FR2875230A1 - CONDENSED PYRAZOLE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF - Google Patents

Abstract

The subject of the present invention is compounds corresponding to formula (1): in which: A represents: a linear (C3-C5) alkylene radical which is unsubstituted or substituted one or more times by a (C1-C3) alkyl; a radical -CH2-CH2-O-CH2-; -W represents a direct bond or a radical -CH2-; -R1 represents a hydrogen atom or a (C1-C3) alkyl; R2 represents a (C1-C8) ) alkyl or a group -B-R4; R3 represents a phenyl substituted with one or more substituents independently selected from a halogen atom, a (C1-C3) alkyl, a (C1-C3) alkoxy, a trifluoromethyl radical, a trifluoromethoxy radical, in the form of bases or addition salts with an acid, as well as with the hydrate or solvate state.Procedure for preparation and therapeutic application.

Description

R3 W-N N-

  C-NR1 R2 0 (1) 2875230 1 CONDENSED PYRAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE.

  The present invention relates to novel condensed pyrazole derivatives, their preparation and their therapeutic application.

  The compounds of the present invention have affinity for cannabinoid CB2 and / or CB1 receptors and are agonists of said receptors.

  A9-THC is the major active ingredient extracted from Cannabis sativa [Paton, Annual Review in Pharmacology (1975) 15: 191-220].

  Numerous articles have described not only the psychotropic effects of cannabinoids, but also their influence on immune function [Klein et al., Immunology Today (1998) 19: 373-381], the control of pain [Pertwee, Progress in Neurobiology (2001) 63: 569611], food intake [Cota et al. International Journal of Obesity (2003) 27: 289-301] and many other biological functions [Nahas et al. Marihuana and medicine (1999) Humana Press: Totowa, New Jersey, USA].

  The effects of cannabinoids are due to an interaction with specific high affinity G protein-coupled receptors present at the central and peripheral level [Howlett et al., Pharmacological Reviews (2002) 54: 161-202].

  The central effects of cannabinoids are of a first type of receptor (CB1) present mainly in the brain but also on the periphery [Matsuda et al., Nature (1990) 346: 561-564]. In addition, Munro et al. [Nature (1993) 365: 61-65] have cloned a second type of cannabinoid receptor called CB2 which is present at the periphery and in particular in the cells of the immune system.

  Certain indole derivatives have been described in EP 0 833 818 and International Application WO 97/00860 as CB2 receptor agonists.

  Certain pyrazole derivatives have been described in international applications WO 97/21682 and WO 01/32629 as CB2 receptor antagonists.

  European Application EP 0 307 801-A discloses compounds of the formula: ## STR1 ## wherein n, m, x, y, R , RI, RIT, RIII, RIV, RV and RN / 1 have different values. These compounds are active ingredients of insecticidal composition.

  Novel pyrazole fused derivatives which have affinity for cannabinoid CB 2 and / or CB 1 receptors and which are agonists of said receptors have now been found.

  The present invention relates to compounds corresponding to formula (I): R3 WNNO, C-NR1R2 in which: A represents: a linear (C3-05) alkylene radical which is unsubstituted or substituted one or more times with C1-C3) alkyl; a radical -CH2-CH2-O-CH2-; W represents a direct bond or a -CH2- radical; R1 represents a hydrogen atom or a (C1-C3) alkyl; R2 represents a (C1-C8) alkyl or a group -B-R4; R3 represents a phenyl substituted with one or more substituents independently selected from a halogen atom, a (C1-C3) alkyl, a (C1-C3) alkoxy, a trifluoromethyl radical, a trifluoromethoxy radical; B represents a direct bond or a (C1-C2) alkylene radical which is unsubstituted or substituted one or more times by a (C1-C3) alkyl; R 4 represents: a phenyl that is unsubstituted or substituted with one or more substituents chosen independently from a halogen atom, a (C 1 -C 3) alkyl, a (C 1 -C 3) alkoxy, a trifluoromethyl radical; a non-aromatic C 3 -C 12 carbocyclic radical, unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl or a (C 1 -C 3) alkoxy.

  The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, form part of the invention. (1)

  The compounds of formula (I) may also exist 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. Such hydrates and solvates are also part of the invention.

  By halogen atom is meant a bromine, chlorine, fluorine or iodine atom.

  (C1-C2) alkylene or linear (C3-05) linear alkylene means a divalent radical of one to two carbon atoms or, respectively, from three to five carbon atoms chosen from the methylene, ethylene, trimethylene and tetramethylene radical, pentamethylene.

  By (C1-C3) alkyl or (C1-8) alkyl, respectively, is meant a linear or branched alkyl radical of one to three carbon atoms or, respectively, of one to eight carbon atoms, such as the methyl, ethyl or propyl radical. isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl.

  The term "(C1-C3) alkoxy" means a linear or branched alkoxy radical of one to three carbon atoms, such as the methoxy, ethoxy, propoxy or isopropoxy radical.

  The non-aromatic C 3 -C 12 carbocyclic radicals include mono or polycyclic condensed or bridged radicals. Monocyclic radicals include cycloalkyls for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. The fused, bridged or spiro di- or tricyclic radicals include, for example, norbornyl, bornyl, iobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptyl, bicyclo [3.2. 1] octyl, bicyclo [3.1.1] heptyl.

  According to the present invention, compounds of formula (I) are distinguished for which: A represents a linear (C 3 -C 5) alkylene radical which is unsubstituted or substituted one or more times by a (C 1 -C 3) alkyl; - W, R1, R2 and R3 being as defined for a compound of formula (I) according to the present invention, there are also compounds of formula (I) for which: A represents a radical -CH2-CH2-O-CH2 -; - W, R1, R2 and R3 being as defined for a compound of formula (I).

  Among the compounds of formula (I) that are the subject of the invention, a first group of compounds consists of the compounds for which: A represents a radical - (CH 2) 3 -, -C (CH 3) 2 -CH 2 -CH 2 - (CH2) 4-, - (CH2) 5-, -CH2-CH2-O-CH2-; and / or W represents a direct bond or a -CH 2 - radical; and / or R1 represents a hydrogen atom; and / or R2 represents a radical 1-adamantyl, 2-adamantyl, (1S) -1-cyclohexyl ethyl, (1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2endo-yl, endo- bicyclo [3.2.1] oct -3-yl, 1,1-dimethyl-2-phenylethyl, 1,1-dimethylpropyl, tert-butyl, 4-ethylcyclohexyl; and / or R3 is 4-chlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl; in the basic state and in the state of hydrate or solvate.

