ZA200105739B - Pyrazolecarboxylic acid derivatives, their preparation, pharmaceutical compositions containing them. - Google Patents

Pyrazolecarboxylic acid derivatives, their preparation, pharmaceutical compositions containing them. Download PDF

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Publication number
ZA200105739B
ZA200105739B ZA200105739A ZA200105739A ZA200105739B ZA 200105739 B ZA200105739 B ZA 200105739B ZA 200105739 A ZA200105739 A ZA 200105739A ZA 200105739 A ZA200105739 A ZA 200105739A ZA 200105739 B ZA200105739 B ZA 200105739B
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ZA
South Africa
Prior art keywords
dichlorophenyl
alkyl ester
compound
acid
formula
Prior art date
Application number
ZA200105739A
Inventor
Philippe Camus
Serge Martinez
Murielle Rinaldi
Francis Barth
Original Assignee
Sanofi Synthelabo
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Application filed by Sanofi Synthelabo filed Critical Sanofi Synthelabo
Publication of ZA200105739B publication Critical patent/ZA200105739B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/80—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings

Description

¥
PYRAZOLECARBOXYLIC ACID DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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 WO0-97/19063 describe pyrazole derivatives with affinity for cannabinoid receptors.
More particularly, patent appliction 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 v 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 agonists WIN 55212-2 (J. Pharmaccl. Exp. Ther., 1003, 264, 1352-1363) or CP 55,940 (J. Pharmacol. Exp. Ther., 1988, 247, 1046-1051). The pharmacology of the CB; and
CB; cannabinoid receptor subtypes is outlined in
Pharmacol. Ther., 1997, 74, 1295-130.
A novel N-piperidino-3-pyrazolecarboxamide derivative has now been found which has very good affinity for the CB; subtype of cannabinoid receptors (CB; 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:
H.C,
CoN XD)
NY oT ))
Cl ‘
oC , 20015739 i 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:
CH,CH,
COOH
Br Cl a1
Cl is treated with l-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;-C4 alkyl ester in which the alkyl is straight or branched, an activated ester, for n . 20015739 i 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 (ITI) 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.
{ IC vi
SCHEME 1 0] 1) LIHMDS O Lit
Br —_— Br )
Et 2) (CO,Ev), COE NH-NH,
CH t (In 3 2 Cl 0] cH, ca — om a s
N
N AcOH 0
La 2 Oe
Cl
Br oS CH, CO,Et av)
Yo
Cl
NBS cc, 0 CI
CH,Br oF CH, [1 ‘ OE
NN -N
Me,CuLi N
Cl
Br Br Ci (VID) a Cl
VD KOH/MeOH
H,0 (In 5 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 l-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;-Cg)alkyl and represents an ethyl.
SCHEME 2 0)
I 1) LIHMDS 0 0
Br C-(CH,),-CH —_— Br
DCH, — Al ~ HH con
Xc—C Et 2) So (VIID)
N
[1]
N Cl
NH-NH,
Cl 0 N— NH Cl , 1
Cl _— . Et (IX) 0
Et
OAlk
NY — » (I
Br Pr
De 1 (VID)
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;-C4 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;-C, alcohol, preferably ethanol.
According to the invention, the alkyl ester, preferably the ethyl ester, of 4-bromobenzoyl- 2-oxopentanoic acid 1s prepared by the action of LiHMDS and then of an alkyl ester, preferably the ethyl ester, of 2-(l-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-(l-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;-C4 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: 0 O
HY Hco mu (VIII)
Et
Cl f N—NH Cl wd) Cr cox IX)
Et in which Alk represents a (C;-Cg)alkyl are novel and form part of the invention. Preferably, Alk represents i0 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 or the succinate.
The compound of formula (I) can be isolated in the form of one of its salts, for example the hydrochloride or the oxalate; in this case, the free base can be prepared by neutralizing the said salt with an inorganic or organic base, such as sodium hydroxide or ammonium hydroxide, triethylamine or an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate, and converted into another salt such as the methanesulphonate, fumarate or 2-naphthalenesulphonate.
When the compound of formula (I) is obtained in the form of the free base, the salification is carried out by treatment with the acid chosen in an organic solvent. By treating the free base, dissolved, for example, in an ether such as diethyl ether or in acetone, with a solution of the acid in the same solvent, the corresponding salt is obtained and is then isolated according to the conventional techniques.
The compounds of formula (I) have very good in vitro affinity for the CB; cannabinoid receptors, under the experimental conditions described by Devane et al., Mol. Pharmacol., 1988, 34, 605-613.
Thus, the compound according to the invention has very strong affinity for human CB; cannabinoid receptors (Ki = 5.4 nM) which compares favourably with that of SR 141716 for the same receptors, determined under the same conditions (Ki = 34 nM).
The compound according to the invention was also compared with N-piperidino-5-(4-bromophenyl) - 1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, (compound A). The affinity of this compound for human
CB; cannabinoid receptors, measured under the same conditions, is reflected by a Ki value of 8 nM.
Moreover, the duration of occupation of the
CB; receptors present in the brain by the 3 compounds below was compared: - the compound of formula (I) according to the invention, - SR 141716, - compound A.
The study was performed in vivo in mice, after oral administration of each of the compounds at a dose of 10 mg/kg, according to the technique described in M. Rinaldi-Carmona et al., Life Sciences, 1995, 56, 1941-1947. The results obtained are collated in the table below.
TABLE 1
Compound of 82% 44% mrs | ~~
ERT EES
Compound A 89% a
Surprisingly, it is observed that the compound of formula (I) according to the invention is the only compound which shows appreciable occupation (44%) 24 hours after its administration.
Moreover, the antagonist nature of the compound of formula (I) was demonstrated by the results obtained in models of adenylate-cyclase inhibition as described in M. Rinaldi-Carmona et al., J. Pharmacol.
Exp. Ther., 1996, 278, 871-878.
More particularly, the compound of the present invention, in its native form or in the form of one of its pharmaceutically acceptable salts, is a powerful and selective antagonist of the CB: cannabinoid receptors.
The antagonist nature of the compound according to the invention, as well as its good penetration into the central nervous system, are confirmed by the results obtained in the model of

