Pyrrole derivatives, their preparation and their therapeutic application

The present invention relates to 1,5-diphenylpyrrole-3-carboxamide derivatives, to their preparation and to their therapeutic application.

Derivatives of 1,5-diphenylpyrrole-3-carboxamide, which are active as anti-obesity agents, have been described in patent application WO 2003/027 069. Derivatives of 1,5-diphenylpyrrole-3-carboxamide, exhibiting affinity for the CB 1 cannabinoid receptors, have been described in patent applications WO 2004/058 249 and WO 2005/080 328. Application WO 2006/024 777 claims 4,5-diphenylpyrrole-2-carboxamides exhibiting affinity for the CB 1 cannabinoid receptors.

Novel 1,5-diphenylpyrrole-3-carboxamide derivatives carrying a particular substituent at the 2-position of the pyrrole have now been found which possess antagonist properties for the CB 1 cannabinoid receptors. In particular, these novel derivatives have antagonist properties for the peripheral CB 1 receptors and exhibit low penetration at the level of the brain.

The subject of the present invention is compounds corresponding to the formula:

in which:

A represents a (C 1 -C 6 )alkylene group which is unsubstituted or substituted one or more times with a (C 1 -C 3 )alkyl group or a fluorine atom; R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group which is unsubstituted or substituted with one or more fluorine atoms; R 2 represents:

either a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being unsubstituted or substituted once or twice with a substituent each independently chosen from a fluorine atom, a group (C 1 -C 4 )alkoxyl, (C 1 -C 4 )alkyl, trifluoromethyl, —OCF 3 , —CH 2 OH, —CONH 2 and/or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF 3 group, a methoxyl group and/or a trifluoromethoxyl group; or an amino(C 1 -C 6 )alkyl group which is unsubstituted or substituted with one or several substituents each independently chosen from a fluorine atom, a hydroxyl group, a —CONH 2 group and/or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF 3 group, a methoxyl group and/or a trifluoromethoxyl group;

or R 1 and R 2 together with the nitrogen atom to which they are attached constitute:

either a piperazin-1-yl or 1,4-diazepan-1-yl radical, the said radicals being unsubstituted or substituted with a phenyl, benzodioxolyl, benzodioxolylmethyl, tetrahydrofuranylcarbonyl, —COR 11 , and/or —CH 2 COR 11 group; the phenyl group being itself unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; or a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being unsubstituted or substituted once or twice with a substituent each independently chosen from: a fluorine atom, a cyano, —COR 11 , —CONR 12 R 13 , —NR 12 R 13 , —NHCOR 14 , —CH 2 COR 11 , —SO 2 R 14 group; and/or —SO 2 NR 12 R 13 ; and/or a (C 1 -C 4 )alkyl group which is unsubstituted or substituted with one or more substituents each independently chosen from a halogen atom and/or a hydroxyl, and/or a phenyl or pyridinyl group; the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or a benzyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl group, the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a fluorine atom, a (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyl, hydroxyl, trifluoromethyl and/or —OCF 3 group; and/or an aminophenyl or aminobenzyl group, the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or an amino(C 3 -C 7 )cycloalkyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyl and/or cyano group, the said (C 1 -C 4 )alkyl group being unsubstituted or substituted once or several times with a fluorine atom;

R 3 , R 4 , R 5 , R 6 , R 7 , R 8 each independently represent a hydrogen atom, a halogen atom, a —CN, —S(O) n R 14 or —OS(O) n R 14 group, or a (C 1 -C 6 )alkyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a fluorine atom, an —OH, —OR 14 , —S(O) n R 14 , —OSO 2 R 14 and/or —NHSO 2 R 14 group, or a (C 1 -C 6 )alkoxyl group, which is unsubstituted or substituted with one or more substituents each independently chosen from a fluorine atom, an —OH, —OR 14 , —S(O) n R 14 , —OSO 2 R 14 and/or —NHSO 2 R 14 group; R 9 represents an —OR 12 , —CN, —CO 2 H, NR 12 R 13 , —CONR 12 R 13 , —NR 1 COR 12 , —CONHNH 2 , —CONHOH, —CONHSO 2 R 14 , —S(O) n R 14 , —SO 2 NR 12 R 13 , —NR 18 SO 2 R 14 or —NR 15 SO 2 NR 12 R 13 group, or an aromatic heterocycle chosen from:

R 10 represents a hydrogen or a (C 1 -C 4 )alkyl group;