  Among the compounds of the latter group, there may be mentioned compounds of formula (I) for which: A represents a radical - (CH2) 3-, -C (CH3) 2 -CH2-CH2-, - (CH2) 4- - (CH2) 5-, -CH2-CH2-O-CH2-; - W represents a direct bond or a -CH2- radical; - R1 represents a hydrogen atom; R2 represents a 1-adamantyl, 2-adamantyl, (1S) -1-cyclohexylethyl, (1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2endo-yl, endo-bicyclo [3.2. 1] oct-3-yl, 1,1-dimethyl-2-phenylethyl, 1,1-dimethylpropyl, tert-butyl, 4-ethylcyclohexyl; R 3 represents a 4-chlorophenyl, a 3,4-dichlorophenyl, a 2,4-dichlorophenyl, a 4-methylphenyl; in the basic state and in the state of hydrate or solvate.

  Among the compounds of formula (I) which are subjects of the invention, mention may notably be made of the following compounds: N-1-adamantyl-1- (3,4-dichlorophenyl) -1,4,5,6-tetrahydrocyclopenta [ c] pyrazole e-3-carboxamide; N - [(1S) -1-cyclohexylethyl] -1- (3,4-dichlorophenyl) -6,6-dimethyl-1,4,5,6-tetrahydro-cyclopenta [c] pyrazole-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorophenyl) -6,6-dimethyl-1,4,5,6-tetrahydrocyclo penta [c] pyrazole-3-carboxamide; N-1-adamantyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3carboxamide; 1- (3,4-Dichlorophenyl) -N- [(1S) -1,3,3-trimethylbicyclo [2,2,1] hept-2endo-yl] -4,5,6,7- tetrahydro-1H-indazole-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N- [endo-bicyclo [3.2.1] oct-3-yl] -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorophenyl) -N- (1,1-dimethyl-2-phenylethyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorophenyl) -N- (1,1-dimethylpropyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N- (cyclohexylmethyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxamide; 1- (3,4-Dichlorophenyl) -N- (2,2-dimethylpropyl) -4,5,6,7-tetrahydro-1H-indazol-3-carboxamide; N- (2-cyclohexylethyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxamide; N- [endo-bicyclo [3.2.1] oct-3-yl] -1- (2,4-dichlorophenyl) -1H--4,5,6,7tétrahydro indazo1e-3-carboxamide; 1- (2,4-dichlorophenyl) -N- (2,2-dimethylpropyl) -4,5,6,7-tetrahydro-1H-indazol-3-carboxamide; N-1-adamantyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3carboxamide; 1- (2,4-Dichlorophenyl) -N- (1,1-dimethylpropyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (2,4-dichlorophenyl) -N- (1,1-dimethyl-2-phenylethyl) -4,5,6,7-tetrahydro-1H-indazol-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorophenyl) -1,4,5,6,7,8-hexahydro cyclohepta [c] pyrazole-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorophenyl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxamide; N-2-adamantyl-1- (4-chlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (4-chlorobenzyl) -N- (1,1-dimethylpropyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxamide; -N-1-adamantyl-1- (3,4-dichlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N-2-adamantyl-1- (3,4-dichlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorobenzyl) -N- (1,1-dimethylpropyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N- (tert-butyl) -1- (3,4-dichlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorobenzyl) -N- (4-ethylcyclohexyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N-1-adamantyl-1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-indazole-3carboxamide; N- (1,1-dimethylpropyl) -1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxamide; in the basic state and in the state of hydrate or solvate.

  According to the invention, the compounds of formula (I) can be prepared according to a process which is characterized in that: an acid or a functional derivative of this acid of formula: R 3 W N N N

COOH

  wherein A, W and R3 are as defined for a compound of formula (I), with an amine of formula: wherein R1 and R2 are as defined for a compound of formula (I).

  When the acid of formula (II) itself is used, the reaction is carried out in the presence of a coupling agent used in peptide chemistry such as 1,3-dicyclohexyl carbodiimide or benzotriazol-1-yloxytris hexafluorophosphate ( dimethylamino) phosphonium or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate or 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl uronium tetrafluoroborate, in the presence of a base such as triethylamine, N, N-diisopropylethylamine or 4-dimethylaminopyridine, in a solvent such as dichloromethane, dichloroethane, N, N-dimethylformamide or tetrahydrofuran at a temperature of between -10 ° C. and the reflux temperature of solvent.

  As functional derivative of the acid (II) it is possible to use the acid chloride, the anhydride, a mixed anhydride, a C 1 -C 4 alkyl ester in which the alkyl is straight or branched, an activated ester, for example the p-nitrophenyl ester.

  Thus, in the process according to the invention, it is also possible to react the chloride of the acid obtained by reaction of thionyl chloride or oxalyl chloride with the acid of formula (II), with an amine HNR1R2, in a solvent, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an atmosphere inert, at a temperature between 0 C and room temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.

  One variant consists in pre-preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and in doing so react with an amine HNR1R2, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.

  The compounds of formula (I) thus obtained may subsequently be separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography.

  The compounds of formula (II) are prepared by conventional hydrolysis of an ester of formula: ## STR2 ## in which A, W and R 3 are as defined for a compound of formula (I) and Alk represents a (C 1 -C 3) alkyl.

  Thus, the reaction is carried out by hydrolysis in an alkaline medium using, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, in a solvent such as water, methanol, 1,4 -dioxane or a mixture of these solvents and at a temperature between 0 C and the reflux temperature of the solvent.

  The compounds of formula (III) are commercially available or described in the literature, or they can be prepared according to methods described therein or which are known to a person skilled in the art such as in WO 97/21682 or in US Pat. Chem. Soc. Perkin Trans II, 1984, 1369-1376.

  The compounds of formula (IV) in which W represents a bond are prepared by reaction of a compound of the formula:

VS

Li 000 / / / / Ç-COOAlk 25 (V)

O

  in which A is as defined for a compound of formula (I) and Alk represents a (C1-C3) alkyl, with a hydrazine derivative of formula: R3NHNH2 (VI) wherein R3 is as defined for a compound of formula (I), in the presence of an acid.

  The reaction of the compound of formula (V) with the compound of formula (VI) is carried out by refluxing in acetic acid.

  The compounds of formula (IV) in which W represents a -CH 2 - radical prepare by reaction of a compound of formula: (VII) CO-Alk O / in which A is as defined for a compound of formula (I) and Alk represents a (C1-C3) alkyl, with a compound of formula: R3-CH2-Hal (VIII) wherein R3 is as defined for a compound of formula (I) and Hal represents a halogen atom, preferably bromine.

  The reaction is carried out in the presence of a strong base such as sodium hydride or sodium amide, in a solvent such as toluene and at a temperature between room temperature and the reflux temperature of the solvent.

