HK1116781A - N-[(4, 5-diphenyl-3-alkyl-2-thienyl) methyl] amine (amide, sulfonamide, carbamate and urea) derivatives as cannabinoid cb1 receptor antagonists - Google Patents

Description

N- [ (4, 5-diphenyl-3-alkyl-2-thienyl) methyl ] amine (amide, sulfonamide, carbamate and urea) derivatives as cannabinoid CB1 receptor antagonists

The invention relates to substituted N- [ (4, 5-diphenyl-3-alkyl-2-5-thienyl) methyl ] amine derivatives, to their preparation and to their therapeutic use.

Patents US 5624941, EP 0576357, EP 0656354, EP 1150961 and WO 2005/073197 describe in particular CB to the chemical composition of cannabis₁Diphenylpyrazole derivative derivatives having receptor affinity.

International application WO 91/19708 describes 4, 5-diarylthiophene derivatives having anti-inflammatory and analgesic properties. International application WO 2005/035488 describes thiophene-2-carboxamide derivatives.

It has now been found that substituted N- [ (4, 5-diphenyl-3-alkyl-2-thienyl) methyl groups]Amine derivatives, their CB for cannabinoids₁The receptors have antagonistic properties.

The object of the present invention is a compound corresponding to the formula:

in the formula:

-X represents

-R₁Represents:

.(C₁-C₇) An alkyl group;

.(C₃-C₁₂) Non-aromatic carbocyclic radicals not covered byIs substituted or substituted by (C)₁-C₄) Alkyl substitution one or more times;

.(C₃-C₇) Cycloalkylmethyl, which is unsubstituted or has its carbocyclic ring replaced by (C)₁-C₄) Alkyl substitution one or more times;

phenyl, unsubstituted or mono-, di-or trisubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, cyano, trifluoromethyl, trifluoromethoxy, S (O)_nAlk group, (C)₁-C₄) An alkylcarbonyl group; or from phenyl, phenoxy, pyrrolyl, imidazolyl, pyridyl or pyrazolyl, said radicals being unsubstituted or substituted by (C)₁-C₄) Alkyl substitution one or more times;

benzyl which is unsubstituted or whose phenyl radical is mono-or disubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl, or substituted in the alpha position by one or two similar or different groups selected from (C)₁-C₄) Alkyl, (C)₃-C₇) A cycloalkyl group;

phenylethyl which is unsubstituted or mono-or disubstituted in its phenyl radical by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl;

benzhydryl; benzhydryl methyl;

an aromatic heterocyclic group selected from the group consisting of pyrrolyl, imidazolyl, furyl, thienyl, pyrazolyl, indolyl which is unsubstituted or substituted one or more times by substituents independently selected from the group consisting of halogen atom, (C)₁-C₄) Alkyl, trifluoromethyl;

-R₂represents a hydrogen atom or(C₁-C₃) An alkyl group;

-R₃is represented by (C)₁-C₅) Alkyl or (C)₃-C₇) A cycloalkyl group;

-R₄represents phenyl which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

-R₅represents phenyl which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

-R₆represents a hydrogen atom or (C)₁-C₃) An alkyl group;

-n represents 0, 1 or 2;

-Alk represents (C)₁-C₄) An alkyl group.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. Thus, they may exist as enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures thereof, are part of the present invention.

These compounds of formula (I) may also be present in the form of hydrates or solvates, i.e. associated or bound to one or more water molecules or to a solvent. Such hydrates or solvates are also part of the present invention.

Halogen atoms are understood to be bromine, chlorine, fluorine or iodine atoms.

(C₁-C₃) Alkyl or respectively (C)₁-C₄) Alkyl, (C)₁-C₅) Alkyl or (C)₁-C₇) Theory of alkyl radicalsAre straight-chain or branched alkyl groups having from 1 to 3 carbon atoms or, respectively, from 1 to 4 carbon atoms, from 1 to 5 carbon atoms or from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl.

(C₁-C₄) Alkoxy is understood to mean straight-chain or branched alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy.

(C₃-C₇) Cycloalkyl is understood to be a cycloalkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

C₃-C₁₂Non-aromatic carbocyclic groups include monocyclic or fused, bridged or helical polycyclic groups. These monocyclic groups include such cycloalkyl groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Such fused, bridged or spiro bicyclic or tricyclic groups include, for example, norbornyl, bornyl, isobornyl, (noralcalamantyl), adamantyl, spiro [5.5 ]]Undecyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl, bicyclo [3.1.1]A heptyl group.

Among these compounds of formula (I), objects of the present invention are distinguished:

a compound of formula (IA) wherein-X-represents a-CO-group, a substituent R₁-R₅Is as defined for compounds of formula (I);

a compound of formula (IB) wherein-X-represents-SO₂-radical, substituent R₁-R₅Is as defined for compounds of formula (I);

a compound of formula (IC) wherein-X-represents-CON (R)₆) Radical, substituent R₁-R₆Is as defined for compounds of formula (I);

a compound of formula (ID) wherein-X-represents a-COO-group, a substituent R₁-R₅Is as followsAs defined for compounds of formula (I);

a compound of formula (IE) in which-X-represents a-SO-group, a substituent R₁-R₅As defined for the compounds of formula (I).

According to the invention, preference is given to compounds of the formula (I) in which:

-X represents

-R₁Represents:

.(C₁-C₇) An alkyl group;

.(C₃-C₇) Cycloalkyl which is unsubstituted or substituted by (C)₁-C₃) Alkyl groups are substituted one or more times;

.(C₃-C₇) Cycloalkylmethyl, which is unsubstituted or has its carbocyclic ring replaced by (C)₁-C₃) Alkyl substitution one or more times;

phenyl, unsubstituted or mono-, di-or trisubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, cyano, trifluoromethyl, trifluoromethoxy, S (O)_nAlk group, (C)₁-C₄) An alkylcarbonyl group, phenyl;

benzyl which is unsubstituted or mono-or disubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl;

an indolyl group;

-R₂represents a hydrogen atom or (C)₁-C₃) An alkyl group;

-R₃is represented by (C)₁-C₅) Alkyl or (C)₃-C₇) A cycloalkyl group;

-R₄represents phenyl which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

-R₅represents phenyl which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

-R₆represents a hydrogen atom or (C)₁-C₃) An alkyl group;

-n represents 0, 1 or 2;

-Alk represents (C)₁-C₄) An alkyl group, a carboxyl group,

they are in the base state as well as in the hydrate or solvate state.

In these compounds of formula (I), object of the present invention, a first group of compounds consists of these compounds, in which:

x represents a group-CO-or-SO₂A group, -SO-group or-CON (CH)₂CH₃)

-a group;

-R₁represents:

1-ethylpropyl, 1-methylpentyl, tert-butyl, ethyl;

cycloheptyl, 1-methylcyclopropyl;

3- (trifluoromethyl) phenyl;

4- (trifluoromethyl) phenyl;

-and/or R₂Represents a hydrogen atom;

-and/or R₃Representative nailA group;

-and/or R₄Represents 4-bromophenyl, 4-chlorophenyl;

-and/or R₅Represents 2, 4-dichlorophenyl;

and hydrates or solvates thereof.

