MXPA06007985A - Derivatives of n-`(1,5-diphenyl-1h-pyrazol-3-yl) sulphonamide with cb1 receptor affinity - Google Patents

Abstract

The invention relates to compounds having formula (I), the preparation method thereof and the use of same in therapeutics, wherein:R1 represents a (C1-C6)alkyl, a (C3-C7)cycloalkyl which is unsubstituted or is mono- or poly-substituted, a (C3-C7)cycloalkylmethyl which is unsubstituted or is mono- or poly-substituted, a phenyl which is unsubstituted or substituted;a benzyl which is unsubstituted or is mono- or disubstituted, a thienyl which is unsubstituted or substituted;R2 represents a hydrogen atom or a (C1-C3)alkyl;R3 represents a hydrogen atom or a (C1-C5)alkyl;R4, R5, R6, R7, R8 and R9 each represent, independently of each other, a hydrogen atom, a halogen atom, a (C1-C7)alkyl, a (C1-C5)alkoxy, a trifluoromethyl radical or a S(O)nAlk group;n represents 0, 1 or 2;and Alk represents a (C1-C4)alkyl. The invention also relates to the preparation method thereof and to the use of same in therapeutics.

Description

GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, What are the codes? deux lettres et autres abrévia- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, UK, TJ, TM), tions, are referenced aux "Notes explanations concerning aux codes et européen (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, abréviations "figurant au debut of morning coat number ordinaire de FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO, the PCT Gazette. SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Publiée: - avec rapport de recherche intemationale DERIVATIVES OF N- (1, 5-DIFENIL-1 H-PI RAZOL-3-IL) SULPHONE I DA WITH AFFINITY FOR RECEPTORS CB1 The subject of the present invention is the derivatives of N - [(1, 5-diphenyl-1 H-pyrazol-3-M) methyl] sulfonamide, its preparation and its application in therapy. The diphenylpyrazole derivatives, which have an affinity for CB-? of cannabinoids have been described mainly in patents EP 0 576 357, EP 0 656 354 and EEU U 5 624 941. We have now discovered novel N - [(1, 5-diphenyl-1-pyrazol-3-yl) methyl] sulfonamide derivatives which exhibit antagonistic properties of the C BT receptors of cannabinoids. The subject of the present invention is the compounds which correspond to formula (I): wherein: - R - represents • alkyl (C -? - C6); • (C3-C7) cycloalkyl unsubstituted or substituted one or more times with an alkyl group (C? -Cs); • cycloalkylmethyl (C3-C7) unsubstituted or substituted one or more times in the carbocycle with alkyl -CS); • unsubstituted or mono, di or trisubstituted phenyl with a substituent independently selected from a halogen atom, alkyl (C? -C4), alkoxy ^ -Cs), cyano, trifluoromethyl radical, trifluoromethoxy radical, group S (O) nAlk, alkylcarbonyl group (C? -C3) or phenyl; • unsubstituted or mono- or di-substituted benzyl with a substituent independently selected from a halogen atom, alkyl-Cs), alkoxy CT-Cs) or trifluoromethyl radical; • thienyl unsubstituted or substituted with a halogen atom or with an isoxazolyl; - R2 represents a hydrogen atom or alkyl ^ -Cs); - R3 represents a hydrogen atom or alkyl (C? -C5); - R, R5, R6, R7, e and g each independently represent a hydrogen atom, halogen atom, alkyl (C- | -C7), alkoxyCi-Cs), trifluoromethyl radical or group S (O) nAlk; - n represents 0, 1 or 2; - Alk represents (C1-C4) alkyl. The compounds of formula (I) may contain one or more asymmetric carbon atoms. Therefore, they can exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers as well as their mixtures, including the racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or acid addition salts. Said addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids although the salts of other acids useful for the purification or isolation of the compounds of formula (I) also form part of the invention. The compounds of formula (I) can also exist in the form of hydrates or solvates, that is, in the form of associations or combinations with one or more water molecules or with a solvent. Said hydrates and solvates are also part of the invention. By halogen atom is meant a bromine, chlorine, fluorine or iodine atom. By alkyl-Cs) or respectively (C 1 -C 4) alkyl, C 1 -C 4 alkylamino, (C 6 -C 6) alkyl or (C 1 -C 7) alkyl, it is meant a linear or branched alkyl radical of one to three carbon atoms or respectively one to four carbon atoms, one to five carbon atoms, one to six carbon atoms or one to seven carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec radical -butyl, ert-butyl, pentyl, isopentyl, hexyl, isohexyl or heptyl. By alkoxycyc-Cs) or respectively alkoxy-Cs)is meant a straight or branched alkoxy radical of one to three carbon atoms or one to five carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, fer-butoxy, pentoxy or Sopentoxi. By "(C3-C7) cycloalkyl" is meant a cyclic alkyl group of 3 to 7 carbon atoms, such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group. Among the compounds of formula (I), object of the invention, there may be mentioned the preferred compounds which are defined as follows: - Ri represents • ethyl, isopropyl or n-butyl; • cyclohexyl; • cyclohexylmethyl; • 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-ethylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 3,5-dimethylphenyl, 3-methoxyphenyl, -methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 3,5-bis (trifluoromethyl) phenyl, 2- (trifluoromethoxy) phenyl, 3- (trifluoromethoxy) ) phenyl, 2- (methylsulfonyl) phenyl, 3- (methylsulfonyl) phenyl, 3-acetylphenyl, 3-biphenyl or 2-biphenyl; • 3-chlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 3- (trifluoromethyl) benzyl or 4- (trifluoromethyl) benzyl; • 5-bromo-2-thienyl or 5-isoxazol-3-yl-2-thienyl; - and / or R2 represents a hydrogen or methyl atom; - and / or R3 represents methyl or ethyl; - and / or R4 represents a hydrogen atom; - and / or R5 is in position -4- of the phenyl and represents a bromine, chlorine, fluorine or methoxy atom; - and / or R6 represents a hydrogen atom; - and / or R7 represents a hydrogen atom; - and / or R8 is in position -4- of the phenyl and represents a hydrogen atom, chlorine atom or fluorine atom; - and / or R9 is in position -2- of the phenyl and represents a chlorine or fluorine atom; in the form of a base or acid addition salt, as well as in the form of a hydrate or solvate. Among the latter preferred compounds, compounds of formula (I) in which: - R- \ represents • ethyl, isopropyl or n-butyl; • cyclohexyl; • cyclohexylmethyl; • 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-ethylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 3,5-dimethylphenyl, 3-methoxyphenyl, -methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 3,5-bis (trifluoromethyl) phenyl, 2- (trifluoromethoxy) phenyl, 3- (trifluoromethoxy) ) phenyl, 2- (methylsulfonyl) phenyl,, 3- (methylsulfonyl) phenyl, 3-acetylphenyl, 3-biphenyl or 2-biphenyl; • 3-chlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 3- (trifluoromethyl) benzyl or 4- (trifluoromethyl) benzyl; • 5-bromo-2-thienyl or 5-isoxazol-3-yl-2-thienyl; - R2 represents a hydrogen or methyl atom; - R3 represents methyl or ethyl; - R4 represents a hydrogen atom; - R5 is in position -4- of the phenyl and represents a bromine, chlorine, fluorine or methoxy atom; - R6 represents a hydrogen atom; - R7 represents a hydrogen atom; - R8 is in position -4- of the phenyl and represents a hydrogen atom, chlorine atom or fluorine atom; - Rg is in position -2- of the