Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-07
2003-11-11
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S211000
Reexamination Certificate
active
06645985
ABSTRACT:
The present invention relates to a novel pyrazole derivative, to its salts and to the solvates thereof, to a process for their preparation and to pharmaceutical compositions containing them.
Patent applications EP-A-576 357, EP-A-658 546 and WO-97/19063 describe pyrazole derivatives with affinity for cannabinoid receptors. More particularly, patent application EP-A-656 354 describes N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, also known as SR 141 716, and the pharmaceutically acceptable salts thereof which have very good affinity for the central cannabinoid receptors.
Compounds similar to SR 141716 have been described in the literature, in particular N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, referred to hereinbelow as compound A, which is described by B. F. Thomas et al. in J. Pharm. Exp. Therap., 1998, 285, 285-292.
The effects of cannabinoids are due to an interaction with specific high-affinity receptors present at the central level (Devane et al., Mol. Pharmacol., 1988, 34, 605-613) and at the peripheral level (Nye et al., Pharmacol. and Experimental Ther., 1985, 234, 784-791; Kaminski et al., 1992, Mol. Pharmacol., 42, 736-742; Munro et al., Nature, 1993, 365, 61-65).
Characterization of the receptors was made possible by the development of synthetic ligands specific for cannabinoid receptors, such as the agonist WIN 55212-2 (J. Pharmacol. Exp. Ther., 1993, 264, 1352-1363) or CP 55,940 (J. Pharmacol. Exp. Ther., 1988, 247, 1046-1051). The pharmacology of the CB
1
and CB
2
cannabinoid receptor subtypes is outlined in Pharmacol. Ther., 1997, 74, 129-130.
A novel N-piperidino-3-pyrazolecarboxamide derivative has now been found which has very good affinity for the CB
1
subtype of cannabinoid receptors (CB
1
receptors) with long-lasting action, which is useful in the therapeutic fields in which cannabinoids are known to be involved.
According to one of its aspects, the present invention relates to N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide, of formula:
to its pharmaceutically acceptable salts and to the solvates thereof.
According to another of its aspects, the present invention relates to a process for preparing compound (I) above, its salts and the solvates thereof, characterized in that a functional derivative of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid, of formula:
is treated with 1-aminopiperidine, in an organic solvent and in the presence of a base; and the compound thus obtained is optionally converted into one of its salts or one of the solvates thereof.
The reaction is carried out in basic medium, for example in the presence of triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran.
Functional derivatives of the acid (II) which may be used are the acid chloride, the anhydride, a mixed anhydride, a C
1
-C
4
alkyl ester in which the alkyl is straight or branched, an activated ester, for example the p-nitrophenyl ester, or the suitably activated free acid, for example activated with N,N-dicyclohexylcarbodiimide or with benzotriazole-N-oxotris(dimethylamino)phosphonium (BOP) hexafluorophosphate.
Thus, by means of the process according to the invention, it is possible to react the acid chloride of formula (II) obtained by reacting thionyl chloride with the acid of formula (II) in an inert solvent, such as benzene or toluene, or a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), an ether (for example tetrahydrofuran or dioxane), or an amide (for example N,N-dimethylformamide) under an inert atmosphere, at a temperature of between 0° C. and the reflux point of the solvent.
One variant of the procedure 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.
The acid of formula (II) can be prepared according to the reaction scheme described below, in which:
LiHMDS=lithium hexamethyldisilazide
NBS=N-bromosuccinimide.
The first step is carried out according to J. Heterocyclic. Chem., 1989, 26, 1389. In the penultimate step, the conversion of the 4-bromomethyl substituent of the pyrazole into 4-ethyl is carried out according to J. Am. Chem. Soc., 1968, 90, 5615.
The 1-aminopiperidine used is a commercial product.
The ester of formula (VII) and the acid of formula (II) can be prepared according to another process which constitutes a further subject of the present invention.
This process is illustrated by the reaction scheme below, in which Alk represents a (C
1
-C
6
)alkyl and represents an ethyl.
This process is characterized in that an alkyl ester, preferably the ethyl ester, of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid is prepared by cyclization of an alkyl ester, preferably the ethyl ester, of 3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl)hydrazono)pentanoic acid (IX).
This reaction is carried out in a protic solvent such as an alcohol, for example a C
1
-C
4
alcohol, preferably ethanol, at a temperature of between room temperature and 80° C., preferably in reluxing ethanol.
According to the invention, the alkyl ester, preferably the ethyl ester, of 3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl)hydrazono)pentanoic acid is prepared by the action of a 2,4-dichlorophenylhydrazine salt, preferably the hydrochloride, on an alkyl ester, preferably the ethyl ester, of 4-bromobenzoyl-2-oxopentanoic acid (VIII).
The reaction is carried out in a protic solvent, for example a C
1
-C
4
alcohol, preferably ethanol.
According to the invention, the alkyl ester, preferably the ethyl ester, of 4-bromobenzoyl-2-oxopentanoic acid is prepared by the action of LiHMDS and then of an alkyl ester, preferably the ethyl ester, of 2-(1-imidazolyl)-2-oxoacetic acid on bromobutyrophenone.
The reaction is carried out in an organic solvent such as an aromatic solvent or an ether, preferably methyl tert-butyl ether. The first step of this reaction is carried out at low temperature, for example at a temperature between 0° C. and −60° C., preferably at a temperature in the region of −20° C.; the second step is carried out at a temperature of between room temperature and −20° C., preferably at room temperature.
Thus, according to Scheme 2, the preparation of an alkyl ester of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid (VII) is carried out starting with 4-bromobenzoyl-2-oxopentanoic acid (VIII) by the action of a 2,4-dichlorophenylhydrazine salt, followed by cyclization.
Bromobutyrophenone is commercially available.
The ethyl ester of 2-(1-imidazolyl)-2-oxoacetic acid is described and prepared according to J. Org. Chem., 1981, 46 (1), 211-213.
The present invention also comprises a process for preparing an alkyl ester, preferably the ethyl ester, of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid, from 4-bromobenzoyl-2-oxopentanoic acid, by the action of a 2,4-dichlorophenylhydrazine salt, preferably the hydrochloride, in a protic solvent, for example a C
1
-C
4
alcohol, preferably ethanol. The reaction is carried out at a temperature of between room temperature and 80° C., preferably in reluxing ethanol.
The compounds of formula:
in which Alk represents a (C
1
-C
6
)alkyl are novel and form part of the invention. Preferably, Alk represents an ethyl.
The compound of formula (I) obtained by the process according to the invention is isolated, in the form of the free base or of a salt or solvate, according to the conventional techniques.
The pharmaceutically acceptable salts of the compound of formula (I) comprise the addition salts with acids, such as the hydrochloride, the hydrobromide, the sulphate, the hydrogen sulphate, the dihydrogen phosphate, the methanesulphonate, the methyl sulphate, the oxalate, the maleate, the fumarate, the 2-naphthalenesulphonate, the glyconate, the gluconate, the citrate, the isethionate, the para-toluenesulphonate o
Barth Francis
Camus Philippe
Martinez Serge
Rinaldi Murielle
LandOfFree
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