Specification
PYRAZOLECARBOXYLIC ACID DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates tc a novel pyrazole derivative, to its salts and to the solvates cne:: eor , to a process for their preparation and to pharmaceutical compositions containing them.
Patent applications EP-A-576 357, EP-A--553 546 and WO-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-carboxami.de, 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. Pharrnacol . , 1988, 34, 605-613) and at the peripheral
level. (Nye *••::. ai,, Fharmaco 1 . and Exper imental Ther., 1985, 23-1, ..... ••••J--79L ; Kamnski et al . , 1992, Mel. Pharmaco ; . , •-.;, 736-M3 ; Munr: et al . , Nature, 1993,
,:-;:or. ists WIN ~:;-212-2 (J. Ph.arrr.ac: 1 . Exp. Ther., 19' ..:_-..•:, I 35/'-l 3n :) or C? 55,94.:- ( .. . Pharmaco!. Exp. :^8S, 2'}1, '; •.'•••i^-i 051) . The pharmacology of the CB: and CE; cannabinc 1.0 receptor subtypes is outlined in Pharmaco.!. Ther., 1997, 74, 12-130.
A ::cvei N-piper idino-3-pyrazolecarboxamide derivative has now been found which has very good affinity for the CB; subtype of cannabinoid receptors (CB: receptors) with long-lastinq 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)-
I-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide,
of formula:
to its pharmaceutically acceptable salts and to the soivates thereof.
According to another of its aspects, the present invention relates to a process for preparing compound ( L< above, its salts and the soivates thereof characterized in that a functional derivative of 5 - i 4 • bromoiji :er:y I • - 1- ('.. , 4 -cich1 oropheny 1} --4 - ethylpyra;:.oIe-3-carboxylic acid, of (Formula Remove)
COOH
CH
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 soivates thereof.
The reaction is carried out in basic medium, for example;; in the presence of triethylamine in an inert solvent such as dichloromethane or t e t ra hydro f ur an.
Functional derivatives of the acid (II) which may be used are the acid chloride, the anhydride, a mixed anhydride, a C_-C,; 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-dicyc lohexy Icarbodiimide or with benzotriazole-N- oxotr ;. s ( a irnechylamino) phosphoniurn (BOP) hexaf luor op; .osphate -
': MUS , by means of the process according to trie invent •,'.•:;.. it is possible to react the acid chloride or 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), OL an amide (for example
N,N-dimethy1formamide) 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 t r i e t hyLamin e.
The acid of formula (II) can be prepared according to the reaction scheme described below, in which:
Li HMDS ;- lithium hexamethyldisilazi.de NBS -- N brc.mosuccinimide .
CH CO,Ei
This process is characterized in that an alkyl ester, preferably the ethyl ester, of 5- !4 • -beomophenyl) - 1 -(2,4-dichlorophenyl)-4 -ethylpyrazole-3-carboxylie acid is prepared by cyo i i zat: ion o : an alkyl ester, preferably the ethyl ester, of 3 (4 • bromobenzoyl)-2-(2-(2,4-dichlorcphenyl)-hycr a zono }p•.:'! also be used as a medicinal product in the treatment of memory disorders, cognitive disorders, in pa i :.. ou'...-.; r LH the treatment of senile dementia and Alzheimer's disease, as well as in the treatment, of attention disorders or vigilance disorders. Furthermore, the compound of formula (I) may be useful as a neuroprotective agent, in the treatment of n e u r o d e u e n e r. a t i v e diseases.
The compound of formula (I) according to the invention can be used as a medicinal product in the treatment of appetite disorders, cravings (for sugars, carbohydrates, drugs, alcohol or any appetizing substance) arid/or eating disorders, in particular as an anorexigenic agent or for the treatment of obesity or bulimia, as well as for the treatment of type II diabetes or non-insulin-dependent diabetes. Furthermore, the compound of formula (I) according to the invention can be used as a medicinal product in the treatment of gastrointestinal disorders, diarrheic disorders, ulcers, vomiting, urinary and bladder disorders, cardiovascular disorders, fertility disorders, inflammatory phenomena, infectious diseases and as ! KOH in 6.85' ml or water is added. The reaction medium is re fluxed for 3 hours and then concentrated under vacuum. The residue is taken up in ice-cold water., acidified to pH = 1 with 1 N HCl and then extracted with DCM. 3.3 g of the expected compound are obtained, m.p. -- 218°C.