phenyl and represents a chlorine or fluorine atom; in the form of a base or acid addition salt, as well as in the form of a hydrate or solvate. Among the compounds of formula (I) which are the subject of the invention, mention may be made, in particular, of the following compounds: N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1- -pyrazol-3-yl] met i I] butane-1-sulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -cyclohexane-hexaphon id a; N - [[5- (4-bro-mofen-I) -1- (2,4-d-chloroform) -1-methyl-1H-pi-I-3-yl] methyl] -cyclohexylmethanesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-chlorobenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1-pyrazol-3-yl] methyl] -4-fer-butyl-I-benzenesulfon-one a; N - [[5- (4-bromophenyl) -1 - (2,4-d-chloro-phenyl) -4-methyl-1-1H-pyrazol-3-yl] methyl] -3-methoxybenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -4-methoxybenzenesulfonamide; N - [[5- (4-brom of enyl) -1- (2,4-d iclorof in 1) -4-methy1H-pyrazo I-3-yl] m and il] -4- (trif I uorom eti I) benzenesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1-pyrazol-3-ylmethyl] -2- (methylsulfonyl) benzenesulfonamide; N - [[5- (4-bro-mofenyl) -1- (2,4-d-chloro-en-yl) -4-methyl-1H-pyrazol-3-yl] methyl] -1- (3-chlorophenyl) ) methanesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 AV-pyrazol-3-yl] methyl] -1 - [3- (trifluoromethyl) phenyl] methanesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-chloro-4-fluorobenzenesulfonamide; N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -butane-1-sulfone mid a; - 3-chloro-N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] benzenesulfonamide; - 4-yerc-buti lN - [[5- (4-bro-mofenyl) -1- (2,4-d-chloro-en-yl) -4-methyl-1H-pyrazole l-3-i I] methyl] benzene ulfone measure; N - [[5- (4-bromophenyl) -1 - (2,4-d-chloro-phenyl) -4-methyl-1-W-pyrazol-3-yl] methyl] -3-methoxy-benzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 tf-pyrazol-3-yl] methyl] -3-cyanobenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yI] methyl] -4- (trif I uorom eti I) benzenesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 / - / - pyrazol-3-yl] m eti] -2- (trifl uorom ethoxy) bence us ulfon a mide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -2- (methylsulfonyl) benzenesulfonamide; 3-Chloro-N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H-pi-3-I] met] il] -4-f luoro benzenesulf ona measure; 4-bromo-N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1-pyrazol-3-yl] methyl] -2-ethylbenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3-ethanesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] propane-2-sulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 W -pyrazol-3-yl] methyl] butan or-1-sulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] cyclohexane-ulfon a mida; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] met i I] -1-cid ohexy I methanesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3-chlorobenzenesulfonamide; - Nr [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -2-chlorobenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3-methyl-benzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-d-chloro-phenyl) -4-ethyl-1H-pyrazol-3-yl] -methyl] -4-fet "c-butylbenzenesulfonamide; N - [[5- (4-bromophenyl) -1- (2,4-d-chloro-phenyl) -4-ethyl-1H-pyrazol-3-yl] -methyl] -4-methoxy-benzenesulfonamide; N- [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1-pyrazol-3-yl] methyl] -3-methoxybenzenesulfonamide; - N - [[5- (4 -bromophenyl) -1- (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -4- (trifl uorom eti I) benzenesulfonamide; N - [[5- (4 -bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] met il] -3- (trif I uorom eti I) benzenesulfonamide; N - [[5- ( 4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -2- (trif I uorom eti I) benzenesulfonamide; N - [[5- ( 4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3- (trifluoro methoxy) benzenesulfone mida; N - [[5- (4 -bromophenyl) -1- (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -2- (trifl uorom ethoxy) benfines ulfona mide; -3-acetyl-N- [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H-pira zol-3-i I] methyl] benzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] biphenyl-3-sulfonamide; N - [[5- (4-bromophen? L) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -1 - [4- (tpfluoromethyl) phenyl] ] methanesulfonamide; N - [[5- (4-bromophenyl) -1- (2,4-d-chloro-phenyl) -4-ethyl-1H-pyrazol-3-yl] methyl] -1- [3- (trifl uorom eti l ) phenyl] meta we ulfone measure; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3,5-dimethylbenzenesulfone at; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] m and yl] -3,5-bis (trifluoromethyl) benzenesulfonamide; - 3-Chloro-N - [[1- (2-chlorophenyl) -5- (4-chlorophenyl) -4-methyl-1 H-pyrazole-3-yl]]]]]]]]]]]]]]] <5> methylcholines; N - [[1 - (2-chlorophenyl) -5- (4-chlorophenyl) -4-methyl-1 H -pyrazol-3-yl] m and i] -2-f luoro benzenesulfone mida; N - [[1- (2-chlorophenyl) -5- (4-chlorophenyl) -4-methyl-1 / -pyrazol-3-yl] methyl] -3-cyanobenzenesulfonamide; N - [[1- (2-chlorophenyl) -5- (4-chlorophenyl) -4-methyl-1-pyrazol-3-yl] methyl] -3-methoxybenzenesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-d-chloro-phenyl) -4-methyl-1 / -pyrazol-3-yl] -methyl] -3-methoxy-benzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-cyanobenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-d-chloro-phenyl) -4-ethyl-1? -pyrazol-3-yl] methyl] -1- (2-fluorophenyl) methanesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 V-pyrazol-3-yl] methyl] -1 - (4-fluorophenyl) methanesulfonamide; 5-brom or N - [[5- (4-bromofenyl) -1- (2,4-d iclorofeni l) -4-eti 1-1 H-pyrazol-3-yl] methyl] thiophen-2-sulf onamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -5-isoxazol-3-ylthiophen-2-sulfonamide; - 3-chloro- N - [[1- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -4-methyl-1H-pyrazol-3-yl] methyl] benzenesulfonamide; N - [[1 - (2,4-d-chloroform) -5- (4-methoxy-en-yl) -4-methy-1-1 H-pi-I] -3-yl] -m-y-] m eti I benzenesulfonamide; in the form of a base or acid addition salt, as well as in the form of a hydrate or solvate. In the following, the protective group Pg is understood to be a group which allows, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function at the end of the synthesis. . Examples of protecting groups as well as protection and deprotection methods appear in "Protective Group in Organic Synthesis", Green et al. , 2nd Edition (John Wiley &Sons, I nc., New York), 1 991. By "leaving group" is meant, hereinafter, a group that can be easily cleaved from a molecule by breaking a heterolitic bond, with the output of an electronic pair. This group can easily be replaced by another group during a substitution reaction, for example. Said leaving groups are, for example, halogens or an activated hydroxyl group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation appear in "Advances in Organic Chemistry", J. March, 3rd Edition, Wiley Interscience, 1985, p. 310-31 6. According to the invention, the compounds of formula (I) can be prepared according to a process characterized in that: a compound of the formula is reacted in the presence of a base and in a solvent: wherein R2, R3, R, R5, R6, R7, R8 and Rg are as defined for a compound of formula (I), with a sulfonyl halide of the formula: wherein Ri is as defined for a compound of formula (I) and Hal represents a halogen atom. Optionally, the compound of formula (I) is transformed into one of its acid addition