Claims (12)

1. N-Piperidino-5- (4-bromophenyl) - 1-(2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide, of formula: Be comm N ) \ / ~N N Br Cl @ Cl its pharmaceutically acceptable salts and the solvates thereof.
2. Process for preparing N-piperidino- 5- (4-bromophenyl)-1-(2,4-dichlorophenyl) - 4-ethylpyrazole-3-carboxamide, 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:
CHC, TT] COOH Br Cl (II) Cl is treated with l-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.
3. Process according to Claim 2, for preparing an alkyl ester of 5-(4-bromophenyl) - 1-(2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxylic acid by cyclization of an alkyl ester of 3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl) - hydrazono)pentanoic acid (IX). .
4, Process according to Claim 3, for preparing an alkyl ester of 3-(4-bromobenzoyl)- 2-(2-(2,4-dichlorophenyl)hydrazono)pentanoic acid by the action of a 2,4-dichlorophenylhydrazine salt on an alkyl ester of 4-bromobenzoyl-2-oxopentanoic acid (VIII).
5. Process according to Claim 4, for preparing an alkyl ester of 4-bromobenzoyl- 2~oxopentanoic acid by the action of LiHMDS and then an k alkyl ester of 2-(l-imidazolyl)-2-oxoacetic acid on bromobutyrophenone.
6. Process according to Claim 2, for preparing an alkyl 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, followed by cyclization.
7. Compound of formula: 0 0 neon (VIII) Et in which Alk represents a (Ci1-Cg)alkyl.
8. Compound of formula Cl i N—NH 28s Eco (IX) Et in which Alk represents a (C;-Ce)alkyl.
9. Pharmaceutical composition containing, as active principle, a compound according to Claim 1.
10. Pharmaceutical composition according to Claim 9, containing from 0.1 to 1000 mg of active principle, in unit dosage form, in which the active principle is mixed with at least one pharmaceutical excipient.
11. Use of a compound according to Claim 1 for the preparation of medicinal products intended for treating diseases involving the CB; cannabinoid receptors.
12. Use of a compound according to Claim 11 for the treatment of psychotic disorders, for the treatment of appetite disorders and obesity, for the treatment of memory and cognitive disorders; for the treatment of alcohol dependency and for withdrawal from tobacco.
ZA200105739A 1999-02-01 2001-07-12 Pyrazolecarboxylic acid derivatives, their preparation, pharmaceutical compositions containing them. ZA200105739B (en)

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JP2005533748A (en) 2002-03-08 2005-11-10 シグナル ファーマシューティカルズ，インコーポレイテッド Combination therapies to treat, prevent, or manage proliferative disorders and cancer
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