R 11 represents:

a (C 1 -C 4 )alkyl, phenyl, benzyl, (C 1 -C 4 )alkoxyl, or (C 1 -C 3 )alkylene-O—(C 1 -C 3 )alkyl group, the said groups being unsubstituted or substituted with one or more substituents each independently chosen from a (C 1 -C 4 )alkoxyl group, a hydroxyl group and/or a fluorine atom; a trifluoromethyl; and/or an NR 16 R 17 group;

R 12 and R 13 each independently represent a hydrogen atom or a (C 1 -C 6 )alkyl group optionally substituted with one or more substituents each independently chosen from a halogen atom, a (C 3 -C 7 )cycloalkyl, cyano, —OH and/or —OR 14 group;

or R 12 and R 13 together with the nitrogen atom to which they are attached constitute a 4- to 7-membered heterocyclic radical which may contain a second heteroatom chosen from a nitrogen, oxygen or sulphur atom;

n represents 0, 1 or 2;

R 14 represents a (C 1 -C 4 )alkyl group which is unsubstituted or substituted with one or more fluorine atoms;

R 15 represents a hydrogen atom or a (C 1 -C 4 )alkyl group;

R 16 and R 17 each independently represent:

a hydrogen atom; and/or a benzyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or a (C 1 -C 6 )alkyl group which is optionally substituted with one or more substituents each independently chosen from a halogen atom, a (C 3 -C 7 )cycloalkyl, cyano —OH, and/or —OR 14 group;

R 18 represents a hydrogen atom or a (C 1 -C 4 )alkyl group which is unsubstituted or substituted with one or more fluorine atoms;

in the form of bases (=correspond to the free forms of the compounds) and the salts thereof which are pharmaceutically acceptable or acceptable for the purification and/or isolation of the said compounds of formula (I).

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

The compounds of formula (I) may exist in the form of bases (that is to say as they are in their free forms), of addition salts with acids or of addition salts with bases. These salts are advantageously prepared with pharmaceutically acceptable salts but the salts of other acids which are useful, for example, for the purification or isolation of the compounds of formula (I) also form part of the invention.

The expression (C 1 -C 3 )alkyl, (C 1 -C 4 )alkyl or (C 1 -C 6 )alkyl group is understood to mean respectively a linear or branched alkyl radical of one to three carbon atoms, of one to four carbon atoms or of one to six carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, n-hexyl or isohexyl radical. The methyl group is preferred for a (C 1 -C 3 )alkyl, for a (C 1 -C 4 )alkyl and for a (C 1 -C 6 )alkyl.

The expression (C 1 -C 3 )alkylene or (C 1 -C 6 )alkylene group is understood to mean respectively a linear bivalent carbon radical of one to three carbon atoms or of one to six carbon atoms such as —(CH 2 )—, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 — and —(CH 2 ) 6 .

The expression (C 1 -C 4 )alkoxyl is understood to mean an oxygen atom attached to a linear or branched carbon radical of one to four carbon atoms such as methoxyl, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy radical. The methoxyl group is preferred.

The expression halogen atom is understood to mean a fluorine, chlorine, bromine or iodine atom, the fluorine, chlorine or bromine atoms being preferred.

The expression (C 3 -C 7 )cycloalkyl group is understood to mean a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

The expression amino-cycloalkyl group is understood to mean, for the cycloalkyl part, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl carbon radical.

The expression 4- to 7-membered saturated or unsaturated heterocyclic radical, containing or not containing a second heteroatom such as O, N or S, is understood to mean in particular radicals such as homopiperidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, the piperidin-1-yl and pyrrolidin-1-yl radicals being preferred.

According to a first variant of the invention, the compounds of formula (IA) are differentiated in which:

R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group which is unsubstituted or substituted with one or more fluorine atoms; R 2 represents:

either a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being substituted once or twice with a substituent each independently chosen from a fluorine atom, a group (C 1 -C 4 )alkoxyl, (C 1 -C 4 )alkyl, trifluoromethyl, —OCF 3 , —CH 2 OH, —CONH 2 and/or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF 3 group, a methoxyl group and/or a trifluoromethoxyl group; or an amino(C 1 -C 6 )alkyl group which is substituted with one or several substituents each independently chosen from a fluorine atom, a hydroxyl group, a —CONH 2 group and/or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF 3 group, a methoxyl group and/or a trifluoromethoxyl group;

the other substituents being as defined for the compounds of formula (I).