salts. The reaction is carried out in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, and at a temperature between room temperature and the reflux temperature of the solvent. The reaction is preferably carried out using a compound of formula (III) in which Hal represents a chlorine atom. According to another variant of the process, a compound of formula (I) in which R2 represents (C -, - C3) alkyl can be prepared by reacting a compound of formula (I) in which R2 = H with an alkyl halide. -Cs) in the presence of a base such as sodium hydride or potassium carbonate, in a solvent such as N, N-dimethylformamide and at a temperature between room temperature and the reflux temperature of the solvent. The compounds of formula (I) obtained in this way can subsequently be separated from the reaction medium and purified according to conventional methods, for example by crystallization or chromatography. The compounds of formula (I I) are prepared by reaction of a compound of formula: where R3? R4, R5, R6, R7, R8 and Rg are as defined for a compound of formula (I) and Y represents a leaving group as defined hereinabove, preferably a halogen atom or a group activated hydroxyl such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate or triflate group, with a compound of the formula: wherein R2 is as defined for a compound of formula (I). The reaction is carried out in a solvent such as N, N-dimethylformamide, acetonitrile, dichloromethane, toluene or propan-2-ol, and in the presence or absence of a base. When a base is used, it is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine. The reaction is carried out at a temperature between 0 ° C and the reflux temperature of the solvent. According to a variant, it is also possible to prepare a compound of formula (II) in which R2 = H by reaction of a compound of formula (IV) in which Y = Cl with 1, 3,5,7-tetraazatricyclo [3.3. 13, 7] decane (or hexamethylenetetramine) followed by hydrolysis by a strong acid such as hydrochloric acid. The compounds of formula (11) are commercially available or are described in the literature, or can be prepared according to methods that are described such as in J. Org. Chem. USSR, 1 970, 6, 2454-2458; J. Am. Chem. Soc, 1 952, 74, 2008; J. Med. Chem., 1977, 20 (10), 1235-1239; EP0469 984; WO95 / 18105. For example, the compounds of formula (11) can be prepared by halogenation of the corresponding sulphonic acids or their salts, for example, their sodium or potassium salts. The reaction is carried out in the presence of a halogenating agent such as phosphorus bicarbonate, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, without solvent or in a solvent such as a halogenated hydrocarbon or N, N-dimethylformamide and a temperature between -10 ° C and 200 ° C. The compounds of formula (IV) are prepared from the compounds of formula: wherein R3, R4, R5, R6, R7, R8 and Rg are as defined for a compound of formula (I), according to the classical methods cited above. Thus, for example, when a compound of formula (IV) Y represents a halogen atom, a compound of formula is treated (VI) with a halogenating agent such as PCI5, PBr3, HBr or BBr3, in a solvent such as dichloromethane and at a temperature between 0 ° C and room temperature. When, in a compound of formula (IV), Y represents a methanesulfonate, benzenesulfonate, p-toluenesulfonate or trifluoromethanesulfonate, a compound of formula (VI) is reacted with a sulfonyl chloride of formula X-SO2-CI in which X represents methyl, phenyl, p-tolyl or trifluoromethyl. The reaction is carried out in the presence of a base such as triethylamine, pyridine or N, N-diisopropylethylamine, in a solvent such as dichloromethane or toluene and at a temperature between -20 ° C and the reflux temperature of the solvent. The compounds of formula (V) are known. The compounds of formula (VI) are prepared by a reduction reaction of the compounds of formula: wherein R3, R4, R5, R6, R7, R8 and Rg are as defined for a compound of formula (I) and Z represents a hydroxyl or (C1-C2) alkoxy. The reaction is carried out in the presence of a reducing agent such as sodium borohydride or aluminum and lithium hydride, in a solvent such as tetrahydrofuran, and at a temperature between -20 ° C and room temperature. When a compound of formula (VII) is reduced in which Z = OH, the acid can be pre-activated by reaction with ethyl chloroformate in the presence of triethylamine. The compounds of formula (VI) are known and are prepared according to known methods such as those described in EP 0656 354, EP 0576 357 or in WO 00/46209. The following EXAMPLES describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the exemplified compounds correspond to those shown in the following TABLE V, which illustrates the chemical structures and physical properties of some compounds according to the invention. The following abbreviations are used in the Preparations and Examples: ether: diethyl ether iso ether: diisopropyl ether DMSO: dimethylsulfoxide DMF: N, N-dimethylformamide THF: tetrahydrofuran DCM: dichloromethane AcOEt: ethyl acetate DIPEA: diisopropylethylamine TFA: trifluoroacetic acid 2N hydrochloric acid: 2N solution of hydrochloric acid in diethyl ether F: melting point TA: room temperature Eb: boiling point CLHP: high performance liquid chromatography Silica H: 60 H silica gel marketed by Merck (DARMSTAD) pH buffer solution = 2: dissolution of 16.66 g of KHSO4 and 32.32 g of K2SO4 in 1 liter of water. Nuclear magnetic resonance spectra are recorded at 200 MHz in DMSO-d6. For the interpretation of the spectra, the following abbreviations are used: s: singlet, d: doublet, t: triplet, m: massive, mt: multiplet, se: wide singlet. The compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / detection UV / mass spectrometry). The molecular peak (MH +) and the retention time (tr) are measured in minutes. The apparatus used, marketed by Agilent, is composed of an HP 1 1 00 chromatograph equipped with an Agilent diode network detector and a MSD Quad cudripolar mass spectrometer. Method A: An Xterra Waters® MS C18 column, marketed by Waters, of 2, 1 x 30 mm, 3.5 μm, was used at room temperature, flow 1 ml / minute. The eluent has the following composition: solvent A: 0.025% trifluoroacetic acid (TFA) in water; - solvent B: 0.025% TFA in acetonitrile. Gradient: The percentage of solvent B varies from 0 to 100% in 2 minutes with a plate at 100% B for 1 minute. The UV detection is carried out between 21 0 nm and 400 nm and the detection of masses in chemical ionization mode at atmospheric pressure. Method B: A Symmetry C1 8 column of 2, 1 x 50 mm, 3.5 μm, at 30 ° C, flow 0.4 ml / minute is used. The eluent has the following composition: solvent A: 0.005% trifluoroacetic acid (TFA) in water at pH 3.15; - solvent B: 0.005% TFA in acetonitrile. Gradient: 15 twenty UV detection is done to? = 21 0 nm and mass detection is performed in positive electrospray mode (ESI). Method C: 25. A Symmetry C1 8 column of 2, 1 x 50 mm, 3.5 μm, at 30 ° C, flow 0.4 ml / minute is used. The eluent has the following composition: solvent A: 0.005% TFA in water at pH 3.15; - solvent B: 0.005% TFA in acetonitrile. Gradient: UV detection is done to? = 21 0 nm and mass detection is performed in positive electrospray mode (ESI). Method D: An Xterra MS C18 column of 2.1 x 50 mm, 3.5 μm, at 30 ° C, flow 0.4 ml / minute is used. The eluent has the following composition: solvent A: ammonium acetate (AcONH4) 10 nM in water at pH 7; - solvent B: acetonitrile.

