HK1117841A - Derivatives of n-[(4,5-diphenyl-3-alkyl-2-thienyl) methyl] amine (amide, thiourea and urea) as cannabinoid cb1 receptor antagonists - Google Patents

Description

N- [ (4, 5-diphenyl-2-thienyl) methyl ] amine derivatives, their preparation and therapeutic use

The present invention relates to substituted N- [ (4, 5-diphenyl-2-thienyl) methyl ] amine derivatives, their preparation and 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 derivatives having affinity for the receptor.

International application WO 91/19708 and patent applications EP0024042, EP 0055470, EP0055471 and US 4432974 describe 4, 5-diarylthiophene derivatives with 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-2-thienyl) methyl groups]Amine derivatives, their use as cannabinoids (a)) CB of₁The receptors have antagonistic properties.

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

in the formula:

-X representsA group;

-R₁represents:

·(C₆-C₁₂) An alkyl group;

·(C₃-C₁₂) A non-aromatic carbocyclic group (C) unsubstituted or substituted₁-C₄) Alkyl substitution one or more times;

quilt C₃-C₁₂Methyl substituted by a non-aromatic carbocyclic group, which is unsubstituted or the carbocyclic ring is substituted by (C)₁-C₄) Alkyl substitution one or more times;

phenyl mono-, di-or trisubstituted by a substituent independently selected from the group consisting of: halogen atom, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino, cyano, trifluoromethyl, trifluoromethoxy, S (O)_nAlk group, (C)₁-C₄) Alkylcarbonyl group, methylenedioxy (mthyl neoxy); 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 whose phenyl group is mono-or disubstituted independently with substituents selected from: halogen atom, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl, (trifluoromethyl) thio, or in alpha position by one or two radicals, which may be the same or different, selected fromSubstituted benzyl groups: (C)₁-C₄) Alkyl, (C)₃-C₇) Cycloalkyl or pyrrolyl;

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

1, 2, 3, 4-tetrahydronaphthyl or 5, 6, 7, 8-tetrahydronaphthyl which is unsubstituted or mono-or disubstituted by substituents independently selected from the group consisting of: (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl;

benzhydryl (benzhydryl), benzhydrylmethyl;

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

-R₃represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from the group consisting of: halogen atom, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

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

-R₅represents a hydrogen atom or (C)₁-C₃) An alkyl group;

-n represents 0, 1 or 2;

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

These 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 exist in the form of hydrates or solvates, i.e. in combination or combination with one or more water molecules or solvents. Such hydrates and 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 or (C)₆-C₁₂) Alkyl is understood to mean a straight-chain or branched alkyl radical having from 1 to 3 carbon atoms or respectively from 1 to 4 carbon atoms or from 6 to 12 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl, isohexyl, pentyl, octyl, nonyl, decyl, undecyl, dodecyl.

(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 groups 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, adamantyl, spiro [5.5 ] s]Undecyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl, bicyclo [3.1.1]Heptyl, bicyclo [2.2.1]Hept-5-en-2-yl.

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-R₄Is as defined for compounds of formula (I);

a compound of formula (IB) wherein-X-represents-CON (R)₅) -radical, substituent R₁-R₅Is as defined for compounds of formula (I);

a compound of formula (IC) wherein-X-represents-CSN (R)₅) -radical, 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 representsA group;

-R₁represents:

·(C₆-C₁₂) 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 the carbocyclic ring is substituted by (C)₁-C₃) Alkyl substitution one or more times;

phenyl mono-, di-or trisubstituted by a substituent independently selected from the group consisting of: halogen atom, (C)₁-C₄) Alkoxy, cyano, trifluoromethyl, trifluoromethoxy, S (O)_nAlk group, (C)₁-C₄) An alkylcarbonyl group, phenyl;

a benzyl group mono-or disubstituted by substituents independently selected from: halogen atom, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl;

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

-R₃represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from the group consisting of: halogen atom, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

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

-R₅represents a hydrogen atom or (C)₁-C₃) An alkyl group;

-n represents 0, 1 or 2;

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

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

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-CO-group, -CONH-group or-CSNH-group;

-and/or R₁Represents:

1-propylbutyl, 1-ethylpentyl, 1-methylpentyl;

cycloheptyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, bicyclo [2.2.1] hept-2-yl, bicyclo [2.2.1] hept-5-en-2-yl;

cyclohexylmethyl, cycloheptylmethyl, bicyclo [2.2.1] hept-2-ylmethyl;

4-bromophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3, 5-difluorophenyl, 2-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethoxy) phenyl, 3-acetylphenyl, biphenyl-2-yl, biphenyl-4-yl, 1, 3-benzodioxol (benzodioxol) -5-yl, 4-phenoxyphenyl, 4- (1H-pyrrol-1-yl) phenyl;

2-fluorobenzyl, 3-fluorobenzyl, 4- (trifluoromethyl) benzyl, 4- [ (trifluoromethyl) thio ] benzyl, α -cyclohexylbenzyl, α - (1H-pyrrol-1-yl) benzyl;

4- (trifluoromethyl) phenethyl;

benzhydryl, benzhydrylmethyl;

1, 2, 3, 4-tetrahydronaphthalen-2-yl, 1, 2, 3, 4-tetrahydronaphthalen-1-yl, 5, 6, 7, 8-tetrahydronaphthalen-1-yl;

-and/or R₂Represents a hydrogen atom or a methyl group;

-and/or R₃Represents 4-bromophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 4-methoxyphenyl;

-and/or R₄Represents 4-chlorophenyl, 2, 4-dichlorophenyl, 4-methoxyphenyl;

and hydrates or solvates thereof.

