl 3) d (ppm): 7.70 (s, 1 H); 7.55 (m, 2H); 7.45 (d, 1 H); 6, 1 5 (broad m, 1 H); 5.50 (broad m, 1 H); 4.65 (s, 2H); 3.65 (m + s, 6H); 2.85 (m, 4H); 1.95 (m, 2H). Example 3 (compound No. 130) 4-. { 2 - [(4-chlorophen I) oxy] ethyl} 2- (methylamino) -2-oxoethyl piperazin-1-carboxylate 3. 1 . 4-Nitrophenyl and 2- (methylamino) -2-oxoethyl carbonate To a suspension of 2.62 g (29.4 mmol) of 2-hydroxy-N-methylacetamide and 16.5 g (58.7 mmol) of Diisopropylethylamine in the support (Argonaut's Ps-DIEA, loading = 3.56 mmol / g) in 250 ml of dichloromethane, 5.93 g (29.4 mmol) of 4-nitrophenyl chloroformate are added in small portions at room temperature. . Orbital shaking is maintained at room temperature for 16 hours. The resin is filtered, it is washed with 1 50 ml of dichloromethane and the filtrate is concentrated under reduced pressure. 6 g of product are obtained in the form of a light yellow solid which is used as such in the next step. 3.2. Piperazin-1, 1,1-dimethylethyl and 2- (methylamino) -2-oxoethyl-dicarboxylate To a solution cooled to 0 ° C of 1.1 g (3 mmol) of 4-nitrophenyl carbonate and of 2 - (methylamino) -2-oxoethyl, prepared in step 3.1, in 10 ml of 1,2-dichloroethane, a solution of 0.53 g (2.85 mmoles) is added dropwise at about 0 ° C. 1, 1 -dimethylethyl piperazin-1-carboxylate in 5 ml of 1,2-dichloroethane. The agitation is maintained 0 ° C for 1 hour and then at room temperature for 3 hours.

Concentrate at reduced pressure. The residue is purified by chromatography on silica gel eluting with a 20/80 mixture of ethyl acetate and cyclohexane and then the gradient is progressively increased to terminate with ethyl acetate. It is triturated in diisopropylether to obtain 0.61 g of product as a white solid which is used as such in the next step. 3.3. 2- (Methylamino) -2-oxoethyl piperazine-1-carboxylate hydrochloride To a solution of 2.68 g (8.9 mmol) piperazin-1,4-dicarboxylic acid 1,1-dimethylamino and -2- ( methylamino) -2-oxoethyl, obtained according to step 3.2. 25 ml of a solution of 6N hydrochloric acid in isopropanol are added in 25 ml of dichloromethane. Stirring is maintained at room temperature for 1 hour. The organic phase is separated by filtration through a hydrophobic cartridge and the filtrate is concentrated under reduced pressure. After trituration in isopropanol, 2.05 g of product are obtained. Melting Point (° C): 167-169 ° C 3.4. 4-. { 2 - [(4-chlorophenyl) oxy] ethyl} piperazine-1-2- (methylamino) -2-oxoethyl carboxylate A solution of 0.073 g (0.3 mmol) of piperazine-1-carboxylate hydrochloride of 2- (methylamino) is heated at 85 ° C for 1 6 hours. -2-oxoethyl prepared in step 3.3, 0.1 g (0.9 mmol) of potassium carbonate and 0.069 g (0.29 mmol) of 1- (2-bromo-ethoxy) -4-chlorobenzene in 3 ml of acetonitrile. After cooling to room temperature, the minerals are filtered through a cartridge provided with a frit containing celite. Wash with acetone and concentrate under reduced pressure. After chromatography on silica gel eluting with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 0.089 g of product are obtained as a white solid. LC-MS: M + H = 356. Melting point: 159-1 61 ° C. 1 H NMR (CDCl 3) d (ppm): 7.25 (dd, 2H); 6.85 (dd, 2H); 6.05 (broad s, 1 H); 4.60 (s, 2H); 4, 10 (t, 2H); 3.55 (m, 4H); 2.90 (d, 3H); 2.85 (t, 2H); 2.60 (m, 4H). Example 4 (compound No. 25) 4- (2-naphthalene-2-yl-I) piperazine-1-carboxylate of 2- (methylamino) -2-oxoethyl To a solution cooled