Gradient: UV detection is done to? = 220 nm and mass detection is performed in positive electrospray mode (ESI). Method E: A Xterra MS C18 column of 2.1 x 50 mm, 3.5 μm, at 30 ° C, flow 0.4 ml / minute is used. The eluent has the following composition: solvent A: 1 0 nM AcONH 4 in water at pH 7; - solvent B: acetonitrile. Gradient: PREPARATIONS 1. Preparations of the compounds of formula (VII). Preparation 1 .1 5- (4-Brom-of-enyl) -1- (2,4-d-chloroform) -1-methyl-1-pyrazole-3-carboxylic acid. (VII): R3 = -CH3; R4 = H; R5 = 4-Br; R6 = H; R7 = H; R8 = 4- Cl; R9 = 2-CI; Z = -OH. A) Lithium salt of ethyl 4- (4-bromophenyl) -3-methyl-2-oxo-4-oxidobut-3-enoate. A solution of 43 g of lithium salt of hexamethyldisilazane in 300 ml of ether is cooled to -60 ° C, and a solution of 50 g of 4-bromopropiophenone in 500 ml of ether is added dropwise and left with stirring until the temperature reaches -30 ° C. Then 38 g of diethyl oxalate are added and the mixture is left stirring for 8 hours, allowing the temperature to reach RT. The formed precipitate is filtered off with suction, washed with ether and dried in vacuo. 62 g of the expected product are obtained. B) 5- (4-bromofenyl) -1- (2,4-d i chlorofenyl) -4-m ethyl-1 H-pyrazole I-3-ethyl carboxylate. To a solution of 30 g of the compound obtained in the preceding step in 150 ml of acetic acid is added 20 g of 2,4-dichlorophenylhydrazine hydrochloride and heated at reflux for 3 hours. After cooling to RT, the reaction mixture is poured into a water / ice mixture, extracted with ether, the organic phase is washed with a saturated solution of NaCl, dried over MgSO 4, the solvent is partially evaporated under vacuum and Suction filters the crystalline product formed. 33.4 g of the expected product are obtained. C) 5- (4-Bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid. To a solution of 26 g of the compound obtained in the preceding step in 50 ml of EtOH are added 6.5 g of KOH and 20 ml of water and heated at reflux for 2 hours. After cooling to RT, the reaction mixture is poured into a water / ice mixture containing 10 ml of concentrated HCl, the formed precipitate is filtered off with suction, washed with water and dried under vacuum. 24 g of the expected product are obtained. Preparation 1 .2 5- (4-Cl orofenyl) -1- (2,4-d-chloroform in yl) -4-m eti 1-1 H-pirazo I-3-carboxylic acid methyl ester. (VII): R3 = -CH3; R4 = H; R5 = 4-Cl; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI; Z = -OCH3. A) 5- (4-Chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H-pyrazole-3-carboxylic acid. This compound is prepared according to the operating methods described in EP 0 656 354B. B) 5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H-pyrazole-3-carboxylic acid methyl ester. To a solution of 30 g of the compound obtained in the preceding step in 500 ml of MeOH, add 3 g of paratoluenesulfonic acid and heat at reflux for 2 hours. Concentrate in vacuo to half the reaction mixture, filter the formed precipitate with suction, wash with MeOH and dry. 30 g of the expected product are obtained. Preparation 1 .3 5- (4-Bromophenyl) -1 - (2,4-d-chloro-phenyl) -4-ethyl-1H-pyrazole-3-carboxylic acid. (VII): R3 = -CH2CH3; R4 = H; R5 = 4-Br; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI; Z = -OH. This compound is prepared according to the operating modes described in WO 00/46209. Following the operating modes described in Preparations 1 above, the compounds of formula (VII) set out in the following TABLE I are prepared. TABLE 1 2. Preparations of the compounds of formula (VI). Preparation 2.1 [5- (4-Bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-ylmethanol. (VI): R3 = -CH3; R4 = H; R5 = 4-Br; R6 = H; R7 = H; R8 = 4- Cl; R9 = 2-CI. A mixture of 24 g of the compound obtained in Preparation 1.1 is cooled to -10 ° C in 200 ml of THF, 7.8 ml of triethylamine are added and, dropwise, 5.38 ml of ethyl chloroformate and Allow 5 minutes with stirring at -10 ° C. Then, 6.3 g of sodium borohydride and, dropwise, 1 00 ml of MeOH are added all at once and at a temperature below -10 ° C and left for 30 minutes with stirring at 0 ° C. The reaction mixture is hydrolyzed by the addition of 100 ml of 1% HCl, concentrated in vacuo, the residue is resuspended with water, extracted with AcOEt, the organic phase is washed with a saturated solution of NaCl, Dry over MgSO4 and evaporate the solvent in vacuo. The remainder is chromatographed on silica gel eluting with the cyclohexane / AcOEt mixture (75/25; v / v). 22 g of the expected product are obtained. Preparation 2.2 [5- (4-Cl orofenyl) -1- (2,4-d-chloroform) -1-methyl-1H-pi-I-3-yl-methanol. (VI): R3 = -CH3; R4 = H; R5 = 4-Cl; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI. A solution of 30 g of the compound obtained in Preparation 1.2 is cooled to -5 ° C in 500 ml of THF and added in small portions and maintaining the temperature between -5 ° C and 0 ° C, 4.6 g of lithium aluminum hydride and left for 1 hour with stirring at RT. The reaction mixture is cooled to 0 ° C, hydrolyzed by the addition of 20 ml of 1 N NaOH, the minerals are filtered, washed with THF and the filtrate is concentrated in vacuo. The residue is extracted with ether, the organic phase is washed with a saturated solution of NaCl, dried over Na 2 SO 4 and the solvent is evaporated in vacuo. The formed precipitate is filtered off with suction, washed with ether and dried. 