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

-X represents a-CO-group, -CONH-group or-CSNH-group;

-R₁represents:

1-propylbutyl, 1-ethylpentyl, 1-methylpentyl;

cycloheptyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, bicyclo [2.2.1] hept-2-yl, bicyclo [2.2.1] hept-5-en-2-yl;

cyclohexylmethyl, cycloheptylmethyl, bicyclo [2.2.1] hept-2-ylmethyl;

4-bromophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3, 5-difluorophenyl, 2-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethoxy) phenyl, 3-acetylphenyl, biphenyl-2-yl, biphenyl-4-yl, 1, 3-benzodioxol-5-yl, 4-phenoxyphenyl, 4- (1H-pyrrol-1-yl) phenyl;

2-fluorobenzyl, 3-fluorobenzyl, 4- (trifluoromethyl) benzyl, 4- [ (trifluoromethyl) thio ] benzyl, α -cyclohexylbenzyl, α - (1H-pyrrol-1-yl) benzyl;

4- (trifluoromethyl) phenethyl;

benzhydryl, benzhydrylmethyl;

1, 2, 3, 4-tetrahydronaphthalen-2-yl, 1, 2, 3, 4-tetrahydronaphthalen-1-yl, 5, 6, 7, 8-tetrahydronaphthalen-1-yl;

-R₂represents a hydrogen atom or a methyl group;

-R₃represents 4-bromophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 4-methoxyphenyl;

-R₄represents 4-chlorophenyl, 2, 4-dichlorophenyl, 4-methoxyphenyl;

and hydrates or solvates thereof.

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

-X represents a-CO-group or a-CONH-group;

-R₁represents:

1-propylbutyl, 1-ethylpentyl, 1-methylpentyl;

cycloheptyl;

cycloheptylmethyl;

biphenyl-2-yl;

-R₂represents a hydrogen atom or a methyl group;

-R₃represents 4-bromophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl;

-R₄represents 4-chlorophenyl, 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-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -2-propylpentanamide (pentanamide);

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -2-ethylhexanoamide (hexanamide);

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

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -cycloheptanecarboxamide (carboxamide);

-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -2-cycloheptylacetamide (ac tamide);

-N-biphenyl-2-yl-N' - [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -urea;

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

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

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

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

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -N-methylcycloheptane carboxamide;

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

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -2-cycloheptyl-N-methylacetamide;

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

-N- [ [5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -N-methylcycloheptane carboxamide;

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

-4-chloro-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] benzamide (benzamide);

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

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

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

-N- [ [5- (2, 4-dichlorophenyl) -4- (4-methoxyphenyl) -2-thienyl ] methyl ] bicyclo [2.2.1] heptane-2-carboxamide;

-N- [ [5- (2, 4-dichlorophenyl) -4- (4-methoxyphenyl) -2-thienyl ] methyl ] -2-propylpentanamide;

-N- [ [4- (2, 4-dichlorophenyl) -5- (4-methoxyphenyl) -2-thienyl ] methyl ] -2-propylpentanamide;

and hydrates or solvates thereof.

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, WileyInterscience, 1985, p.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、R₃And R₄Is as defined for a compound of formula (I):

or else compounds of formula (I) should be prepared, in which formula-X-represents a-CO-group, using an acid or a functional derivative of such an acid of formula:

HOOC-R₁(III)

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

or a compound of formula (I) wherein-X-represents-CON (R)₅) When a group is selected, a haloformate of the formula:

HalCOOAr(IV)

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

in the formula R₂、R₃And R₄Is defined as a compound of formula (I) which is then reacted with an amine of the formula:

HN(R₅)R₁ (VI)

in the formula R₁And R₅As defined for the compounds of formula (I).

Or else compounds of formula (I) should be prepared, in which formula-X-represents a-CSNH-group, using an isothiocyanate of formula:

S＝C＝N-R₁ (XX)

in the formula R₁As defined for the compounds of formula (I).

If necessary, the compounds of formula (I) can be prepared by alkylation with the corresponding compounds of formula (I) in which R5 represents a hydrogen atom₅Is represented by (C)₁-C₃) An alkyl group.

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, such coupling agents are, for example, 1, 3-dicyclohexylcarbodiimide (dicyclohexylcarbodiimide) or benzotriazol-1-oxytri (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-oxytri (pyrrolidino) phosphonium hexafluorophosphate or 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, operating in the presence of a base such as triethylamine, N-diisopropylethylamine or 4-dimethylaminopyridine.

As acid (III) -functional derivatives, it is possible to use acyl radicalsChlorine, acid anhydride, mixed acid anhydride, C₁-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 it is also possible to react the acid chloride obtained by reacting a sulfonyl chloride or oxalyl chloride with an acid of formula (III) 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 treating the compound of formula (II) with a haloformate of formula (IV), the procedure is carried out in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature of from 0 ℃ to room temperature. The intermediate compound of formula (V) thus obtained is then reacted with an amine of formula (VI) 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 (I) may be prepared by reaction of a compound of formula (II) wherein-X-represents-CON (R) in which-X-represents-CON (R) in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature from room temperature to the reflux temperature of the solvent, by reaction with an isocyanate of formula R1-N ═ C ═ o (vii)₅) A group of formula (II) wherein R₅＝H。

According to another embodiment of the process, the compound of formula (II) is reacted with a compound of formula ClCON (R) in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature of from 0 ℃ to room temperature₅)R₁(VIII) CompoundCan prepare a compound of formula (I) wherein-X-represents-CON (R)₅) -a group.