  The compounds of formula (V) are prepared by reaction of a compound of formula: (A (IX) CH 2 0 / C in which A is as defined for a compound of formula (I) with the lithium salt of hexamethyldisilazane, in a solvent such as diethyl ether and at a temperature of between -70 ° C. and -30 ° C. The alkali metal salt obtained intermediately with a di (C1-C3) oxalate is then reacted in situ. ) at a temperature of between -30 ° C. and room temperature to obtain the ketoester salt of formula (V).

  The compounds of formula (VI) are known or are prepared according to known methods. 30 35

  The compounds of formula (VII) are prepared by reacting the compounds of formula (V) with hydrazine H 2 N -NH 2 by refluxing in acetic acid.

  The compounds of formula (VIII) and the compounds of formula (IX) are known or are prepared according to known methods.

  The compounds of formula (II) and formula (IV) are new.

  The invention according to another of its aspects, also relates to the compounds of formula (II) and the compounds of formula (IV). These compounds are useful as synthesis intermediates for the compounds of formula (I).

  Thus, the subject of the invention is compounds of formula: R 3 W N (II) N

COOH

  wherein: A represents: (C3-05) linear alkylene unsubstituted or substituted one or more times by (C1-C3) alkyl; a radical -CH2-CH2-O-CH2-; - W represents a direct bond or a -CH2- radical; - R3 represents a phenyl substituted with one or more substituents chosen independently from a halogen atom, a (C1-C3) alkyl, a (C1-C3) alkoxy, a trifluoromethyl radical, a trifluoromethoxy radical.

  The invention also relates to compounds of formula: embedded image in which: Alk represents a (C 1 -C 3) alkyl; - A represents: a linear (C3-05) alkylene radical which is unsubstituted or substituted one or more times with a (C1-C3) alkyl; a radical -CH2-CH2-O-CH2-; W represents a direct bond or a -CH2- radical; - R3 represents a phenyl substituted with one or more substituents chosen independently from a halogen atom, a (C1-C3) alkyl, a (C1-C3) alkoxy, a trifluoromethyl radical, a trifluoromethoxy radical.

  The following EXAMPLES describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and only illustrate the present invention. The numbers of the compounds exemplified refer to those given in TABLE (I) below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

  In the Preparations and in the Examples the following abbreviations are used: ether: diethyl ether diisopropyl ether DMSO: dimethylsulfoxide DMF: N, N-dimethylformamide THF: tetrahydrofuran DCM: dichloromethane AcOEt: ethyl acetate DIPEA: diisopropylethylamine TFA: acid trifluoroacetic acid BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoro phosphate PyBOP: benzotri azol-1-ylyloxytris (pyrolidino) phosphonium hexafluorophosphate 2N hydrochloric ether: 2N solution of hydrochloric acid in diethyl ether F: melting TA: ambient temperature Eb: boiling temperature HPLC: high performance liquid chromatography Silica H: 60 H silica gel marketed by Merck (DARMSTAD) Buffer solution pH = 2: 16.66 g solution of KHSO4 and 32.32 g of K2SO4 in 1 liter of water.

  Proton nuclear magnetic resonance spectra (1 H NMR) are recorded at 200 MHz in DMSO-d6. The chemical shifts 8 are expressed in parts per million (ppm). For the interpretation of spectra, the following abbreviations are used: s: singlet, d: doublet, t: triplet, q: quadruplet: m: massive, mt: multiplet, se: expanded singlet, dd: doublet doubled.

PREPARATIONS

  1. Preparations of compounds of formula (V) Preparation 1.1 2- [Ethoxy (oxo) acetyl] cyclopent-1-en-1-ololate lithium. (V): -A- = - (CH2) 3-; Alk = -CH2-CH3.

  A suspension of 27.17 g of lithium salt of hexamethyldisilazane in 150 ml of ether is cooled down to 65 ° C., 13.25 ml of cyclopentanone are added over 30 minutes and then stirred, allowing the temperature to rise to -30 ° C. 21.39 ml of diethyl oxalate are then added and the mixture is stirred for 18 hours at RT. The precipitate formed is filtered off, washed with ether and dried. 17.44 g of the expected compound are obtained.

  Preparation 1.2 Lithium (ethoxy (oxo) acetyl] -5,5-dimethylcyclopent-1-en-1-olate. (V): -A- -C (CH 3) 2 -CH 2 -CH 2 -; Alk = -CH2-CH3.

  A suspension of 31.65 g of lithium salt of hexamethyldisilazane in 250 ml of ether is cooled to 65 ° C., a solution of 20 g of 2,2-dimethylcyclopentanone in 150 ml of ether is added dropwise. and leave stirring while allowing the temperature to rise to 30 ° C. A solution of 25 ml of diethyl oxalate in 80 ml of ether is then added and the mixture is left stirring overnight, allowing the temperature to rise to RT. The precipitate formed is filtered off, washed with ether and dried. 33.55 g of the expected compound are obtained.

  Preparation 1.3 2- (Ethoxy (oxo) acetyl] cyclohex-1-en-1-ol-lithium (V): -A- = - (CH2) 4; Alk = -CH2-CH3.

  A suspension of 50 g of lithium salt of hexamethyldisilazane in 300 ml of ether is cooled down to 65 ° C., a solution of 29.5 ml of cyclohexanone in 200 ml of ether is added dropwise and the mixture is left stirring. allowing the temperature to rise to 30 ° C. A solution of 40.6 ml of diethyl oxalate in 100 ml of ether is then added and the mixture is left stirring for 18 hours, allowing the temperature to rise to RT. The precipitate formed is filtered off. 57.45 g of the expected compound are obtained in the form of a yellow powder.

  Preparation 1.4 2- [Ethoxy (oxo) acetyl] cyclohept-1-en-1-lithium oleate. (V): -A- = - (CH2) 5-; Alk = -CH2-CH3.

  A suspension of 50 g of lithium salt of hexamethyldisilazane in 300 ml of ether is cooled to 65 ° C. and a solution of 33.5 ml of cycloheptanone in 200 ml of ether is added dropwise. then left stirring while allowing the temperature to rise to 30 ° C. A solution of 40.6 ml of diethyl oxalate in 100 ml of ether is then added and the mixture is left stirring for 18 hours, allowing the temperature to rise to RT. The precipitate formed is filtered off. 50.76 g of the expected compound are obtained.

  Preparation 1.5 - (Ethoxycarbonyl) -3,6-dihydro-2H-pyran-4-olate lithium.

  (V): -A- = -CH2-CH2-O-CH2; Alk = -CH2-CH3.