25 g of the expected product are obtained. Preparation 2.3 [5- (4-Bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methanol. (VI): R3 = -CH2CH3; R4 = H; R5 = 4-Br; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI. A mixture of 24.6 g of the compound obtained in Preparation 1 .3 in 200 ml of THF is cooled to -1 0 ° C, 7.8 ml of triethylamine and, dropwise, 5.38 ml of chloroformate are added. of ethyl and left for 5 minutes with stirring at -1 0 ° C. Then, 6.3 g of sodium borohydride and, dropwise, 1 00 ml of MeOH are added once and at a temperature below -10 ° C. The reaction mixture is hydrolysed at 0 ° C by the addition of 100 ml of 10% HCl and concentrated in vacuo. The residue is extracted with AcOEt, the organic phase is washed twice with 50 ml of a saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated in vacuo. The remainder is chromatographed on silica gel eluting with the cyclohexane / AcOEt mixture (60/40; v / v). 20 g of the expected product are obtained. Following the operative modes described in Preparations 2 above, the compounds of formula (VI) assembled in the following TABLE I are prepared. TABLE I I 3. Preparations of the compounds of formula (IV) Preparation 3.1 5- (4-Bromophenyl) -3- (chloromethyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H-pyrazole. (IV): R3 = -CH3; R4 = H; R5 = 4-Br; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI; Y = Cl. A solution of 20 g of the compound obtained in Preparation 2.1 in 250 ml of DCM is cooled to 0 ° C under nitrogen, and added in small portions at a temperature below 5 ° C 10, 6 g of phosphorus pentachloride and leave for 2 hours with stirring, allowing the temperature to reach RT. The reaction mixture is poured into 50 ml of a water / ice mixture and the mixture is left stirring for 10 minutes. Extract with DCM, wash the organic phase with a 5% NaHCO3 solution, with a saturated NaCl solution, dry over MgSO4 and evaporate the solvent in vacuo. 24 g of the expected product are obtained. Preparation 3.2 3- (Chloromethyl) -5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H-pyrazole. '(IV): R3 = -CH3; R4 = H; R5 = 4-Cl; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI; Y = Cl. A solution of 25 g of the compound obtained in Preparation 2.2 in 250 ml of DCM is cooled to 0 ° C under nitrogen, and added in small portions at a temperature between 0 ° C and 5 ° C. C 14.8 g of phosphorus pentachloride and leave for 3 hours with stirring allowing the temperature to reach RT. The reaction mixture is poured into 200 ml of water and left stirring for 10 minutes. After decanting, the organic phase is washed with a saturated solution of NaHCO3, with a saturated NaCl solution, dried over Na2SO and the solvent is evaporated in vacuo. 25 g of the expected product are obtained in the form of a foam. Preparation 3.3 5- (4-Bromophenyl) -3- (chloromethyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H-pyrazole. (IV): R3 = -CH2CH3; R4 = H; R5 = 4-Br; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI; Y = Cl. This compound is prepared according to the procedure described in Preparation 3.2 from 9 g of the compound obtained in Preparation 2.3 in 200 ml of DCM and 4.6 g of phosphorus pentachloride. 9.4 g of the expected product are obtained. Following the operating modes described in Preparations 3 above, the compounds of formula (IV) assembled in the following TABLE III are prepared. TABLE l l l 4. Preparations of the compounds of formula (I I). Preparation 4.1 [[5- (4-Bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] amine hydrochloride. (I I), HCl: R2 = H; R3 = -CH3; R4 = H; R5 = 4-Br; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI. To a solution of 20 g of the compound obtained in the Preparation 3.1 in 200 ml of chloroform, add 7 g of hexamethylenetetramine and leave for 5 days with stirring at RT. Then 50 ml of ether are addedThe precipitate formed is suction filtered and dried. The precipitate is resuspended in 50 ml of EtOH, 1 ml of concentrated HCl is added and the mixture is heated at 50 ° C for 5 hours. The insoluble white part is filtered and the filtrate concentrated in vacuo. The residue is re-suspended with ether, the organic phase is washed with 50 ml of 5N NaOH, dried over Na2SO and the solvent is evaporated in vacuo. The residue is resuspended with a 2N hydrochloric ether solution, the formed precipitate is filtered off with suction, washed with ether and dried. 14.37 g of the expected product are obtained. Preparation 4.2 [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] amine hydrochloride. (I I), HCl: R2 = H; R3 = -CH3; R4 = H; R5 = 4-Cl; R6 = H; R7 = H; R8 = 4-Cl; R9 = 2-CI. This compound is prepared according to the procedure described in Preparation 4.1 from 25 g of the compound obtained in Preparation 3.2 in 150 ml of chloroform, 9 g of hexamethylenetetramine, 100 ml of ether, 250 ml of EtOH and 30 ml of Concentrated HCl. 24 g of the expected product are obtained. Preparation 4.3 [[5- (4-Bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] amine hydrochloride. (II), HCl: R2 = H; R3 = -CH2CH3; R4 = H; R5 = 4-Br; R6 = H; R7 = H; R8 = 4-Cl; Rg = 2-CI. To a solution of 9 g of the compound obtained in the Preparation 3.3 in 100 ml of chloroform, 2.9 g of hexamethylenetetramine were added and the mixture was left stirring at RT for 10 days. Then 50 ml of ether are added, the mixture is left stirring for 10 minutes, the reaction mixture is concentrated in vacuo, 50 ml of ether are added again and the precipitate formed is filtered off with suction. The precipitate is resuspended in 50 ml of EtOH, added ml of concentrated HCl and reflux for 2 hours. The white insoluble part is filtered and the filtrate is concentrated in vacuo. The residue is extracted with ether, the organic phase is washed with 20 ml of NaOH 1 N, with a saturated solution of NaCl, is dried over Na 2 SO 4 and the solvent is evaporated in vacuo. The remainder is resuspended with a 2N hydrochloric ether solution and the formed precipitate is filtered off with suction. 8.5 g of the expected product are obtained. Following the operating modes described in the above Preparations 4, the compounds of formula (I I) assembled in the following TABLE IV are prepared.