Among the compounds of this latter group, mention may be made of the compounds of formula (I) in which:

x represents a group-CO-or-SO₂A group, -SO-group or-CON (CH)₂CH₃)

-a group;

-R₁represents:

1-ethylpropyl, 1-methylpentyl, tert-butyl, ethyl;

cycloheptyl, 1-methylcyclopropyl;

3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl;

-R₂represents a hydrogen atom;

-R₃represents a methyl group;

-R₄represents 4-bromophenyl, 4-chlorophenyl;

-R₅represents 2, 4-dichlorophenyl;

and hydrates or solvates thereof.

Among the compounds of this latter group, mention may be made of the compounds of formula (I) in which:

x represents a group-CO-or-SO₂-a group;

-R₁represents:

1-ethylpropyl, 1-methylpentyl;

cycloheptyl;

3- (trifluoromethyl) phenyl;

-R₂represents a hydrogen atom;

-R₃represents a methyl group;

-R₄represents 4-bromophenyl;

-R₅represents 2, 4-dichlorophenyl;

and hydrates or solvates thereof.

Among the compounds of formula (I), object of the present invention, the following compounds may be cited in particular:

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-ethylbutanamide;

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] cycloheptanecarboxamide;

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -3- (trifluoromethyl) benzenesulfonamide;

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylhexanamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2, 2-dimethylpropanamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-ethylbutanamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -1-methylcyclopropanecarboxamide;

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -4- (trifluoromethyl) benzamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylpropane-2-sulfinamide (sulfinamide);

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylpropane-2-sulfonamide;

-3- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -1, 1-diethylurea, and hydrates or solvates thereof.

In the following, the protecting group Pg is to be understood as meaning a group which, on the one hand, is capable of protecting a reactive function, such as a hydroxyl group or an amine, during synthesis and, on the other hand, is capable of regenerating the intact original reactive function after synthesis has ended. Examples of protecting groups and methods of protection and deprotection are given in 1991 in Protective Group in organic Synthesis, Green et al, 2 nd edition (John Wiley & Sons, Inc., New York).

In the following, a leaving group is understood to be a group which is easily cleaved from the molecule by heterolytic bond cleavage and which has an electron pair leaving it. For example, in the case of substitution reactions, this group is therefore easily replaced by other groups. Such leaving groups are, for example, halogens or reactive hydroxyls, like methane sulfonate, benzene sulfonate, p-toluene sulfonate, trifluoromethyl sulfonate, acetate, etc. Examples of leaving groups and references to their preparation are given in "Advances in Organic Chemistry", J.March, 3 rd edition, Wiley Interscience, 1985, pages 310-316.

According to the invention, the compounds of formula (I) can be prepared according to a process characterized in that:

a compound of the formula:

in the formula R₂、R₃、R₄And R₅Is as defined for a compound of formula (I):

or when a compound of formula (I) should be prepared, in which-X-represents a-CO-group, reacting an acid of formula:

HOOC-R₁ (III)

in the formula R₁Is as defined for the compound of formula (I);

or when a compound of formula (I) is to be prepared, wherein-X-represents-SO₂-when a group, a sulfonyl halide of the formula:

Hal-SO₂-R₁ (IV)

in the formula R₁Is as defined for a compound of formula (I), Hal represents a halogen atom, preferably chlorine;

or when a compound of formula (I) should be prepared, wherein-X-represents-CON (R)₆) -when a group, haloformates of the formula:

HalCOOAr (V)

in which Hal represents a halogen atom and Ar represents phenyl or 4-nitrophenyl, to give an intermediate compound of formula:

in the formula R₂、R₃、R₄And R₅Is defined as a compound of formula (I) and then reacted with an amine of the formula:

HN(R₆)R₁ (VII)

in the formula R₁And R₆Is as defined for the compound of formula (I);

or when a compound of formula (I) should be prepared in which-X-represents a-COO-group, using a haloformate of formula:

HalCOO-R₁ (XXIV)

in which Hal represents a halogen atom, R₁As defined for the compounds of formula (I),

or when a compound of formula (I) should be prepared in which-X-represents an-SO-group, using a sulphenylidene halide of formula:

Hal-SO-R₁ (XXV)

in the formula R₁Is as defined for a compound of formula (I) and Hal represents a halogen atom.

When the compound of formula (II) is treated with the acid of formula (III) as such, in a solvent such as dichloromethane, dichloroethane, N-N-dimethylformamide or tetrahydrofuran, at a temperature of-10 ℃ to the reflux temperature of the solvent, in the presence of a coupling agent used in peptide chemistry, operating in the presence of a base such as triethylamine, N-diisopropylethylamine or 4-dimethylaminopyridine, examples of such coupling agents are 1, 3-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate or 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate.

As acid (III) functional derivatives, acid chlorides, acid anhydrides, mixed acid anhydrides, C can be used₁-C₄Alkyl esters, wherein the alkyl group is a linear or branched, active ester, such as p-nitrophenyl ester.

Thus, in the process of the invention, the acid chloride obtained by reacting thionyl chloride or oxalyl chloride with an acid of formula (III) can also be reacted with a compound of formula (II) in a solvent such as a chlorine-containing solvent (e.g. dichloromethane, dichloroethane, chloroform), an ether (e.g. tetrahydrofuran, dioxane) or an amide (e.g. N, N-dimethylformamide) under an inert atmosphere at a temperature of from 0 ℃ to ambient temperature in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.

One embodiment is to prepare a mixed anhydride of the acid of formula (III) by reacting ethyl chloroformate with the acid of formula (III) in the presence of a base such as triethylamine and to react the mixed anhydride with the compound of formula (II) in a solvent such as dichloromethane at room temperature under an inert atmosphere in the presence of a base such as triethylamine.

When the compound of formula (II) is treated with the sulfonyl halide of formula (IV), the operation is carried out in a solvent such as methylene chloride or tetrahydrofuran in the presence of a base such as triethylamine or diisopropylethylamine at a temperature ranging from room temperature to the reflux temperature of the solvent.

According to one embodiment of the process, the compound of formula (I) may be prepared by reaction of a compound of formula (I) wherein-X-represents-SO-group with an oxidizing agent₂-a group. As the oxidizing agent, 3-chloroperbenzoic acid can be used in a solvent such as methylene chloride at a temperature of 0 ℃ to room temperature.

When treating the compound of formula (II) with a haloformate of formula (V), the procedure is carried out in a solvent such as dichloromethane in the presence of a base such as triethylamine at a temperature of from 0 ℃ to ambient temperature. The intermediate compound of formula (VI) thus obtained is then reacted with an amine of formula (VII) in a solvent such as dichloromethane in the presence of a base such as triethylamine at a temperature of from 0 ℃ to the reflux temperature of the solvent.