According to another embodiment of the process, a compound of formula (I) wherein R is a compound of₂H, 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:

in the formula R₃And R₄Is as defined for the compound of formula (I) and Y represents a leaving group (group partial) as defined previously, preferably a halogen atom or an active hydroxyl group, such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate or trifluoromethylsulfonate group, with a compound of formula (II):

H₂N-R₂ (X)

in the formula R₂Is (I) as defined for the compound 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, by a compound of formula (IX), formula (IX)Where Y is 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, the compound of the formula:

in the formula R₃And R₄Is as defined for the compound of formula (I), and also to the preparation of compounds of formula (II) wherein R is₂H. 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 the formulae (IV), (VI), (VII) and (VIII) are known or can be prepared according to known methods.

The compound of formula (IX) is prepared according to the general procedures outlined above from a compound of the formula:

in the formula R₃And R₄As defined for the compounds of formula (I).

Thus, for example, in the compound of formula (IX), Y represents a halogen atom, in a solvent such as dichloromethane at a temperature of from-10 ℃ to room temperature, using, for example, PCl₅、PBr₃HBr or BBr₃Treating the compound of formula (XII) with a halogenating agent of (XII).

In the compound of formula (IX), Y represents methanesulfonate, benzeneWhen sulfonate, p-toluenesulfonate or trifluoromethanesulfonate, the compound of the formula (XII) is reacted with a compound of the 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 dichloromethane 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 formula (X) are known.

The compound of formula (XI) is prepared by the reaction of an acid or a functional derivative of such an acid of formula with aqueous ammonia (ammoniaque):

in the formula R₃And R₄As defined for the compounds of formula (I).

Preparing a compound of formula (XII) by reduction of a compound of the formula:

in the formula R₃And R₄Is 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 (XIV) wherein Z ═ OH, the acid may be preactivated by reaction with ethyl chloroformate in the presence of triethylamine.

By general hydrolysis of compounds of formula (XIV) wherein Z ═ C₁-C₂) Alkoxy, preparing a compound of formula (XIII) or (XIV)Wherein Z ═ 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 (XIV), wherein Z ═ C, are prepared according to scheme I below₁-C₂) An alkoxy group.

Scheme I

In the step of scheme Ia1The reaction of the compound of formula (XV) with the compound of formula (XVI) is carried out, for example, in the presence of an alkali metal salt of hexamethyldisilazane, like the sodium salt, in a solvent, for example tetrahydrofuran, at a temperature ranging from-70 ℃ to 0 ℃.

In the step ofb1The compound of formula (XVII) thus obtained is reacted with an N, N-dimethylformamide/phosphorus oxychloride mixture in a solvent such as 1, 2-dichloroethane at a temperature of from-10 ℃ to the reflux temperature of the solvent.

In the step ofc1In, for example, 1, 8-diazabicyclo [5, 4, 0]]The compound of formula (XVIII) thus obtained is reacted with the compound of formula (XIX) in the presence of a base of 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 formulae (XV), (XVI), (XIX) and (XX) are known or may 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: tetrafluoroboric acid 2- (1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium salt

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 (DAJRMSTAD)

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: triple-foldPeak, q: quartet, m: bulk, mt: multiplet, se: broadened singlet, dd: double two lines.

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 a 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/m.

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 0.4ml/m 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.

The method 3 comprises the following steps:

XTerra MS C18 column, 2.1X 50mm, 3.5 μm, 30 ℃ flow 0.8ml/m was used.

The eluent composition was as follows:

-solvent a: 0.025% trifluoroacetic acid (TFA) in water,

-solvent B: 0.025% TFA in acetonitrile.

Gradient:

time (minutes)	％A	％B
			0	100	0
2	0	100
			2.7	0	100
2.75	100	0

UV detection was performed at 210-400nM using a diode array detector and mass detection was performed by positive ESI chemical ionization.

Preparation of

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

preparation 1.1

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

Under a nitrogen atmosphere, 420ml of a 2M solution of sodium hexamethyldisilazane salt in THF was cooled to-60 ℃ and 350ml of THF were added, then a solution of 57.6g of 4-chlorophenylacetic acid in 70ml of THF was added dropwise and stirred at-60 ℃ for 1 hour. 66g of methyl 2, 4-dichlorobenzoate were then added dropwise at-60 ℃ and stirred for 40 minutes at-60 ℃ and the temperature was then raised to 0 ℃. The reaction mixture was poured into ice/1 l of 2N HCl mixture, extracted with ether and the organic phase was saturated with NaHCO₃The solution and water are washed, and the organic phase is washed with Na₂SO₄Drying, evaporation of the solvent under vacuum to a volume of 150ml, addition of 200ml of pentane and dehydration of the crystalline product formed. 60g of the expected compound are obtained.

Preparation 1.2

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

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. Then, 67.9g of methyl 2, 4-dichlorobenzoate was added dropwise, and stirring was further carried out for 30 minutes, after which the 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 in vacuo to a volume of 200ml, addition of pentane and dehydration of the crystalline product formed. 80g of the expected compound are obtained.

Preparation 1.3

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

411ml of a 2M solution of sodium hexamethyldisilazane in THF are cooled to-60 ℃ under a nitrogen atmosphere, 350ml of THF are added and 67.7g of 2, 4-dichloro-silazane are then added dropwiseA solution of phenylacetic acid in 70ml THF was stirred for 2 hours while maintaining the temperature below-40 ℃. Then, 53.5g of methyl 4-chlorobenzoate was added dropwise at-60 ℃ and further stirred while the temperature was raised to 10 ℃. The reaction mixture was poured into ice/1 l of 2N HCl mixture and the organic phase was saturated with NaHCO₃Washing the solution with water, extracting with ether, and extracting the organic phase with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue was dissolved with pentane and the resulting crystalline product was dehydrated. 70g of the expected compound are obtained.