  A suspension of 28.8 g of lithium salt of hexamethyldisilazane in 170 ml of ether is cooled to 60 ° C., a solution of 15 ml of tetrahydro-4H-pyran-4-one in 110 ml of water is added dropwise. ml of ether and then stirred, allowing the temperature to rise to 30 C. A solution of 22.7 ml of diethyl oxalate in 60 ml of ether is then added and the mixture is left stirring for 16 hours, allowing the temperature to rise to YOUR. The precipitate formed is filtered off. 31.5 g of the expected compound are obtained.

  2. Preparations of compounds of formula (IV)

  Preparation 2.1 1 - (3,4-Dichlorophenyl) -1,4,5,6-tetrahydrocyclopenta [c] pyrazole-3-ethyl carboxylate. 20

  (IV): -A- = - (CH2) 3-; W = linkage; R3 Cl; Alk = -CH2-CH3. Cl

  A mixture of 7 g of the compound obtained in Preparation 1.1, 8.1 g of 3,4-dichlorophenylhydrazine hydrochloride and 175 ml of acetic acid is heated at reflux overnight. After cooling, the acetic acid is concentrated in vacuo, the residue is taken up in toluene and the solvent is concentrated under vacuum again. The residue is chromatographed on silica gel, eluting with DCM. 3.72 g of the expected compound are obtained, which is used as such.

  Preparation 2.2 Ethyl 1- (3,4-dichlorophenyl) -6,6-dimethyl-1,4,5,6-tetrahydro-cyclopenta [c] pyrazole-3-carboxylate. Cl

  (IV): -A- -C (CH 3) 2 -CH 2 -CH 2 -; W = linkage; R3 Cl; Alk = -CH 2 -CH 3 To a solution of 10 g of the compound obtained in Preparation 1.2 in 200 ml of acetic acid is added 10.09 g of 3,4-dichlorophenylhydrazine hydrochloride and refluxed for 3 hours. The reaction mixture is poured into water and extracted with ether, the organic phase is washed with saturated NaHCO 3 solution and with water, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. 14.89 g of the expected compound are obtained, mp = 88 ° C.

Preparation 2.3 Ethyl 1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxylate.

  (IV): -A- - - (CH2) 4-; W = linkage; R3 Cl; Alk = -CH2-CH3.

  To a mixture of 18 g of the compound obtained in Preparation 1.3 in 375 ml of acetic acid is added 15.75 g of 4chlorophenylhydrazine hydrochloride and refluxed for 5 hours. The reaction mixture is poured into ice water and extracted with ether, the organic phase is washed with saturated NaHCO 3 solution and with saturated NaCl solution and dried over MgSO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM / MeOH (99/1; v / v) mixture. 9.25 g of the expected compound are obtained.

  Preparation 2.4 Ethyl 1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

  (IV): -A- - - (CH2) 4-; W = linkage; Embedded image To a mixture of 20.4 g of the compound obtained in Preparation 1.3 in 400 ml of acetic acid, 23.7 g of 3,4-chlorophenylhydrazine hydrochloride are added. at reflux for 5 hours and left stirring for 2 days at RT. The reaction mixture is poured into an ice / H 2 O mixture, extracted with ether, the organic phase is washed with saturated NaHCO 3 solution, with water, with saturated NaCl solution, dried over Na 2 SO 4 and the solvent evaporated under vacuum. . 33.3 g of the expected compound are obtained.

  Preparation 2.5 Ethyl 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazol-3-carboxylate.

  (IV): -A- = - (CH2) 4-; W = linkage; R3 = CI; Alk = -CH2-CH3. Cl

  To a mixture of 15.8 g of the compound obtained in Preparation 1.3 in 400 ml of acetic acid is added 16.53 g of 2,4-dichlorophenylhydrazine hydrochloride and refluxed for 18 hours. The reaction mixture is poured into water and extracted with ether, the organic phase is washed with saturated NaCl solution and dried over Na 2 SO 4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt mixture (80/20, v / v). 9.83 g of the expected compound are obtained in the form of an orange oil.

Preparation 2.6 Ethyl 1- (3,4-dichlorophenyl) -1,4,5,6,7,8-hexahydrocyclohepta [c] pyrazole-3-carboxylate.

  (IV): -A- = - (CH2) 5-; W = linkage; R3 Cl; Alk = -CH 2 -CH 3 C1 To a mixture of 15 g of the compound obtained in Preparation 1.4 in 300 ml of acetic acid, 14.7 g of 3,4-dichlorophenylhydrazine hydrochloride are added and refluxed for 5 hours. The reaction mixture is poured into a water / ice mixture, extracted with ether, the organic phase is washed with saturated NaHCO 3 solution, with water, with saturated NaCl solution, dried over MgSO 4 and the solvent is evaporated under vacuum. . The residue is chromatographed on silica gel, eluting with a DCM / MeOH (99/1; v / v) mixture. 7.48 g of the expected compound is obtained.

Preparation 2.7 Ethyl 1- (3,4-dichlorophenyl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylate.

  (IV): -A- = -CH2-CH2-O-CH2; W = linkage; R3 = Cl; Alk = -CH2-CH3. Cl

  To a mixture of 10.93 g of the compound obtained in Preparation 1.5 in 300 ml of acetic acid is added 11.32 g of 3,4-dichlorophenylhydrazine hydrochloride, heated at 70 ° C. for 24 hours and left stirring for 48 hours at YOUR. The reaction mixture is poured into water and extracted with ether, the organic phase is washed with saturated NaCl solution and dried over Na 2 SO 4, and the solvent is evaporated under vacuum. The residue is extracted with DCM, the organic phase is washed with a 10% NaOH solution and with saturated NaCl solution and dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt / DCM mixture (65/20/15, v / v / v). Two compounds are separated: - a less polar compound which gives 3.74 g corresponding to 2 (3,4-dichlorophenyl) -2,4,6,7-tetrahydropyrano [4,3-c] pyrazole e-3 ethyl carboxylate; a more polar compound from which 1.06 g corresponding to the compound of Preparation 2.7.Preparation 2.8 is obtained

  1- (4-Chlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester.

  (IV): -A- - (CH2) 4-; W = -CH2-; R3 Cl; Alk = -CH 2 -CH 3 A) 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester.

  To a mixture of 35 g of the compound obtained in Preparation 1.3 in 824 ml of acetic acid is added 18 g of hydrazine dihydrochloride and refluxed for 8 hours. After cooling to RT, the reaction mixture is poured into water and extracted with ether, the organic phase is washed with saturated NaHCO 3 solution and with saturated NaCl solution, dried over MgSO 4 and the solvent is evaporated under vacuum. The residue is taken up in toluene and the solvent is concentrated in vacuo. 33.3 g of the expected compound are obtained.

  B) 1- (4-Chlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester.

