JP2008019205A - N-[(1,5-diphenyl-1h-pyrazol-3-yl)methyl]sulfonamide derivative, method for preparing the same and its application in treatment - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new N-[(1,5-diphenyl-1H-pyrazol-3-yl)methyl]sulfonamide derivative having antagonist properties of cannabinoid receptor CB<SB>1</SB>, localized to a central and/or peripheral level. <P>SOLUTION: The compound is represented by formula (I). The compound is used for preparing a medicinal product. The compound is applied to treatment. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to N-[(1,5-diphenyl-1H-pyrazol-3-yl) methyl] sulfonamide derivatives, their preparation and their application in therapy.

Diphenylpyrazole derivatives exhibiting affinity for the cannabinoid receptor CB ₁ are disclosed, inter alia, in EP 0 576 357, 0 656 354 and US 5 624 941.

International patent application WO2005 / 073 197 discloses an antagonist of cannabinoid receptor CB ₁ N- [1,5- diphenyl-4-methyl -1H- pyrazole-3 -yl) methyl] sulfonamide derivatives .

Novel N-[(1,5-diphenyl-1H-pyrazol-3-yl) methyl] sulfonamide derivatives having antagonistic properties of cannabinoid receptor CB _{1 now} localized at the central and / or peripheral level Was discovered.

  The present invention relates to a compound corresponding to the following formula (I)

［式中、
Ｒ_１は、
非置換の、またはフッ素原子、ヒドロキシル、（Ｃ_１〜Ｃ_４）アルコキシ、（Ｃ_１〜Ｃ_４）アルキルチオ、フェノキシ、トリフルオロメトキシ基、ジフルオロメトキシ基、ジフルオロメチルチオ基、トリフルオロメチルチオ基から独立に選択される置換基によって１回または複数回置換されている（Ｃ_１〜Ｃ_１２）アルキル；
非置換の、または（Ｃ_１〜Ｃ_４）アルキル、（Ｃ_１〜Ｃ_４）アルコキシ、（Ｃ_１〜Ｃ_４）アルキルチオ、フッ素原子、ヒドロキシル、トリフルオロメチル、ジフルオロメチル、トリフルオロメトキシ、ジフルオロメトキシ、トリフルオロメチルチオ、ジフルオロメチルチオ基から独立に選択される置換基によって１回または複数回置換されている非芳香族の（Ｃ_３〜Ｃ_１２）炭素環基；
（Ｃ_１〜Ｃ_４）アルキル、（Ｃ_１〜Ｃ_４）アルコキシ、（Ｃ_１〜Ｃ_４）アルキルチオ、フッ素原子、ヒドロキシル、トリフルオロメチル、ジフルオロメチル、トリフルオロメトキシ、ジフルオロメトキシ、トリフルオロメチルチオ、ジフルオロメチルチオ基から独立に選択される置換基によって１回または複数回置換されているまたは置換されていない非芳香族の（Ｃ_３〜Ｃ_１２）炭素環基によって置換されているメチル；
フェニル、ベンジル、ベンズヒドリル、ベンズヒドリルメチル基（各フェニル基は、ハロゲン原子、ヒドロキシル、メチレンジオキシ、シアノ、ニトロ、（Ｃ_１〜Ｃ_４）アルキルカルボニル基、またはＡｌｋ、ＯＡｌｋ、Ｓ（Ｏ）_ｎＡｌｋもしくはＯＳ（Ｏ）_ｎＡｌｋ基から独立に選択される置換基によって１回または複数回置換されているまたは置換されていない。）；
ピロリル、イミダゾリル、ピリジルまたはピラゾリルから選択される複素環基によって置換されているフェニル基（前記複素環基は、ハロゲン原子または（Ｃ_１〜Ｃ_４）アルキル基から独立に選択される１つまたは複数の置換基によって１回または複数回置換されているまたは置換されていない。）；
フェニル基（各フェニル基は、ハロゲン原子、ヒドロキシル、メチレンジオキシ、シアノ、ニトロ、（Ｃ_１〜Ｃ_４）アルキルカルボニル基、またはＡｌｋ、ＯＡｌｋ、Ｓ（Ｏ）_ｎＡｌｋもしくはＯＳ（Ｏ）_ｎＡｌｋ基から独立に選択される置換基によって１回または複数回置換されているまたは置換されていないフェニルまたはフェノキシによって置換されている。）；
チエニル、フリル、オキサゾリル、チアゾリル、イミダゾリル、ピロリル、ピリジル基（前記基は、ハロゲン原子、（Ｃ_１〜Ｃ_４）アルキル、トリフルオロメチル基から独立に選択される１つまたは複数の置換基によって置換されているまたは置換されていない。）；
非置換の、またはハロゲン原子、（Ｃ_１〜Ｃ_４）アルキル、ジ（Ｃ_１〜Ｃ_４）アルキルアミノまたはトリフルオロメチル基から独立に選択される１つまたは複数の置換基によって置換されているテトラヒドロナフタレニルまたはナフチル；
非置換の、または（Ｃ_１〜Ｃ_４）アルキル基によって１回または複数回置換されている２，３−ジヒドロベンゾフラニル；
インドール−２−イルまたはＮ−メチルインドール−２−イル
を表し、
Ｒ_２は、水素原子、（Ｃ_１〜Ｃ_４）アルキルまたは（Ｃ_１〜Ｃ_４）アルキルスルホニル基を表し、
Ｒ_３は、シアノ、ヒドロキシル、（Ｃ_１〜Ｃ_４）アルコキシ、シアノメチル、ヒドロキシメチル、（Ｃ_１〜Ｃ_４）アルコキシメチル、フルオロメチル、テトラゾリルメチル、Ｎ−（メチル）テトラゾリルメチル、テトラゾリル、Ｎ−（メチル）テトラゾリル、ＣＯＮＲ_６Ｒ_７基、ＣＨ_２Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_４）アルキル基、ＣＯＯＲ_８基またはＣＨ_２ＮＲ_６Ｒ_７基を表し、
Ｒ_４およびＲ_５はそれぞれ独立にフェニルを表し（このフェニル基は、ハロゲン原子によって、フッ素原子により１回または複数回置換されているまたは置換されていない（Ｃ_１〜Ｃ_７）アルキル基、ＯＡｌｋ、Ｓ（Ｏ）_ｎＡｌｋまたはＯＳ（Ｏ）_ｎＡｌｋ基から独立に選択される１つまたは複数の置換基によって置換されているまたは置換されていない。）、
Ｒ_６およびＲ_７はそれぞれ独立に、水素原子または（Ｃ_１〜Ｃ_４）アルキルを表すか、または、
Ｒ_６およびＲ_７は、これらが結合している窒素原子と一緒になって、非置換の、または（Ｃ_１〜Ｃ_４）アルキルによって１回または複数回置換されているピロリジニル、ピペリジニル、モルホリニル、ピペラジニルから選択される複素環基を構成し、
Ｒ_８は（Ｃ_１〜Ｃ_４）アルキルを表し、
ｎは、０、１または２を表し、
Ａｌｋは、非置換の、またはフッ素原子によって１回または複数回置換されている（Ｃ_１〜Ｃ_４）アルキルを表す。］。

[Where:
R ₁ is
Independently of unsubstituted or fluorine atom, hydroxyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio, phenoxy, trifluoromethoxy group, difluoromethoxy group, difluoromethylthio group, trifluoromethylthio group (C ₁ -C ₁₂ ) alkyl substituted one or more times by selected substituents;
Non substituted, or _(C 1 _{~C 4) alkyl, (C} 1 _{~C 4) alkoxy, (C} 1 _{~C 4)} alkylthio, a fluorine atom, a hydroxyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy A non-aromatic (C ₃ -C ₁₂ ) carbocyclic group substituted one or more times by a substituent independently selected from a trifluoromethylthio, difluoromethylthio group;
(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio, fluorine atom, hydroxyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, Methyl substituted by a substituent selected independently from a difluoromethylthio group one or more times, or by a non-aromatic (C ₃ -C ₁₂ ) carbocyclic group;
Phenyl, benzyl, benzhydryl, benzhydryl methyl (each phenyl group may be substituted with a halogen atom, hydroxyl, methylenedioxy, cyano, _{nitro, (C} 1 -C ₄₎ alkylcarbonyl group, or Alk,, OAIk, S (O) _n Alk or OS (O) _n substituted or unsubstituted one or more times by substituents independently selected from _n Alk groups);
A phenyl group substituted by a heterocyclic group selected from pyrrolyl, imidazolyl, pyridyl or pyrazolyl (wherein the heterocyclic group is one or more independently selected from a halogen atom or a (C ₁ -C ₄ ) alkyl group) Substituted or unsubstituted one or more times by the substituents of
Phenyl group (each phenyl group is a halogen atom, hydroxyl, methylenedioxy, cyano, nitro, (C ₁ -C ₄ ) alkylcarbonyl group, or Alk, OAlk, S (O) _n Alk or OS (O) _n Alk Substituted by phenyl or phenoxy, substituted or unsubstituted one or more times by substituents independently selected from groups);
A thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, pyridyl group (wherein the group is substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, trifluoromethyl groups) Or not substituted);
Unsubstituted or substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, di (C ₁ -C ₄ ) alkylamino or trifluoromethyl groups Tetrahydronaphthalenyl or naphthyl;
2,3-dihydrobenzofuranyl which is unsubstituted or substituted one or more times by a (C ₁ -C ₄ ) alkyl group;
Represents indol-2-yl or N-methylindol-2-yl,
R ₂ represents a hydrogen atom, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkylsulfonyl group,
R ₃ is cyano, hydroxyl, (C ₁ -C ₄ ) alkoxy, cyanomethyl, hydroxymethyl, (C ₁ -C ₄ ) alkoxymethyl, fluoromethyl, tetrazolylmethyl, N- (methyl) tetrazolylmethyl, Represents tetrazolyl, N- (methyl) tetrazolyl, CONR ₆ R ₇ group, CH ₂ S (O) _n (C ₁ -C ₄ ) alkyl group, COOR ₈ group or CH ₂ NR ₆ R ₇ group,
R ₄ and R ₅ each independently represent phenyl (this phenyl group is substituted by a halogen atom one or more times by a fluorine atom or is not substituted (C ₁ -C ₇ ) alkyl group, OAlk , Substituted or unsubstituted by one or more substituents independently selected from the group S (O) _n Alk or OS (O) _n Alk).
R ₆ and R ₇ each independently represent a hydrogen atom or (C ₁ -C ₄ ) alkyl, or
R ₆ and R ₇ together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl, morpholinyl, unsubstituted or substituted one or more times by (C ₁ -C ₄ ) alkyl Constituting a heterocyclic group selected from piperazinyl;
R ₈ represents (C ₁ -C ₄ ) alkyl;
n represents 0, 1 or 2;
Alk represents (C ₁ -C ₄ ) alkyl which is unsubstituted or substituted one or more times by fluorine atoms. ].