According to this first variant (IA), preference is given to the compounds in which the radical R 2 represents a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being substituted once or twice with a substituent each independently chosen from a fluorine atom, a (C 1 -C 4 )alkoxyl, trifluoromethyl, —OCF 3 , —CH 2 OH or —CONH 2 group and/or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF 3 group, a methoxyl group and/or a trifluoromethoxyl group.

According to this first variant (IA), preference is given to the compounds in which R 1 represents a hydrogen atom.

According to a second variant of the invention, the compounds of formula (IB) are differentiated in which R 1 and R 2 together with the nitrogen atom to which they are attached constitute:

either a piperazin-1-yl or 1,4-diazepan-1-yl radical, the said radicals being substituted with a phenyl, benzodioxolyl, benzodioxolylmethyl, tetrahydrofuranylcarbonyl, —COR 11 , and/or —CH 2 COR 11 group; the phenyl group being itself substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; or a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being substituted once or twice with a substituent each independently chosen from: a fluorine atom, a cyano, —COR 11 , —CONR 12 R 13 , —NR 12 R 13 , —NHCOR 14 , —CH 2 COR 11 , —SO 2 R 14 group; and/or —SO 2 NR 12 R 13 ; and/or a (C 1 -C 4 )alkyl group which is unsubstituted or substituted with one or more substituents each independently chosen from a halogen atom and/or a hydroxyl, and/or a phenyl or pyridinyl group; the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or a benzyl group which is substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl group, the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a fluorine atom, a (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyl, hydroxyl, trifluoromethyl and/or —OCF 3 group; and/or an aminophenyl or aminobenzyl group, the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or an amino(C 3 -C 7 )cycloalkyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyl and/or cyano group, the said (C 1 -C 4 )alkyl group being unsubstituted or substituted once or several times with a fluorine atom; the other substituents being as defined for the compounds of formula (I).

According to this second variant, preference is given to the compounds in which:

R 1 and R 2 together with the nitrogen atom to which they are attached constitute a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radical being substituted once or twice with a substituent each independently chosen from:

a fluorine atom, a cyano, —COR 11 , —CONR 12 R 13 , —NR 12 R 13 , —NHCOR 14 , —CH 2 COR 11 , —SO 2 R 14 group; and/or —SO 2 NR 12 R 13 ; and/or a (C 1 -C 4 )alkyl group which is unsubstituted or substituted with one or more substituents each independently chosen from a halogen atom and/or a hydroxyl, and/or a phenyl or pyridinyl group; the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or a benzyl group which is substituted once or several times with a substituent each independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and cyano group; and/or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl group, the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a fluorine atom, a (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyl, hydroxyl, trifluoromethyl and/or —OCF 3 group; and/or an aminophenyl or aminobenzyl group, the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )alkoxyl and/or cyano group; and/or an amino(C 3 -C 7 )cycloalkyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyl and/or cyano group, the said (C 1 -C 4 )alkyl group being unsubstituted or substituted once or several times with a fluorine atom;

the other substituents being as defined for the compounds of formula (I).

According to this second variant (IB), preference is given in particular to the compounds in which R 1 and R 2 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is substituted once or twice with a substituent. The substituent(s) are each independently chosen from those indicated above for this second variant (IB).

For the 2 variants according to the invention, preference is given to the compounds in which:

A represents an unsubstituted (C 1 -C 5 )alkylene group; R 9 represents an —OR 12 , —NR 12 R 13 , —CONR 12 R 13 , —NR 15 COR 12 , —CONHNH 2 , —CONHOH, —S(O) n R 14 , —SO 2 NR 12 R 13 , —NR 18 SO 2 R 14 , or —NR 15 SO 2 NR 12 R 13 group; the other substituents being as defined above for the compounds of formula (I).

In particular, for R 9 , preference is given to an —OR 12 , —NR 12 R 13 , —CONR 12 R 13 ,

—NR 15 COR 12 or —NR 18 SO 2 R 14 group. As regards the −OR 12 and —NR 12 R 13 groups, preference is given more particularly to R 12 and R 13 which are different from hydrogen.

According to the present invention, preference is given to the compounds in which R 10 represents a hydrogen.