Preparation 1.4

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

Under a nitrogen atmosphere, 413ml of a 2M solution of sodium hexamethyldisilazane salt in THF were cooled to-65 ℃ and 300ml of THF were added, then a solution of 55g of 4-methoxyphenylacetic acid in 70ml of THF was added dropwise and stirred at a temperature below-45 ℃ for 3 hours. Then, 64.5g of methyl 2, 4-dichlorobenzoate was added dropwise thereto, followed by stirring while the temperature was raised to 0 ℃. The reaction mixture was poured into ice/1 l of 2N HCl mixture, extracted with ether and the organic phase was saturated with NaHCO₃Washing with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue was purified by chromatography on silica eluting with heptane and then with a heptane/AcOEt mixture until (90/10; v/v). 29g of the expected compound are obtained.

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

preparation 2.1

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

A solution of 28.7ml DMF in 60ml 1.2-dichloroethane was cooled to-5 ℃ and 30ml POCl was added dropwise₃Then stirring was carried out while the temperature was raised to TA. Then, a solution of 30g of the compound obtained in preparation 1.1 in 300ml of 1.2-dichloroethane was added and heated at 60 ℃ overnight. After cooling, the reaction mixture was poured into ice and NaHCO was added₃The pH was adjusted to 7, extracted with DCM and the organic phase was taken up with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue was purified by silica gel chromatography eluting with DCM. 35g of the expected compound are obtained.

Preparation 2.2

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

A solution of 33.7ml DMF in 75ml 1.2-dichloroethane was cooled to-5 ℃ and 40.6ml POCl was added dropwise₃. Stirring was then carried out while the temperature was raised to TA. Then, 40g of a solution of the compound obtained in preparation 1.2 in 300ml of 1, 2-dichloroethane was added and 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 Na₂SO₄Drying and vacuum evaporating to remove solvent. 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 2.3

3-chloro-3- (4-chlorophenyl) -2- (2, 4-dichlorophenyl) propenal

A solution of 28.7ml DMF in 60ml 1.2-dichloroethane was cooled in an ice bath and 30ml POCl was added dropwise₃. Stirring was then carried out while the temperature was raised to TA. Then, a solution of 30g of the compound obtained in preparation 1.3 in 300ml of 1, 2-dichloroethane was added and heated at 60 ℃ overnight. After cooling, the reaction mixture was poured into ice and NaHCO was added₃The pH was adjusted to 7, extracted with DCM and the organic phase was taken up with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue was chromatographed on silica gel, eluting with DCM. 30g of the expected compound are obtained.

Preparation 2.4

3-chloro-3- (2, 4-dichlorophenyl) -2- (4-methoxyphenyl) propenal

36.9ml of DMF in 70ml of 1, 2-dichloroethaneThe solution in (1) is cooled to 0-5 ℃, and 41ml of POCl is added dropwise₃. Stirring was then carried out while the temperature was raised to TA. Then, a solution of 20g of the compound obtained in preparation 1.4 in 200ml of 1, 2-dichloroethane was added, and the mixture was heated at 40 ℃ overnight and then heated under reflux for 4 hours. After cooling, the reaction mixture was poured into ice, basified by addition of sodium acetate, extracted with DCM and the organic phase was taken up with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue was chromatographed on silica gel, eluting with DCM. 25g of the expected compound are obtained.

3. Preparation of a Compound of formula (XIV), Z ═ C₁-C₂) Alkoxy groups:

preparation 3.1

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

To a solution of 33g of the compound obtained in preparation 2.1 in 300ml of acetonitrile was added 8.53ml of methyl thioglycolate, followed by 10.51ml of DBU, and the mixture was stirred overnight under TA. The resulting crystalline product was dehydrated and dried in vacuo. 22g of the expected compound are obtained.

Preparation 3.2

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

To a solution of 39g of the compound obtained in preparation 2.2 in 300ml of acetonitrile was added 26.8ml of methyl thioglycolate, followed by 45.5ml of DBU, and the mixture was stirred overnight under TA. The resulting crystalline product was dehydrated and dried in vacuo. 13g of the expected compound are obtained.

Preparation 3.3

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

To a solution of 30g of the compound obtained in preparation 2.3 in 150ml of acetonitrile was added 17.1ml of methyl thioglycolate, followed by 10ml of DBU, and the mixture was stirred for 24 hours under TA. Further, 2ml of DBU was added thereto, and the mixture was stirred for 2 hours under TA, cooled for 30 minutes in an ice bath, and the resulting crystalline product was dehydrated to obtain 24g of the desired compound.

Preparation 3.4

5- (2, 4-dichlorophenyl) -4- (4-methoxyphenyl) thiophene-2-carboxylic acid methyl ester.

A mixture of 10g of the compound obtained in preparation 2.4 and 5.76ml of methyl thioglycolate in 100ml of acetonitrile was heated at 45 ℃ and 4.84ml of DBU was added dropwise with stirring while the temperature was allowed to return to room temperature. The reaction mixture was concentrated in vacuo, the residue was taken up in 0.5N HCl solution, extracted with ether and the organic phase was taken up with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue was chromatographed on silica gel using heptane/AcOEt until (80/20; v/v). 6.8g of the expected compound are obtained.

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

preparation 4.1

[4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methanol.