  The compound of formula (I) may contain one or more asymmetric carbon atoms. Thus, this compound can exist in the form of enantiomers or diastereoisomers. Such enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, form part of the present invention.

  The compounds of formula (I) can exist in the form of bases or acid addition salts. Such addition salts form part of the present invention.

  These salts are advantageously prepared with pharmaceutically acceptable acids, but other acid salts that can be used to purify or isolate 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, ie in the form of associations or conjugates with one or more water molecules or solvents. Such hydrates and solvates also form part of the invention.

  “Halogen atom” means an atom of bromine, chlorine, fluorine or iodine.

“(C ₁ -C ₄ ) alkyl or (C ₁ -C ₇ ) alkyl or (C ₁ -C ₁₂ ) alkyl respectively” means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- A butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl group or the like means 1 to 4 carbon atoms or a linear or branched alkyl group of 1 to 7 or 1 to 12 carbon atoms, respectively.

“(C ₁ -C ₄ ) alkyl substituted one or more times by a fluorine atom” specifically means a difluoromethyl, trifluoromethyl, difluoromethyl, trifluoroethyl group.

“(C ₁ -C ₄ ) alkoxy” means ₁ to ₄ carbon atoms or 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy group, etc. Or a straight or branched alkoxy group.

“(C ₃ -C ₇ ) cycloalkyl” means a cyclic alkyl group of 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl group and the like.

  “Tetrazolyl” means a tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl group.

More particularly, the present invention provides:
R ₁ is
_(C 1 ~C ₇₎ alkyl;
(C ₃ -C ₇ ) cycloalkyl which is unsubstituted or substituted one or more times by a (C ₁ -C ₄ ) alkyl group;
(C ₃ -C ₇ ) cycloalkylmethyl which is unsubstituted or substituted one or more times on the carbocycle by a (C ₁ -C ₄ ) alkyl group;
Unsubstituted or halogen atom, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, trifluoromethyl group, trifluoromethoxy group, S (O) _n Alk group, (C _1- C ₄ ) an alkylcarbonyl group, phenyl substituted by one or more substituents independently selected from phenyl;
Benzyl that is unsubstituted or substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, trifluoromethyl groups;
A thienyl, furyl, oxazolyl, thiazolyl, imidazolyl group (wherein said group is substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, trifluoromethyl groups or Not substituted);
Naphthyl that is unsubstituted or substituted by one or more substituents independently selected from (C ₁ -C ₄ ) alkyl, di (C ₁ -C ₄ ) alkylamino;
Represents 2,3-dihydrobenzofuranyl which is unsubstituted or substituted one or more times by a (C ₁ -C ₄ ) alkyl group,
R ₂ represents a hydrogen atom or (C ₁ -C ₄ ) alkyl,
R ₃ is cyano, hydroxyl, (C ₁ -C ₄ ) alkoxy, cyanomethyl, hydroxymethyl, (C ₁ -C ₄ ) alkoxymethyl, fluoromethyl, tetrazolylmethyl, N- (methyl) tetrazolylmethyl, Represents tetrazolyl, N- (methyl) tetrazolyl, CONR ₆ R ₇ group, CH ₂ S (O) _n Alk group, COOR ₈ group,
R ₄ and R ₅ are each independently selected from unsubstituted or halogen atoms, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₄ ) alkoxy, trifluoromethyl groups or S (O) _n Alk Represents phenyl substituted by one or more substituents,
R ₆ and R ₇ each independently represent a hydrogen atom or (C ₁ -C ₄ ) alkyl, or R ₆ and R ₇ together with the nitrogen atom to which they are attached, are unsubstituted Or a heterocyclic group selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl substituted one or more times by (C ₁ -C ₄ ) alkyl,
R ₈ represents (C ₁ -C ₄ ) alkyl;
n represents 0, 1 or 2,
It relates to compounds corresponding to formula (I), in which Alk represents (C ₁ -C ₄ ) alkyl.

Among the compounds of formula (I) according to the invention,
_A compound of formula IA wherein R ₃ is cyano;
R ₃ is A compound of formula _{I B} is hydroxyl;
R _{3 is,} compounds of formula _{I C} is a _(C 1 _{~C 4)} alkoxy;
A compound of formula _{ID wherein} R ₃ is cyanomethyl;
A compound of formula _{IE wherein} R ₃ is hydroxymethyl;
R _{3 is,} compounds of formula _{I F} is _(C 1 _{~C 4)} alkoxymethyl;
R ₃ is A compound of formula _{I G} is fluoromethyl;
A compound of formula I _{H wherein} R ₃ is a CH ₂ S (O) _n Alk group;
A compound of formula I _{I wherein} R ₃ is a CONR ₆ R ₇ group;
R ₃ is A compound of formula _{I J} is COOR _8;
R ₃ is a compound of Formula _{I K} is a tetrazol-5-yl;
R ₃ is A compound of formula _{I L} is N- (methyl) tetrazol-5-yl;
R ₃ is A compound of formula _{I M} is a tetrazol-5-ylmethyl;
R ₃ is a compound of Formula _{I N} is N- (methyl) tetrazol-5-ylmethyl;
A compound of formula I 2 _{O wherein} R ₃ is tetrazol-1-ylmethyl or tetrazol-2-ylmethyl;
As R ₃ is _the distinction between a compound of formula _{I P} is CH 2 _NR 6 _{R 7} group is made, group _Alk, R 6, _{R 7} and _{R 8} are as defined below for (I) It is.

Among the compounds of formula (I) which are the object of the present invention, in the form of bases or acid addition salts, as well as in the form of hydrates or solvates,
R ₁ is
Phenyl, benzyl, benzhydryl, benzhydryl methyl (phenyl group, a halogen atom, _{hydroxyl, (C} 1 -C _{4) alkyl, (C} 1 -C ₄₎ alkoxy, methylenedioxy, cyano, nitro, trifluoromethyl , Difluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, difluoromethylthio, S (O) _n Alk group, OS (O) _n Alk group, (C ₁ -C ₄ ) alkylcarbonyl group independently selected Substituted or unsubstituted one or more times by a substituent));
Represents a furyl group which is unsubstituted or substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, trifluoromethyl groups;
R ₂ represents a hydrogen atom or a (C ₁ -C ₄ ) alkylsulfonyl group,
R ₃ is cyano, hydroxyl, (C ₁ -C ₄ ) alkoxy, hydroxymethyl, (C ₁ -C ₄ ) alkoxymethyl, CONR ₆ R ₇ group, COOR ₈ group, tetrazol-1-ylmethyl or tetrazol-2-ylmethyl The groups R ₆ , R ₇ , R ₈ are the same as defined for (I),
R ₄ represents 4-chlorophenyl, 4-methoxyphenyl or 4-OSO ₂ -Alk, and Alk represents (C ₁ -C ₄ ) alkyl which is unsubstituted or substituted one or more times by a fluorine atom. ,
Compounds in which R ₅ represents 2-chlorophenyl, 2-bromophenyl or 2,4-dichlorophenyl are preferred.

More particularly, in the form of bases or acid addition salts, as well as hydrates or solvates.
R ₁ is 3-chlorophenyl, 3-fluorophenyl, 3,6-difluorophenyl, 2,6-difluorophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, benzyl, 4- Represents a trifluoromethylbenzyl or 2-trifluoromethyl-4-methylfuryl group,
R ₂ represents a hydrogen atom,
R ₃ represents a cyano, methoxy or dimethylaminocarbonyl group,
R ₄ represents 4-chlorophenyl, 4-methoxy or 4-propanesulfonyloxy,
Preference is given to compounds of the formula (I) in which R ₅ represents 2,4-dichlorophenyl or 2-chlorophenyl.

In particular, the following compounds in the form of bases or acid addition salts as well as hydrates or solvates are preferred:
-N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-cyanobenzenesulfonamide,
-N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-trifluorobenzenesulfonamide,
-N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -2-trifluoromethoxybenzenesulfonamide;
-N-([5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-methoxybenzenesulfonamide,
-N-([5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-chlorobenzenesulfonamide,
-N-{[5- (4-chlorophenyl) -4-cyano-1- (2-chlorophenyl) -1H-pyrazol-3-yl] methyl} -3-fluorobenzenesulfonamide,
-N-{[5- (4-chlorophenyl) -4-cyano-1- (2-chlorophenyl) -1H-pyrazol-3-yl] methyl} -2-fluorobenzenesulfonamide,
-N-{[5- (4-chlorophenyl) -4-cyano-1- (2-chlorophenyl) -1H-pyrazol-3-yl] methyl} -2-trifluoromethoxybenzenesulfonamide,
-N-{[5- (4-methoxyphenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3.5-difluorobenzenesulfonamide;
-N-{[5- (4-propanesulfonyloxyphenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3.5-difluorobenzenesulfonamide,
-N-{[5- (4-chlorophenyl) -4-methoxy-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-chlorobenzenesulfonamide;
-5- (4-chlorophenyl) -3-({[(3-chlorophenyl) sulfonyl] amino} methyl) -1- (2,4-dichlorophenyl) -N-methyl-1H-pyrazole-4-carboxamide;
-N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -1-phenylmethanesulfonamide,
—N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -5-methyl-2- (trifluoromethyl) furan -3-sulfonamide.

  According to the invention, the compound of formula (I) is a compound of the formula

［式中、Ｒ_２、Ｒ_４、Ｒ_５は、式（Ｉ）の化合物に対して定義された通りであり、Ｒ’_３は、Ｒ_３またはＲ_３の前駆体を表す。］
を、塩基および溶媒の存在下、式ＨａｌＳＯ_２Ｒ_１［式中、Ｒ_１は、式（Ｉ）の化合物に対して定義された通りであり、Ｈａｌは、ハロゲン原子を表す。］のハロゲン化スルホニルと反応させることを特徴とする方法に従って調製することができる。

[Wherein R ₂ , R ₄ , R ₅ are as defined for the compound of formula (I), and R ′ ₃ represents R ₃ or a precursor of R ₃ . ]
The presence of a base and a solvent, wherein HalSO ₂ R ₁ [in the formula, _{R 1} is as defined for compounds of formula (I), Hal represents a halogen atom. The compound can be prepared according to a method characterized by reacting with a sulfonyl halide.

  Where appropriate, the resulting compound:

［式中、Ｒ’_３は、Ｒ_３またはＲ_３の前駆体である。］
を、式（Ｉ）の化合物に転換する。

[Wherein R ′ ₃ is a precursor of R ₃ or R ₃ . ]
Is converted to a compound of formula (I).

  In some cases, the compound of formula (I) is converted to one of its acid addition salts.

Compounds of formula (I) in which R ₂ represents (C ₁ -C ₃ ) alkyl are the corresponding compounds of formula (I) in which R ₂ represents a hydrogen atom by methods selected from methods known to those skilled in the art It can also be prepared from Among the latter, we can mention alkylation with alkyl halides, reductive amination with aldehydes in a reducing medium, or acylation with acyl chloride followed by reduction.