to 0 ° C of 0.1 g (0.75 mmol) of 2-naphthalene-2-ylethanol and 0.1 1.9 ml (1.13 mmol) of diisopropylethylamine in 7.5 ml of dichloromethane, is added 0.07 ml (0.9 mmol) of methanesulfonyl chloride. The stirring is kept cold for 0.5 hours and then at room temperature for 2 hours. Concentrate at reduced pressure. The residue is taken up in 5 ml of acetonitrile, 0.1 2 g (0.5 mmol) of 2- (methylamino) -2-oxoethyl piperazine-1-carboxylate hydrochloride prepared according to example 3.3, and 0 are added, 20 g (1.5 mmol) of potassium carbonate. It is heated at 70 ° C for 16 hours. After cooling to room temperature, it is concentrated under reduced pressure. The residue is suspended in dichloromethane and washed with water and a saturated aqueous solution of sodium bicarbonate. The organic phase is recovered by filtration on a hydrophobic membrane and the filtrate is concentrated under reduced pressure. After chromatography on silica gel eluting with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 0.069 g of product are obtained as a white solid. LC-MS: M + H = 356. Melting point: 133-135 ° C. 1 H NMR (CDCl 3) d (ppm): 7.85 (m, 3H); 7.65 (s, 1 H); 7.55-7.30 (m, 3H); 6.05 (broad s, 1 H); 4.60 (s, 2H); 3.55 (m, 4H); 3.05-2.65 (m, 7H); 2.55 (m, 4H). Example 5 (compound No. 50) 2- (methylamino) -2-oxoethyl 4- (3-biphenyl-3-yl-1,1 -dimethylpropyl) piperazin-1-carboxylate hydrochloride . 1 . 1- (2,2-dimethylpropanoyl) -4- (1,1-dimethylprop-2-yn-1-yl) piperazine 0.756 g (6 mmol) of 1,1-dimethylprop-2-in-1 acetate are dissolved. -ilo. { J. Org. Chem. 1 994, 59, 2282-2284) and 2,235 g (12 mmol) of 1,1-dimethylethyl piperazine-1-carboxylate in 9 ml of tetrahydrofuran and then 0 is added., 059 g (0.6 mmol) of cuprous chloride. Heat to reflux for 3 hours. After cooling to room temperature, 100 ml of ethyl acetate, 10 ml of 1 N aqueous sodium hydroxide and 2 ml of 30% ammonia are added. The organic phase is decanted, washed with 2 times 10 ml of water and then with 10 ml of a saturated aqueous solution of sodium chloride. Dry over sodium sulfate and evaporate. The product is purified by chromatography on silica gel eluting with an 85/15 mixture, and then 75/25 and 65/35 of cyclohexane and ethyl acetate to obtain 1.9 g (4.71 mmol) of product in the form of a pale yellow solid. Melting point: 1 06-1 09 ° C. 5.2. 1- (3-biphenyl-3-yl-1,1-dimethylprop-2-yn-1-yl) -4- (2,2-dimethylpropanoyl) piperazine 1. 05 g (4.5 mmol) of 3 are dissolved. -bromo-biphenyl and 0.9 g (3.6 mmol) of 1- (2,2-dimethylpropanoyl) -4- (1,1-dimethylprop-2-yn-1-yl) piperazine, prepared in step 5.1, 0.75 ml (5.38 mmole) of triethylamine and 0.028 g (0.1 mmole) of triphenylphosphine in 8 ml of tetrahydrofuran. 0.12 g (0.1.1 mmol) of the palladium bis (triphenylphosphine) dichloride complex are added under an argon atmosphere. Stir for 15 minutes and then add 0.014 g (0.07 mmol) of cuprous iodide. It is stirred at room temperature for 4 hours and then at 60 ° C overnight. After cooling to room temperature, it is diluted with 25 ml of ethyl acetate and filtered on paper. The solid is washed with 4 times 10 ml of ethyl acetate. 4 g of silica are added to the filtrate and evaporated to dryness. Purify by chromatography on silica gel eluting with a 90/1 0 mixture and then 80/20 and 70/30 of cyclohexane and ethyl acetate to obtain 0.90 g (2.22 mmol) of product as an oil orange.5. 