According to one embodiment of the process, the compound of formula (II) is reacted with an isocyanate compound of formula R in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature ranging from room temperature to the reflux temperature of the solvent₁(viii) compounds of formula (I) wherein-X-represents-CON (R)₆) A group of formula (II) wherein R₆＝H。

According to another embodiment of the process, the reaction of a compound of formula (II) with a compound of formula ClCON (R) in the presence of a base such as triethylamine or 4-dimethylaminopyridine in a solvent such as dichloromethane at a temperature of from 0 ℃ to the reflux temperature of the solvent₆)R₁(IX) reaction of a Compound of formula (I) wherein-X-represents-CON (R)₆) -a group.

When the compound of formula (II) is treated with a haloformate of formula (XXIV), the operation is carried out in a solvent such as methylene chloride in the presence of, for example, a triethylamine base at a temperature of from 0 ℃ to the reflux temperature of the solvent.

When a compound of formula (II) is treated with a sulfinyl halide of formula (XXV), the operation is carried out in a solvent such as dichloromethane in the presence of a base such as triethylamine at a temperature ranging from room temperature to the reflux temperature of the solvent.

According to another embodiment of the process, a compound of formula (I) wherein R is a compound of formula₂H and (C)₁-C₃) Reaction of an alkyl halide to produce a compound of formula (I) wherein R₂Is represented by (C)₁-C₃) An alkyl group.

The compound of formula (I) thus obtained is isolated and purified from the reaction medium according to usual methods, for example by crystallization or chromatography.

By the following formula (X):

in the formula R₃、R₄、R₅Is as defined for compounds of formula (I) and Y represents a leaving group as defined previously, preferably a halogen atom or a reactive hydroxyl group, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate or trifluoromethanesulfonate, with a compound of formula (XI) below to prepare a compound of formula (II):

H₂N-R₂ (XI)

in the formula R₂As defined for the compounds of formula (I).

This reaction is carried out in a solvent such as N, N-dimethylformamide, acetonitrile, dichloromethane, toluene or propan-2-ol, in the presence or absence of a base. When a base is used, it is selected from organic bases such as triethylamine, N-diisopropylethylamine or N-methylmorpholine. The reaction is carried out at a temperature of from 0 ℃ to the reflux temperature of the solvent.

According to one embodiment, compounds of the formula (X) are prepared by reacting a compound of the formula (X), wherein Y ═ Cl, with 1, 3, 5, 7-tetraazatricyclo [ 3.3.1%^3，7]The compounds of formula (II) wherein R is₂＝H。

According to another embodiment, it is also possible to prepare compounds of the formula (II) in which R is₂By reduction of a compound of the formula:

in the formula R₃、R₄And R₅As defined for the compounds of formula (I). This reduction reaction is carried out using a reducing agent such as borane in a solvent such as tetrahydrofuran at a temperature ranging from room temperature to the reflux temperature of the solvent, followed by acid hydrolysis.

The compounds of the formula (III) are known.

The compounds of formula (IV) are commercially available or described in the literature or can be prepared, for example, according to the following methods: J.org.chem.USSR, 1970, 6, 2454-2458; book of j.am.chem.soc., 1952, 74, 2008; temporary slurry, "J.Med.chem., 1977, 20(10), 1235-1239; EP 0469984; WO 95/18105.

For example, the compounds of formula (IV) may be prepared by halogenating the corresponding sulfonic acids or their salts, for example their sodium or potassium salts. This reaction is carried out in the presence of a halogenating agent such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, either neat or in a solvent such as a halohydrocarbon or N, N-dimethylformamide, at a temperature of from-10 ℃ to 200 ℃.

The compounds of the formulae (V), (VII), (VIII) and (IX) are known or can be prepared according to known methods.

The compounds of formula (X) are prepared according to the general methods outlined above from compounds of the formula:

in the formula R₃、R₄、R₅As defined for the compounds of formula (I).

Thus, for example, in the case of compounds of formula (X) in which Y represents a halogen atom, use is made of, for example, PCl₅、PBr₃HBr or BBr₃Treating the compound of formula (XIII) in a solvent such as dichloromethane at a temperature of from 0 ℃ to room temperature.

When the compound of formula (X) and Y represents methanesulfonate, benzenesulfonate, p-toluenesulfonate or trifluoromethanesulfonate, the compound of formula (XIII) is reacted with a compound of formula W-SO₂-Cl sulfonyl chloride, wherein W represents methyl, phenyl, p-tolyl or trifluoromethyl. This reaction is carried out in a solvent such as methylene chloride or toluene in the presence of a base such as triethylamine, pyridine or N, N-diisopropylethylamine at a temperature of-20 ℃ to the reflux temperature of the solvent.

The compounds of the formula (XI) are known.

The compounds of formula (XII) are prepared by reaction of an acid of formula or a functional derivative of such an acid with ammonia, according to the aforementioned method for the reaction of compound (II) with compound (III):

in the formula R₃、R₄And R₅Is (I) as defined for the compound of formula (I).

Preparing a compound of formula (XIII) by reduction of a compound of formula:

in the formula R₃、R₄、R₅Is as defined for the compound of formula (I), Z represents hydroxy or (C)₁-C₂) An alkoxy group.

This reaction is carried out in a solvent such as tetrahydrofuran in the presence of a reducing agent such as sodium borohydride or lithium aluminum hydride at a temperature of-20 ℃ to room temperature. When reducing a compound of formula (XV) wherein Z ═ OH, the acid can be preactivated by reaction with ethyl chloroformate in the presence of triethylamine.

By general hydrolysis of a compound of formula (XV) wherein Z ═ C₁-C₂) Alkoxy to prepare a compound of formula (XIV) or (XV) wherein Z is OH.

This reaction is carried out by hydrolysis in an alkaline medium using, for example, an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent such as water, methanol, 1, 2-dimethoxyethane, 1, 4-dioxane or a mixture of these solvents, at a temperature of from 0 ℃ to the reflux temperature of the solvent.

The compounds of formula (XV), wherein Z ═ C, are prepared according to scheme I below₁-C₂) Alkoxy, wherein Hal represents a halogen atom, preferably bromine.

Scheme I

In step a1 of scheme I, the reaction of the compound of formula (XVI) with the compound of formula (XVII) is carried out, for example, in the presence of an alkali metal salt of hexamethyldisilazane, for example the sodium salt, in a solvent such as tetrahydrofuran, at a temperature of-70 ℃ to 0 ℃.

In step b1, the compound of formula (XVIII) thus obtained is reacted with a mixture of N, N-dimethylformamide/phosphorus oxychloride in a solvent, for example 1, 2-dichloroethane, at a temperature of from-10 ℃ to the reflux temperature of the solvent.

In step C1, the compound of formula (XIX) thus obtained is reacted with a halide (C) in a solvent such as tetrahydrofuran at a temperature of-20 ℃ to room temperature₁-C₃) Alkyl magnesium or halogenated (C)₃-C₇) And (4) carrying out reaction on the naphthenic magnesium.