  A solution of 6.5 g of the compound obtained in the previous step in 50 ml of toluene is cooled in an ice bath and 1.14 g of 60% sodium hydride are added in portions under a nitrogen atmosphere. in the oil and leave stirring, allowing the temperature to rise to RT. A solution of 8.26 g of 4chlorobenzyl bromide in 15 ml of toluene is then added dropwise at RT and the mixture is refluxed for 18 hours. After cooling to RT, the reaction mixture is poured into a saturated solution of NH 4 Cl, the organic phase is washed with saturated NaCl solution, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt mixture (70/30, v / v) and then (60/40, v / v). 3.84 g of the expected compound are obtained.

  Preparation 2.9 Ethyl 1- (3,4-dichlorobenzyl) -4,5,6,7-tetrahydro-1H-indazol-3-carboxylate.

  (IV): -A- - (CH2) 4-; W = -CH2-; Cl; Alk = -CH2-CH3. Cl

  To a solution of 6.5 g of the compound obtained in step A of Preparation 2.8 in 50 ml of toluene is added at RT and in portions, 1.9 g of 60% sodium hydride in oil and leave stirring for 1 hour at RT. 9.62 g of 3,4-dichlorobenzyl bromide in 30 ml of toluene are then added and the mixture is refluxed for 18 hours. After cooling to RT, the reaction mixture is poured into a saturated solution of NH 4 Cl, decanted and the organic phase is concentrated under vacuum. The residue is extracted with AcOEt, the organic phase is washed with NaCl solution and dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt mixture (80/20, v / v). 7.16 g of the expected compound is obtained in the form of an orange oil.

Preparation 2.10 Ethyl 1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxylate.

  (IV): -A- = - (CH2) 4-; W = -CH2-; CH3; Alk = -CH2-CH3.

  To a mixture of 6.5 g of the compound obtained in step A of Preparation 2.8 in 50 ml of toluene is added at RT and in portions 1.14 g of 60% sodium hydride in the oil. and left stirring for 1 hour at RT. A solution of 7.43 g of 4-methylbenzyl bromide in 15 ml of toluene is then added dropwise at RT and the mixture is refluxed for 18 hours. After cooling to RT, the reaction mixture is poured into a saturated solution of NH 4 Cl, decanted, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt mixture (70/30, v / v). 4.58 g of the expected compound are obtained.

  3. Preparations of compounds of formula (II)

  Preparation 3.1 1- (3,4-Dichlorophenyl) -1,4,5,6-tetrahydro-cyclopenta [c] pyrazole-3-carboxylic acid.

  (II): -A- - - (CH2) 3-; W = linkage; R3 = Cl Cl A suspension of 3.72 g of the compound obtained in Preparation 2.1 in 22 ml of MeOH is added a solution of 1.3 g of KOH in 8 ml of water and refluxed for 3 hours. A solution of 0.7 g of KOH in 4 ml of water and 11 ml of MeOH is added and the reflux is continued for 3 hours. The reaction mixture is poured into a 10% aqueous solution of HCl, the precipitate formed is filtered off and washed with water. 3.19 g of the expected compound are obtained after drying.

  Preparation 3.2 1- (3,4-Dichlorophenyl) -6,6-dimethyl-1,4,5,6-tetrahydro-cyclopenta [c] pyrazole-3-carboxylic acid.

  (II): -A- = -C (CH3) 2-CH2-CH2-; W = linkage; R3 = (C1 Cl) A suspension of 14.89 g of the compound obtained in Preparation 2.2 in 83 ml of MeOH is added a solution of 4.73 g of KOH in 32 ml of water and refluxed for 1 hour. hour The reaction mixture is poured into a 10% aqueous solution of HCl, extracted with ether, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated off under vacuum to give 13.7 g of the expected compound, mp 181 vs.

  Preparation 3.3 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxylic acid (II): -A- = - (CH2) 4-; W = linkage; R 3 = (1 Cl) To a solution of 3.41 g of KOH in 23 ml of water is added a suspension of 9.25 g of the compound obtained in Preparation 2.3 in 52 ml of MeOH and refluxed for 1 hour. After cooling to RT, the reaction mixture is poured into a 10% aqueous solution of HCl, left stirring for 2 days at RT and the precipitate formed is filtered off to give 8 g of the expected compound, mp = 125.7 ° C.

  Preparation 3.4 1- (3,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxylic acid.

  (II): -A- = - (CH2) 4-; W = linkage; R3 = Cl Cl A mixture of 12.4 g of the compound obtained in Preparation 2.4 in 70 ml of MeOH is added a solution of 4.1 g of KOH in 25 ml of water and refluxed for 1 hour. The reaction mixture is poured onto a 10% aqueous solution of HCl, the precipitate formed is wrung out, washed with water and dried. 11.22 g of the expected compound are obtained. Mp = 248 C.

  Preparation 3.5 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxylic acid. 35

  (II): -A- = - (CH2) 4-; W = linkage; R3 = ClCl A mixture of 9.83 g of the compound obtained in Preparation 2.5 in 60 ml of MeOH is added a solution of 3.25 KOH in 20 ml of water and refluxed for 1 hour. The reaction mixture is poured into 200 ml of 10% HCl, the precipitate formed is filtered off and dried to give 8.17 g of the expected compound, mp = 239 ° C.

  Preparation 3.6 1- (3,4-Dichlorophenyl) -1,4,5,6,7,8-hexahydrocyclohepta [c] pyrazole-3-carboxylic acid.

  (II): -A- = - (CH2) 5-; W = linkage; To a solution of 2.38 g of KOH in 16 ml of water, a solution of 7.48 g of the compound obtained in Preparation 2.6 in 42 ml of MeOH was added and refluxed for 1 hour. After cooling to RT, the reaction mixture is poured into an aqueous solution of 10% HCl, left stirring for 2 days at RT, the precipitate formed is filtered off and dried. 5.41 g of the expected compound is obtained. Mp = 165.8 ° C.

  Preparation 3.7 1- (3,4-Dichlorophenyl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylic acid.

  (II): -A- - CH 2 -CH 2 -O-CH 2 -; W = linkage; R3 = (C1 Cl) To a solution of 1.06 g of the compound obtained in Preparation 2.7 in 8 ml of MeOH is added a solution of 0.38 g of KOH in 3 ml of water and then refluxed for 2 hours. The reaction mixture is added dropwise to a 10% aqueous solution of HCl and the precipitate formed is dried and dried to give 0.87 g of the expected compound, mp = 208 ° C.

  Preparation 3.8 1- (4-Chlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid.