3- (1,1-dimethyl-ethyl 4- (3-biphenyl-3-yl-1,1-dimethylpropyl) piperazin-1-carboxylate) 0.87 g (2.1 mmol) of 1 - (3-) are dissolved. bifenyl-3-yl-1, 1-dimethylprop-2-yn-1-yl) -4- (2,2-dimethyl-propanoyl) piperazine, prepared in step 5.2, in a mixture of 5 ml of methanol and 1.5 ml of ethyl acetate. 0.2 g of platinum oxide is added and stirred under a hydrogen atmosphere at 40 psi for 6 hours. It is filtered on paper and washed with 3 times 10 ml of ethyl acetate. 2 g of silica are added to the filtrate and evaporated to dryness. Purify by chromatography on silica gel eluting with a 90/1 0 mixture and then 85/1 5 and 80/20 of cyclohexane and ethyl acetate to obtain 0.36 g (0.88 mmol) of product in the form of a colorless oil. 5.4. 1- (3-biphenyl-3-yl-1,1-dimethylpropyl) piperazine 0.65 ml (8.4 mmol) of trifluoroacetic acid are added to a solution of 0.35 g (0.86 mmol) of 4- (1,1-dimethylethyl 1,3-biphenyl-3-yl-1,1-dimethylpropyl) piperazin-1-carboxylate, prepared in step 5.3, in 5 ml of dichloromethane. It is stirred for 2 hours and then 0.65 ml of trifluoroacetic acid are added again. It is stirred for a further 2 hours and then diluted with 10 ml of 1,2-dichloroethane and evaporated to dryness. The residue is taken up in a mixture of 50 ml of dichloromethane and 20 ml of a 15% aqueous solution of sodium hydroxide. Decant and extract the aqueous phase with twice 20 ml of dichloromethane. The organic phases are washed with 10 ml of water and then with 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulphate and evaporated to give 0.25 g (0.81 mmol) of the product in vacuo. shape of a yellow oil. 5.5 2- (Methylamino) -2-oxoethyl 4- (3-biphenyl-3-yl-1,1-dimethylpropyl) piperazine-1-carboxylate hydrochloride A solution of 0.25 g is heated overnight at 60 ° C. (0.81 mmol) of 1- (3-biphenyl-3-yl-1,1-dimethylpropyl) piperazine, prepared in step 5.4, and 1.5 g (1.22 mmol) of. { [(phenyloxy) carbonyl] oxy} ethyl acetate and then evaporated to dryness. The residue is redissolved in a mixture of 4 ml of a solution of 2M methylamine (8 mmol) in tetrahydrofuran and 2 ml of ethanol. It is left to react overnight and then 1 g of silica is added and evaporated. The product is purified by chromatography on silica gel eluting with a 98/2 mixture and then 96/4 and 94/6 dichloromethane and methanol to obtain 0.23 g (0.54 mmol) of product as a colorless gum. . The product is redissolved in 5 ml of ethyl acetate and 1 ml of a solution of 5N hydrochloric acid in isopropanol is added. It evaporates to dryness. The residue is taken up in 1.5 ml of hot ethyl acetate. The solid is filtered, washed with 2 times 3 ml of ethyl acetate and dried to obtain 0.215 g (0.46 mmoles) of product as a white powder. LC-MS: M + H = 424. Melting point: 21-2-216 ° C (dec.). 1 H NMR (CDCl 3) d (ppm): 1.50 (broad s, 1 H); 7.55 (d, 2H); 7.40 (m, 6H); 7.20 (d, 1 H); 6.05 (broad s, 1 H); 4.60 (s, 2H); 4.30-4, 10 (m, 4H); 3.55 (broad s, 2H); 3.05-2.75 (m + d, 5H); 2, 15 (m, 2H); 1.70 (s, 8H). Example 6 (Compound No. 29) 4-. { 2- [3- (4-chlorophenyl) isoxazol-5-yl] ethyl} 2- (methylamino) -2-oxoethyl piperazin-1-carboxylate 6. 1 . 2- [3- (4-chlorophenyl) isoxazol-5-yl] ethanol 1.63 ml (1 1, 58 mmol) of triethylamine are added dropwise to a solution of 1.8 ml (1.5.57 mmol) ) of but-4-in-1 -ol and 2.0 g (1 0.52 mmoles) of 4-chloro-N-hydroxybenzenecarboximidoyl chloride. { J. Med. Chem: 1 998, 41, 4556-4566) in 30 ml of dichloromethane cooled in an ice bath. It is left to react overnight at room temperature. 