Compounds of formula (I) in which R ₂ represents a _(C 1 ~C ₄₎ alkylsulfonyl, R ₂ using methods known to those skilled in the art replacing the compound of formula (I) is a hydrogen atom Can be prepared.

By “precursor of R ₃ ” is meant a group that can be readily converted to the substituent R ₃ according to the present invention.

  According to the method of the present invention, the coupling reaction between the compound of formula (II) and the sulfonyl halide is carried out at room temperature and the reflux temperature of the solvent in a solvent such as dichloromethane or tetrahydrofuran in the presence of a base such as triethylamine or diisopropylethylamine. At a temperature between.

  The compound of formula (I) thus obtained can then be separated from the reaction mixture and purified by classical methods such as crystallization or chromatography.

In the case of the compound of formula (I _E ), the precursors of the groups R ′ ₃ and R ₃ represent a CH ₂ OTHP (tetrahydropyranyloxymethyl) group.

  Compounds of the following formula obtained by the process according to the invention

は、次いで、酸媒体中で加水分解されてＲ_３がヒドロキシメチルである式（Ｉ_Ｅ）の化合物が得られる。

Is then hydrolyzed in an acid medium to give a compound of formula (I _E ) wherein R ₃ is hydroxymethyl.

Compounds of formula (I _C ; R ₃ = (C ₁ -C ₄ ) alkoxy) are obtained by dealkylation, for example by the action of BBr ₃ or HBr, to obtain compounds of formula (I _B ; R ₃ = OH) Can be used.

In order to obtain compounds of formula (I _I ) to formula (I _M ) in which R ₃ is of various values, the hydroxylmethyl group is converted using an appropriate process known to those skilled in the art. Can do.

Formula _(I K; _{R 3} = tetrazolyl) and formula _(I M; _{R 3} = tetrazolylmethyl) compounds also formula _{(I A; R 3 = CN} ) and formula _{(I D; R 3 = CH} 2 CN) Can be prepared from

Intermediates of formula (II) can be prepared in various ways depending on the value of the substituent R ₃ .

When R ₃ represents cyano, the following reaction scheme is employed.

The compounds of formula (IV) are prepared according to the methods disclosed in patent application WO2005 / 000820. Selective reduction of the ester functional group with KBH ₄ or LiAlH ₄ is carried out in step a1. The compound of formula (V) is halogenated in step b1, for example with PCl ₅ . The compound of formula (VI) thus obtained is then treated with potassium phthalimido and then hydrazine hydrate is reacted in step d1 in alcohol to give a compound of formula (II) in which the substituent R ₃ is cyano. The compound of formula (VIII) corresponding to the intermediate is obtained.

When R ₃ represents (C ₁ -C ₄ ) alkoxy, the corresponding intermediate of formula (II) is prepared according to the following reaction scheme.

In step a2, the arylbutane-1,3-dione derivative (X) is prepared by acting acetone, and a hydride such as sodium hydride, on the ester R ₄ CO ₂ Et in THF. The compound of formula (XI) is obtained by bromination and the subsequent acetylation in step c2 produces the compound of formula (XII). In step d2, the action of arylhydrazine hydrochloride results in a mixture of the compound of formula (XIII) and the compound of formula (XIV). The compound of formula (XIV) is hydrolyzed and converted to the compound of formula (XIII). The compound of formula (XIII) is then treated with a halogenated (C ₁ -C ₄ ) alkyl of formula AlkI to produce a compound of formula (XV). In stage g2, the action of N-bromosuccinimide (NBS) is used to prepare the compound of formula (XVI), then in stage h2, the action of hexamethylenetetramine is used to give R ₃ as (C _1- A compound of formula (XVII) corresponding to an intermediate of formula (II) which is C ₄ ) alkoxy is produced.

  In stage g2, bromination can also result in a dibrominated compound of formula (XVIII). Starting from this compound, the compound of formula (XVII) can be prepared according to the following reaction scheme.

  In step a3, the dibrominated derivative of formula (XVIII) is treated with DMSO to give the aldehyde of formula (XIX), then in step b3 the reduction with a metal hydride, such as sodium or potassium borohydride, This results in a compound of (XX). In step c3, the addition of phthalimide is carried out in the presence of diethyl azodicarboxylate (DEAD). The compound of formula (XXI) thus obtained is then treated with hydrazine hydrate to produce the compound of formula (XVII).

When R ₃ represents cyanomethyl, (C ₁ -C ₄ ) alkoxymethyl, fluoromethyl or (C ₁ -C ₄ ) alkylthiomethyl group, the corresponding intermediate of formula (II) follows the reaction scheme shown below Prepare.

  The compound of formula (XXII) is disclosed in EP 576 357.

  In step a4, the methyl group of the compound of formula (XXII) is brominated by the action of NBS.

In step b4, the bromine is replaced by a nucleophilic group X selected from a fluorine atom, cyano, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio. The ester functional group is then reduced by a reducing agent such as LiAlH ₄ or KBH ₄ to produce a compound of formula (XXV). In step d4, this compound is treated with an agent such as PCl ₅ to give a compound of formula (XXVI). In step e4, the sequential action of potassium phthalimide and hydrazine or hexamethylenetetramine and hydrochloric acid results in the formation of a compound of formula (XXVIII) corresponding to a compound of formula (II) where R ₂ is CH ₂ X.

When R ₃ represents a CH ₂ SOAlk or CH ₂ SO ₂ Alk group, the corresponding intermediate of formula (II) is prepared by an oxidation reaction from an intermediate of formula (XXIV) where X = SAlk, and X = An intermediate of formula (XXIV) is obtained which is SOAlk or SO ₂ Alk. The oxidizing agent can be metachloroperbenzoic acid or alternatively hydrogen peroxide. The intermediate of formula (XXIV) is then treated as in formula 4.

In order to prepare an intermediate of formula (II) in which R ′ ₃ is a precursor of hydroxymethyl, ie a tetrahydropyranyloxymethyl group (CH ₂ OTHP), the following reaction scheme is followed.

Step a5 is performed in the same manner as described above for step a4. In step b5, substitution of bromine with OH group and hydrolysis of the ester in basic medium yields a compound of formula (XXVIII). This compound is esterified in an acidic medium to produce a compound of formula (XXIX), and then in step d5 the hydroxyl group is protected by a group such as tetrahydropyranyl or t-butoxymethyl. Steps e5, f5 and g5 then prepare compounds of formula (XXXIII) corresponding to intermediates of formula (II) where R ′ ₃ is a tetrahydropyranyloxymethyl group, as described above for formula 1. To implement.

  The process according to the invention is applied to a compound of formula (XXXIII) to prepare a compound of the formula

In order to obtain a compound according to the invention of formula (I) wherein R ₃ is hydroxymethyl, the compound of formula (XXXIII) is treated in an alcoholic solvent such as methanol in an acid medium.

  From the compound of the following formula thus obtained,

以下の式のピラゾール−カルボン酸誘導体を酸化によって調製する。

A pyrazole-carboxylic acid derivative of the following formula is prepared by oxidation.

  The compounds of the following formulas according to the present invention can then be prepared using methods known to those skilled in the art.

Starting from the compound according to the invention of the formula R ₃ is hydroxymethyl or cyanomethyl (XXXV) or (XXXX), according to one of the following reaction scheme, wherein R ₃ is tetrazolylmethyl (I ) Of the compounds according to the invention can be prepared.

Starting from a compound according to the invention of formula (I) in which R ₃ represents cyano, a compound of formula (I) in which R ₃ represents tetrazolyl by the action of tributyltin azide in a solvent such as xylene according to the following reaction scheme: Can be prepared.

Where appropriate, compounds according to the invention of the formula (I) in which R ₃ is N- (methyl) tetrazolyl or N- (methyl) tetrazolylmethyl are prepared by alkylating tetrazole with an alkylating agent. .

When R ₃ represents the group —CH ₂ NR ₆ R ₇ , the compound of formula (II) is prepared by the following reaction scheme.

The oxidation in step a9 is Heterocyclic. Chem. 1997, 34, 963, for example by the action of pyridinium chlorochromate.
Reductive amination is carried out in step b9.

  In step c9, the resulting compound of formula (XXXXIV) is treated according to steps e5, f5 and g5 described in formula 5 to give the compound of formula (II).

  The following examples illustrate the preparation of some compounds according to the present invention. These examples are non-limiting and are merely illustrative of the invention. For compound example numbers, refer to the numbers shown in Tables 1 and 2 below, which show the chemical structure and physical properties of some compounds according to the invention.

The following abbreviations are used in the preparation methods and examples.
Ether: Diethyl ether isoether: Diisopropyl ether DMSO: Dimethyl sulfoxide DMF: N, N-dimethylformamide THF: Tetrahydrofuran DCM: Dichloromethane AcOEt: Ethyl acetate MeOH: Methanol EtOH: Ethanol AcOH: Acetic acid DIPEA: Diisopropylethylamine TFA: Trifluoroacetic acid 2N hydrochloric acid ether: 2N hydrochloric acid diethyl ether solution NBS: N-bromosuccinimide AIBN: 2,2′-azobis (2-methylpropionitrile)
PPh ₃ : Triphenylphosphine DEAD: Diethyl azodicarboxylate PTSOH: Paratoluenesulfonic acid BOP: Benzotriazol-1-yloxotris (dimethylamino) phosphonium hexafluorophosphate m. p. : Melting point RT: room temperature b. p. : Boiling point HPLC: high performance liquid chromatography Silica H: silica gel 60H commercially available from Merck (Darmstadt)
Buffer solution pH = 2: a solution of 16.66 g of KHSO ₄ and 32.32 g of K ₂ SO _{4 in} 1 liter of water

Proton nuclear magnetic resonance spectra ( ¹ H-NMR) are recorded in DMSO-d ₆ at 200 MHz. The chemical shift δ is expressed in parts per million (ppm). The following abbreviations are used to interpret the spectrum: spectrum: s: singlet, d: doublet, t: triplet, q: quartet, m: massive, mt: multiplet, bs: Broad singlet, dd: doublet doublet is used.

The compounds according to the invention are analyzed by the LC / UV / MS combination (liquid chromatography / UV detection / mass spectrometry). The molecular peak (MH ⁺ ) and retention time (tr) in minutes are measured.

Condition A:
Column used: Symmetry C18, 2.1 × 50 mm, 3.5 μm, 30 ° C., flow rate 0.4 ml / min The eluent has the following composition.

Solvent A: 0.005% aqueous solution of trifluoroacetic acid (TFA) at pH 3.15 Solvent B: 0.005% TFA acetonitrile solution

  UV detection is performed at λ = 210 nm and mass detection is performed in positive ESI (electrospray ionization) chemical ionization mode.

Condition MS2
Column used: XTERRA MS C18, 2.1 × 30 mm, 3.5 μm, flow rate 0.8 ml / min The eluent has the following composition.

Solvent A: 0.025% TFA aqueous solution Solvent B: 0.025% TFA acetonitrile solution

  UV detection is performed with an iodine array detector between 210 nm and 400 nm, and mass detection is performed in positive ESI mode.