Among the compounds according to the invention, mention may be made in particular of the compounds below, as they are and the salts thereof:

Chemical structure

IUPAC name (ACDName)

1′-{(1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-1,4′-bipiperidine-4′- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulfphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-1,4′- bipiperidine-4′-carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- {[(trifluoromethyl)sulfonyl]amino}- propyl)-1H-pyrrol-3-yl]carbonyl}- 1,4′-bipiperidine-4′-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-phenylpiperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3-pyrrolidin-1- ylpropyl)-1H-pyrrol-3-yl]carbonyl}- 4-phenylpiperidine-4-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4- phenylpiperidine-4-carboxamide

1′-({1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-[3-(2- hydroxyethoxy)propyl]-1H-pyrrol-3- yl}carbonyl)-1,4′-bipiperidine-4′- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(hydroxymethyl)- 1H-pyrrol-3-yl]carbonyl}-1,4′- bipiperidine-4′-carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-1,4′- bipiperidine-4′-carboxamide

4-(4-chlorophenyl)-1-{[1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}piperidine- 4-carboxamide

4-(4-chlorophenyl)-1-{[1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}piperidine- 4-carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-1,4′- bipiperidine-4′-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4- phenylpiperidine-4-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4- phenylpiperidine-4-carboxamide

4-amino-1-{[1-(4-chlorophenyl)-5- (2,4-dichlorophenyl)-2-(4- hydroxybutyl)-1H-pyrrol-3- yl]carbonyl}piperidine-4- carboxamide-1,1,1-trifluorobutane (1:1)

1{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(3,3,3- trifluoropropyl)amino]piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4,4- difluoro-1,4′-bipiperidine-4′- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4,4- difluoro-1,4′-bipiperidine-4′- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4,4- dimethyl-1,4′-bipiperidine-4′- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(4- fluorobenzyl)amino]piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(4- fluorobenzyl)amino]piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4,4- dimethyl-1,4′-bipiperidine-4′- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(3- fluorobenzyl)amino]piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(3- fluorobenzyl)amino]piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4,4- dimethyl-1,4′-bipiperidine-4′- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4,4-dimethyl-1,4′- bipiperidine-4′-carboxamide

4-(4-chlorophenyl)-1-{[1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}piperidine- 4-carboxamide

4-(4-chlorophenyl)-1-{[1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4,4-difluoro-1,4′- bipiperidine-4′-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4,4- difluoro-1,4′-bipiperidine-4′- carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-phenylpiperidine-4- carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4- [(cyclopropylmethyl)amino]pipe- ridine-4-carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-N-(2- hydroxyethyl)piperidine-4- carboxamide

1-{[2-(5-amino-5-oxopentyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1-{[2-(3-amino-3-oxopropyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1-{[2-(3-amino-3-oxopropyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-phenylpiperidine-4- carboxamide

1-{[2-(5-amino-5-oxopentyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-phenylpiperidine-4- carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1-{[2-(4-amino-4-oxobutyl)-5-(2- chlorophenyl)-1-(4-chlorophenyl)- 1H-pyrrol-3-yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4- [(cyclopropylmethyl)amino]pipe- ridine-4-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4- [(cyclopropylmethyl)amino]pipe- ridine-4-carboxamide

N-{3-[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-3-{[4-(3- hydroxypropyl)piperidin-1- yl]carbonyl}-1H-pyrrol-2- yl]propyl}methanesulphonamide

3-[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-3-{[4-(3- hydroxypropyl)piperidin-1- yl]carbonyl}-1H-pyrrol-2-yl]propan- 1-ol

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

1-{[2-(5-amino-5-oxopentyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

Among the compounds listed above, preference is given to:

1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(4-hydroxybutyl)-1H-pyrrol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide; 1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(2-hydroxyethyl)-1H-pyrrol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide; 1′-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(4-hydroxybutyl)-1H-pyrrol-3-yl]carbonyl}-4,4-difluoro-1,4′-bipiperidine-4′-carboxamide; 4-(4-chlorophenyl)-1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-hydroxy propyl)-1H-pyrrol-3-yl]carbonyl}piperidine-4-carboxamide;

and their salts.

The subject of the present invention is also a method for preparing the compounds according to the invention.

This method is characterized in that the acid of formula (II) or a functional derivative of this acid of formula

in which R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 and A-R 9 are as defined for (I), is treated with an amine of formula HNR 1 R 2 in which R 1 and R 2 are as defined for (I).

Optionally, the compound thus obtained is converted to one of its salts.

As a functional derivative of the acid (II), use may be made of the acid chloride, the anhydride, a mixed anhydride, a C 1 -C 4 alkyl ester in which the alkyl is straight or branched, a benzyl ester, an activated ester, for example the p-nitrophenyl ester, or the free acid opportunely activated, for example, with N,N-dicyclohexylcarbodiimide or with benzotriazol-1-yloxotris(dimethylamino)phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yloxotris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) or N—[N-(dimethylamino)-1-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium N-oxide]hexafluorophosphate (HBTU). These functional derivatives of the acid (II) correspond to the compounds (IIbis).