The compound of formula (XXI) thus obtained is subjected to oxidation in step d1 in the presence of an oxidizing agent such as pyridinium dichromate and molecular sieves in a solvent such as dichloromethane at room temperature.

In step c1, compound (XXII) thus obtained is reacted with compound (XXIII) in the presence of a base such as 1, 8-diazabicyclo [5, 4, 0] undec-7-ene in a solvent such as acetonitrile at a temperature ranging from room temperature to the reflux temperature of the solvent.

The compounds of the formulae (XVI), (XVII), (XX), (XXIII), (XXIV) and (XXV) are known or can be prepared according to known methods.

The following examples describe the preparation of certain compounds of the invention. These examples are not intended to be limiting and merely illustrate the invention. Exemplary compound numbers are set forth in table I below, which illustrates the chemical structure and physical properties of some of the compounds of the present invention.

The following abbreviations are used in the preparations and examples:

ether: ether (A)

Iso-ether: isopropyl ether

DMSO, DMSO: dimethyl sulfoxide

DMF: n, N-dimethylformamide

THF: tetrahydrofuran (THF)

TBTU: 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate

DCM: methylene dichloride

AcOEt: ethyl acetate

DIPEA: diisopropylethylamine

DBU: 1, 8-diazabicyclo [5, 4, 0] undec-7-ene

TFA: trifluoroacetic acid

2N hydrochloric acid ether: 2N Ether Hydrochlorid solution

F: melting Point

TA: at room temperature

Eb: boiling temperature

CLHP: high performance liquid chromatography

Silica H: silica gel 60H sold by Merck (DARMSTAD)

Buffer pH 2: 16.66g KHSO₄And 32.32g K₂SO₄Solution in 1 liter of water.

Recording in DMSO-d at 200MHz₆Proton nuclear magnetic resonance spectrum of (1), (b)¹H NMR). Chemical shift δ is expressed in ppm. For the explanation of the spectra, the following abbreviations are used: s: singlet, d: doublet, t: triplet, q: quartet, m: miscellaneous (masssf), mt: multiplet, se: broadened singlet, dd: double doublet.

The compounds of the invention were analyzed using a combination of LC/UV/MS (liquid chromatography/UV detection/mass spectrometry). Measurement of molecular Peak (MH)⁺) And retention time (tr) in minutes.

The method comprises the following steps:

a Symmetry C18 column was used, 2.1X 50mm, 3.5 μm, 30 ℃ and a flow rate of 0.4 ml/min.

The eluent composition was as follows:

-solvent a: 0.005% trifluoroacetic acid (TFA) in water, pH 3.15;

-solvent B: 0.005% TFA in acetonitrile.

Gradient:

time (minutes)	％A	％B
			0	100	0
10	10	90
			15	10	90
16	100	0
			20	100	0

UV detection was performed at λ 210nM and mass detection was performed by positive ESI chemical ionization.

The method 2 comprises the following steps:

XTerra MS C18 column, 2.1X 50mm, 3.5 μm, 30 ℃ flow 0.4 ml/min was used.

The eluent composition was as follows:

-solvent a: 10mM ammonium acetate (AcONH)₄) Aqueous solution, pH 7;

-solvent B: and (3) acetonitrile.

Gradient:

time (minutes)	％A	％B
			0	100	0
10	10	90
			15	10	90
16	100	0
			20	100	0

UV detection was performed at λ 220nM and mass detection was performed by positive ESI chemical ionization.

Preparation of

1. Preparation of a Compound of formula (XVIII):

preparation 1.1

2- (4-bromophenyl) -1- (2, 4-dichlorophenyl) ethanone.

(XVIII)：

Under a nitrogen atmosphere, 436ml of a 2M solution of sodium hexamethyldisilazane salt in THF was cooled to-60 deg.C, 400ml of THF was added, and then a solution of 75g of 4-bromophenyl acetic acid in 100ml of THF was added dropwise, and stirred at-70 deg.C for 1 hour and 30 minutes. 67.9g of 2, 4-dichlorobenzoic acid methyl ester were then added dropwise, stirred for 30 minutes and the temperature was then adjustedThe temperature was raised to 5 ℃. The reaction mixture was poured into ice/1 l of 2N HCl mixture, extracted with ether and the organic phase was washed with NaHCO₃The saturated solution was washed with water and Na₂SO₄Drying, evaporation of the solvent under vacuum to a volume of 200ml, addition of pentane and dehydration of the crystalline product formed. 80g of the expected compound are obtained.

Preparation 1.2

2- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) ethanone.

(XVIII)：

417ml of a 2M solution of sodium hexamethyldisilazane salt in THF is cooled to-60 ℃ under a nitrogen atmosphere, 350ml of THF are added, then a solution of 57g of 4-chlorophenylacetic acid in 70ml of THF is added dropwise, stirring is carried out for 2 hours, while the temperature is raised to-40 ℃. The reaction mixture was cooled to-60 ℃ and 65.3g of methyl 2, 4-dichlorobenzoate were added dropwise and the mixture was stirred while the temperature was raised to 0 ℃. The reaction mixture was poured into ice/1 l 2N HCl mixture, extracted with ether and the organic phase was taken up with Na₂SO₄Dry and concentrate the solvent in vacuo to a volume of 150 ml. The remaining solution was poured into 300ml of pentane and the resulting crystalline product was dehydrated. 60g of the expected compound are obtained.

2. Preparation of a compound of formula (XIX):

preparation 2.1

2- (4-bromophenyl) -3-chloro-3- (2, 4-dichlorophenyl) acrolein.

(XIX)：

A solution of 33.7ml DMF in 75ml 1, 2-dichloroethane was cooled to-5 ℃ and 40.6ml POCl was added dropwise₃Then stirring was carried out while the temperature was raised to TA. Then adding 40g of the mixture inPreparation 1.1A solution of the compound obtained in 300ml of 1, 2-dichloroethane was heated under reflux for 48 hours. After cooling, the reaction mixture was poured into 1.5 l ice water and NaHCO was added₃The pH was adjusted to 7, extracted with DCM and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with a gradient of heptane/DCM mixture (90/10; v/v) to (50/50; v/v). 39g of the expected compound are obtained.

Preparation 2.2

3-chloro-2- (4-chlorophenyl) -3- (2, 4-dichlorophenyl) acrolein.

(XIX)：

A solution of 54.5ml of DMF in 80ml of 1, 2-dichloroethane is cooled to 0 ℃ and 60.7ml of POCl are added dropwise₃. Stirring was then carried out while the temperature was raised to TA. A solution of 30g of the compound of preparation 1.2 in 300ml of 1, 2-dichloroethane is then added and heated at 80 ℃ for 4 hours. After cooling, the reaction mixture was poured into ice, sodium acetate was added to add pH to 7, extracted with DCM and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue was chromatographed on silica gel, eluting with DCM. 35g of the expected compound are obtained.