A suspension of 1.43g of lithium aluminum hydride in 100ml of THF is cooled to-20 ℃ and a solution of 10g of the compound obtained in preparation 3.1 in 20ml of THF is added dropwise and stirred for a further hour at-20 ℃. The reaction mixture was hydrolyzed by adding water until a white turbidity appeared, the inorganic salts were filtered over celite and the filtrate was concentrated in vacuo. The residue was dissolved in pentane and stirred, and the resulting crystalline product was dehydrated. 7g of the expected compound are obtained.

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

preparation 5.1

5- (chloromethyl) -3- (4-chlorophenyl) -2- (2, 4-dichlorophenyl) thiophene.

A solution of 7g of the compound obtained in preparation 4.1 in 80ml of DCM is cooled to-10 ℃ and 4.14g of PCl are added₅And stirred for another 24 hours while the temperature was raised to TA. To the reaction mixture was added water, and the mixture was stirred for 15 minutesExtracting with AcOEt, and mixing the organic phase with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue was dissolved in pentane and stirred, and the resulting crystalline product was dehydrated. 6.8g of the expected compound are obtained.

6. Preparing formula (XIII) or formula (XIV): z ═ OH compounds

Preparation 6.1

4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) thiophene-2-carboxylic acid.

To a mixture of 16g of the compound from preparation 3.2 in 80ml of 1, 2-dimethoxyethane and 40ml of MeOH, 24ml of 30% NaOH solution are added and the mixture is stirred for 2 hours under TA. The reaction mixture was concentrated in vacuo, the residue was extracted with water, the aqueous phase was washed with ether, the aqueous phase was acidified to pH 2 by addition of 30% HCl solution, extracted with AcOEt, the organic phase was MgSO₄Drying and vacuum evaporating to remove solvent. Crystallization in isopropyl ether gives 12.4g of the expected compound.

Preparation 6.2

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

To a solution of 10g of the compound from preparation 3.3 in a minimum of 1, 2-dimethoxyethane were added 50ml of MeOH, 1.5g of NaOH pellets and a few drops of water, followed by heating at 60 ℃ for 3 hours. The reaction mixture was concentrated in vacuo and the residue was extracted with water, the aqueous phase was washed with ether, then acidified to pH 2 by addition of 30% HCl solution, extracted with DCM and the resulting crystalline product was dehydrated. 8g of the expected compound are obtained.

Preparation 6.3

5- (2, 4-dichlorophenyl) -4- (4-methoxyphenyl) thiophene-2-carboxylic acid.

A mixture of 10g of the compound obtained in preparation 3.4 and 2.1g of KOH in 50ml of 1, 2-dimethoxyethane and 100ml of 95% EtOH is stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo and the residue was extracted with waterThe aqueous phase was washed with ether, then acidified to pH 2 by addition of 30% HCl solution, extracted with ether and the organic phase was washed with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue was dissolved in isoether, pentane was added and the resulting crystalline product was dehydrated. 7.5g of the expected compound are obtained.

7. Preparation of the Compound of formula (XI)

Preparation 7.1

4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) thiophene-2-carboxamide.

A mixture of 14g of the compound obtained in preparation 6.1 and 8.35ml of thionyl chloride in 140ml of 1, 2-dichloroethane is heated under reflux for 2 hours; the reaction mixture is concentrated in vacuo, the residue is taken up in 1, 2-dichloroethane and the solvent is evaporated off in vacuo. The acid chloride thus formed was dissolved in 150ml of DCM and the solution was added dropwise to a mixture of 32ml of 2M ammonia in MeOH and 4.4ml of triethylamine and stirred for 30 minutes. Concentration in vacuo, crystallisation in water and drying in vacuo gives 13.6g of the expected compound.

Preparation 7.2

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiophene-2-carboxamide.

A mixture of 8g of the compound obtained in preparation 6.2 and 6ml of thionyl chloride in 80ml of 1, 2-dichloroethane is heated at 80 ℃ for 3 hours; the reaction mixture was concentrated in vacuo, the residue was taken up in toluene and the solvent was evaporated in vacuo. The acid chloride thus formed was dissolved in 50ml of DCM, and 21ml of a 2M ammonia solution in MeOH were added dropwise, the reaction mixture was concentrated in vacuo, the residue was dissolved in an ether/water mixture, and the resulting precipitate was dehydrated. 5.3g of the expected compound are obtained.

Preparation 7.3

5- (2, 4-dichlorophenyl) -4- (4-methoxyphenyl) thiophene-2-carboxamide.

7.5g of the compound obtained in preparation 6.3 and 7.22ml of thionyl chlorideA mixture of chlorine in 100ml of 1, 2-dichloroethane is heated under reflux for 3 hours; the reaction mixture was concentrated in vacuo, the residue was taken up in toluene and the solvent was evaporated in vacuo. The acid chloride thus formed is dissolved in 20ml of DCM and this solution is added dropwise to a mixture of 28.3ml of 2M ammonia in MeOH and 4ml of triethylamine in 30ml of DCM, the mixture being cooled to 0-5 ℃ in advance and then stirred and the temperature allowed to rise to room temperature again. The reaction mixture was concentrated in vacuo, the residue was taken up in 0.5N HCl, extracted with an ether/AcOEt mixture and the organic phase was taken up with Na₂SO₄Drying and vacuum evaporating to remove solvent. The residue is taken up in an ether/isoether mixture and the precipitate formed is dehydrated. 6g of the expected compound are obtained.