TABLE IV . Preparations of the compounds of formula (11 l). Cyclohexanesulfonyl chloride.

A mixture of 25 g of cyclohexanothiol in 83 ml of acetic acid and 4 ml of water is cooled to 0 ° C, and chlorine gas is bubbled for 3 hours until the yellow color is maintained. The reaction mixture is poured into water, extracted three times with ether, the organic phases are washed twice with water, dried over Na 2 SO 4 and the solvent is evaporated in vacuo. The rest is distilled under a pressure of 4 Pa and 13.3 g of the expected product are obtained, Eb = 154 ° C.

EXAMPLE 1: Compound No. 8 N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -4- (trifluo romethyl) benzenesulfonamide.

R.5 * = H; R7 ^ H, Rβ = 4-Cl-R. = 2-C1.

To a solution of 0.7 g of the compound obtained in Preparation 4.1 in 20 ml of DCM is added 0.42 ml of triethylamine and, dropwise, 0.39 g of 4- (trifluoromethyl) benzenesulfonyl chloride and is left a night with agitation at TA. 1 ml of water are added and 10 minutes are left with stirring. After decanting, the organic phase is washed twice with a saturated solution of NaHCO3, twice with a buffer solution pH = 2, twice with a saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated in vacuo. The product obtained is crystallized from a cyclohexane / AcOEt mixture (95/5; v / v). 0.75 g of the expected product are obtained, F = 195 ° C. 1 H NMR: DMSO-d 6: d (ppm): 1.95: s: 3H; 4, 1 5: s: 2H; 7.0: d: 2H; 7.2-8, 1: m: 9H; 8.5: s: 1 H. EXAMPLE 2: Compound No. 28 N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl ] methyl] -3-chlorobenzenesulfonamide.

© Ry ~. { ¿; R6 = H R7 «H. Rβ = 4-Cl; Rp = 2-Cl.

To a solution of 0.7 g of the compound obtained in the Preparation 4.3 in 30 ml of DCM, add 0.4 ml of triethylamine and, dropwise, 0.32 g of 3-chlorobenzenesulfonyl chloride and leave overnight with stirring at RT. The reaction mixture is concentrated in vacuo, the residue is extracted with AcOEt, the organic phase is washed twice with a saturated solution of NaHCO3, twice with a buffer solution pH = 2, twice with a saturated solution of NaCl, Dry over Na2SO4 and evaporate the solvent in vacuo. The remainder is chromatographed on silica gel eluting with the cyclohexane / AcOEt mixture (90/1 0; v / v) to (75/25; v / v). The product obtained is resuspended in 1.5 ml of AcOEt, cyclohexane is added, the precipitate formed is filtered off with suction and dried. 0.31 g of the expected product are obtained, F = 169 ° C. 1 H NMR: DMSO-d 6: d (ppm): 1.0: t: 3H; 2.4: q: 2H; 4, 15: s: 2H; 7.0: d: 2H; 7.2-7.9: m: 9H; 8.4: s: 1 H. EXAMPLE 3: Compound No. 42 N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 Hp -razol-3-yl ] methyl] -1- [3- (trifl uorom eti l) phen i I-methanesulfonamide.

Ré ^ H; R7 = H, Rg ^ 4-C! R ^ -CL To a solution of 0.5 g of the compound obtained in Preparation 4.3 in 25 ml of DCM, 0.3 ml of triethylamine and 0.28 g of [3- (trifluoromethyl) phenyl] methanesulfonyl chloride are added and a night with agitation at TA. The reaction mixture is concentrated in vacuo, the residue is resuspended with water, extracted with AcOEt, the organic phase is washed with a saturated solution of NaHCO3, with a buffer solution pH = 2, with a saturated solution of NaCl, dried Na2SO4 and the solvent is evaporated in vacuo. The remainder is chromatographed on silica gel eluting with the cyclohexane / AcOEt mixture (90/1 0; v / v) to (85/15; v / v). 0.3 g of the expected compound are obtained, F = 1 08 ° C. 1 H NMR: DMSO-d 6: d (ppm): 1, 03: t: 3H; 2.5: mt: 2H; 4.23: d: 2H; 4.5: s: 2H; 7, 13: d: 2H; 7.4-7.75: m: 9H; 7.80: t: 1 H. EXAMPLE 4: Compound No. 73 N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl ] methyl] -3-chloro-N-methylbenzenesulfonamide.

Rg = H; R7 = H. RS = 4-C1 * R9 = 2-CL To a mixture of 0.41 g of compound No. 28 and 0.1 g of K2CO3 in 34 ml of DMF is added 0.05 ml of methyl iodide, heated to reflux for 2 hours and left overnight with stirring at RT. The reaction mixture is concentrated in vacuo, the residue is resuspended with water, extracted with DCM, the organic phase is washed with a buffer solution pH = 2, with a saturated solution of NaHCO3, with a saturated solution of NaCl, dried Na 2 SO 4 and the solvent is evaporated in vacuo. The remainder is chromatographed on silica gel, eluting with the cyclohexane / AcOEt mixture (90/10, v / v) to (80/20, v / v). 0.263 g of the expected compound are obtained after drying under vacuum, F = 78 ° C. The following table illustrates the chemical structures and physical properties of some examples of compounds according to the invention. In this table: - in the column "salt", "-" represents a compound in the form of a free base, while "HCl" represents a compound in the form of a hydrochloride; - in the column, "method" represents one of the analysis methods used to determine the molecular peak MH + and the retention time as described above.