Condition MS5
These conditions for LC / MS analysis are similar to condition MS2 and the flow rate is 1 ml / min.

Preparation 1
3- (aminomethyl) -1- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazole-4-carbonitrile hydrochloride A) 1- (2,4-dichlorophenyl) -3-hydroxy Methyl-5- (4-methoxyphenyl) -1H-pyrazole-4-carbonitrile 4-cyano-1- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazole-3-carboxylic acid A solution of 11.5 g of ethyl (prepared according to patent application WO2005 / 000820) in 150 ml of THF is prepared, 1.8 g of KBH ₄ and 1.5 g of LiCl are added, then this is stirred at room temperature overnight and refluxed for 2.5 hours. Heat. The reaction mixture is cooled to room temperature, then filtered and washed with THF. The filtrate is evaporated to dryness, then the residue is diluted with AcOEt and washed with water. The organic layer is dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue is triturated in pentane and then filtered. 10 g of the expected compound is obtained.

B) 7.2 g of 3- (chloromethyl) -1- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazole-4-carbonitrile PCl ₅ were obtained in the previous step. 10 g of the above compound are added in portions to a solution of 200 ml DCM and this is stirred at 0 ° C. for 20 minutes and then at room temperature for 24 hours. The reaction mixture is poured onto a water / ice mixture, then the organic layer is separated and the aqueous phase is extracted again with DCM. The organic layers are combined and dried over Na ₂ SO ₄ then filtered and evaporated to dryness. The residue is triturated in pentane to give 9.3 g of the expected compound.

C) 1- (2,4-Dichloromethyl) -3-((1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl) -5- (4-methoxy) -1H- Pyrazole-4-carbonitrile 5.3 g of potassium phthalimide and 3.5 g of NaI are added to a solution of 9.3 g of the compound obtained in the previous step in 100 ml of DMF, which is heated at 65 ° C. for 2.5 hours. . After returning to room temperature, the DMF is evaporated, then the residue is dissolved in AcOEt and washed with 1N aqueous NaOH. The organic layer is dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue is dissolved in DCM and washed with 1N aqueous NaOH and then with a saturated NaCl solution. The organic layer is dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the desired compound. (P = 10.53)

D) 3- (Aminomethyl) -1- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazole-4-carbonitrile hydrochloric acid 10.5 g of the phthalimide derivative obtained in the previous step Is suspended in 250 ml of ethanol, 2.1 ml of hydrazine monohydrate is added and this is heated under reflux for 1 hour. The reaction mixture is filtered and then the organic layer is evaporated to dryness. Dissolve the residue in ether and add HCl in ethereal hydrochloric acid. The formed precipitate is filtered and then rinsed with pentane. 5 g of the expected compound is obtained, with a melting point of 128 ° C.

Preparation 2
1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazol-3-yl) methanamine LC / MS analysis is performed according to Condition A.

A) A solution prepared by dissolving 45 g of ethyl 1- (4-chlorophenyl) butane-1,3-dione 4-chlorobenzoate in 235 ml of anhydrous THF and a solution of 19.50 g of NaH (60% in mineral oil) dissolved in 235 ml of anhydrous THF. Place the containing mixture under nitrogen. 36 ml of acetone and an additional 750 ml of anhydrous THF are added dropwise at 0 ° C. and this is heated under reflux for 3 hours. The mixture is acidified to pH = 5 by adding 2N HCl, then extracted with ether, washed with water, then with a saturated solution of NaHCO ₃ , dried over MgSO ₄ and concentrated. The crude product is dissolved in a minimum amount of toluene, the insolubles are filtered and then purified by chromatography on silica, eluting with a cyclohexane / AcOEt mixture (95/5; v / v). 47.9 g of the expected compound are obtained.
LC / MS: MH ⁺ = 197.0; tr = 9.67 min.

B) 2-Bromo-1- (4-chlorophenyl) butane-1,3-dione 15.35 g of the compound from the previous step in 20 ml of DCM are placed under nitrogen and 4.04 ml of bromine are added dropwise at 0 ° C. Add. When the addition is complete, evaporate to dryness and then add 300 ml of DCM. Washed with water, dried over _Na 2 SO _4, then filtered and evaporated to dryness. 21.15 g of the expected compound are obtained.

C) 1- (4-Chlorobenzoyl) -2-oxopropylacetic acid 16.74 g of potassium acetate dissolved in 76.76 ml of hot acetic acid are placed under nitrogen and 21.5 g of the bromine derivative obtained in the previous step. Is added in portions at 100 ° C. and heated at 120 ° C. for 3 hours. The reaction mixture is poured into 1 liter of water and extracted with 500 ml of ether. The ether phase is washed twice with 250 ml saturated NaHCO ₃ solution, then dried over Na ₂ SO ₄ , filtered and evaporated to dryness. 16.28 g of the expected compound is obtained.
LC / MS: MH ⁺ = 255.0; tr = 8.42 min

D) 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -3-methyl-1H-pyrazol-4-ylacetic acid 16.23 g of the compound from the previous step and (2,4-dichlorophenyl) A mixture containing 13.92 g of hydrazine hydrochloride is heated under reflux for 3 hours. After returning to room temperature, 400 ml of water are added and the organic layer is then washed with a saturated solution of NaHCO ₃ and then with water and then dried over Na ₂ SO ₄ . Filter and evaporate to dryness. The product obtained is purified by chromatography on silica, eluting with a DCM / MeOH mixture (98/2; v / v). 5.80 g of the expected compound are obtained (LC / MS: MH ⁺ = 395.0; tr = 10.80 min) and 4.63 g of the deacetylated compound identical to that prepared in the next step is obtained. .

E) 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -3-methyl-1H-pyrazol-4-ol 16.2 g of the compound obtained in the previous step in 82 ml of methanol Mix with 7.1 g of potassium (v / v) in water and stir at room temperature for 4 hours. The reaction mixture is concentrated and then diluted by adding 500 ml of water and extracted with 500 ml of DCM. The organic phase is washed with a buffer solution from distilled water at pH 2 and then dried over Na ₂ SO ₄ , filtered and evaporated to dryness. 11.56 g of the expected compound is obtained.
LC / MS: MH ⁺ 355.0, tr = 9.69 min.

F) 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-3-methyl-1H-pyrazole 16.25 g of the compound obtained in the previous step dissolved in 200 ml of DMF Place underneath, add 7.05 g of K ₂ CO _{3 and} 7.21 g of CH ₃ I, then heat at 60 ° C. under nitrogen and stir for 3 h. After returning to room temperature, the reaction mixture is filtered. 100 ml water is added to the filtrate and extracted with 100 ml DCM (twice). The organic phase is washed with 100 ml of water (5 times) and then dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue is purified on a silica column. 9.07 g of the expected compound is obtained.
LC / MS: MH ^<+> = 367.0; tr = 11.10 min

G) 9.07 g of the compound obtained in this previous step in 125 ml of 3-bromomethyl-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazole CCl ₄ Place under nitrogen, add 4.87 g NBS, 0.79 g benzoyl peroxide and 0.1 g AIBN, then heat at reflux for 60 hours. Upon returning to room temperature, filter through Celite®, evaporate to dryness, then purify by chromatography on silica, eluting with cyclohexane / AcOEt (95/5; v / v). In addition to the expected monobromine compound (2.67 g), 3,3-dibromo-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazole is obtained ( 5g).
LC / MS: MH ⁺ = 446.8; tr = 11.67 min LC / MS: MH ⁺ = 524.8; tr = 12.06 min

H) 1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazol-3-yl) methanamine 2.65 g of the monobromine compound obtained in the previous step And a mixture of 2.52 g of hexamethylenetetramine and 0.90 g of NaI in 50 ml of EtOH are placed under nitrogen. This is stirred at room temperature for 18 hours, then 10 ml of concentrated hydrochloric acid and 12 ml of ethanol are added and this is heated under reflux for 12 hours. After returning to room temperature, the mixture is filtered, then evaporated until the filtrate is dry and then dissolved in DCM. The organic phase is extracted with 100 ml of 10% HCl. The aqueous phase is washed with DCM, then basified and extracted with DCM. The organic phase is dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue is purified on silica and eluted with DCM / MeOH (93/7; v / v). 1.47 g of the expected compound are obtained.
LC / MS: MH ⁺ = 382.0; tr = 6.83 min.

I) 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazole-3-carbaldehyde 3,3-dibromo-5- (obtained in Step G under nitrogen 4 g of 4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazole is placed in 30 ml of DMSO and heated at 120 ° C. for 6 hours. The reaction mixture is poured into 100 ml of water and extracted twice with 100 ml of AcOEt. The organic phase is washed with 100 ml of saturated NaCl solution and then dried over Na ₂ SO ₄ . After evaporating to dryness, 4 g of the expected crude compound is obtained.
LC / MS: MH ⁺ = 381.0; tr = 11.06 min.

J) (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazol-3-yl) methanol 4 g of the compound obtained in the previous step are placed in 104 ml of methanol. Add 0.99 g NaBH ₄ at 0 ° C. and stir it at 0 ° C. for 45 minutes. Add 3 ml of AcOH to destroy excess NaBH ₄ . Evaporate until it is dry, then dissolve the residue in 100 ml DCM and wash with 100 ml saturated NaHCO ₃ solution (twice), then dry the organic phase and concentrate to dryness. 3.6 g of the crude compound is obtained.
LC / MS: MH ⁺ = 383.0; tr = 9.68 min.

K) 2-((5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazol-3-yl) methyl) -1H-isoindole-1,3- (2H ) -Dione A solution of 3.6 g of the compound obtained in the previous step, 2.46 g of PPh ₃ and 1.38 g of phthalimide in 156 ml of THF is mixed together. 1.63 g of DEAD is added dropwise at −10 ° C. and left overnight at room temperature. The reaction mixture is treated with 100 ml of buffer solution to pH2. The organic phase is diluted with 200 ml of ether and then washed with 100 ml of saturated NaHCO ₃ solution and then with 100 ml of saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The product obtained is purified on silica and eluted with a DCM / MeOH mixture (98/2; v / v). 3.4 g of the expected compound is obtained.
LC / MS: MH ⁺ = 512.0; tr = 11.43 min.

L) 1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazol-3-yl) methanamine 3.4 g of the compound obtained in the previous step, and hydrazine A solution of 0.67 g monohydrate in 95 ml methanol is placed under nitrogen and heated at reflux for 3 hours. The reaction mixture is evaporated to dryness and the residue is dissolved in 150 ml of ether. The organic phase is washed with 10% NaOH solution, then with NaHCO ₃ saturated solution, then with NaCl saturated solution. This is extracted with DCM and then evaporated to dryness. 2.45 g of the expected compound identical to those obtained in stage H are obtained.