8. Preparing a compound of formula (II):

preparation 8.1

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

A mixture of 6.8g of the compound obtained in preparation 5.1, 2.75g of sodium iodide and 2.95g of hexamethylenetetramine in 100ml of EtOH was stirred for 48 hours under TA and then heated at 60 ℃ for 3 hours. Then 28ml of concentrated HCl was added and heated to reflux for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 100ml of ether, 100ml of water was added thereto, and the mixture was stirred for 30 minutes, and the resulting precipitate was dehydrated. 7g of the expected compound are obtained.

Preparation 8.2

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

To a solution of 13.5g of the compound obtained in preparation 7.1 in 35ml of THF was added 150ml of a solution of 1M borane in THF, followed by heating under reflux for 2 hours. After cooling to TA, 40ml of MeOH were added dropwise. The reaction mixture was cooled to 5 ℃ and 16ml of 2N ethereal hydrochloride were added dropwise and stirred overnight at TA to dehydrate the resulting crystalline product. 8.2g of the expected compound are obtained.

Preparation 8.3

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

To a solution of 5.3g of the compound obtained in preparation 7.2 in 30ml of THF was added 55.4ml of a solution of 1M borane in THF, followed by heating under reflux for 15 hours. After cooling to room temperature, 30ml of MeOH are added dropwise, then 2N ethereal hydrochloride is added dropwise and concentrated in vacuo. The residue was dissolved with AcOEt and the resulting precipitate was dehydrated. 4.2g of the expected compound are obtained.

Preparation 8.4

1- [5- (2, 4-dichlorophenyl) -4- (4-methoxyphenyl) -2-thienyl ] methanamine hydrochloride.

To a solution of 6g of the compound obtained in preparation 7.3 in 60ml of THF was added 63.5ml of a solution of 1M borane in THF, followed by heating under reflux for 4 hours. After cooling to room temperature, MeOH was added dropwise until gassing ceased. The reaction mixture was cooled to 5 ℃ and 20ml of 2N ethereal hydrochloride were added and stirred for 30 minutes. The reaction mixture was concentrated in vacuo to a volume of 15ml, which was added dropwise to an ether/isoether mixture (70/70; v/v), and the resulting precipitate was dehydrated. 3g of the expected compound are obtained.

Preparation 8.5

1- [4- (2, 4-dichlorophenyl) -5- (4-methoxyphenyl) -2-thienyl ] methanamine hydrochloride.

This compound was prepared according to the operating modes described successively for preparations 1.4, 2.4, 3.4, 6.3, 7.3 and 8.4.

Example 1: compound I

N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -2-propylpentanamide

A mixture of 0.35g of the compound obtained in preparation 8.1, 0.125g of 2-propylpentanoic acid, 0.36ml of triethylamine and 0.3g of TBTU in 30ml of DCM is stirred for 48 hours at TA. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and extracted with AcOEtThe organic phase is Na₂SO₄Drying and vacuum evaporation of the solvent. The residue was purified by chromatography on silica gel eluting with a gradient of heptane/AcOEt mixture (100/1; v/v) to (90/10; v/v). 0.25g of the expected compound is obtained.

Example 2: compound 6

N-biphenyl-2-yl-N' - [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] urea

A mixture of 0.5g of the compound obtained in preparation 8.1, 0.25g of 2-biphenyl isocyanate and 0.52ml of triethylamine in 20ml of DCM is stirred for 3 hours 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 Na₂SO₄Drying and vacuum evaporation of the solvent. After crystallization from ether, 0.6g of the expected compound is obtained.

Example 3: compound 7

N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -4-propylpentanamide

A mixture of 0.47g of the compound obtained in preparation 8.2, 0.19ml of 2-propylpentanoic acid, 0.6ml of triethylamine and 0.4g of TBTU in 10ml of DCM is stirred for 15 hours under TA. The reaction mixture was concentrated in vacuo, the residue was taken up in water, extracted with ether, the organic phase was washed with water and Na₂SO₄Drying and vacuum evaporation of the solvent. The residue is purified by chromatography on silica, eluting with a heptane/AcOEt mixture (50/50; v/v). After crystallization in pentane, 0.3g of the expected compound is obtained.

Example 4: compound 11

N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -N-methylcycloheptane carboxamide.

To a mixture of 0.68g of compound 10 in 7ml of DMF under nitrogen atmosphere was added 60% 0.08g of sodium hydride in oil and stirred under TA for 1 hour. Then 0.3g of methyl iodide was added and stirred overnight under TA. Reacting the mixtureThe mixture is poured into 50ml of water, extracted with 30ml of AcOEt and the organic phase is extracted with Na₂SO₄Drying and vacuum evaporation of the solvent. Crystallization in pentane gives 0.43g of the expected compound.

Example 5: compound 14

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

A mixture of 1g of the compound obtained in preparation 8.3, 0.37g of cycloheptanecarboxylic acid, 1ml of triethylamine and 0.87g of TBTU in 40ml of DCM is stirred for 15 hours 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 Na₂SO₄Drying and vacuum evaporation of the solvent. This residue was dissolved in a minimum amount of DCM, the isoether was added, followed by pentane and the resulting crystalline product was dehydrated. 0.8g of the expected compound is obtained.