  (II): -A- - - (CH2) 4-; W = -CH2-; R3 Cl To a solution of 3.84 g of the compound obtained in Preparation 2.8 in 21 ml of MeOH is added a solution of 1.35 g of KOH in 9 ml of water and then heated at reflux for 1 hour. After cooling to RT, the reaction mixture is poured into a solution of 10% HCl, left stirring overnight at RT, the precipitate formed is filtered off and dried. 3.2 g of the expected compound are obtained. Mp = 167.4 ° C.

  Preparation 3.9 1- (3,4-Dichlorobenzyl) -4,5,6,7-tetrahydro-THindazole-3-carboxylic acid.

  (H): -A- - - (CH2) 4-; W = -CH2-; R3 = Cl Cl To a solution of 7.1 g of the compound obtained in Preparation 2.9 in 40 ml of MeOH, a solution of 2.25 g of KOH in 15 ml of water is added and then refluxed for 1 hour. After cooling to RT, the reaction mixture is poured into a 10% solution of HCl, stirred overnight at RT, the precipitate formed is filtered off and dried. 6.27 g of the expected compound is obtained. Mp 189 C.

  Preparation 3.10 1- (4-Methylbenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid.

  (II): -A- - (CH2) 4-; W = -CH2-; To a solution of 1.72 g of KOH in 11.6 ml of water is added a solution of 4.58 g of the compound obtained in Preparation 2.10 in 26 ml of MeOH and then heated at reflux for 1 hour. After cooling to RT, the reaction mixture is poured into a 10% solution of HCl, stirred overnight at RT, the precipitate formed is filtered off and dried. 3.37 g of the expected compound are obtained. F = 165 C.

  EXAMPLE 1 Compound No. 1 N-1-Adamantyl-1- (3,4-dichlorophenyl) -1,4,5,6-tetrahydro-cyclopenta [c] pyrazole-3-carboxamide.

  To a solution of 0.5 g of the compound obtained in Preparation 3.1 and 0.51 ml of triethylamine in 30 ml of DCM, 0.335 g of 1-adamantylamine hydrochloride and then 0.93 g of PyBOP are added and left overnight. stirring at TA. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a DCM / MeOH (100/2; v / v) mixture. 0.51 g of the expected compound is obtained, mp 105.degree.

  1 H NMR: DMSO-d6: b (ppm): 1.6: s: 6H; 2.05: s: 9H; 2.55: mt: 2H; 2.7: mt: 2H; 3.1: mt: 2H; 7.15: s: 1H; 7.7: mt: 2H; 8.1: d: 1H.

  EXAMPLE 2 Compound No. 1 - (3,4-Dichlorophenyl) -N- [(1S) -1,3,3-trimethylbicyclo [2.2,1] heptoxenyl] -4,5,6,7 -tetrahydro-1H-indazole-3-carboxamide.

  To a solution of 0.754 g of the compound obtained in Preparation 3.4 and 0.7 ml of triethylamine in 45 ml of DCM was added 0.46 g of (1S) -2endoamino-1,3,3-trimethylbicyclo [2-chlorohydrate. , 2.1] heptane, then 1.26 g of PyBOP and left stirring for 2 days at RT. The organic phase is washed with a buffer solution pH = 2, with water, with saturated NaHCO 3 solution, with saturated NaCl solution, dried over Na 2 SO 4 and the solvent evaporated in vacuo. The residue is chromatographed on silica gel, eluting with a DCM / MeOH (99/1; v / v) mixture. 0.2 g of the expected compound is obtained, mp = 136 ° C.

  1 H NMR: DMSO-d6: δ (ppm): 0.8: s: 3H; 0.9-1.8: 2s + 2mt: 17H; 2.7: 2mt: 4H, 3.6: d: 1H, 7.0: d: 1H, 7.6: dd: 1H, 7.7: d: 1H, 7.9: d: 1H.

  The following TABLE I illustrates the chemical structures and the physical properties of some examples of compounds according to the invention. TABLE I R3 NR-NR1R2 Compounds -A- -W- R1 R2 R3 FC n NMR 1 - (CH2) 3- H-Linkage HCl 105 Cl 2 \ / H HH link, and 75 -c-cs) Cl 3H3C CH, H-bond and 96 \ / and NMR 4 - (CH 2) 4-H bond and 88 (I) - (CH 2) 4-bond HH H'c Cl 136 3 Cl CH3 (1S) -2endo 6 - (CH2) 4- HCl linkage 135 Cl NMR 7 - (CH 2) 4 H -b linkage 7) bc] 172 endo Cl 8 - (CH 2) 4 - link H CHCH 2 Cl 57 CH 3 and 9 - (CH 2) 4 - HC bond and C NMR HCH 2 -CH 3 and CH 3 - (CH 2) 4 - linkage CH 2 Cl 2 Cl 2 - (CH 2) 4 - linkage CH 3 to Cl 2 CH 2 CH 3 CH 3 Cl 2 CH 2 CH 2 CH 2 Cl 2 Cl 13 - (CH 2) 4 - H-endo bond 76 and 14 - (CH 2) 4 - link H CH 3 and CH 2 CH 3 to CH 3 Cl - (CH 2) 4 - H bond and 125 and 16 - (CH 2) 4 - H-3H2-CH3- and CH3-bond and 17- (CH2) 4- HCHCH2- and CH3- and CH3- (CH2) 5- H bond and 85C1- (CH2) 2 -o-CH2H-bond and 105 and - (CH 2) 4 -CH 2 -H and 69.5 21 - (CH 2) 4 -CH 2 -H 165- (CH 2) 4 -CH 2 -H -HcH 2 -CH 3 c] 80.1 CH 3 23 - (CH 2) 4 -CH 2 -H and 145 and 24 - (CH 2) 4 -CH 2 -H and 81 c CH 3 CH 2 Cl 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 Cl 2 (CH 2) 4 -CH 2 -H CH 3 141.5 29 - (CH 2) 4 -CH 2 -H CH 81 -C-CH 2 -CH 3 CH 3 CH 3 Compound No. 3: 1 H NMR: DMSO-d 6: S (ppm) : 1.2: s: 6H; 1.45-2.0: 2s: 15H; 2.35: t: 2H; 2.65: t: 2H; 7.0: s: 1H; 7.55: dd: 1H; 8.85: d: 1H; 8.9: d: 1H.

  Compound No. 6: 1 H NMR: DMSO-d 6: 8 (ppm): 1.6: m: 10H; 2.0: s: 9H; 3.7: 2mt: 4H; 7.0: s: 1H; 7.6: dd: 1H; 7.7: d: 1H; 7.9: d: 1H.

  Compound No. 9: 1 H NMR: DMSO-d 6: 8 (ppm): 0.8: t: 3H; 1.2: s: 6H; 1.6: mt: 6H; 2.6: 2mt: 4H; 7.0: s: 1H; 7.55: dd: 1H; 7.75: d: 1H; 8.85: d: 1H.