50 ml of dichloromethane are added, washed with 2 times 50 ml of water and then with 50 ml of a saturated aqueous solution of sodium chloride. Dry over sodium sulfate and evaporate. The residue is purified by chromatography on silica gel eluting with an 80/20 mixture and then 70/30 of cyclohexane and ethyl acetate to obtain 1.1 g (4.91 mmol) of product as a white solid. Melting point: 65-67 ° C. 6.2. 4-. { 2- [3- (4-chlorophenyl) isoxazol-5-yl] ethyl} piperazin-1-carboxylate 2- (methylamino) -2-oxoethyl To a solution of 0.100 g (0.447 mmol) of 2- [3- (4-chlorophenyl) isoxazol-5-yl] ethanol, prepared in step 6.1, and 0.082 ml (0.47 mmoles) of diisopropylethylamine in 5 ml of dichloromethane is added 0.036 ml (0.469 mmoles) of methanesulfonyl chloride. It is stirred at room temperature for 4 hours and then washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride. Concentrate at reduced pressure. The residue is taken up in 5 ml of acetonitrile, 0.1 07 g (0.45 mmol) of 2- (methylamino) -2-oxoethyl piperazine-1-carboxylate hydrochloride prepared according to Example 3.3, and , 1 86 g (1.35 mmol) of potassium carbonate. It is heated at 75 ° C for 16 hours. After cooling to room temperature, it is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated aqueous solution of sodium chloride. The residue is evaporated and the residue is purified by chromatography on silica gel eluting with dichloromethane and then with a 90/1 0 mixture of dichloromethane and methanol. 0.054 g (0.132 mmoles) of product are obtained in the form of a white solid. LC-MS: M + H = 407. Melting point: 1 30-1 32 ° C. 1 H NMR (DMSO-d 6) d (ppm): 7.85 (d, 2H); 7.75 (mass, 1 H); 7.55 (d, 2H); 6.85 (s, 1 H); 4.40 (s, 2H); 3.40 (m, 4H); 2.95 (t, 2H); 2.70 (t, 2H); 2.55 (d, 3H); 2.40 (m, 4H). Example 7 (compound No. 52) 4- [3- (3'-Chloro-biphenyl-3-yl) propyl] piperazine-1-carboxylic acid 2- (methylamido) -2-oxoethyl ester 7. 1 . 3- (3-Bromo-phenyl) propan-1-ol To a suspension of 1.84 g (8 mmol) of 3- (3-bromo-phenyl) propionic acid and of 0.91 g (24 mmol) of borohydride of sodium in 20 ml of THF, cooled to 0 ° C, 3.2 ml (25 mmoles) of the trifluoroborane-diethylether complex is added in small portions. The stirring is kept cold for 1 hour and then at room temperature for 16 hours. The reaction medium is cooled to 0 ° C and neutralized to pH 7 ~ 8 by the addition of a 1 N aqueous sodium hydroxide solution. Concentrate under reduced pressure and then collect the residue in water. It is extracted with dichloromethane and dried over sodium sulfate. After filtration, the organic phase is concentrated under reduced pressure. 1.62 g (7.53 mmoles) of product are obtained in the form of an oil which is used as such in the next step. 7.2. 2- (Methylamino) -2-oxoethyl 4- [3- (3-bromo-phenyl) propyl] piperazine-1-carboxylate To a solution of 1.57 g (6.7 mmol) of 3- (3-bromophenyl) ) propan-1 ol, prepared in step 7.1, and 1.73 ml (10.1 mmol) of diisopropylethylamine in 38 ml of dichloromethane, cooled to 0 ° C, is added 0.63 ml (8.14 mmol) of methanesulfonyl chloride. The stirring is kept cold for 0.5 hour and then at room temperature for 2 hours. It is concentrated under reduced pressure and then the residue is suspended in 35 ml of acetonitrile. 1.34 g (5.35 mmol) of 2- (methylamino) -2-oxoethyl piperazine-1-carboxylate hydrochloride prepared according to Example 3.3, and 2.2 g (1 6 mmol) of potassium carbonate are added. . It is heated at 75 ° C for 16 hours.