Thus, in the method according to the invention, it is possible to cause the acid chloride, obtained by the reaction of thionyl chloride with the acid of formula (II), to react with an amine HNR 1 R 2 , in an inert solvent, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N,N-dimethylformamide for example) under an inert atmosphere, at a temperature between 0° C. and room temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.

One variant consists in preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and to cause it to react with an amine HNR 1 R 2 , in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.

Alternatively, the compounds of formulae (I) may be prepared according to the procedure of scheme 1 below.

According to scheme 1, the acid of formula (IIa) or one of its functional derivatives in which Z represents a group which is a chemical precursor of the group A-R 9 is treated with an amine of formula HNR 1 R 2 as defined above in order to obtain an amide of formula (Ia).

Next, the group Z of the compound of formula (Ia) thus obtained is converted to a group A-R 9 by a method known to a person skilled in the art in order to obtain the product of formula (I).

By way of examples, the compounds of formula (I) in which R 9 corresponds to NHSO 2 Alk, may be synthesized from the derivatives (IIa) in which Z corresponds to A-OCH 2 Ph by reacting with an amine HNR 1 R 2 , followed by debenzylation as described in step (d2) of scheme 2 below, and application of the reaction sequence described in scheme 4 below.

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

The compounds of formula (II) and their precursors may be prepared according to scheme 2 below:

Step (a2) is a regioselective alkylation of methyl acetoacetate according to the procedure described in particular in JACS 96(4) 1974, page 1082 to 1087.

Step (b2) is an alkylation of compound (III) with a bromoacetophenone, in the presence of NaH.

Step (c2) is a cyclization of the diketone (III) with a substituted aniline (Paal-Knorr reaction). This cyclization is conventionally carried out in a solvent such as toluene under reflux in the presence of para-toluenesulphonic acid, or in acetic acid. It is also possible to carry out this cyclization with better yields in the presence of catalysts such as Montmorillonite K10 and in a microwave oven, as described in Adv. Synth. Catal. 2006, 348, 2191-2196.

Step (d2) is a benzyl ether deprotection which may be carried out for example with the aid of BBr 3 or BCl 3 in dichloromethane.

The alcohol (VI) obtained is then saponified, preferably with LiOH, at 70° C. in a methanol-water mixture.

The acid (II) thus obtained is treated with the amine HN—R 1 R 2 to form the product (I) of the invention.

According to the various values of the group A, it is possible to use various methods, known to a person skilled in the art, to prepare the compounds of formula (II) and the compounds of formula (I) according to the invention.

In particular, when A corresponds to —CH 2 —, the synthesis of the compound (III) is carried out by treating methyl 4-chloroacetoacetate with benzyl alcohol in the presence of NaH as described in scheme 3 below:

According to the various values of the R 9 group, it is possible to use various methods, known to a person skilled in the art, to prepare the compounds of formula (II) and the compounds of formula (I) according to the invention.

Thus, when a compound of formula (I) is prepared in which A-R 9 represents the group —(CH 2 ) 3 NHSO 2 Alk, it is possible to carry out the procedure as according to scheme 4 below:

In this method, the alcohol (VI) is converted to a compound with a mesylate group (VIII) which is then treated with the sulphonamide H 2 NSO 2 Alk in order to obtain the alkylsulphonamide derivative (IX).

One variant consists in carrying out the procedure according to scheme 5 below by converting the compound with the mesylate group (VIII) to an amine, and then treating the latter with a compound of the AlkSO 2 Cl type in order to obtain the ester (IX). The conversion of the alcohol (VI) to an amine (XIV) may be carried out by various methods known to a person skilled in the art, such as for example the Mitsunobu method.

The remainder of the synthesis is carried out by saponifying the ester (IX) and by coupling the acid obtained with the appropriate amine, as described in the general scheme 2.

In the case where the group R 9 represents COOH, the synthesis may be carried out according to scheme 6 below by oxidizing the compound (VI) to an acid with the aid of an oxidizing agent such as CrO 3 , the acid obtained being protected with a t-butyl ester group. The methyl ester of the compound (XI) is saponified in order to obtain the acid (XII), which is then coupled with the amine HNR 1 R 2 in order to obtain the ester (XIII) which is finally deprotected to give the compound according to the invention (I).

It is also possible, where appropriate, to directly oxidize a compound of formula (I), R 9 being equal to OH, with chromium VI in order to obtain the desired acid. This acid may then be treated so as to obtain the R 9 groups whose definition is given in the general formula.