3. Preparation of a compound of formula (XXI):

preparation 3.1

3- (4-bromophenyl) -4-chloro-4- (2, 4-dichlorophenyl) but-3-en-2-ol.

(XXI)：R₃＝-CH₃；

A solution of 10g of the compound obtained in preparation 2.1 in 100ml of THF is cooled to-20 ℃ and 25ml of 1.4M methyl bromide are added dropwiseSolutions of magnesium in THF. Pouring the reaction mixture into NH₄Saturated Cl solution, extraction with ether, and Na extraction of the organic phase₂SO₄Dried and the solvent evaporated under vacuum. 11g of the expected compound are obtained.

Preparation 3.2

4-chloro-3- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) but-3-en-2-ol.

(XXI)：R₃＝-CH₃；

A solution of 35g of the compound obtained in preparation 2.2 in 200ml of THF is cooled to-20 ℃ and 54.2ml of a 1.4M solution of methylmagnesium bromide in THF are added dropwise. The reaction mixture was poured into saturated NH₄Extracting with ether in Cl solution, and extracting the organic phase with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with heptane and then with a heptane/AcOEt mixture up to (80/20; v/v). 16g of the expected compound are obtained.

4. Preparation of a compound of formula (XXII):

preparation of 4.13- (4-bromophenyl) -4-chloro-4- (2, 4-dichlorophenyl) but-3-en-2-one.

(XXII)：R₃＝-CH₃；

A mixture of 7g of the compound obtained in preparation 3.1, 12.8g of pyridinium dichromate and 15g of 4 Å molecular sieve in 200ml of DCM was stirred for 24 hours at TA. The reaction mixture is filtered over celite and the filtrate is concentrated in vacuo. The residue is chromatographed on silica, eluting with heptane and then with a heptane/AcOEt mixture (96/4; v/v). 7g of the expected compound are obtained.

Preparation 4.2

4-chloro-3- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) but-3-en-2-one.

(XXII)：R₃＝-CH₃；

A mixture of 16g of the compound obtained in preparation 3.2, 41.6g of pyridinium dichromate and 40g of 4 Å molecular sieve in 200ml of DCM was stirred at room temperature overnight. The reaction mixture is filtered over celite and the filtrate is concentrated in vacuo. The residue is chromatographed on silica, eluting with a heptane/AcOEt mixture (90/10; v/v). 15g of the expected compound are obtained.

5. Preparation of a compound of formula (XV):

preparation 5.1

4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methylthiophene-2-carboxylic acid methyl ester.

(XV)：Z＝-OCH₃；R₃＝-CH₃；

To a solution of 2.7g of the compound obtained in preparation 4.1 in 25ml of acetonitrile was added 1.49ml of methyl thioglycolate, followed by 2.4ml of DBU, and stirred overnight under TA. The reaction mixture was poured into 12.5ml of 1N HCl, extracted with AcOEt, the organic phase washed with water and Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with a heptane/AcOEt mixture (95/5; v/v). 1.21g of the expected compound are obtained.

Preparation 5.2

4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methylthiophene-2-carboxylic acid methyl ester.

(XV)：Z＝-OCH₃；R₃＝-CH₃；

A mixture of 7.5g of the compound obtained in preparation 4.2 and 4.4g of methyl thioglycolate was heated to 80 ℃ and 3ml of DBU was added dropwise and stirred at 60 ℃ overnight. The reaction mixture was concentrated in vacuo, the residue was taken up in 1N HCl, extracted with an ether/AcOEt mixture and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with heptane and then with a heptane/AcOEt mixture up to (90/10; v/v). Crystallization in MeOH gave 3.5g of the expected compound.

6. Preparing a compound of formula (XIV):

preparation 6.1

4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methylthiophene-2-carboxylic acid

(XIV)：R₃＝-CH₃；

To a solution of 1.21g of the compound obtained in preparation 5.1 in 6ml of 1, 2-dimethoxyethane was added 3ml of MeOH, followed by 1.73ml of 30% NaOH solution and stirred at 50 ℃ for 24 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in water, the aqueous phase was washed with ether, the aqueous phase was acidified to pH 2 by addition of concentrated HCl solution, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. After crystallization from a pentane/isoether mixture (75/25; v/v), 0.75g of the expected compound is obtained.

Preparation 6.2

4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methylthiophene-2-carboxylic acid.

(XIV)：R₃＝-CH₃；

To a solution of 3.5g of the compound obtained in preparation 5.2 in 15ml of 1, 2-dimethoxyethane, 15ml of MeOH and then 0.68g of flake NaOH were added, stirred overnight at room temperature and then heated at 60 ℃ for 3 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in water, the aqueous phase was washed with ether, the aqueous phase was acidified to pH 2 by addition of concentrated HCl solution, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. After crystallization in a DCM/isoether mixture, 3g of the expected compound are obtained.

7. Preparation of a compound of formula (XII):

preparation 7.1

4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methylthiophene-2-carboxamide.

(XII)：R₃＝-CH₃；

A mixture of 3g of the compound obtained in preparation 6.1 and 1.98ml of sulfonyl chloride in 60ml of 1, 2-dichloroethane is heated at 70 ℃ for 4 hours. The reaction mixture was concentrated in vacuo, the residue was dissolved in 1, 2-dichloroethane, and the solvent was evaporated in vacuo to give 3g of acid chloride. A solution of 6.51ml of 2M ammonia in MeOH and 1.37ml of triethylamine in 10ml of DCM was cooled to 5 ℃ and a solution of 3g of acid chloride in 5ml of DCM was added dropwise with stirring overnight while the temperature was raised to TA. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with AcOEt and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. After crystallization from an ether/isoether mixture, 2.5g of the expected compound are obtained.

Preparation 7.2

4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methylthiophene-2-carboxamide.

(XII)：R₃＝-CH₃；

A mixture of 3g of the compound obtained in preparation 6.2 and 2.2ml of thionyl chloride in 60ml of 1, 2-dichloroethane is heated under reflux for 2 hours and 30 minutes. The reaction mixture was concentrated in vacuo, the residue was dissolved with 1, 2-dichloroethane, and the solvent was distilled off in vacuo to give 3g of acid chloride. A solution of 7.21ml of 2M ammonia in MeOH and 1.52ml of triethylamine in 20ml of DCM is cooled to 0 ℃ and a solution of 3g of acid chloride in 20ml of DCM is added dropwise and stirred overnight while the temperature is raised to room temperature. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with DCM and then with the DCM/propan-2-ol mixture up to (95/5; v/v). After crystallization from isoether 2g of the expected compound are obtained.

8. Preparing a compound of formula (II):

preparation 8.1

1- [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methanamine hydrochloride.

(II)：R₂＝H；R₃＝-CH₃；

To a solution of 2.5g of the compound obtained in preparation 7.1 in 50ml of THF was added 22.67ml of a 1M solution of borane in THF, which was then heated under reflux for 15 hours. MeOH was then added until no gas was evolved and 10ml of 2N HCl ether solution was added. The reaction mixture is concentrated in vacuo to a volume of 10ml, and it is added dropwise to 150ml of isoether under TA, stirred overnight under TA, and the precipitate formed is dehydrated. 1.9g of the expected compound are obtained.