Preparation 3
1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4- (tetrahydro-2H-pyran-2-yloxymethyl) -1H-pyrazol-3-yl) methanamine A) 4- (Bromomethyl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -1H-pyrazole-3-carboxylate methyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4 19 g of methyl 1H-pyrazole-3-carboxylate are placed in 200 ml of CCl ₄ , 8.54 g of NBS and then 1 g of benzoyl peroxide are added and heated under reflux overnight. After returning to room temperature, the precipitate formed is filtered and washed with CCl ₄ . All filtrates are evaporated, then dissolved in AcOEt and washed with saturated NaCl solution (twice). This is dried over MgSO ₄ and evaporated. The expected compound is crystallized in iso ether, filtered and dried to give 19.4 g of the expected compound.

B) 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-hydroxymethyl-1H-pyrazole-3-carboxylic acid 17 g of the compound obtained in the previous step and 1.5 g of LiOH, H ₂ O Is taken up in 100 ml of THF and 50 ml of water, heated for 3 hours and then stirred at room temperature overnight. The formed precipitate is filtered and then the filtrate is evaporated. The residue is dissolved in AcOEt and then washed with a saturated NaCl solution. This is dried over MgSO ₄ , filtered and the filtrate is concentrated to give 11 g of the expected compound.

C) 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-hydroxymethyl-1H-pyrazole-3-carboxylate 10 g of the acid formed in the previous step is dissolved in 100 ml of MeOH and concentrated H Add 1 ml of ₂ SO ₄ and heat at reflux for 2 hours. After cooling and evaporating the solvent, it is dissolved in AcOEt. This is washed with NaHCO ₃ solution, then with saturated NaCl solution and dried over MgSO ₄ . This is purified by chromatography, eluting with an AcOEt / cyclohexane mixture (10/90, then 20/80; v / v). 2.8 g of the expected compound which crystallizes with iso ether are obtained.

D) methyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4- (tetrahydro-2H-pyran-2-yloxymethyl) -1H-pyrazole-3-carboxylate obtained in the previous step 2.8 g of the compound obtained are dissolved in 48 ml of DCM and 0.68 g of 3,4-dihydro-2H-pyran and 0.07 g of PTSOH are added, which is then stirred at room temperature for 1 hour. The reaction mixture is washed with a NaHCO ₃ solution and then with a saturated NaCl solution. This is dried over MgSO ₄ and evaporated. The product obtained is purified by chromatography on silica, eluting with an AcOEt / cyclohexane mixture (5/95, then 90/10; v / v). The expected compound crystallizes in cyclohexane / AcOEt. 2.2 g are obtained.

E) 2- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4- (tetrahydro-2H-pyran-2-yloxymethyl) -1H-pyrazol-3-yl) methyl)- 1,3-bis (methylene) isoindoline 2.6 g of the compound obtained in the previous step, 0.97 g of phthalimide, and then 1.74 g of PPh ₃ are dissolved in 50.5 ml of THF, and 1.16 g of DEAD is added dropwise at 10 ° C. . This is left to return to room temperature and then stirred at room temperature for 96 hours. This is extracted with ether, washed with NaCl saturated solution, then dried over MgSO ₄ and evaporated. The resulting product is purified by chromatography on silica, eluting with AcOEt / cyclohexane (5/95; v / v). 2.2 g of the expected compound is obtained.

F) 1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4- (tetrahydro-2H-pyran-2-yloxymethyl) -1H-pyrazol-3-yl) methanamine 2.2 g of the compound obtained in the stage are taken up in 40 ml of MeOH, 0.40 ml of hydrazine hydrate is added and heated under reflux for 1.5 hours. It is allowed to cool and the solvent is evaporated and dissolved in DCM. This is washed with a 10% NaOH solution and then with a saturated NaCl solution, dried over MgSO ₄ and evaporated. 1.57 g of the expected crude product is obtained.

Preparation 4
1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4- (methoxymethyl) -1H-pyrazol-3-yl) methanamine A) 5- (4-Chlorophenyl) -1- ( Methyl 2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylate 1- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl) -1H-pyrazole- 20 g of 3-carboxylic acid are placed in 200 ml of MeOH, 0.5 g of toluenesulfonyl chloride is added and this is heated under reflux overnight. This is evaporated to half and then the precipitate that forms is filtered. This is washed with ether and then dried to give 20.6 g of the expected compound.

B) 4- (Bromophenyl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4- (bromomethyl) -1H-pyrazole-3-carboxylate Compound obtained in the previous step 16.5 g is placed in 200 ml of CCl ₄ , 7.42 g of NBS and 0.1 g of benzoyl peroxide are added and then heated under reflux overnight. The precipitate that forms is filtered and then washed with CCl ₄ . After evaporating the solvent, it is dissolved in DCM, then the organic phase is washed with water and then with a saturated NaCl solution. This is dried over MgSO ₄ and evaporated. The expected compound is crystallized with DCM and isoether to give 1.3 g of the expected compound.

C) 2.5 g of methyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4- (methoxyphenyl) -1H-pyrazole-3-carboxylate was washed with 100 ml of toluene and then with 100 ml of ether. And then cut into small pieces and placed in 500 ml of MeOH. 13 g of the bromine derivative obtained in the previous step are added to the sodium methylate solution thus prepared, which is stirred for 30 minutes and the reaction mixture is left at room temperature for 72 hours. The precipitate that forms is filtered and then the filtrate is evaporated. This is treated with 25% HCl and dissolved in AcOEt. After decantation, the organic phase is washed with a saturated NaCl solution (twice). This is dried over Na ₂ SO ₄ and concentrated. The expected compound crystallizes in iso ether. 1 g of the expected compound is obtained.

D) 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxyphenyl-1H-pyrazol-3-yl) methanol Dissolve 5.8 g of the compound obtained in the previous step in 100 ml of THF. , 0.82 g of LiAlH ₄ is added in small portions at 0 ° C. This is stirred for 30 minutes at room temperature and then hydrolyzed by adding 15 ml of 1N NaOH solution. The precipitate that forms is filtered and then washed with THF and the filtrate is evaporated. This is dissolved in AcOEt and washed with NaCl saturated solution. This is dried over MgSO ₄ and evaporated. This is crystallized in AcOEt / isoether. 4.6 g of the expected compound is obtained.

E) 3- (Chloromethyl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxymethyl-1H-pyrazole 4.5 g of the compound obtained in the previous step is dissolved in 50 ml of DCM Then 2.6 g of PCl ₅ is added in portions at 0 ° C. and this is stirred for 1 hour at room temperature. Add 25 ml of water and leave at room temperature overnight. After decantation, the organic phase is washed with a saturated NaCl solution (twice), dried over Na ₂ SO ₄ and evaporated. This is chromatographed on silica, eluting with an AcOEt / cyclohexane mixture (10/90; v / v). 2.17 g of the expected compound and 2 g of an equivalent compound having a dichloromethyl substituent in the 3 position are obtained.

F) 1- (5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4- (methoxymethyl) -1H-pyrazol-3-yl) methanamine 2 g of the compound obtained in the previous step Dissolve in 50 ml and add 0.80 g of hexamethylenetetramine, then stir it at room temperature for several days. This is evaporated to half and 50 ml of ether is added. The precipitate that forms is filtered and then dissolved in 100 ml EtOH and 15 ml concentrated KCl solution. This is heated under reflux for 2 hours and then left at room temperature overnight. The NH ₄ Cl precipitate that forms is filtered. The filtrate is evaporated, dissolved in DCM and then washed with a NaHCO ₃ solution and then with a saturated NaCl solution (twice). This is dried over MgSO ₄ and evaporated. This is dissolved in iso ether. This is evaporated again to obtain 1.7 g of the expected compound.

  NMR: 7.1: d: 2H; 7.45: d: 2H; 7.55: dd: 1H; 7.6: d: 1H; 7.75: d: 1H.

Compound No. 52
3-Chloro-N-((5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methoxy-1H-pyrazol-3-yl) methyl) benzenesulfonamide Compound obtained in Preparation 2 0.32 g is mixed with 0.09 g triethylamine and 0.19 g 3-chlorobenzenesulfonyl in 20 ml dichloromethane and stirred for 1 hour at room temperature. This is diluted with 100 ml DCM, then washed with 10% HCl solution, then with 25% NaOH solution, then with saturated NaCl solution and extracted with DCM. This is dried, filtered and evaporated to dryness. The residue is purified by chromatography on silica, eluting with a DCM / MeOH mixture (96/4; v / v). 0.21 g of the expected compound is obtained.

Compound No. 53
3-chloro-N-((5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-hydroxymethyl-1H-pyrazol-3-yl) methyl) benzenesulfonamide A) 3-chloro- N-((5- (4-chlorophenyl) -1-((tetrahydro-2H-pyran-2-yloxy) methyl) -1H-pyrazol-3-yl) methyl) benzenesulfonamide Compound 0 obtained in Preparation 3 Starting from 0.7 g, 0.35 g 3-chlorobenzenesulfonyl and 0.33 g triethylamine, following the procedure described in the previous example gives 0.847 g of the expected compound.

B) 3-Chloro-N-((5- (4-chlorophenyl) -4- (hydroxymethyl) -1H-pyrazol-3-yl) methyl) benzenesulfonamide 0.847 g of the compound obtained in the previous step Is dissolved in 40 ml of MeOH. Add 1 ml of concentrated HCl and heat at reflux for 10 minutes. It is allowed to cool, then the solvent is evaporated and the residue is dissolved in AcOEt. This is washed with NaCl saturated solution (twice), then dried over MgSO ₄ and evaporated. The resulting product is purified by chromatography, eluting with an AcOEt / cyclohexane mixture (10/90, then 20/80, then 25/75; v / v). 176 mg of the expected compound and 289 mg of the compound corresponding to formula (I) in which R ₃ is a methoxymethyl group are obtained.

Compound No. 48
3-chloro-N-((5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4- (methoxymethyl) -1H-pyrazol-3-yl) methyl) benzenesulfonamide obtained in Preparation 4. 0.45 g of the amine obtained is placed in 20 ml of DCM. Add 0.26 g of 3-chlorobenzenesulfonyl and 0.25 g of triethylamine, then stir at room temperature for 3 hours. Add 15 ml of water and stir for 10 minutes. After decantation, the organic phase is washed with a NaHCO ₃ / KHSO ₄ solution and then with a saturated NaCl solution (twice). This is dried over MgSO ₄ and evaporated. This is dissolved in iso ether and then purified by chromatography on silica, eluting with an AcOEt / cyclohexane mixture (5/95; v / v). 0.230 g of the expected compound is obtained, and its melting point is 154 ° C.