TABLE I (a) Compound prepared according to the procedure described in Example 1 from the compound obtained in Preparation 4.1 and the corresponding compound of formula (11). (b) Compound prepared according to the procedure described in Example 1 from the compound obtained in Preparation 4.2 and the corresponding compound of formula (I I I). (c) Compound prepared according to the procedure described in Example 1 from the compound obtained in Preparation 4.3 and the corresponding compound of formula (III). (d) Compound prepared according to the procedure described in Example 1 from the compound obtained in Preparation 4.4 and the corresponding compound of formula (11). (e) Compound prepared according to the procedure described in Example 1 starting from the compound obtained in Preparation 4.5 and of the corresponding compound of formula (11). (f) Compound prepared according to the procedure described in Example 1 from the compound obtained in Preparation 4.6 and the corresponding compound of formula (11). (g) Compound prepared according to the procedure described in Example 1 from the compound obtained in Preparation 4.7 and the corresponding compound of formula (11). (h) Compound prepared according to the procedure described in Example 1 from the compound obtained in Preparation 4.8 and the corresponding compound of formula (11). (i) Compound prepared according to the procedure described in Example 1 from the compound obtained in Preparation 4.9 and the corresponding compound of formula (11). The compounds of formula (I) have very good affinity in vitro (Cl50 <5.10"7M) for the CB-i cannabinoid receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1 994, 350. 240-244) The antagonistic nature of the compounds of formula (I) has been demonstrated by the results obtained in models of adenylate cyclase inhibition as described in M.

Bouaboula et al. , J. Biol. Chem., 1995, 270. 13973-13980, M. Rinaldi- Carmona et al. , J. Pharmacol. Exp. Ther. , 1996, 278, 871-878 and M. Bouaboula et al. , J. Biol. Chem. , 1997, 272. 22330-22339. The toxicity of the compounds of formula (I) is compatible with their use as medicaments. Thus, according to another of its aspects, the invention relates to medicaments comprising a compound of formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid, or a solvate or hydrate of the compound of formula (I). Thus, the compounds according to the invention can be used in humans or animals, in the treatment or prevention of diseases in which the CB cannabinoid receptors are involved. For example, and without limitation, the compounds of formula (I) are useful as psychotropic drugs, mainly for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders, obsessive disorders, psychosis in general, schizophrenia, attention and hyperactivity disorders (ADHD) in hyperkinetic children, as well as for the treatment of disorders linked to the use of psychotropic substances, mainly in the case of abuse of a substance and / or dependence on a substance, including alcohol dependence and nicotinic dependence.

The compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, diseases of psychosomatic origin, attacks of panic attacks, epilepsy, movement disorders, in particular dyskinesias or Parkinson's disease, tremors and dystonia. The compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, Alzheimer's disease, as well as in the treatment of disorders of attention or surveillance. In addition, the compounds of formula (I) can be useful as neuroprotectants, in the treatment of ischemia, head injuries and in the treatment of neurodegenerative diseases: including chorea, Huntington's chorea and Tourrette's syndrome. The compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pains, peripheral acute pains or chronic pains of inflammatory origin. The compounds of formula (I) according to the invention can be used as medicaments in the treatment of disorders of appetite, appetite (for sugars, carbohydrates, drugs, alcohols and any appetizing substance) and / or eating behaviors, mainly for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin dependent diabetes and for the treatment of dyslipidemias or metabolic syndrome. In this way, the compounds of formula (I) according to the invention are useful in the treatment of obesity and the risks associated with obesity, mainly cardiovascular risks. In addition, the compounds of formula (I) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, shock. septic, chronic cirrhosis of the liver, hepatic steatosis, steatohepatitis, asthma, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, immune system diseases, especially autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases involving demyelination, plaque sclerosis, infectious and viral diseases such as encephalitis, cerebral vascular accidents and as drugs for anticancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of osteoporosis. According to the present invention, the compounds of formula (l) are especially useful for the treatment of psychotic disorders, especially schizophrenia, attention disorders and hyperactivity (ADHD) in hyperkinetic children (MBD); for the treatment of appetite and obesity disorders; for the treatment of memory and cognitive deficits; for the treatment of alcohol dependence, nicotinic dependence, that is, for alcohol withdrawal and smoking cessation. According to one of its aspects, the present invention relates to the use of a compound of formula (I), its pharmaceutically acceptable salts and 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 an active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or of a pharmaceutically acceptable salt, 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, among 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 salt, solvate or hydrate Optionally, it can be administered in unit dosage form, mixed 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 and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal, inhalation, forms of administration. Topical, transdermal, subcutaneous, intramuscular or intravenous administration, forms of rectal administration 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 the tablet form can comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg orally, the dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or several doses, preferably from 0.02 to 50 mg / kg. There may be particular cases in which higher or lower doses are appropriate; said doses are not outside the scope of 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 present invention, according to another of its aspects, also refers to a method of treating the pathologies indicated above, comprising the administration, to a patient, of an effective dose of a compound according to the invention, or of one of its salts acceptable from a pharmaceutical point of view or hydrates or solvates.

Claims (7)