Example 6: compounds 16-34, 58-69

The compound of formula (I) is prepared using combinatorial chemistry according to the method described below, wherein-X ═ CO —:

the carboxylic acid of formula (III) was dissolved in DMF at a concentration of 0.25M in the presence of 3 equivalents of DIPEA. 120ml of these solutions were placed in each 2ml well and 120. mu.l of TBTU in DMF was added at a concentration of 0.25M. To each well was added 300. mu.l of a 0.1M solution containing the corresponding compound of formula (II) in DMF and 3 equivalents of DIPEA. The plates were stirred at room temperature for 16 hours and then evaporated. These products formed in each well were dissolved by adding 500. mu.l AcOEt, and 400. mu.l 0.1M Na was added₂CO₃The plates were stirred. After decantation, 430. mu.l of the aqueous phase was separated, 300. mu.l of 5% NaCl was added and the plates were stirred. The 350. mu.l aqueous phase was separated and the compounds obtained were analyzed by LC/UV/MS.

Example 7: compounds 35-53, 70-73

Compounds of formula (I) wherein-X-CONH-or-X-CSNH-:

the compound of formula (II) was dissolved in DMF at a concentration of 0.1M in the presence of 3 equivalents of DIPEA. Mu.l of these solutions are placed in each 2ml well and 120. mu.l of a 0.25M solution containing the isocyanate compound of formula (VII) or the corresponding isothiocyanate compound of formula (XX) in THF are added. The plates were stirred at room temperature for 16 hours. These products formed in each well were dissolved by adding 500. mu.l AcOEt, and 400. mu.l 0.1M Na was added₂CO₃The plates were stirred. After decantation, 430. mu.l of the aqueous phase was separated, 300. mu.l of 5% NaCl was added and the plates were stirred. The 350. mu.l aqueous phase was separated and the compounds obtained were analyzed by LC/UV/MS.

The following table illustrates the chemical structures and physical properties of certain examples of compounds of the present invention.

In this table:

column "method" means determination of MH⁺Molecular peaks and retention time as described previously.

"-" indicates that this compound was not observed in mass spectrometry, and tr corresponds to tr of most peaks.

-Me represents a methyl group.

TABLE 1

Compound N ° 1: R-MN¹H：DMSO-d₆：δ(ppm)：0,83：t：6H；1,05-1,65：m：8H；2,20：mt：1H；4,81：d：2H；7,00-7,55：m：7H；7,70：d：1H；8,56：t：1H.

Compound N ° 7: RMN¹H：DMSO-d₆：δ(ppm)：0,83：t：6H；1,05-1,65：m：8H；2,20：mt：1H；4,48：d：2H；6,95-7,55：m：7H；7,69：d：1H；8,55：t：1H.

Compound N ° 9: RMN¹H：DMSO-d₆：δ(ppm)：0,80：t：6H；1,05-1,65：m：8H；2,08：mt：1H；4,49：d：2H；6,95-7,55：m：7H；7,69：d：1H；8,55：t：1H.

The compounds of formula (I) were tested against the cannabis chemical component CB under the experimental conditions described in M.Rinaldi-Carmona et al (FEBS Letters), 1994, 350, 240-244)₁The receptor has very good affinity (IC) in vitro₅₀≤5.10^-7M)。

Antagonistic properties of the compounds of formula (I) were demonstrated according to results obtained from the hydrazone-cyclase inhibiting models described in, for example, M.Bouadoula et al, J.biol.chem., 1995, 270, 13973-13980, M.Rinaldi-Carmona et al, J.Pharmacol.exp.The., 1996, 278, 871-878 and M.Bouadoula et al, J.biol.chem.), 1997, 272, 22330-22339.

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

Thus, according to another aspect, the present invention is directed to pharmaceutical products comprising 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 (les rouble del' humours), insomnia, delirium disorders, obsessive compulsive disorders, psychosis in general, 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 drugs of abuse and/or dependence on substances, 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, epilepsy, dyskinesias, in particular dyskinesias or parkinson's disease, tremors and dystonias.

The compounds of formula (I) of the present invention may also be used as medicaments for the treatment of memory disorders, cognitive disorders, in particular senile dementia, alzheimer's disease, and as medicaments 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) according to the invention can be used as medicaments for the treatment of the following pain: neuropathic pain, peripheral acute pain, chronic pain of inflammatory origin.

The compounds of formula (I) according to the invention can be used as medicaments for the treatment of appetite (app tit), desire (app tension) (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, asthma, raynaud's syndrome, glaucoma, fertility disorders, early pregnancy interruptions, inflammatory phenomena, diseases of the immune system, in particular autoimmune and neuroinflammatory diseases of the immune system, such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, plateaus sclerosis, infectious and viral diseases, such as encephalitis, cerebrovascular accidents, and as anti-cancer, treatment of guillain-barr syndrome and treatment of osteoporosis.

According to the invention, these compounds of formula (I) are very 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 appetite and obesity disorders; treating memory and cognitive deficits; can be used for treating alcohol dependence and nicotine dependence (i.e. alcoholic intoxication and smoking cessation).

According to one of its aspects, the present invention relates to the use of compounds of formula (I) and their pharmaceutically acceptable salts, 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 said 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 compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above or a salt, possible solvate or hydrate thereof may be mixed with usual pharmaceutical excipients and administered in unit dosage forms for animal or human administration 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 compound of the invention in the form of a tablet contains the following components:

compound of the 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 a pharmaceutically acceptable salt, hydrate or solvate thereof.