Compound No. 55
5- (4-Chlorophenyl) -3-((((3-chlorophenyl) sulfonyl) amino) methyl) -1- (2,4-dichlorophenyl) -N, N-dimethyl-1H-pyrazole-4-carboxamide A) 5- (4-Chlorophenyl) -3-((((3-chlorophenyl) sulfonyl) amino) methyl) -1- (2,4-dichlorophenyl) -1H-pyrazole-4-carboxylic acid Cr ₂ O ₃ 13.36 g Is added to a mixture of 11.5 ml of concentrated H ₂ SO ₄ solution diluted in 50 ml of cold water to prepare Jones reagent. 0.5 g of the compound from Example 2 is dissolved in 15 ml of acetone and then 5 ml of Jones reagent is slowly added at a temperature between 0 ° C and 5 ° C. This is stirred for 2 days. Add 10 ml of isopropanol to destroy excess reagent and filter the precipitate that forms. The filtrate is extracted with 30 ml of ether. The organic phase is washed with a saturated NaCl solution (twice) and then dried over MgSO ₄ . This is evaporated and dissolved in hot isoether. The expected compound crystallizes. 440 mg are obtained, the melting point of which is 211 ° C.

B) 5- (4-Chlorophenyl) -3-((((3-chlorophenyl) sulfonyl) amino) methyl) -1- (2,4-dichlorophenyl) -N, N-dimethyl-1H-pyrazole-4-carboxamide Dissolve 0.4 g of the acid obtained in the previous step in 20 ml DCM, add 0.37 g BOP and 0.05 g methylamine and stir at room temperature overnight. 10 ml of water are added and then the organic phase is decanted. After evaporation, the residue is dissolved in AcOEt. This is washed in succession with K ₂ SO ₄ , NaHCO ₃ and NaCl (saturated solution) solution, dried over MgSO ₄ and evaporated to dryness. The residue is dissolved in hot Et ₂ O and then crystallized. 0.35 g of the expected compound is obtained, with a melting point of 178 ° C.

Compound No. 57
0.69 g of the compound from Example 1 is taken up in 15 ml of DCM, 12.36 mg of BBr ₃ is added at −20 ° C. and then stirred at −20 ° C. for 1 hour and then at room temperature for 3 hours. 100 ml of water and 100 ml of DCM are added to the reaction mixture, decanted and then the organic phase is washed with 100 ml of dilute hydrochloric acid. It is dried over MgSO ₄ and evaporated to dryness. The residue is dissolved in 100 ml DCM. The expected compound precipitates and 373 mg of the expected product is obtained.

LC / MS: MH ⁺ = 541.8; tr = 10.69 min.

The compounds of formula (I _A ) listed in Table 1 are prepared according to the methods described above or by combinatorial chemistry by the methods described below.

The pyrazole methylamine derivative of formula (II) is dissolved in DMF at a concentration of 0.1 M in the presence of 3 equivalents of DIPEA. 300 μl of this solution is placed in each 2 ml well and 120 μl of a 0.25 M sulfonyl chloride (R ₁ SO ₂ Cl) solution in THF is added. The plate is stirred for 16 hours at room temperature and then evaporated. The resulting product is placed in each well with 500 μl AcOEt, 400 μl 0.1 M Na ₂ CO ₃ is added and the plate is agitated. After decantation, 350 μl of the aqueous phase is removed, then 40 μl of DMF and then 300 μl of CH ₃ CN are added.

Compound No. 45
N-((4-cyano-1- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) -2,6-difluorobenzenesulfonamide triethylamine 0.98 ml And 0.75 g of 2,6-difluorobenzenesulfonyl chloride in DCM solution are added to a solution containing 1.2 g of the compound from Preparation 1. After stirring at room temperature overnight, the DCM is concentrated, the residue is dissolved in AcOEt, the organic phase is washed with a pH 2 buffer solution, then with a saturated NaHCO ₃ solution, then with a saturated NaCl solution, dried over MgSO ₄ and dried under vacuum. Concentrate until solid. This is purified by chromatography on silica, eluting with a cyclohexane / AcOEt mixture (90/10; v / v). 1.5 g of the expected compound is obtained, with a melting point of 170 ° C.

Compound No. 72
N-((4-cyano-1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -1H-pyrazol-3-yl) methyl) -2,6-difluorobenzenesulfonamide Previous implementation 1 g of the compound obtained in the example is placed in 15 ml of DCM. 4.56 g of BBr _{3 in} 1M DCM solution of BBr ₃ is introduced dropwise at −20 ° C. under nitrogen, stirred for 1 hour at −20 ° C. and then the temperature is raised. After 72 hours at room temperature, the reaction mixture is poured onto a water / ice / DCM mixture and the organic phase is washed with 30 ml of NaHCO ₃ saturated solution, 30 ml of pH 2 buffer solution and then 2 × 30 ml of NaCl saturated solution. This is decanted and dried under vacuum to obtain 0.782 g of the expected compound, whose melting point is 196 ° C.

Compound No. 73
N-((4-cyano-1- (2,4-dichlorophenyl) -5- (4-((propylsulfonyl) oxy) phenyl) -1H-pyrazol-3-yl) methyl) -2,6-difluorobenzene Sulfonamide A solution containing 0.35 g of the compound from the previous example in 20 ml DCM is prepared and 1.44 ml NEt ₃ is added followed by 0.103 g n-propanesulfonyl chloride. After stirring for 1.5 hours at room temperature, 10 ml of water are added, then decanted and the organic phase is washed with 15 ml of saturated NaCl solution. After the solvent has been removed, it is purified by chromatography on silica, eluting with a cyclohexane / AcOEt mixture (90 / 10-70 / 30; v / v). 0.144 mg of the expected compound is obtained with a melting point of 77 ° C.

  The following table shows some chemical structures and physical properties of the compounds according to the invention.

  In these tables, Me and tBu represent methyl and t-butyl groups, respectively.

The compounds of formula (I) are described in M.I. Rinaldi-Carmona. (FEBS Letters, 1994, 350, 240-244) have very good in vitro affinity (IC ₅₀ ≦ 5.10 ⁻⁷ M) for the cannabinoid receptor CB ₁ in the experimental conditions described.

  The antagonistic properties of the compounds of formula (I) are Bouaboula et al. Biol. Chem. 1995, 270, 1397-13980, M. Rinaldi-Carmona et al. Pharmacol. Exp. Ther. 1996, 278, 871-878 and M.M. Bouaboula et al. Biol. Chem. , 1997, 272, 22330-22339, is actually demonstrated by the results obtained in the adenylate cyclase inhibition model.

Interaction with the receptor CB ₁ in the brain of the compounds according to the invention, M. Rinaldi-Carmona et al., FEBS Letters 1994, 350, 240-244 and Rinaldi-Carmona et al. , Life Sciences 1995, 56, 1941-1947, as determined in mice by the ex vivo binding test of [3H] -CP55940 after intravenous administration.

The interaction of the compounds according to the invention with the receptor CB _{1 in} the periphery is Rinaldi-Carmona et al. Pharmacol. Exp. Ther. , 2004, 310, 905-914, as determined in mice by a reversal test of the inhibitory effect of CP55940 on gastrointestinal transit following oral administration.

  The toxicity of the compound of formula (I) is compatible with its use in drug therapy.

  Thus, according to another aspect, the present invention relates to a human comprising a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid, or a solvate or hydrate of a compound of formula (I) Or it relates to a medicinal product as a veterinary medicine.

Accordingly, the compounds according to the invention, a human or animal, especially, but not limited to, use a dog, cat, horse, in the treatment or prevention of diseases cannabinoid receptors CB ₁ in mammalian, including bovine and ovine are involved.

  For example, but not limited to, compounds of formula (I) are among others anxiety, depression, mood disorders, insomnia, illusion disorders, delusional disorders, general psychosis, schizophrenia, hyperactive children's attention deficit hyperactivity disorder (ADHD) ) For the treatment of mental disorders including, and for disorders associated with the use of psychotropic substances, especially for the treatment of substance abuse and / or substance dependent patients, including alcohol and nicotine addictions It can be used as a sex medicinal product.

  The compounds of formula (I) according to the invention can be used as medicinal products for the treatment of migraine, stress, psychosomatic disorders, seizures, epilepsy, movement disorders, in particular movement disorders or Parkinson's disease, tremor and dystonia.

  The compounds of formula (I) according to the invention can also be used as medicinal products for the treatment of memory disorders, cognitive disorders, in particular the treatment of senile dementia of Alzheimer's disease, as well as the treatment of attention or arousal disorders.

  Furthermore, the compounds of formula (I) are used as neuroprotective agents in the treatment of ischemic head trauma and in the treatment of acute or chronic neurodegenerative diseases including chorea, Huntington's chorea, Tourette syndrome it can.

  The compounds of formula (I) according to the invention can be used as medicinal products in the treatment of pain such as neuropathic pain, acute peripheral neuralgia, pain of chronic inflammatory origin, pain from anti-cancer therapy.

  The compounds of formula (I) according to the invention are for the prevention and treatment of appetite disorders, cravings (sugars, carbohydrates, drugs, alcohol or any appetite-enhancing substance) and / or eating disorders, in particular for obesity or bulimia It can be used as a medicinal product in human or veterinary medicine for therapy and for the treatment of type II diabetes or non-insulin dependent diabetes and for the treatment of dyslipidemia and metabolic syndrome. Thus, the compounds of formula (I) according to the invention can be used in the treatment of obesity and the risks associated with obesity, in particular the risks of the circulatory system.

  Furthermore, the compounds of formula (I) according to the invention are useful for the treatment and prevention of digestive tract diseases, diarrhea, ulcers, vomiting, bladder and urine diseases, liver diseases such as chronic cirrhosis, fibrosis, liver steatosis, steatohepatitis Medicinal products; and diseases of endocrine origin, cardiovascular disorders, hypotension and atherosclerosis, hemorrhagic shock, septic shock, asthma, chronic bronchitis, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma , Fertility disorder, premature birth, miscarriage, inflammatory signs, immune system diseases, especially autoimmune and neuroinflammation such as rheumatoid arthritis, reactive arthritis, diseases leading to demyelination, multiple sclerosis, contagious and viruses such as encephalitis Used as a medicinal product for the treatment and prevention of sexually transmitted diseases, cerebrovascular disorders; and for the treatment of anti-cancer chemotherapy, Guillain-Barre syndrome, and bone and osteoporosis It can be.

  According to the invention, the compounds of formula (I) are very particularly medicinal products for use in the prevention and treatment of psychotic disorders, in particular schizophrenia, attention deficit hyperactivity disorder (ADHD) in hyperactive children. Products; medicinal products for the prevention and treatment of memory and cognitive impairment; medicinal products for the treatment of alcoholism and nicotine addiction when abandoning alcohol and smoking; acute or chronic nerves It can be used to prepare medicinal products for degenerative diseases.

  More particularly, the compounds of formula (I) according to the invention are used in the treatment and prevention of appetite disorders, metabolic disorders, gastrointestinal diseases, inflammatory signs, immune system diseases, psychotic disorders, alcoholism and nicotine dependence. Can be used.

  According to one aspect, the present invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, and a solvate or hydrate thereof for the treatment of the disorders and diseases mentioned above. It is.

  According to another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention as an active ingredient. Such pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, solvate or hydrate of said compound, and at least one pharmaceutically acceptable excipient.

  Said excipients are selected from the usual excipients known to the person skilled in the art depending on the pharmaceutical form and the desired method of administration.