  Compound 25: 1 H NMR: DMSO-d 6: 8 (ppm): 0.8: t: 3H; 1.3: s: 6H; 1.7: mt: 6H; 2.6: mt: 4H; 5.3: s: 2H; 6.75: s: 1H; 7.0: d: 1H; 7.4: d: 1H; 7.6: d: 1H.

  The compounds according to the invention have been the subject of pharmacological tests.

  The compounds according to the invention have shown good in vitro affinity for the cannabinoid receptors CRI and / or CB2 whether they are human receptors or rodent receptors. The binding affinity assays were performed according to the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-244), with cell line derived membranes in which CB1 receptors (Matsuda et al., Nature 1990, 346, 561-564) and CB2 (Munro et al., Nature 1993 , 365, 61-65) were expressed. For human receptors, the in vitro affinity to cannabinoids CB1 and CB2 expressed as IC50 (inhibitory concentration 50) is less than 500 nM for at least one of the receptors.

  On the other hand, the compounds according to the invention behave in vitro as agonists of the CB1 and / or CB2 cannabinoid human receptors, they reduce the production of cAMP in forskolin-stimulated cells by inhibiting adenylate. cyclase. The tests were carried out according to the experimental conditions described by M. RinaldiCarmona et al., J. Pharmacol. Exp. Ther., 1996, 278, 871-878 and M. Bouaboula et al., J. Biol. Chem., 1997, 272, 22330-22339.

  According to another of its aspects, the present invention relates to the use of the compounds of formula (I), or one of their solvates and / or pharmaceutically acceptable hydrates, for the preparation of medicaments intended to treat and prevent diseases. involving cannabinoid receptors CB1 and / or CB2.

  The compounds according to the invention can therefore be used for the preparation of medicaments, in particular agonists CB2 receptor agonists and / or CB1 cannabinoids.

  Thus according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or a hydrate or a solvate of the compound of formula (I).

  These drugs find their use in therapeutics especially as psychotropic medication, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders, psychoses in general, schizophrenia.

  The compounds of formula (I) according to the invention can be used as a medicament for the treatment of migraine, stress, psychosomatic diseases, spinal cord injuries, vertigo, panic attack attacks. , epilepsy, movement disorders, tremors and dystonia.

  The compounds of formula (I) according to the invention can also be used as a medicament for the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease. In addition, the compounds of formula (I) may be useful as a neuroprotector, in the treatment of ischemia, head trauma and in the treatment of neurodegenerative diseases, including chorea, Huntington's disease, syndrome Tourette, Parkinson's disease, multiple sclerosis.

  The compounds of formula (I) according to the invention can be used as a medicament for the treatment of pain and inflammation: neuropathic pain, diabetic neuropathy, peripheral acute pain, chronic inflammatory pain, cancer pain, pain associated with multiple sclerosis. Ocular conditions such as ocular hypertension, glaucoma or inflammation of the uvea.

  The compounds of formula (I) according to the invention may be used as a medicament for the treatment of appetite disorders such as loss of appetite (cachexia) associated or not with chemotherapeutic treatments. In addition, the compounds of formula (I) according to the invention may be used as a medicament for the treatment of diseases of the gastrointestinal system (Crohn's disease, irritable or inflammable bowel disease (in English IBS and IBD), ulcer, ulcerative colitis, GERD and its consequences (chronic laryngitis), regurgitation, intestinal spasm, uterine spasms, loosening vomiting (especially those following chemotherapy), bladder and urinary disorders, glomerulonephritis, cystitis, renal ischemia, and the compounds of formula (I) according to the invention may be used as a medicament in the treatment of cardiovascular diseases (particularly hypertension, arteriosclerosis, myocardial infarction and cardiac ischemia), hemorrhagic shock, septic shock, chronic cirrhosis hepatic, hepatitis, acute or chronic pancreatitis, lung diseases such as respiratory diseases, asthma, cough, chronic bronchitis, chronic airway obstruction (in English COPD: chronic obstructive pulmonary disease) or emphysema, Raynaud's disease, glaucoma, fertility disorders, bone diseases such as osteoporosis, Paget's disease. In addition, the compounds of formula (I) according to the invention may be used as a medicament for the treatment of disorders of the immune system, in particular autoimmune diseases such as psoriasis, lupus erythematosus, eczema, connective tissue or connective tissue disease, Sj6grer syndrome, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, undifferentiated spondyloarthritis, Behcet's disease, hemolytic autoimmune anemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis , transplant rejection, diseases affecting plamocyte lineages, parasitic, viral or bacterial infectious diseases such as AIDS (AIDS), meningitis, encephalitis. In addition, the compounds of formula (I) according to the invention can be used as a medicament for the treatment of inflammatory diseases, especially joint diseases (rheumatoid arthritis, arthritis, osteoarthritis, spondylitis, synovitis tendons, gout), vasculitis. In addition, the compounds of formula (I) according to the invention can be used as a medicament in the treatment of allergic diseases such as delayed or immediate hypersensitivity, seasonal allergic rhinitis, contact dermatitis or dermatitis. allergic conjunctivitis.

  In addition, the compounds of formula (I) according to the invention can be used as a medicament in the treatment of cancers: benign tumors of the skin, papillomas and cancerous tumors (melanoma), prostate tumors, tumors (glioblastomas, medullo-epitheliomas, medulloblastomas, neuroblastomas, embryonic origin tumors, astrocytomas, astroblastomas, ependymomas, oligodendrogliomas, plexus tumors, neuroepitheliomas, epiphysis tumors, ependymoblastomas, neuroectodermosis, malignant meningiomas, sarcomatoses, melanomas malignancies, schwannomas) and for the treatment of Guillain-Barré syndrome.

  According to the present invention, the compounds of formula (I) are particularly useful for the treatment of appetite disorders such as loss of appetite (cachexia), for the treatment of neurodegenerative diseases, demyelinating diseases and as neuroprotective and antitumor agents, for the treatment of disorders of the immune system, in particular autoimmune diseases, for the treatment of diseases of the respiratory tract and bone, in particular osteoporosis, for the treatment of pain (acute and / or or chronic) as well as for the treatment of inflammatory diseases.

  According to one of its aspects, the present invention relates to the use of a compound of formula (I), its solvates or hydrates for the treatment of the disorders and diseases indicated above.

  According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, a solvate or hydrate of said compound, as well as at least one pharmaceutically acceptable excipient.

  Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

  In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of disorders or diseases above.

  Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

  By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate: 3.0 mg Orally, the dose of active principle administered per day may reach 0.01 to 100 mg / kg, in one or more doses, preferentially 0.02 to 50 mg / kg.