1. REIVI NDICATIONS 1. Compound that corresponds to the formula (I): wherein - R - represents • (C - C7) cycloalkyl unsubstituted or substituted one or more times with an alkyl group (C ^ Cs); • cycloalkylmethyl (C3-C7) unsubstituted or substituted one or more times in the carbocycle with d-Cs alkyl); • unsubstituted or mono, di or trisubstituted phenyl with a substituent independently selected from a halogen atom, (C1-C4) alkyl, cyano, trifluoromethyl radical, trifluoromethoxy radical, S (O) nAlk group, alkylcarbonyl group (C? -C3) or phenyl; • unsubstituted or mono- or disubstituted benzyl with a substituent independently selected from a halogen atom, alkyl-Ca), alkoxy (C-? -C3) or trifluoromethyl radical; • thienyl unsubstituted or substituted with a halogen atom or with an isoxazolyl; - R2 represents a hydrogen atom or alkyl ^ -Cs); - R3 represents a hydrogen atom or alkyl-Cs); - R4, R5, R6, R7, R3 and Rg each independently represent a hydrogen atom, halogen atom, C alquilo-C7alkyloxy), d-Cs alkoxy), trifluoromethyl radical or group S (O) nAlk; - n represents 0, 1 or 2; - Alk represents (C1-C4) alkyl. in the form of a base or acid addition salt, as well as in the form of a hydrate or solvate.
2. 2. Compound of formula (I) according to claim 1, wherein: Ri represents ethyl, isopropyl or n-butyl; • cyclohexyl; • cyclohexylmethyl; • 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-ethylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 3,5-dimethylphenyl, 3-methoxyphenyl, -methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 3,5-bis (trifluoromethyl) phenyl, 2- (trifluoromethoxy) phenyl, - (trifluoromethoxy) phenyl, 2- (methylsulfonyl) phenyl, 3- (methylsulfonyl) phenyl, 3-acetylphenyl, 3-biphenyl or 2-biphenyl; • 3-chlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 3- (trifluoromethyl) benzyl or 4- (trifluoromethyl) benzyl; • 5-bromo-2-thienyl or 5 -soxazol-3-yl-2-thienyl; - R2 represents a hydrogen or methyl atom; - R3 represents methyl or ethyl; - R4 represents a hydrogen atom; - R5 is in position -4- of the phenyl and represents a bromine, chlorine, fluorine or methoxy atom; - Rß represents a hydrogen atom; - R7 represents a hydrogen atom; - R8 is in position -4- of the phenyl and represents a hydrogen atom, chlorine atom or fluorine atom; - R9 is in position -2- of the phenyl and represents a chlorine or fluorine atom; in the form of a base or acid addition salt, as well as in the form of a hydrate or solvate.
3. 3. Compound of formula (I) according to claim 1 chosen from: N - [[5- (4-brom of enyl) -1- (2,4-d iclorof in il) -4-m eti 1-1 H -pirazo I-3-yl] methyl] butane-1-sulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 W -pyrazol-3-yl] methyl] cyclohexanesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1-Ay-pyrazol-3-ylmethyl-cyclohexy-1-methanesulfonamide; N - [[5- (4-brom of enyl) -1- (2,4-d-chlorofenyl) -4-methyl-1 H-pyrazo I-3-yl] methyl] -3-chlorobenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -4-fer-butylbenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichiorof in yl) -4-methy1 H-pyrazole I-3- i I] met yl] -3-methoxy benzenesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] m and yl] -4-m-ethoxy-benzenes ulfon a measure; N - [[5- (4-bromofenyl) -1 - (2,4-dioriorof eni l) -4-methy1 H-pyrazol-3-ylmet-yl] -4- (trifluoromethyl) benzenesulfonamide; N - [[5- (4-bromofenyl) -1- (2, 4-dioriorof eni l) -4-methy1-H-pyrazole-3-i I] methyl] -2- (met ils ulfon i I) benzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -1- (3-chlorophenyl) methanesulfonamide; N - ['[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -1 - [3- (trifluoromethyl) phenyl] methanesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-chloro-4-fluorobenzenesulfonamide; N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl]] methyl] -butan or-1-sulfone; 3-Chloro-N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl]] benzenes ulfon a mide; - 4-te? C-butyl-N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] benzenesulfonamide; N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-methoxybenzenesulfonamide; - N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-cyano not benzenesulfonamide; N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -4- (trifluoromethyl) benzenesulfonamide; N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -2- (trifl uorom ethoxy) benzene sulfonamide; N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -2- (methylsulfonyl) benzenesulfonamide; 3-Chloro-N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H-pi-razo L-3-i I] methyl] -4-fluoroben sulphonates measure; - 4-bromo-N - [[5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -2-ethylbenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yI] met il] -3-ethanesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] propane-2-sulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-ylmethyl] butane-1-sulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] cyclohexanesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -1-cyclohexylmethanesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3-chlorobenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -2-chlorobenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3-methylbenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -4-ert-butyl-benzenesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -4-methoxybenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3-methoxybenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -4- (trifl uorom eti I) ben fills ulfona mida; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] met il] -3- (trif I uorom eti I) benzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -2- (trifluoromethyl) benzenesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-ylmethyl] -3- (trifluoromethoxy) benzenes ulf onamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -2- (trifluoromethoxy) benzenesulfon a ida; 3-acetyl-N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl]]]]]]]]]]]]]]]]] <-fillimethous amines; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] biphenyl-3-sulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -1 - [4- (trifluoromethyl) phenyl] methanesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 Hp -razol-3-yl] methyl] -1 - [3- (trifluoromethyl) phenyl] methanesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] -3,5-d im eti I benzenesulfone mida; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-ylmethyl] -3,5-bis (trif I uorom eti I) benzenesulf onamide; - 3-chloro- N - [[1 - (2-chlorophen-1) -5- (4-chlorophen-1) -4-methyl-1H-pyrazo I-3-yl] m eti I] benzenesulfonamide; N - [[1- (2-chlorophenyl) -5- (4-chlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -2-fluorobenzenesulfonamide; - N - [[1 - (2-chlorophenyl) -5- (4-chlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-cyanobenzenesulfonamide; N - [[1- (2-chlorophenyl) -5- (4-chlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-methoxybenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-methoxybenzenes ulphanamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-yl] methyl] -3-cyanobenzenesulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-d-chloro-phenyl) -4-ethyl-1 H -pyrazol-3-ylmethyl]] - 1 - (2-fluorophenyl) methanesulfonamide; - N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazole-3-i]] i] i]] - 1 - (4-f luorof in i) methanesulphonamide; 5-bromo-N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-yl] methyl] thiophen-2-sulfonamide; N - [[5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethyl-1 H -pyrazol-3-ylmet-yl] -5-isoxazol-3-ylthiophen-2-sulfonamide; - 3-chloro- N - [[1- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -4-methyl-1H-pyrazol-3-yl] methyl] benzenesulfonamide; N - [[1 - (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -4-methyl-1 H -pyrazol-3-yl] meth i] 3-m ethi I ben-benzenesulfonamide; in the form of a base or acid addition salt, as well as in the form of a hydrate or solvate. Process for preparing the compounds of formula (I) according to claim 1, characterized in that: a compound of the formula is reacted in the presence of a base and in a solvent: wherein R2, R3, R
4. 4, R5, R6, R7, R8 and Rg are as defined for a compound of formula (I) in claim 1, with a sulfonyl halide of the formula: wherein R ^ is as defined for a compound of formula (I) in claim 1 and Hal represents a halogen atom.
5. 5. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or an addition salt of this compound with an acid acceptable from a pharmaceutical point of view, or a hydrate or solvate of the compound of formula (I)
6. 6. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient.
7. 7. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment and prevention of appetite disorders, gastrointestinal disorders, inflammatory phenomena, diseases of the immune system, psychotic disorders , of alcohol dependence or nicotinic dependence.