The amines of formula HNR 1 R 2 are known or prepared by known methods, for example that described in J. Med. Chem.; 7; 1964; 619, 622.

The subject of the present invention is also the compounds of formula (II) and their functional derivatives (IIbis), used for the preparation of the compounds of formula (I). Among these compounds of formula (II) and (IIbis), those of formula (IIter) are differentiated in particular:

in which:

X represents a halogen atom, a hydroxyl, (C 1 -C 4 )alkoxyl or benzyloxy group; and A, R 3 , R 4 , R 5 , R 6 , R 7 , R 3 and R 10 are as defined for the compounds of formula (I).

More particularly, the subject of the present invention is the compounds of formula:

in which

X represents a halogen atom, a hydroxyl, (C 1 -C 4 )alkoxyl or benzyloxy group; A represents a group —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —; and R 9 represents a group —OR 12 , —NR 12 R 13 , —CONR 12 R 13 , —NR 15 COR 12

or —NR 18 SO 2 R 14 .

As regards the —OR 12 and —NR 12 R 13 groups in the compounds of formula (IIter), preference is given more particularly to R 12 and R 13 which are different from hydrogen. More particularly, preference is given to R 9 which represents —OH, —NHSO 2 CH 3 , —NHSO 2 CF 3 , —O—(CH 2 ) 2 —OH.

The following examples describe the preparation of some compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention. The numbers for the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

In the examples, the following abbreviations are used:

AcOEt: ethyl acetate BCl 3 : boron trichloride DCM or CH 2 Cl 2 : dichloromethane DIPEA: diisopropylethylamine DMAP: dimethylaminopyridine DMF: N,N-dimethylformamide. HPLC: high-performance liquid chromatography HBTU: N—[N-(dimethylamino)-1-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium N-oxide]hexafluorophosphate HOBt: 1-hydroxybenzotriazole NaHCO 3 : sodium hydrogen carbonate MeOH: methanol PyBOP: benzotriazol-1-yloxotris(pyrrolidino)phosphonium hexafluorophosphate RT: room temperature TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate THF: tetrahydrofuran HPLC: ‘Ultra Performance’ liquid chromatography

The nuclear magnetic resonance spectra are recorded at 250 MHz or at 400 MHz in DMSO-d6. For the interpretation of the spectra, the following abbreviations are used:

s: singlet, t: triplet, u.c.: unresolved complex, bm: broad multiplet, mt: multiplet, bs: broad singlet, bd: broad doublet, d: doublet, dd: doublet of doublet, dt: doublet of triplet, bt: broad triplet, 2s: 2 singlet, q: quadruplet, quin: quintuplet.

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

Conditions A (HPLC)

Use is made of a Symmetry C18 column of 2.1×50 mm, 3.5 μm.

The eluent is made up as follows:

solvent A: 0.005% of trifluoroacetic acid (TFA) in water at pH 3.1; solvent B: 0.005% of TFA in acetonitrile.

Gradient:

Column temperature: 30° C., flow rate 0.4 ml/minute.

The UV detection is carried out at λ=210 nM and the mass detection in positive ESI chemical ionization mode.

The UV detection is carried out with a diode array detector between 210 and 400 nm and the mass detection in positive ESI mode.

Conditions B (HPLC)

Use is made of an Xterra MS C18 column of 2.1×50 mm, 3.5 μm.

The eluent is made up as follows:

solvent A: 10 mM AcONH 4 at about pH 7 solvent B: acetonitrile

Gradient:

Column temperature: 30° C., flow rate: 0.4 ml/minute.

Detection: λ=220 nm

Conditions C (HPLC):

Use is made of an Acquity BEH C18 column (50×2.1 mm; 1.7 μm)

The eluent is made up as follows:

solvent A: 0.005% of TFA in water at about pH 3.1/acetonitrile (97/3) solvent B: 0.035% of TFA in acetonitrile

Gradient:

Column temperature: 40° C., flow rate: 1 ml/minute.

Detection: λ=220 nm

Conditions D

Use is made of an Xterra MS C18 column of 2.1×50 mm, 3.5 μm.

The eluent is made up as follows:

solvent A: 0.005% of TFA in water at about pH 3.1/acetonitrile (97/3) solvent B: acetonitrile

Gradient:

Column temperature: ambient, flow rate: 0.4 ml/minute.