Preparation 8.2

1- [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methanamine hydrochloride.

(II)：R₂＝H；R₃＝-CH₃；

To a solution of 2g of the compound obtained in preparation 7.2 in 20ml of THF was added 20.2ml of a 1M solution of borane in THF, followed by heating under reflux for 5 hours. MeOH was then added until no gas evolved and 10ml of 2N HCl ether solution was added and stirred for 30 minutes. The reaction mixture was concentrated in vacuo to a volume of 10ml, which was added dropwise to 150ml of an ether/isoether mixture (50/50; v/v) at room temperature and stirred overnight at room temperature, and the resulting precipitate was dehydrated. 1.5g of the expected compound are obtained.

Example 1: compound No. 1

N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-ethylbutanamide.

A mixture of 0.35g of the compound obtained in preparation 8.1, 0.32ml of triethylamine and 0.1g of 2-ethylbutyryl chloride in 20ml of DCM is stirred for 1 hour under TA. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with AcOEt and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue was dissolved in DCM and the isoether was added and the crystalline product formed was dehydrated. 0.28g of the expected compound is obtained.

MH⁺524; tr is 11.86 (method 2)

¹H NMR：DMSO-d₆：δ(ppm)：0.8：t：6H；1.4：mt：4H；1.85-2.15：m：4H；4.45：d：2H；6.9-7.7：m：7H；8.5：t：1H。

Example 2: compound No. 2

N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] cycloheptanecarboxamide.

A mixture of 0.35g of the compound obtained in preparation 8.1, 0.11g of cycloheptanecarboxylic acid, 0.32mg of triethylamine and 0.27g of TBTU in 20ml of DCM is stirred overnight at TA. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with AcOEt and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue was dissolved in DCM and isoether was added and the crystalline product formed was dehydrated. 0.27g of the expected compound is obtained.

MH⁺550; tr is 12.4 (method 2)

¹H NMR：DMSO-d₆：δ(ppm)：1.2-1.9：m：12H；2.02：s：3H；2.3：mt：1H；4.4：d：2H；6.9-7.7：m：7H；8.4：t：1H。

Example 3: compound No. 3

N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -3- (trifluoromethyl) benzenesulfonamide.

A mixture of 0.35g of the compound obtained in preparation 8.1, 0.2g of 3- (trifluoromethyl) benzenesulfonyl chloride and 0.32ml of triethylamine in 20ml of DCM is stirred overnight under TA. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with AcOEt, the organic phase was washed with water and Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with a mixture of DCM/AcOEt (90/10; v/v). 0.25g of the expected compound is obtained.

MH⁺632; tr is 12.28 (method 2)

¹H NMR：DMSO-d₆：δ(ppm)：1.9：s：3H；4.3：s：2H；6.7-8.2：m：11H；8.65：se：1H。

Example 4: compound No. 4

N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylhexanamide.

A mixture of 0.35g of the compound obtained in preparation 8.1, 0.35ml of triethylamine, 0.11g of 2-methylhexanoic acid and 0.29g of TBTU in 20ml of DCM is stirred for 48 hours at TA. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with AcOEt and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. 0.3g of the desired compound is obtained in the form of crystals.

MH⁺538; tr is 12.71 (method 1)

¹H NMR：DMSO-d₆：δ(ppm)：0.8：t：3H；1.0：d：3H；1.05-1.65：m：6H；2.05：s：3H；2.25：mt：1H；4.45：mt：2H；6.9-7.7：m：7H；8.55：t：1H。

Example 5: compound No. 5

N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2, 2-dimethylpropionamide.

A mixture of 0.35g of the compound obtained in preparation 8.2, 0.35ml of triethylamine and 0.11ml of 2, 2-dimethylpropionyl chloride in 20ml of DCM is stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. After crystallization from an ether/isoether mixture, 0.3g of the expected compound is obtained.

¹H NMR：DMSO-d₆：δ(ppm)：1.12：s：9H；2.03：s：3H；4.43：d：2H；7.07：d：2H；7.24-7.40：m：4H；7.58：se：1H；8.19：t：1H。

Example 6: compound No. 6

N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-ethylbutanamide.

A mixture of 0.35g of the compound obtained in preparation 8.2, 0.35ml of triethylamine and 0.12g of 2-ethylbutyryl chloride in 20ml of DCM was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in 0.5N HCl, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. After crystallization from isoether 0.3g of the expected compound is obtained.

¹H NMR：DMSO-d₆：δ(ppm)：0.81：t：6H；1.42：mt：4H；1.91-2.15：m：4H；4.47：d：2H；7.07：d：2H；7.22-7.44：m：4H；7.61：d：1H；8.50：t：1H。

Example 7: no. 7 Compound

N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -1-methylcyclopropanecarboxamide.

A mixture of 0.35g of the compound obtained in preparation 8.2, 0.35ml of triethylamine, 0.09g of 1-methylcyclopropanecarboxylic acid and 0.3g of TBTU in 30ml of DCM was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. After crystallization from isoether 0.2g of the expected compound is obtained.

¹H NMR：DMSO-d₆：δ(ppm)：0.53：q：2H；0.97：q：2H；1.27：s：3H；2.05：s：3H；4.43：d：2H；7.07：d：2H；7.25-7.43：m：4H；7.59：d：1H；8.25：t：1H。

Example 8: compound No. 8

N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -4- (trifluoromethyl) benzamide.

A mixture of 0.35g of the compound obtained in preparation 8.1, 0.17g of 4- (trifluoromethyl) benzoyl chloride and 0.32ml of triethylamine in 20ml of DCMStir at room temperature overnight. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with heptane and then with the heptane/AcOEt mixture up to (90/10; v/v). 0.3g of the expected compound is obtained.

¹H NMR：DMSO-d₆：δ(ppm)：2.12：s：3H；4.68：d：2H；7.02：d：2H；7.25-7.41：m：2H；7.49：d：2H；7.59：d：1H；7.87：d：2H；8.09：d：2H；9.44：t：1H。

Example 9: compound No. 9

N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylpropane-2-sulfinamide.

A mixture of 0.3g of the compound obtained in preparation 8.2, 0.12g of 2-methylpropane-2-sulfinyl chloride and 0.3ml of triethylamine in 20ml of DCM is stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting first with DCM and then with the DCM/AcOEt mixture up to (90/10; v/v). 0.2g of the expected compound is obtained.

¹H NMR：DMSO-d₆：δ(ppm)：1.16：s：9H；2.03：s：3H；4.36：mt：2H；6.03：t：1H；7.07：d：2H；7.22-7.47：m：4H；7.60：d：1H。

Example 10: compound No. 10

N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylpropane-2-sulfonamide.