After cooling to room temperature, it is concentrated under reduced pressure and then the residue is taken up in water. Extract with ethyl acetate and dry over sodium sulfate. After filtration, the organic phase is concentrated under reduced pressure. The residue is purified by chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol. After crystallization from diisopropyl ether, 0.84 g (2.10 mmol) of white crystals are obtained. 7.3. 2- (Methylamino) -2-oxoethyl 4- [3- (3'-chloro-biphenyl-3-yl) propyl] piperazine-1-carboxylate To a suspension of 0.14 g (0.35 mmol) of 4 - [3- (3-bromo-phenyl) propyl] piperazine-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester, prepared in step 7.2, in a mixture of 4 ml of toluene and 0.6 ml of ethanol , 0.08 g (0.07 mole) of the palladium tetrakis (triphenylphosphine) complex is added, 1.05 ml (2.1 mmol) of a 2M aqueous solution of sodium carbonate and 0.22 g (1.4 mmol) of 3-chloro-benzeneboronic acid. It is heated at 150 ° C with microwave irradiation for 5 minutes and the organic phase is recovered by filtration in a cartridge provided with a frit and containing celite and sodium sulfate. It is washed with toluene and the filtrate is concentrated under reduced pressure. The product is purified by chromatography on silica gel eluting with a 90/10 mixture of ethyl acetate and methanol. It is then taken up in n-heptane to obtain 0.086 g (0.18 mmol) of product in the form of white crystals. LC-MS: M + H = 430. Melting point: 82-85 ° C.

H NMR (ppm): 7.35 (m, 8H); 6.05 (broad s, 1 H); 4.6 (s, 2H); 3.55 (m, 4H); 2.85 (d, 3H); 2.75 (t, 2H); 2.45 (m, 6H); 1, 9 (m, 2H). Table 1 below illustrates the chemical structures and physical properties of some compounds according to the invention. In the "base or salt" column, "base" represents a compound in the form of a free base, while "HCl" represents a compound in the form of a hydrochloride. Table 1 3- (4-CI- bond (CH 2) 3 H -CHS 136-138 phenol base) -phenyl 3- (3-CH 30 -link (CH 2); H -CHa (426) phenyl base) -phenyl 3- (4-CH30- linkage (CH2) to H-CH3 135-137 phenyl base) -phenyl 3- (3-CN- bond (CH2) to H -CH3 152-154 phenyl base) -phenol 3_ ( 4-CN- bond (CH2) to -CHa 137-139 phenol base) -phenol 4- (3-CI- bond (CH2) 3 -CHa 101-103 phenyl base) -phenyl 4- (4- CI- link (CH2): -CHa 125-128 phenyl base) -phenyl 4 (3-CH30- (CH2) bond 3 H -CH; 97-100 phenyl base) -phenol 4- (4- CH30- (CH2) bond: H -CH: 128-130 phenyl base) -phenyl 4- (3-CN- bond (CH2) SH -CHa 108-110 phenol base) -phenyl 4- (4-CN- link (CH2) to H-CHa 148-150 phenyl base) -phenyl naphthalene-1-yl bond (CH2) to H-CHa 1 04-1 06 HCl naphthaIen-2-yl bond (CH2) 3 H -C Ha 1 1 0-1 12 base 3- (4-CI-phenyl) -1 H- bond (CH2) 3 H -CHa 157-1 59 base methyl-pyrazole 5 -loyl 5- (4-CI-phenyl) -linkage (CH2): -CHs 125-127 isoxazol-3-yl base The compounds of the invention have been the target of pharmacological tests that allow to determine their inhibitory effect of the enzyme FAAH (amido-hydrolase of fatty acids). The inhibitory activity has been demonstrated in a radioenzymatic assay based on the measurement of the hydrolysis product (ethanolamine [1 -3H]) of anandamide [ethanolamine 1 -3H] by FAAH. { Life Sciences (1995), 56, 1 999-2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734). Thus, the mouse brains are removed (minus the cerebellum) and stored at -80 ° C. The membrane homogenates are prepared extemporaneously by homogenization of the tissues in a Polytron in a buffer solution of 0mM Tris-HCl (pH 8) containing 50mM NaCl and 1mM EDTA. The enzymatic reaction is then carried out in 70 μl of buffer containing bovine serum albumin without fatty acids (1 mg / ml). Subsequently, the compounds tested in different concentrations were added, anandamide [ethanolamine 1 -3H] (specific activity 1 5-20 Ci / mmol) diluted to 1 0 μM with cold anandamide and the membrane preparation (400 μg frozen tissue by trial). 