Detection: λ=220 nm

Conditions E:

Use is made of an Acquity BEH C18 column of 2.1×50 mm; 1.7 μm)

The eluent is made up as follows:

solvent A: 0.05% of TFA in water at about pH 3.1/acetonitrile (97/3) solvent B: 0.035% of TFA in acetonitrile.

Gradient:

Column temperature: 40° C., flow rate: 1 ml/minute.

Detection: λ=220 nm

Preparation 1

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-2-(3-methanesulphonylaminopropyl)-1H-pyrrole-3-carboxylic acid

1A) Methyl ester of 6-benzyloxy-3-oxohexanoic acid (synthesis carried out based on: Angewandte Chemie (Int. Ed) 38(9), 1999, 1263-1266)

9.64 g of NaH are suspended in 300 ml of anhydrous THF. The suspension is cooled to 0° C. 20 g of methyl acetoacetate are added dropwise and the mixture is kept stirred for 45 minutes. The solution is then cooled to −20° C., and 96 ml of a 2.5 molar solution of n-BuLi in hexane are added. After stirring for 15 minutes, 51.8 g of benzyl 2-bromoethyl ether are added and the temperature is allowed to rise to 0° C. The solution is then neutralized with 200 ml of 1N HCl. The solution is diluted with 500 ml of ether, washed with H 2 O, dried over MgSO 4 , and evaporated. 50 g of an oil are obtained which, after chromatography (eluent cyclohexane/ethyl acetate), give 22.6 g of a colourless oil.

LCMS: M Na + =273, tr=8.18.

1B) Methyl ester of 6-benzyloxy 2-2[2-(2,4-dichlorophenyl)-2-oxoethyl]-3-oxo-hexanoic acid

3.61 g of NaH are suspended in 500 ml of anhydrous THF. The mixture is cooled to 0° C. and 22.6 g of the compound of the preceding step 1A) diluted in 200 ml of THF are added dropwise. The mixture is kept stirred for 30 minutes and 24.1 g of 2,4-dichlorophenyl bromomethyl ketone dissolved in 100 ml of THF are added dropwise. The mixture is kept stirred for 3 hours at 0° C., and then for 17 hours at RT. The suspension is cooled to 0° C., and neutralized with 200 ml of N HCl. The mixture is extracted with ether, washed with H 2 O, dried over MgSO 4 , evaporated and chromatographed on 400 g of silica (eluent: cyclohexane/EtOAc). 25.7 g of the target compound are obtained.

LCMS: M=436 (2Cl), tr=11.01.

1C) Methyl ester of 2-(3-benzyloxypropyl)-1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1H-pyrrole-3-carboxylic acid

In a round-bottomed flask provided with a Dean-Stark condenser, 25.7 g of the compound obtained in the preceding step 1B) in 400 ml of toluene are heated under reflux for 3 days with 1 g of para-toluenesulphonic acid and 8.4 g of 4-chlorophenyl amine. The solution is then diluted with EtOAc, washed with saturated NaHCO 3 , N HCl, dried over MgSO 4 and evaporated. The oil obtained is purified by chromatography on 400 g of silica (eluent cyclohexane/EtOAc gradient) to give 23.6 g of the desired compound.

LCMS: MNa + =524.8 (3Cl) tr=9.95.

1D) Methyl ester of 1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-hydroxypropyl)-1H-pyrrole-3-carboxylic acid

23.6 g of the compound obtained above in step 1C) are introduced into 300 ml of CH 2 Cl 2 . The mixture is cooled to −5° C. and a solution of 40 g of BCl 3 dimethyl sulphide in THF is added. The mixture is kept stirred for one hour, and then 70 ml of H 2 O are added, the mixture is allowed to separate by settling, the organic phase is washed with H 2 O, dried over MgSO 4 , concentrated under vacuum and the product obtained is purified by chromatography on silica (eluent cyclohexane/EtOAc gradient). 15.6 g of the desired compound are obtained.

1E) Methyl ester of 1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-methanesulphonyloxypropyl)-1H-pyrrole-3-carboxylic acid

0.5 g of the compound obtained in 1D) is introduced into 10 ml of CH 2 Cl 2 . 0.4 ml of DIPEA and 153 mg of DMAP are added. The mixture is cooled to −10° C. and 150 mg of mesyl chloride are added. The mixture is allowed to react for 2 hours at −10° C., washed with a solution of H 2 O buffered to pH=2. The organic phase is dried over MgSO 4 and then evaporated. 0.59 g of the desired compound is obtained in the form of an oil.

LCMS: MH + =516.1, tr=2.06.