A mixture of 0.35g of Compound No. 9 and 0.3g of 3-chloroperbenzoic acid in 20ml of DCM was stirred at room temperature for 1 hour. Then 10% NaHCO was added₃Extracting the solution with DCM, and collecting the organic phaseWith Na₂SO₄Dried and the solvent evaporated under vacuum. The residue was chromatographed on silica gel, eluting with DCM. After crystallization from isoether 0.18g of the expected compound is obtained.

¹H NMR：DMSO-d₆：δ(ppm)：1.30：s：9H；2.03：s：3H；4.42：d：2H；7.08：d：2H；7.27-7.44：m：4H；7.62：d：1H；7.66：t：1H。

Example 11: compound No. 11

3- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -1, 1-diethylurea.

0.35g of the compound obtained in preparation 8.2, 0.165ml of diethylcarbamoyl chloride, 0.1g of 4-dimethylaminopyridine and 0.11g of 0.11g K₂CO₃The mixture in 30ml DCM was heated at 45 ℃ for 48 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with ether and the organic phase was taken up with Na₂SO₄Dried and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with DCM and then with the DCM/MeOH mixture up to (97.5/2.5; v/v). 0.25g of the expected compound is obtained.

¹H NMR：DMSO-d₆：δ(ppm)：1.03：t：6H；2.05：s：3H；3.22：q：4H；4.41：d：2H；6.95：t：1H；7.07：d：2H；7.24-7.44：m：4H；7.59：d：1H。

The following table illustrates the chemical structures of some examples of compounds of the invention.

TABLE I

In m.rinaldi-Carmona et al (FEBS Letters, 1994,350240-244) on the chemical constituent CB of cannabis, of the compound of the formula (I)₁The receptor has very good in vitro affinity (IC)₅₀≤5.10^-7M)。

According to methods such as M.Bouadoula et al, J.biol.chem., 1995,27013973-,278871-,272the hydrazone glycoside-cyclase inhibiting model described in 22330-22339 demonstrates antagonistic properties of the compounds of formula (I).

The toxicity of the compounds of formula (I) is compatible with their use as medicaments.

Thus, according to another aspect, the invention is directed to medicaments containing a compound of formula (I), or an addition salt of such a compound with a pharmaceutically acceptable acid, or a solvate or hydrate of a compound of formula (I).

Thus, the compounds of the invention may be used in humans or animals for the treatment or prevention of CB, a chemical component involved in cannabis₁A disease of the receptor.

For example, without limitation, these compounds of formula (I) are useful as psychotropic agents, primarily for the treatment of psychiatric disorders including anxiety, depression, humoral disorders, insomnia, delirium disorders, obsessive-compulsive disorders, psychosis, schizophrenia, attention and hyperactivity disorders (TDAH) in children with hyperactivity (MBD), and for the treatment of disorders associated with the use of psychotropic agents, particularly in the case of drug abuse and/or drug dependence, including alcohol dependence and nicotine dependence.

The compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epileptic seizures, dyskinesias, in particular dyskinesias or parkinson's disease, tremors and dystonias.

The compounds of formula (I) according to the invention can be used as medicaments for the treatment of memory disorders, cognitive disorders, in particular senile dementia, Alzheimer's disease, and for the treatment of attention or wake disorders. In addition, these compounds of formula (I) are useful as neuroprotective agents in the treatment of ischemia, cranial trauma, and in the treatment of neurodegenerative diseases including chorea, Huntington's chorea, Tourette's syndrome.

These compounds of formula (I) of the invention are useful as agents for the treatment of pain: neuropathic pain, peripheral acute pain, inflammatory chronic pain.

The compounds of formula (I) according to the invention can be used as medicaments for the treatment of appetite, desire (sugars, carbohydrates, narcotics, alcohols or any appetizing substances) and/or eating behaviour disorders, in particular for the treatment of obesity or bulimia, as well as for the treatment of type II diabetes or non-insulin dependent diabetes mellitus and for the treatment of lipodystrophy, metabolic syndrome. These compounds of formula (I) of the present invention are therefore useful for the treatment of obesity and obesity-related risks, in particular cardiovascular risks. Furthermore, the compounds of formula (I) according to the invention can be used as medicaments for the treatment of gastro-intestinal disorders, diarrhoeal disorders, ulcers, emesis, bladder and urine disorders, disorders of endocrine origin, cardiovascular disorders, hypertension, hemorrhagic shock, septic shock, chronic cirrhosis, steatosis, fatty liver, encephalopathy in patients with chronic liver, asthma, raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, diseases of the immune system, in particular autoimmune and neuroinflammatory diseases, such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, scleroderma, infectious and viral diseases, such as encephalitis, cerebrovascular accidents, and as anti-cancer, treatment of guillain-barre syndrome and treatment of osteoporosis.

According to the invention, these compounds of formula (I) are more particularly useful for the treatment of psychotic disorders, in particular schizophrenia, attention and hyperactivity disorder (TDAH) in children with hyperactivity (MBD); for the treatment of desire and obesity disorders; treating memory and cognitive deficits; can be used for treating alcoholic dependence and nicotine dependence, i.e. alcoholic intoxication and tobacco intoxication.

According to one of its aspects, the present invention relates to compounds of formula (I), the use of pharmaceutically acceptable salts of the compounds and their solvates or hydrates for the treatment of the disorders and diseases indicated above.

According to another aspect, the present invention relates to pharmaceutical compositions containing as active ingredient a compound of the present invention. These pharmaceutical compositions contain an effective amount of at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate or hydrate of the compound, and at least one pharmaceutically acceptable excipient.

The excipients may be selected from the usual excipients known to those skilled in the art depending on the pharmaceutical dosage form and the desired mode of administration.

In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of the above formula (I) or a possible salt, solvate or hydrate thereof may be mixed with usual pharmaceutical excipients and administered in unit dosage form to animals or humans for the prevention or treatment of the above-mentioned disorders or diseases.

Suitable unit dosage forms include oral dosage forms, such as tablets, soft or hard capsules, powders, granules and oral liquids or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal dosage forms by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal dosage forms and implants. For external use, the compounds of the present invention may be used in creams, gels, ointments or lotions.

By way of example, a unit dosage form of a tablet of a compound of the invention may contain the following components:

the compounds of the present invention: 50.0mg

Mannitol: 223.75mg

Croscarmellose sodium: 6.0mg

Corn starch: 15.0mg

Hydroxypropyl methylcellulose: 2.25mg

Magnesium stearate: 3.0mg

When administered orally, the dose of active ingredient may be up to 0.01-100mg/kg per day, administered in one or more doses, preferably 0.02-50 mg/kg.

There may be special cases where the dosage is either high or low; such dosages do not depart from the scope of the invention. According to the usual practice, the appropriate dosage for each patient will be determined by the physician in view of the mode of administration, the weight and response of said patient.

According to another aspect of the invention, the invention also relates to a method of treatment of the above-mentioned diseases, which comprises administering to a patient an effective amount of a compound of the invention or one of its pharmaceutically acceptable salts, hydrates or solvates.