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 for 10 minutes and centrifuged for 15 minutes at 3500 g. An aliquot (30 μL) of the aqueous phase containing the ethanolamine [1 -3 H] is counted by liquid scintillation. Under these conditions, the most active compounds of the invention have values of Cl50 (concentration that inhibits in 50% the control enzymatic activity of the FAAH) comprised between 0.001 and 1 μM. Table 2 below shows the Cl50 of some compounds according to the invention. Table 2 It thus appears that the compounds according to the invention have an inhibitory activity on the FAAH enzyme. The in vivo activity of the compounds of the invention has been evaluated in an analgesic assay. Thus, the intraperitoneal (i.p.) administration of PBQ (phenylbenzoquinone, 2 mg / kg in a 0.9% sodium chloride solution containing 5% ethanol) to male OF1 rats of 25 to 30 g, causes abdominal stretching, 30 twists or contractions on average during the period of 5 to 15 minutes after the injection. The tested compounds are administered orally (p.o.) or intraperitoneally (i.p.) in suspension in 0.5% Tween 80, 60 minutes or 120 minutes before administration of the PBQ. Under these conditions, the most potent compounds of the invention reduce from 35 to 70% the number of stretches induced by the PBQ, in a dose range comprised between 1 and 30 mg / kg. For example, the compounds n ° 49 and n ° 69 of the table reduce respectively in 43% and 47% the number of stretches induced by PBQ, at the dose 10 mg / kg p.o. at 1 20 minutes. The FAAH enzyme. { Chemistry and Physics of Lipids, (2000), 1 08, 1 07-121) catalyzes the hydrolysis of the endogenous derivatives of amides and esters of different fatty acids, such as? / - arachidonoyl-ethanolamine (anandamide),? / - palmitoyl-ethanolamine,? / -oleoylethanolamine, oleamide or 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 rate of these endogenous substances in the tissue. They can be used in the prevention and treatment of pathologies in which endogenous cannabinoids and / or other substrates metabolized by the FAAH enzyme are involved. For example, the following diseases and conditions can be mentioned: pain, mainly acute or chronic pains of the neurogenic type: migraine, neuropathic pains including forms associated with herpes viruses and diabetes, acute or chronic pains associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteo-arthritis, spondylitis, gout, vascularitis, Crohn's disease, irritable bowel syndrome, acute or chronic peripheral pain, dizziness, vomiting, nausea in particular those arising from 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, all forms of depression and anxiety of any nature and origin , mood disorders, psychosis, neurodegenerative diseases s acute and chronic: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, injuries related to cerebral ischemia and with cranial and spinal cord injuries, epilepsy, sleep disorders including sleep apnea, diseases cardiovascular diseases, in particular hypertension, arteriosclerosis, cardiac crisis, cardiac ischemia, renal ischemia, cancers: benign skin tumors, papillomas and brain tumors, prostate tumors, brain tumors (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumors of the embryonic origin, astrocytomas, astroblastomas, ependiomas, oligodendrogliomas, plexus tumor, neuroepiteliomas, tumor of the epiphysis, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanomas, schwennomas), disorders of the immune system, mainly autoimmune diseases: psoriasis, lupus erythematosus , connective tissue diseases or cone ctivitis, Sjógrer syndrome, ankylosing spondylitis, undifferentiated spondylarthritis, Behcet's disease, hemolytic autoimmune anemias, sclerosis in plaques, amyotrophic lateral sclerosis, amyloidosis, rejection of implants, 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, mainly joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease, colon syndrome irritable, osteoporosis, ocular conditions: ocular hypertension, glaucoma, pulmonary diseases: respiratory diseases, bronchospasm, cough, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema, gastrointestinal diseases: irritant colon syndrome able, inflammatory intestinal disorders, ulcers, diarrhea, urinary incontinence and bladder inflammation. The use of the compounds according to the invention, in the form of a base, 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 a pharmaceutically acceptable acid or hydrate or solvate of the compound of formula (I). These drugs find application in therapy, mainly in the treatment of the aforementioned pathologies. According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention, or an addition salt with an acid, or a hydrate, or a pharmaceutically acceptable solvate of said compound, and optionally one or more pharmaceutically acceptable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, among the usual excipients which are known to the person skilled in the art. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active ingredient of formula (I) above, or its addition salt with an optional acid, solvate or hydrate can be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit dosage forms comprise oral forms, such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal, inhalation, forms of subcutaneous, intramuscular or intravenous administration, and forms of rectal or vaginal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions. As an example, a unitary 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 1 5, 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, said doses also belonging to the invention. According to the usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the weight and the response of said patient. The invention according to another of its aspects, also refers to a method of treatment of the pathologies indicated above comprising the administration of an effective dose of a compound according to the invention, of one of its addition salts with a pharmaceutically acceptable acid. , of a solvate or a hydrate of said compound.

Claims (10)

1. CLAIMS A compound that responds to the formula (I): (l) wherein: n represents an integer equal to 1 or 2; p represents an integer ranging from 1 to 7; A is selected from one or more groups X, Y and / or Z; X represents a methylene group optionally substituted by one or two C? _ Alquilo alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl-C C1-alqu alkylene groups; Y represents either a C2 alkenylene group optionally substituted with one or two C1-6 alkyl groups, C3-7 cycloalkyl or C3-7 cycloalkyl C1-3 alkylene; or a C2-alkynylene group; Z represents a group of formulas: or represents an integer ranging from 1 to 5; r and s represent integers and are defined so that r + s is a number ranging from 1 to 5; G represents a single bond, an oxygen or sulfur atom, a SO, SO2, C = O or CH (OH) group; R-i represents a group R4 optionally substituted with one or more groups R5 and / or R6; R represents a group selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, prazrazinyl, triazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthalenyl, diphenylmethyl, quinolinyl. , tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indanyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl , pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl or isothiazolopyridinyl; R5 represents a halogen atom or a cyano, nitro, alkyl group C1 -6, C1-6 alkoxy, hydroxyl, C1 -6 thioalkyl, C1 -6 fluoroalkyl, fluoroalkoxy C1 -6, fluorothioalkyl C1 -6, NR7R8, NR7COR8, NR7CO2R8, NR7SO2R8, COR7, CO2R7, CONR7R8, SO2R, SO2N R7R8 or -O- (C1-3 alkylene) -O; R6 represents a phenyl, phenyloxy, benzyloxy, naphthalenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl group; the R6 group (s) being optionally substituted with one or more R5 groups identical or different from one another; R7 and R8 represent, independently of each other, a hydrogen atom or a C? -6 alkyl group, or form with the atom (s) that contain them a cycle selected from a cyclo azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine, this cycle being optionally substituted with a C 1-6 alkyl or benzyl group; R 2 represents a hydrogen atom or a C 6 -6 alkyl group; R 3 represents a hydrogen atom or a C 1-6 alkyl group, C 3-7 cycloalkyl or C 3-7 cycloalkyl-C 1-3 alkyl; in the form of a base, of addition salt with an acid, hydrate or solvate. Compound of formula (I) according to claim 1, characterized in that: n represents an integer equal to 1 or 2; p represents a whole number ranging from 1 to 7; A is chosen from one or more groups X and / or Y; X represents a methylene group optionally substituted with one or two C1-6 alkyl groups; Y represents either a C2 alkenylene group or a C2 alkynylene group; G represents a single bond, an oxygen atom or a C = O group; R-i represents a group R4 optionally substituted with one or more groups R5 and / or R6; R 4 represents a group chosen from a phenyl, naphthalenyl, diphenylmethyl, quinolinyl, indolyl, pyrazolyl, isoxazolyl, pyrimidinyl or thiazolyl; R 5 represents a halogen atom or a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, or -O- (C 1-3 alkylene) -O-; R6 represents a phenyl, naphthalenyl or benzyloxy group; R2 represents a hydrogen atom or a C-? 