1F) Methyl ester of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(3-methane-sulphonylaminopropyl)-1H-pyrrole-3-carboxylic acid

This step is carried out according to the information published in: Tetrahedron Letters 46 (2005) page 22159-2161.

18 mg of NaH are introduced into 10 ml of anhydrous DMF. The mixture is cooled to 0° C. and 42.7 mg of methyl sulphonamide are added and allowed to react for 15 minutes. A solution of 150 mg of the compound of the preceding step 1E) dissolved in 5 ml of anhydrous DMF is added. The mixture is allowed to return to RT and then the mixture is left for 3 hours at 60° C. The DMF is evaporated under vacuum, the residue is redissolved in CH 2 Cl 2 , washed with H 2 O, dried over MgSO 4 and evaporated. 93 mg of the desired compound are obtained after chromatography (cyclohexane/EtOAc).

LCMS: MH+ (—OMe)=485.0, tr=1.96.

1G) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(3-methanesulphonylaminopropyl)-1H-pyrrole-3-carboxylic acid

3.43 g of the product obtained in step 1F) are dissolved in 200 ml of methanol. 20 ml of water are added and the mixture is kept stirred for 17 hours at 65° C. The methanol is partially evaporated, and then the mixture is diluted with CH 2 Cl 2 and acidified with concentrated HCl to pH=1 while cooling. The organic phase is dried over MgSO 4 , filtered and evaporated, and 3.24 g (97%) of a white solid are obtained.

LCMS: MH+ (—OMe)=485.1, tr=1.74.

Preparation 2

1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-hydroxymethyl-1H-pyrrole-3-carboxylic acid

2A) Methyl ester of 4-benzyloxy-3-oxobutyric acid

13.28 g of NaH are introduced into 200 ml of dry THF. The mixture is cooled to about 0° C. and then 25 g of methyl ester of 4-chloro-3-oxobutyric acid are added dropwise. 17 ml of benzyl alcohol are then added dropwise. The solution takes on a red colour. The mixture is kept stirred at RT for 17 hours and the reaction mixture is poured into 120 ml of 2N HCl. The mixture is extracted with ether. The organic phase is dried over MgSO 4 and evaporated. After chromatography (eluent: cyclohexane/EtOAc), 23.5 g of product are obtained.

2B) Methyl ester of 4-benzyloxy-2-[2-(2,4-dichlorophenyl)-2-oxoethyl]-3-oxobutyric acid

4.13 g of NaH are introduced into 500 ml of dry THF, cooled to 0° C. 23 g of the compound obtained in step 2A) are added dropwise. The mixture is kept stirred for 30 minutes, and then 27.7 g of 2,4-dichlorophenacyl bromide are added dropwise. The mixture is allowed to react for 3 hours at 0° C., and then the temperature is raised to RT for 17 hours. 150 ml of 2N HCl are added, after cooling, followed by extraction with ether, washing with H 2 O, drying and evaporation. 26 g of product are obtained whose analysis by LCMS confirms the structure.

2C) Methyl ester of 2-benzyloxymethyl-1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1H-pyrrole-3-carboxylic acid

To a round-bottomed flask are added 3.8 g obtained in step 2B), 15 ml of CH 2 Cl 2 and 4 g of Montmorillonite K10. The mixture is kept stirred under nitrogen for 72 hours. The mixture is filtered, rinsed with CH 2 Cl 2 , washed with dilute HCl, dried and the organic phase is evaporated. After chromatography, 3 g of the desired pyrrole are obtained.

2D) Methyl ester of 1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-hydroxymethyl-1H-pyrrole-3-carboxylic acid

8 g of the product of step 2C) in 150 ml of CH 2 Cl 2 are dissolved in a round-bottomed flask. The mixture is cooled to 0° C. and 13 g of BCl 3 -dimethyl sulphide complex dissolved beforehand in 50 ml of CH 2 Cl 2 are added dropwise. After reacting for 1 hour, the mixture is neutralized with solid NaHCO 3 until the gaseous release ceases. The organic phase is dried, and 4.5 g of oil are obtained after chromatography whose NMR spectrum confirms the structure.

2E) 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-hydroxymethyl-1H-pyrrole-3-carboxylic acid

2.7 g of the compound of step 2D) are reacted with 1 g of LiOH in a mixture of dioxane and H 2 O 90/10 for 17 hours at 60° C. After evaporation, the mixture is redissolved in CH 2 Cl 2 , washed with a solution pH=2, and purified by chromatography. 350 mg of the desired product are obtained whose structure is confirmed by LCMS and NMR.