  The pharmaceutical composition according to the invention can contain, in addition to the compound of formula (I), one or more other active ingredients that can be used in the treatment of the disorders and diseases mentioned above.

Accordingly, the present invention provides the following classes of treatment:
Another antagonist of cannabinoid receptor CB ₁ ;
Modulators of cannabinoid receptor CB ₂ ;
Antagonists of angiotensin II receptor AT ₁ ;
Inhibitors of converting enzymes;
Calcium antagonists;
Diuretics;
beta-blockers;
Antihyperlipidemic or antihypercholesterolemic agent;
Anti-diabetic agents;
Another anti-obesity agent or an agent acting on metabolic disorders;
Nicotinic agonists, partial nicotinic agonists;
Antidepressants, antipsychotics, anxiolytics;
An anticancer or antiproliferative agent;
Opioid antagonists;
And:
Memory improver;
Drugs for use in the treatment of alcoholism or withdrawal symptoms;
Drugs that can be used to treat osteoporosis;
Non-steroidal or steroidal anti-inflammatory drugs;
Anti-infectious agents;
Analgesics;
It also relates to a pharmaceutical composition comprising a compound of formula (I) according to the invention in combination with one or more active ingredients selected from one of the anti-asthma agents.

By “antagonist of angiotensin II receptor AT ₁ ” is meant compounds such as candesartan cilexetil, eprosartan, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan, each of which is itself hydrochlorothiazide Can be combined with diuretics such as.

  `` Inhibitors of converting enzyme '' means alacepril, benazepril, captopril, cilazapril, enalapril, enalaprilate, focinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, fenomapril However, each of these compounds can itself bind to a diuretic such as hydrochlorothiazide or indapamide, or a calcium antagonist such as amlodipine, diltiazem, felodipine, verapamil.

  `` Calcium antagonist '' refers to amlodipine, alanidipine, benidipine, bepridil, cilnidipine, diltiazem, efonidipine hydrochloride ethanol, fasudil, felodipine, isradipine, rasidipine, lercanidipine hydrochloride, manidipine, mibefradil hydrochloride, nicardipine, nifedipine, nimodipine, nimodipine, It means compounds such as nisoldipine, nitrendipine, terodiline, verapamil.

  `` Beta blocker '' means acebutolol, alprenol, amosulalol, arotinolol, atenolol, befnolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucmolol, bufetrol, bunitrolol, butofilolol, carazolol, carteolol, carvedilol, palorolol, chloranolol , Esmolol, indenolol, labetalol, landiolol, levobunolol, levomoprolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nifenarol, nipradilol, oxprenolol, penbutolol, pindolol, propranolol, sotalolol, sotalolol, sotalolol Timolol, Samoteroru, refers to a compound such as xibenolol.

  “Antihyperlipidemic agent or antihypercholesterolemia agent” means fibrates such as alfibrate, beclobrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate; atorvastatin, fluvastatin sodium, Statins such as lovastatin, pravastatin, rosuvastatin, simvastatin (reductase HMG-CoA inhibitor), or acipimox, aluminum nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicochronate, nicotinic acid, β- It means a compound selected from compounds such as sitosterol and thiadenol.

  `` Antidiabetic agent '' refers to the following classes: acarbose, acetohexamide, carbbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, glyxone, glyoxepide, glybazole, grimidine, metahexamide, metformin, miglitol, Means nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, foliose, sulfonylurea, biguanidine, alpha-glucosidase inhibitor, thiazolidinedione, metiglinide, and compounds belonging to one of insulin and insulin analogues .

“Another anti-obesity agent or drug acting on metabolic disorders” refers to amphetramone, benfluorex, benzphetamine, indanolex, mazindol, mefenolex, methamphetamine, D-norpseudoephedrine, sibutramine, topiramate, lipase inhibition Agents (orlistat cetiristat), PPAR agonists (peroxisome proliferator-activated receptor agonists), dopamine agonists, leptin receptor agonists, serotonin reuptake inhibitors, β-3 agonists, CCK-A agonists, NPY inhibitor, MC4 receptor agonist, MCH (melamine-concentrating hormone) receptor antagonist, orexin antagonist, phosphodiesterase inhibitor, inhibitor of 11βHSD (11-β-hydroxysteroid dehydrogenase), DPP-IV (dipeptidylpe) Peptidase IV) inhibitors, histamine H3 antagonists (or adverse agonists), CNTF (ciliary neurotrophic factor) derivatives, GHS (growth hormone secretagogue) receptor agonists, ghrelin modulators, diacylglycerol acyltransferases ( DGAT) inhibitors, phosphodiesterase (PDE) inhibitors, thyroid hormone agonists, glucocorticoid receptor antagonists, stearoyl-CoA-desaturase (SCD) inhibitors, phosphate esters, glucose, fatty acids, dicarboxylate transport It means compounds such as body modifying substances, 5HT ₂ antagonists, 5HT ₆ antagonists, bombesin agonists.

  “Opioid antagonist” means a compound such as naltrexone, naloxone, or nalmefene.

  A drug for use in the treatment of alcoholism or withdrawal symptoms means acamprosate, benzodiazepine, beta blocker, clonidine, carbamazepine.

  “Drugs used to treat osteoporosis” means, for example, bisphosphonates such as etidronate, clodronate, tiludronate, risedronate.

  According to the invention it is also possible to combine other compounds having antihyperlipidemic, antihypercholesterolemic, antidiabetic or antiobesity properties. More specifically, the following classes: inhibitors of PTP1B (protein tyrosine phosphatase-1B), VPAC-2 receptor agonists, GLK modifiers, retinoid modifiers, glycogen phosphorylase (HGLPa) inhibitors, glucagon Antagonist, glucose-6-phosphate inhibitor, pyruvate dehydrogenase kinase (PKD) activator, RXR, FXR, LXR modifier, SGLT (sodium-dependent glucose transporter) inhibitor, CETP (cholesteryl ester transfer) Protein) inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors, triglyceride synthesis inhibitors, LDL (low density lipoprotein) inducer receptors, IBAT inhibitors, FBPase (fructose-1, 6-biphosphata Inhibitors of zero), CART (cocaine - can be combined modulator amphetamine regulated transcript), MC4 (melanocortin 4) modulators, the compounds belonging to one of orexin receptor antagonists.

  According to another aspect of the present invention, the compound of formula (I), one of its pharmaceutically acceptable salts, or one of its solvates and other combined active ingredients are simultaneously, independently or independently Can be administered over a period of time.

  “Simultaneous use” means administration of a compound of the composition according to the invention contained within one and the same pharmaceutical form.

  “Independent use” means that two compounds of the composition according to the invention are administered simultaneously, each contained within an independent pharmaceutical form.

  “Use over time” means a compound of the first composition of the invention contained within one pharmaceutical form and then a second book contained within a separate pharmaceutical form. It means that the compounds of the composition according to the invention are administered sequentially. In this case, the time elapsed between the administration of the first compound of the composition according to the invention and the second administration of the compound of the same composition according to the invention generally does not exceed 24 hours.

  In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, localized, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of the above formula (I), In some cases, the salts, solvates or hydrates are administered in unit dosage forms mixed with conventional pharmaceutical excipients to animals and humans for the prevention or treatment of the stated disorders or diseases. Can be administered.

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

As an example, the unit form of administration of a compound according to the invention in the form of a tablet comprises the following components:
Compound according to the invention: 50.0 mg
Mannitol: 223.75mg
Croscarmellose sodium: 6.0 mg
Corn starch: 15.0mg
Hydroxypropyl methylcellulose: 2.25mg
Magnesium stearate: 3.0mg
including.

  The dose of active ingredient administered per day by the oral route can reach 0.01-100 mg / kg, preferably 0.02-50 mg / kg, in one or more doses.

  There may be special cases where higher or lower doses are appropriate, but such doses are still within the scope of the invention. According to routine practice, the appropriate dosage for each patient is determined by the physician depending on the method of administration and the weight and response of the patient.

  According to another aspect, the present invention comprises administering to a patient an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates, as described above. It also relates to a method for treating a disease state.

Claims (22)

Compounds corresponding to formula (I) in the form of bases or acid addition salts as well as hydrates or solvates