  There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

  The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its hydrates or solvates. 25 30

Claims (1)

  A compound of formula (I): R3 W N NOT   in which: A represents: a linear (C 3 -C 5) alkylene radical which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl; a radical -CH 2 -CH 2 -O-CH 2 -; - W represents a direct bond or a -CH2- radical; R1 represents a hydrogen atom or a (C1-C3) alkyl; R2 represents a (C1-C8) alkyl or a group -B-R4; - R3 represents a phenyl substituted with one or more substituents independently selected from a halogen atom, a (C1-C3) alkyl, a (C1-C3) alkoxy, a trifluoromethyl radical, a trifluoromethoxy radical; B represents a bond or a radical (C1-C2) alkylene unsubstituted or substituted one or more times by a (C1-C3) alkyl; R 4 represents: a phenyl that is unsubstituted or substituted with one or more substituents chosen independently from a halogen atom, a (C 1 -C 3) alkyl, a (C 1 -C 3) alkoxy, a trifluoromethyl radical; a non-aromatic C 3 -C 12 carbocyclic radical, unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl or a (C 1 -C 3) alkoxy; in the basic state, as well as in the hydrate or solvate state.   2. Compound of formula (I) according to claim 1 characterized in that: - A represents a radical - (CH2) 3-, -C (CH3) 2 -CH2-CH2-, - (CH2) 4-, - ( CH2) 5-, -CH2-CH2-O-CH2-; - W represents a direct bond or a -CH2- radical; - R1 represents a hydrogen atom; R2 represents a 1-adamantyl, 2-adamantyl, (1S) -1-cyclohexyl ethyl, (1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2endo-yl, endo-bicyclo [3. 2.1] oct-3- (I) yl, 1,1-dimethyl-2-phenylethyl, 1,1-dimethylpropyl, tert-butyl, 4-ethylcyclohexyl, - R3 represents a 4-chlorophenyl, a 3,4 -dichlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl; in the basic state and in the state of hydrate or solvate.   3. Compound of formula (I) according to claim 1 selected from: - N-1-adamantyl-1- (3,4-dichlorophenyl) -1,4,5,6-tetrahydro-cyclopenta [c] pyrazole-3-carboxamide; N - [(1S) -1H-cyclohexylethyl] -1- (3,4-dichlorophenyl) -6,6-dimethyl-1, 4,5,6-tetrahydro-cyclopenta [c] pyrazole-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorophenyl) -6,6-dimethyl-1,4,5,6-tetrahydrocyclo penta [c] pyrazole-3-carboxamide; N-1-adamantyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3 carboxamide; 1- (3,4-dichlorophenyl) -N- [(1S) -1,3,3-trimethylbicyclo [2,2,1] hept-2endo-yl] -4,5,6,7-tetrahydro 1H-indazole-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazol-3-carboxamide; N- [endo-bicyclo [3.2.1] oct-3-yl] -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorophenyl) -N- (1,1-dimethyl-2-phenylethyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorophenyl) -N- (1,1-dimethylpropyl) -4,5,6,7-tetrahydro-1Hindazol-3-carboxamide; N- (cyclohexylmethyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorophenyl) -N- (2,2-dimethylpropyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N- (2-cyclohexylethyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazol-3-carboxamide; N- [endo-bicyclo [3.2.1] oct-3-yl] 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazo-3-c arb oxammon ; 1- (2,4-dichlorophenyl) -N- (2,2-dimethylpropyl) -4,5,6,7-tetrahydro-1H-indazol-3-carboxamide; N-1-adamantyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-indazole-3carboxamide; 1- (2,4-dichlorophenyl) -N- (1,1-dimethylpropyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (2,4-dichlorophenyl) -N- (1,1-dimethyl-2-phenylethyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorophenyl) -1,4,5,6,7,8-hexahydro cyclohepta [c] pyrazole-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorophenyl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxamide; N-2-adamantyl-1- (4-chlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (4-chlorobenzyl) -N- (1,1-dimethylpropyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxamide; N-1-adamantyl-1- (3,4-dichlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N-2-adamantyl-1- (3,4-dichlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorobenzyl) -N- (1,1-dimethylpropyl) -4,5,6,7-tetrahydro-lHindazole-3-carboxamide; N- (tert-butyl) -1- (3,4-dichlorobenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; 1- (3,4-dichlorobenzyl) -N- (4-ethylcyclohexyl) -4,5,6,7-tetrahydro-IHindazole-3-carboxamide; N-1-adamantyl-1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; N- (1,1-dimethylpropyl) -1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1Hindazole-3-carboxamide; in the basic state and in the state of hydrate or solvate.   4. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, characterized in that: an acid or a functional derivative of this acid of formula: R 3 W N N COOH 15 20   in which A, W and R3 are as defined for a compound of formula (I) in claim 1, with an amine of the formula: HNR1R2 (III) wherein R1 and R2 are as defined for a compound of formula (I) ) in claim 1.   5. Intermediate compound of formula: R-W N NOT COOH   in which: - A represents: a linear (C3-05) alkylene radical which is unsubstituted or substituted one or more times by a (C1-C3) alkyl; a radical -CH2-CH2-O-CH2-; - W represents a direct bond or a -CH2- radical; - R3 represents a phenyl substituted with one or more substituents chosen independently from a halogen atom, a (C1-C3) alkyl, a (C1-C3) alkoxy, a trifluoromethyl radical, a trifluoromethoxy radical.   6. An intermediate compound of formula: wherein: Alk represents a (C1-C3) alkyl; - A represents - a linear (C3-05) alkylene radical which is unsubstituted or substituted one or more times with a (C1-C3) alkyl; a radical -CH2-CH2-O-CH2-; - W represents a direct bond or a -CH2- radical; - R3 represents a phenyl substituted with one or more substituents chosen independently from a halogen atom, a (C1-C3) alkyl, a (C1-C3) alkoxy, a trifluoromethyl radical, a trifluoromethoxy radical. 35   7. Medicament, characterized in that it contains a compound of formula (I) according to any one of claims 1 to 3, or a hydrate or a solvate of the compound of formula (I).   8. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, a hydrate or a solvate of this compound, and at least one pharmaceutically acceptable excipient.   9. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for treating and preventing diseases involving cannabinoid receptors CB2 and / or CB1.   10. Use according to claim 9 for the treatment and prevention of appetite disorders such as loss of appetite (cachexia), for the treatment of neurodegenerative diseases, demyelinating diseases and as neuroprotective and antitumor agents, for the treatment of disorders of the immune system, in particular autoimmune diseases, for the treatment of diseases of the respiratory tract and bone, in particular osteoporosis, for the treatment of pain (acute and / or chronic) as well as for the treatment of inflammatory diseases. 25 30