Claims (13)

1. A compound corresponding to the formula:

in the formula:

-X represents-SO-，-SO₂-，

-R₁Represents:

·(C₁-C₇) An alkyl group;

·(C₃-C₁₂) Non-aromatic carbocyclic radicals, which are unsubstituted or substituted by (C)₁-C₄) Alkyl substitution one or more times;

·(C₃-C₇) Cycloalkylmethyl, which is unsubstituted or has its carbocyclic ring replaced by (C)₁-C₄) Alkyl substitution one or more times;

phenyl, unsubstituted or mono-, di-or trisubstituted by substituents independently chosen from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, cyano, trifluoromethyl, trifluoromethoxy, S (O)_nAlk group, (C)₁-C₄) An alkylcarbonyl group; or from phenyl, phenoxy, pyrrolyl, imidazolyl, pyridyl or pyrazolyl, said radicals being unsubstituted or substituted by (C)₁-C₄) Alkyl substitution one or more times;

benzyl which is unsubstituted or whose phenyl radical is mono-or disubstituted by substituents independently chosen from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl, or substituted in the alpha position by one or two similar or different groups selected from (C)₁-C₄) Alkyl, (C)₃-C₇) A cycloalkyl group;

phenylethyl which is unsubstituted or mono-or disubstituted in the phenyl radical by substituents independently chosen from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl;

a benzhydryl group; benzhydryl methyl;

an aromatic heterocyclic radical selected from the group consisting of pyrrolyl, imidazolyl, furyl, thienyl, pyrazolyl, indolyl, which is unsubstituted or substituted one or more times by substituents which are unsubstituted or substitutedThe radicals are independently selected from halogen atoms, (C)₁-C₄) Alkyl, trifluoromethyl;

-R₂represents a hydrogen atom or (C)₁-C₃) An alkyl group;

-R₃is represented by (C)₁-C₅) Alkyl or (C)₃-C₇) A cycloalkyl group;

-R₄represents phenyl which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

-R₅represents phenyl which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from halogen atoms, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

-R₆represents a hydrogen atom or (C)₁-C₃) An alkyl group;

-n represents 0, 1 or 2;

-Alk represents (C)₁-C₄) An alkyl group, a carboxyl group,

and hydrates or solvates thereof.

2. A compound of formula (I) according to claim 1, wherein-X-represents the group-CO-, substituent R₁-R₅Is as defined for compounds of formula (I) according to claim 1;

and hydrates or solvates thereof.

3. A compound of formula (I) according to claim 1, wherein-X-represents the group-SO₂-, substituent R₁-R₅Is as defined for compounds of formula (I) according to claim 1;

and hydrates or solvates thereof.

4. A compound of formula (I) according to claim 1, wherein-X-represents the group-CON (R)₆) -, substituent R₁-R₆Is as defined for compounds of formula (I) according to claim 1;

and hydrates or solvates thereof.

5. A compound of formula (I) according to claim 1, wherein-X-represents a radical-COO-, the substituent R₁-R₅Is as defined for compounds of formula (I) according to claim 1;

and hydrates or solvates thereof.

6. A compound of formula (I) according to claim 1, wherein-X-represents the group-SO-, substituent R₁-R₅Is as defined for compounds of formula (I) according to claim 1;

and hydrates or solvates thereof.

7. A compound of formula (I) according to claim 1, wherein-X-represents a-CO-group, -SO₂A group, -SO-group or-CON (CH)₂CH₃) -a group;

-R₁represents:

1-ethylpropyl, 1-methylpentyl, tert-butyl, ethyl;

cycloheptyl, 1-methylcyclopropyl;

3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl;

-R₂represents a hydrogen atom;

-R₃represents a methyl group;

-R₄represents 4-bromophenyl, 4-chlorophenyl;

-R₅represents 2, 4-dichlorophenyl;

and hydrates or solvates thereof.

8. A compound of formula (I) according to claim 1, wherein:

x represents a group-CO-or-SO₂-a group;

-R₁represents:

1-ethylpropyl, 1-methylpentyl;

cycloheptyl;

3- (trifluoromethyl) phenyl;

-R₂represents a hydrogen atom;

-R₃represents a methyl group;

-R₄represents 4-bromophenyl;

-R₅represents 2, 4-dichlorophenyl;

and hydrates or solvates thereof.

9. A compound of formula (I) according to claim 1, selected from:

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-ethylbutanamide;

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] cycloheptanecarboxamide;

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -3- (trifluoromethyl) benzenesulfonamide;

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylhexanamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2, 2-dimethylpropanamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-ethylbutanamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -1-methylcyclopropanecarboxamide;

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -4- (trifluoromethyl) benzamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylpropane-2-sulfinamide;

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -2-methylpropane-2-sulfonamide;

-3- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -3-methyl-2-thienyl ] methyl ] -1, 1-diethylurea;

and hydrates or solvates thereof.

10. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of formula:

in the formula R₂、R₃、R₄And R₅Is as defined for the compound of formula (I) according to claim 1:

or when a compound of formula (I) should be prepared, in which-X-represents a-CO-group, using an acid of formula:

HOOC-R₁ (III)

in the formula R₁Is as defined for the compound of formula (I) according to claim 1;

or when a compound of formula (I) is to be prepared, wherein-X-represents-SO₂-when a group, a sulfonyl halide of the formula:

Hal-SO₂-R₁ (IV)

in the formula R₁Is as defined for a compound of formula (I) according to claim 1, Hal represents a halogen atom;

or when a compound of formula (I) should be prepared, wherein-X-represents-CON (R)₆) -when a group, haloformates of the formula:

HalCOOAr (V)

in which Hal represents a halogen atom and Ar represents phenyl or 4-nitrophenyl, to give an intermediate compound of formula:

in the formula R₂、R₃、R₄And R₅Is a compound of the formula (I) as claimed in claim 1Defined, and then reacting it with an amine of the formula:

HN(R₆)R₁ (VII)

in the formula R₁And R₆Is as defined for the compound of formula (I) according to claim 1;

or when a compound of formula (I) should be prepared in which-X-represents a-COO-group, using a haloformate of formula:

HalCOO-R₁ (XXIV)

in which Hal represents a halogen atom, R₁As defined for the compound of formula (I) according to claim 1,

or when a compound of formula (I) should be prepared in which-X-represents an-SO-group, using a sulphenylidene halide of formula:

Hal-SO-R₁ (XXV)

in the formula R₁Defined for a compound of formula (I) according to claim 1, Hal represents a halogen atom.

11. Medicament, characterized in that it contains a compound of formula (I) according to any one of claims 1 to 9, or a hydrate or solvate of a compound of formula (I).

12. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 9, a hydrate or solvate of such a compound, and at least one pharmaceutically acceptable excipient.

13. Use of a compound of formula (I) according to any one of claims 1 to 9 for the preparation of medicaments for the treatment and prophylaxis of desire disorders, gastro-intestinal disorders, inflammatory phenomena, diseases of the immune system, psychotic disorders, alcohol dependence, nicotine dependence.