Claims (11)

1. A compound corresponding to the following formula (I):

in the formula:

-X representsA group;

-R₁represents:

·(C₆-C₁₂) An alkyl group;

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

quilt C₃-C₁₂Methyl substituted by a non-aromatic carbocyclic group, which is unsubstituted or the carbocyclic ring is substituted by (C)₁-C₄) Alkyl substitution one or more times;

phenyl mono-, di-or trisubstituted by a substituent independently selected from the group consisting of: halogen atom, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino, cyano, trifluoromethyl, trifluoromethoxy, S (O)_nAlk group, (C)₁-C₄) Alkylcarbonyl group, methylenedioxy 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 whose phenyl group is mono-or disubstituted independently with substituents selected from: halogen atom, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl, (trifluoromethyl) thio, or benzyl which is substituted in the alpha position by one or two groups which may be the same or different and are selected from: (C)₁-C₄) Alkyl, (C)₃-C₇) Cycloalkyl or pyrrolyl;

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

1, 2, 3, 4-tetrahydronaphthyl or 5, 6, 7, 8-tetrahydronaphthyl which is unsubstituted or mono-or disubstituted by substituents independently selected from the group consisting of: (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl;

benzhydryl, benzhydrylmethyl;

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

-R₃represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by substituents independently selected from the group consisting of: halogen atom, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or S (O)_nAn Alk group;

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

-R₅represents a hydrogen atom or (C)₁-C₃) An alkyl group;

-n represents 0, 1 or 2;

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

and hydrates or solvates thereof.

2. A compound of formula (I) according to claim 1, wherein-X-represents-CO-group, substituent R₁-R₄Is as defined in the compound 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-CON (R)₅) -radical, substituent R₁-R₅Is as defined in the compound 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-CSN (R)₅) -radical, substituent R₁-R₅Is as defined in the compound 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-CO-group, -CONH-group or-CSNH-group;

-R₁represents:

1-propylbutyl, 1-ethylpentyl, 1-methylpentyl;

cycloheptyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, bicyclo [2.2.1] hept-2-yl; bicyclo [2.2.1] hept-5-en-2-yl;

cyclohexylmethyl, cycloheptylmethyl, bicyclo [2.2.1] hept-2-ylmethyl;

4-bromophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3, 5-difluorophenyl, 2-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethoxy) phenyl, 3-acetylphenyl, biphenyl-2-yl, biphenyl-4-yl, 1, 3-benzodioxol-5-yl, 4-phenoxyphenyl, 4- (1H-pyrrol-1-yl) phenyl;

2-fluorobenzyl, 3-fluorobenzyl, 4- (trifluoromethyl) benzyl, 4- [ (trifluoromethyl) thio ] benzyl, α -cyclohexylbenzyl, α - (1H-pyrrol-1-yl) benzyl;

4- (trifluoromethyl) phenethyl;

benzhydryl, benzhydrylmethyl;

1, 2, 3, 4-tetrahydronaphthalen-2-yl, 1, 2, 3, 4-tetrahydronaphthalen-1-yl, 5, 6, 7, 8-tetrahydronaphthalen-1-yl;

-R₂represents a hydrogen atom or a methyl group;

-R₃represents 4-bromophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 4-methoxyphenyl;

-R₄represents 4-chlorophenyl, 2, 4-dichlorophenyl, 4-methoxyphenyl;

and hydrates or solvates thereof.

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

-X represents a-CO-group or a-CONH-group;

-R₁represents:

1-propylbutyl, 1-ethylpentyl, 1-methylpentyl;

cycloheptyl;

cycloheptylmethyl;

biphenyl-2-yl;

-R₂represents a hydrogen atom or a methyl group;

-R₃represents 4-bromophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl;

-R₄represents 4-chlorophenyl, 4-dichlorophenyl;

and hydrates or solvates thereof.

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

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

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

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

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

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

-N-biphenyl-2-yl-N' - [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -urea;

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

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

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

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

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -N-methylcycloheptane carboxamide;

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

-N- [ [4- (4-bromophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -2-cycloheptyl-N-methylacetamide;

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

-N- [5- (4-chlorophenyl) 4- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] -N-methylcycloheptane carboxamide;

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

-4-chloro-N- [ [4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -2-thienyl ] methyl ] benzamide;

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

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

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

-N- [ [5- (2, 4-dichlorophenyl) -4- (4-methoxyphenyl) -2-thienyl ] methyl ] bicyclo [2.2.1] heptane-2-carboxamide;

-N- [ [5-2, 4-dichlorophenyl) -4- (4-methoxyphenyl) -2-thienyl ] methyl ] -2-propylpentanamide;

-N- [ [4- (2, 4-dichlorophenyl) -5- (4-methoxyphenyl) -2-thienyl ] methyl ] -2-propylpentanamide;

and hydrates or solvates thereof.

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

a compound of the formula:

in the formula R₂、R₃And R₄Is as defined for a compound of formula (I) according to claim 1:

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

HOOC-R₁ (III)

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

or when preparing a compound of formula (I) wherein-X-represents-CON (R)₅) -when a group, a haloformate of the formula:

HalCOOAr (IV)

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

in the formula R₂、R₃And R₄Is as defined for the compound of formula (I) according to claim 1, which is further reacted with an amine of formula:

HN(R₅)R₁ (VI)

in the formula R₁And R₅As defined for the compounds of formula (I),

or when preparing a compound of formula (I) in which-X-represents a-CSNH-group, an isothiocyanate of formula:

S＝C＝N-R₁ (XX)

in the formula R₁Is as defined for compounds of formula (I) according to claim 1.

9. Pharmaceutical product, characterized in that it contains a compound of formula (I) according to any one of claims 1 to 7, or a hydrate or solvate of a compound of formula (I).

10. Pharmaceutical composition, characterized in that it comprises a compound of formula (I), or a hydrate or solvate of this compound, according to any one of claims 1 to 7, and at least one pharmaceutically acceptable excipient.

11. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and prevention of appetite disorders, gastro-intestinal disorders, inflammatory phenomena, diseases of the immune system, psychotic disorders, alcohol dependence, nicotine dependence.