[Where:
R ₁ is
Independently of unsubstituted or fluorine atom, hydroxyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio, phenoxy, trifluoromethoxy group, difluoromethoxy group, difluoromethylthio group, trifluoromethylthio group (C ₁ -C ₁₂ ) alkyl substituted one or more times by selected substituents;
Non substituted, or _(C 1 _{~C 4) alkyl, (C} 1 _{~C 4) alkoxy, (C} 1 _{~C 4)} alkylthio, a fluorine atom, a hydroxyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy A non-aromatic (C ₃ -C ₁₂ ) carbocyclic group substituted one or more times by a substituent independently selected from a trifluoromethylthio, difluoromethylthio group;
(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio, fluorine atom, hydroxyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, Methyl substituted by a substituent selected independently from a difluoromethylthio group one or more times, or by a non-aromatic (C ₃ -C ₁₂ ) carbocyclic group;
Phenyl, benzyl, benzhydryl, benzhydryl methyl (each phenyl group may be substituted with a halogen atom, hydroxyl, methylenedioxy, cyano, _{nitro, (C} 1 -C ₄₎ alkylcarbonyl group, or Alk,, OAIk, S (O) _n Alk or OS (O) _n substituted or unsubstituted one or more times by substituents independently selected from _n Alk groups);
A phenyl group substituted by a heterocyclic group selected from pyrrolyl, imidazolyl, pyridyl or pyrazolyl (wherein the heterocyclic group is one or more independently selected from a halogen atom or a (C ₁ -C ₄ ) alkyl group) Substituted or unsubstituted one or more times by the substituents of
Phenyl group (each phenyl group is a halogen atom, hydroxyl, methylenedioxy, cyano, nitro, (C ₁ -C ₄ ) alkylcarbonyl group, or Alk, OAlk, S (O) _n Alk or OS (O) _n Alk Substituted by phenyl or phenoxy, substituted or unsubstituted one or more times by substituents independently selected from groups);
By one or more substituents independently selected from thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, pyridyl group, wherein said group is independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, trifluoromethyl groups Substituted or unsubstituted.);
Unsubstituted or substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, di (C ₁ -C ₄ ) alkylamino or trifluoromethyl groups Tetrahydronaphthalenyl or naphthyl;
2,3-dihydrobenzofuranyl which is unsubstituted or substituted one or more times by a (C ₁ -C ₄ ) alkyl group;
Represents indol-2-yl or N-methylindol-2-yl,
R ₂ represents a hydrogen atom, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkylsulfonyl group,
R ₃ is cyano, hydroxyl, (C ₁ -C ₄ ) alkoxy, cyanomethyl, hydroxymethyl, (C ₁ -C ₄ ) alkoxymethyl, fluoromethyl, tetrazolylmethyl, N- (methyl) tetrazolylmethyl, Represents tetrazolyl, N- (methyl) tetrazolyl, CONR ₆ R ₇ group, CH ₂ S (O) _n (C ₁ -C ₄ ) alkyl group, COOR ₈ group or CH ₂ NR ₆ R ₇ group,
R ₄ and R ₅ each independently represent phenyl (this phenyl group is substituted by a halogen atom one or more times by a fluorine atom or is not substituted (C ₁ -C ₇ ) alkyl group, OAlk , Substituted or unsubstituted by one or more substituents independently selected from the group S (O) _n Alk or OS (O) _n Alk).
R ₆ and R ₇ each independently represent a hydrogen atom or (C ₁ -C ₄ ) alkyl, or R ₆ and R ₇ together with the nitrogen atom to which they are attached, (C ₁ -C ₄₎ alkyl by one or more times substituted with are or unsubstituted pyrrolidinyl, constitute piperidinyl, morpholinyl, the heterocyclic group selected from piperazinyl,
R ₈ represents (C ₁ -C ₄ ) alkyl;
n represents 0, 1 or 2;
Alk represents (C ₁ -C ₄ ) alkyl which is unsubstituted or substituted one or more times by fluorine atoms. ]. R ₁ is
_(C 1 ~C ₇₎ alkyl;
(C ₃ -C ₇ ) cycloalkyl which is unsubstituted or substituted one or more times by a (C ₁ -C ₄ ) alkyl group;
(C ₃ -C ₇ ) cycloalkylmethyl which is unsubstituted or substituted one or more times on the carbocycle by a (C ₁ -C ₄ ) alkyl group;
Unsubstituted or halogen atom, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, trifluoromethyl group, trifluoromethoxy group, S (O) _n Alk group, (C _1- C ₄ ) an alkylcarbonyl group, phenyl substituted by one or more substituents independently selected from phenyl;
Benzyl that is unsubstituted or substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, trifluoromethyl groups;
A thienyl, furyl, oxazolyl, thiazolyl, imidazolyl group (wherein said group is substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, trifluoromethyl groups or Not substituted);
Naphthyl that is unsubstituted or substituted by one or more substituents independently selected from (C ₁ -C ₄ ) alkyl, di (C ₁ -C ₄ ) alkylamino;
Represents 2,3-dihydrobenzofuranyl which is unsubstituted or substituted one or more times by a (C ₁ -C ₄ ) alkyl group,
R ₂ represents a hydrogen atom or (C ₁ -C ₄ ) alkyl,
R ₃ is cyano, hydroxyl, (C ₁ -C ₄ ) alkoxy, cyanomethyl, hydroxymethyl, (C ₁ -C ₄ ) alkoxymethyl, fluoromethyl, tetrazolylmethyl, N- (methyl) tetrazolylmethyl, Represents tetrazolyl, N- (methyl) tetrazolyl, CONR ₆ R ₇ group, CH ₂ S (O) _n Alk group, COOR ₈ group,
R ₄ and R ₅ are each independently independent of an unsubstituted or halogen atom, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₄ ) alkoxy, trifluoromethyl group or S (O) _n Alk group Represents phenyl substituted by one or more substituents selected from
R ₆ and R ₇ each independently represent a hydrogen atom or (C ₁ -C ₄ ) alkyl, or R ₆ and R ₇ together with the nitrogen atom to which they are attached, are unsubstituted Or a heterocyclic group selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl substituted one or more times by (C ₁ -C ₄ ) alkyl,
R ₈ represents (C ₁ -C ₄ ) alkyl;
n represents 0, 1 or 2,
Alk is, (C 1 _{-C 4)} the form of base or acid addition salt represents an alkyl, becoming not in the form of hydrates or solvates only formula (I), a compound of claim 1. R ₃ is cyano, the substituents _{R 1, R 2, R 4} , R 5 are, of formula _{I A} are as defined in claim 1 for compounds of formula (I), according to claim 1 Compound described in 1. R ₃ is hydroxyl, the substituents _{R 1, R 2, R 4} , R 5 is of formula _{I B} are as defined in claim 1 for compounds of formula (I), according to claim 1 Compound described in 1. A compound wherein R ₃ is (C ₁ -C ₄ ) alkoxy and the substituents R ₁ , R ₂ , R ₄ , R ₅ are as defined for a compound of formula (I) in claim 1 of I _C, a compound according to claim 1. R ₃ is (C ₁ -C ₄ ) alkoxymethyl and the substituents R ₁ , R ₂ , R ₄ , R ₅ are as defined for the compound of formula (I) in claim 1. of formula I _F, compounds of claim 1. R ₃ is a CONR ₆ R ₇ group and the substituents R ₁ , R ₂ , R ₄ , R ₅ , R ₆ and R ₇ are as defined for the compound of formula (I) in claim 1 of formula I _I is the compound of claim 1. R ₃ is COOR ₈ and the substituents R ₁ , R ₂ , R ₄ , R ₅ and R ₈ are as defined for the compound of formula (I) in claim 1 in formula I _J The compound according to claim 1. R ₃ is tetrazol-1-ylmethyl or tetrazol-2-ylmethyl and the substituents R ₁ , R ₂ , R ₄ , R ₅ are as defined for the compound of formula (I) in claim 1 of formula I _O is the compound of claim 1. R ₁ is
Phenyl, benzyl, benzhydryl, benzhydryl methyl (each phenyl group may be substituted with a halogen atom, _{hydroxyl, (C} 1 -C _{4) alkyl, (C} 1 -C ₄₎ alkoxy, methylenedioxy, cyano, nitro, trifluoromethyl Independently selected from methyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, difluoromethylthio, S (O) _n Alk group, OS (O) _n Alk group, (C ₁ -C ₄ ) alkylcarbonyl group Substituted or unsubstituted one or more times by a substituent group));
Represents a furyl group that is unsubstituted or substituted by one or more substituents independently selected from halogen atoms, (C ₁ -C ₄ ) alkyl, trifluoromethyl groups,
R ₂ represents a hydrogen atom or a (C ₁ -C ₄ ) alkylsulfonyl group,
R ₃ is cyano, hydroxyl, (C ₁ -C ₄ ) alkoxy, hydroxymethyl, (C ₁ -C ₄ ) alkoxymethyl, CONR ₆ R ₇ group, COOR ₈ group, tetrazol-1-ylmethyl or tetrazol-2- Represents ylmethyl, the groups R ₆ , R ₇ , R ₈ are as defined for (I),
R ₄ represents 4-chlorophenyl, 4-methoxyphenyl or 4-OSO ₂ -Alk, and Alk represents (C ₁ -C ₄ ) alkyl which is unsubstituted or substituted one or more times by a fluorine atom. ,
R ₅ represents 2-chlorophenyl, 2-bromophenyl or 2,4-dichlorophenyl of formula (I) in the form of a base or acid addition salt as well as in the form of a hydrate or solvate. Compound described in 1. R ₁ is 3-chlorophenyl, 3-fluorophenyl, 3,6-difluorophenyl, 2,6-difluorophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, benzyl, 4- Represents a trifluoromethylbenzyl or 2-trifluoromethyl-4-methylfuryl group,
R ₂ represents a hydrogen atom,
R ₃ represents a cyano, methoxy or dimethylaminocarbonyl group,
R ₄ represents 4-chlorophenyl, 4-methoxy or 4-propanesulfonyloxy,
A compound according to claim 1 of formula (I) in the form of a base or acid addition salt as well as a hydrate or solvate, wherein R ₅ represents 2,4-dichlorophenyl or 2-chlorophenyl. N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-cyanobenzenesulfonamide,
N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-trifluorobenzenesulfonamide,
N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -2-trifluoromethoxybenzenesulfonamide,
N-([5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-methoxybenzenesulfonamide,
N-([5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-chlorobenzenesulfonamide,
N-{[5- (4-chlorophenyl) -4-cyano-1- (2-chlorophenyl) -1H-pyrazol-3-yl] methyl} -3-fluorobenzenesulfonamide,
N-{[5- (4-chlorophenyl) -4-cyano-1- (2-chlorophenyl) -1H-pyrazol-3-yl] methyl} -2-fluorobenzenesulfonamide,
N-{[5- (4-chlorophenyl) -4-cyano-1- (2-chlorophenyl) -1H-pyrazol-3-yl] methyl} -2-trifluoromethoxybenzenesulfonamide,
N-{[5- (4-methoxyphenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3.5-difluorobenzenesulfonamide;
N-{[5- (4-chlorophenyl) -4-methoxy-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -3-chlorobenzenesulfonamide;
5- (4-chlorophenyl) -3-({[(3-chlorophenyl) sulfonyl] amino} methyl) -1- (2,4-dichlorophenyl) -N-methyl-1H-pyrazole-4-carboxamide;
N-{[5- (4-chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -1-phenylmethanesulfonamide,
N-{[5- (4-Chlorophenyl) -4-cyano-1- (2,4-dichlorophenyl) -1H-pyrazol-3-yl] methyl} -5-methyl-2- (trifluoromethyl) furan- 2. A compound according to claim 1 in the form of a base or acid addition salt as well as a hydrate or solvate selected from 3-sulfonamides. Compound of formula

[Wherein R ₂ , R ₄ , R ₅ are as defined for the compound of formula (I), and R ′ ₃ represents R ₃ or a precursor of R ₃ . ]
In the presence of a base in the formula HalSO ₂ R ₁ , wherein R ₁ is as defined for the compound of formula (I) in claim 1 and Hal represents a halogen atom. ] With a sulfonyl halide of
If appropriate, the resulting compound of the formula

[Wherein R ′ ₃ is a precursor of R ₃ or R ₃ . ]
A process for the preparation of a compound of formula (I) according to claim 1, characterized in that is converted to a compound of formula (I).   A pharmaceutical product comprising a compound of formula (I) or a hydrate or solvate of a compound of formula (I) according to any one of claims 1-12.   A medicament comprising a compound of formula (I) according to any one of claims 1 to 12, or a hydrate or solvate of this compound, and at least one pharmaceutically acceptable excipient. Composition. For receptor CB ₁ to prepare a pharmaceutical product for the treatment or prevention of diseases involving the use of a compound of formula (I) according to claims 1 to 12.   Use according to claim 16, characterized in that the diseases are psychiatric disorders, substance dependence and withdrawal symptoms, cognitive disorders, attention and wakefulness disorders, and acute and chronic neurodegenerative diseases.   Use according to claim 16, characterized in that the disease is metabolic disorder, desire disorder, appetite disorder, obesity, type II diabetes, metabolic syndrome and dyslipidemia.   Use according to claim 16, characterized in that the disease is pain, neuropathic pain and pain caused by anticancer therapy.   Use according to claim 16, characterized in that the diseases are gastrointestinal diseases, vomiting, diarrhea, ulcers and liver diseases.   Use according to claim 16, characterized in that the diseases are immune system diseases, rheumatoid arthritis, demyelination, multiple sclerosis and inflammatory diseases.   Use according to claim 16, characterized in that the disease is Alzheimer's disease, Parkinson's disease, schizophrenia, cognitive impairment, diabetes, obesity, metabolic syndrome and tobacco withdrawal symptoms.