6 alkyl group; R3 represents a hydrogen atom or a C1-C6 alkyl, C3-7 cycloalkyl or cycloalkyl C3-7-C1-3 alkyl group; in the form of a base, of addition salt with an acid, hydrate or solvate. 3. Compound of formula (I) according to claim 1 or 2, characterized in that: n represents an integer equal to 1; p represents an integer ranging from 1 to 4; A is chosen from one or more groups X and / or Y; X represents a methylene group optionally substituted with one or two C-? 6 alkyl groups; Y represents a C2 alkynylene group; G represents a single bond or an oxygen atom; R-i represents a group R optionally substituted with one or more groups R5 and / or R6; R4 represents a group chosen from a phenyl, naphthalenyl or isoxazolyl; R5 represents a halogen atom or a cyano group, C6 alkoxy or C6.6 fluoroalkyl; R6 represents a phenyl group; R 2 represents a hydrogen atom or a C 1-6 alkyl group; R3 represents a hydrogen atom or a C1-6 alkyl group, C3-7 cycloalkyl or C3-cycloalkyl-d3 alkyl; in the form of a base, of addition salt with an acid, hydrate or solvate. 4. Compound of formula (I) according to any of claims 1 to 3, characterized in that: R 2 represents a hydrogen atom; R3 represents a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-3 alkyl group. 5. Process for the preparation of a compound of formula (I) according to any of claims 1 to 4, comprising the step consisting of transforming the carbamate ester of the general formula (II) (ID wherein m, R1 t R2, G, A, p and n are as defined in general formula (I) according to claim 1 and R represents a methyl or ethyl group, by aminolysis by an amine of general formula R3N H2 wherein R3 is as defined in the general formula (I) 6. Process for the preparation of a compound of formula (I) according to any of claims 1 to 4, comprising the step consisting of transforming the carbamate-amide of general formula (V) (V) wherein R2, R3 and n are as defined in the general formula (I) according to claim 1, by reaction with a derivative of the general formula Ri-G-fAjp-W (VI) wherein R ^ G, p and A are as defined in the general formula (I) and W represents a chlorine, bromine or iodine atom, or a mesylate or tosylate group. 7. Compound that corresponds to the general formula (II): (ii) in which Ri, R2, G, A, p and n are as defined in the general formula (I) according to claim 1 and R represents a methyl or ethyl group. 8. Compound that corresponds to the general formula (V): (V) wherein R2, R3 and n are as defined in general formula (I) according to claim 1. 9. The compound of formula (I) according to any of claims 1 to 4, in base form, of addition salt with a pharmaceutically acceptable acid, hydrate or solvate, for use as a medicament. 10. A pharmaceutical composition containing at least one compound of formula (I) according to any of claims 1 to 4, in the form of a base, of addition salt with a pharmaceutically acceptable acid, hydrate or solvate and optionally one or more pharmaceutically acceptable excipients . eleven . Use of a compound of formula (I) according to any of claims 1 to 4, in base form, of addition salt with a pharmaceutically acceptable acid, hydrate or solvate, 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. Use of a compound of formula (I) according to any of claims 1 to 4, in pharmaceutically acceptable base, salt, hydrate or solvate form, for the preparation of a medicament intended to prevent or treat acute pains or chronic, dizziness, vomiting, nausea, eating behavior disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancers, immune system disorders, allergic diseases, infectious parasitic diseases , viral or bacterial, inflammatory diseases, osteoporosis, ocular affections, pulmonary affections, gastro-intestinal diseases or urinary incontinence.