NMR: l.LO ppm: t: 3H; 2.70 ppm: q: 2H; 7.25 ppm: d: 2H; 7.60-7.85 ppm: rn: 5H.
PREPARATION 3
Ethyl 3 (4- bromobenzovl)-2-oxopentanoate
A solution of 247 g of 4-bromobutyrophenone in 1500 ml of MTBE is added to a solution of 210 g of LiHMDS in 2500 ml of MTBE, while keeping the temperature at -20°C. After stirring for 3 hours at this temperature, 210 g of ethyl 2-(1-imidazolyl)-2-oxoacetate in 1000 ml of MTBE are added over 1 hour, at 10°C, and the mixture is left stirring for 18 hours at room temperature. The lithium salt formed is iiltered off and then suspended in 800 ml of MTBE.
800 ml of 6 N hydrochloric acid are added to the suspension. After separation of the phases by settling, the ether pnase is washed 4 times with 1000 ml of water and then concentrated under reduced pressure. The expected compound is isolated (263 g). From the NMR analysis, ir is a mixture containing 8% of the 4 -bromobuty • opher.one smarting material . NMR: 0.86 porn: t: 3H; 1.10 ppm: t: 3H; 1.83 ppm: mt : 2H; 4.1L> pp;n: q: 2H; 5.19 ppm: t: 1H; 7.70 ppm: d: 2H; 7.98 ppm: a: 2H .
PREPARATION 4
Ethyl 5 (4-bromophenyl)-1-(2,4-dichlorophenyl)-
4 --ethylpyra'zole- 3 -carboxylate
A) Ethy1 3 - (4-bromobenzoyl)-2 -(2-(2 , 4-dichlorophenyl)-
hydrazono)pentanoate
A suspension of 155 g of
2,4-dichlorophenylhydrazine hydrochloride in 1200 ml of
ethanol is prepared and 263 g of the compound of Preparation 3 in 1000 ml of ethanol are added at room temperature.
A small portion of the intermediate formed can be isolated by filtration and characterized. NMR: 0.92 ppm: t: 3H; 1.04 ppm: t: 3H; 1.89 ppm: mt: 2H; 4.16 ppm: q: 2H; 4.76 ppm: t: 1H; 7.42 ppm: mt: 2H; 7.60 ppm: s: 1H; 7.75 ppm: d: 2H; 7.93 ppm: d: 2H; 12.31 ppm: :- : 1H.
E ) E t hy 1 5 ( 4 - b r omoph eny 1) - 1 - (2, 4-dichlo r oph eny 1 ) -4 -ethylpyra::ole- 3 -carboxylate
'"he suspension obtained is refluxed for 4 hours; and then left stirring for 18 hours at room t einpera : _i e . The product formed is filtered off and then dr,.ed under vacuum at 50°C to give the expected
NMP : 1 . ••:•"' ppm: t: 3H; 1.28 ppm : t: 3H; 2.58 ppm : q: 2H; 4.-: per;: q; 2H; 7.16 ppm: d: 2H; 7.53 ppm: dc : 1H; 7.59 ppir, : c: : 2H; 7.73 ppm: d + small d: 2H.
EXAMPLE IN -• Piper idino- 5- ( 4 -bromophenyl ) -
1 - ( 2 , 4 -dich 1 orophenyl ) ~4-ethylpyrazole-3 -carboxamide
A) 5 - ( 4 -Bromophenyl ) -1- (2 , 4-dichlorophenyl ) -
4 -ethyl pyrazo le-.3 -carboxylic acid chloride
] . 2 q of the acid obtained in the above step are placed in suspension in 32 ml of toluene, 1.6 ml of thionyl chloride are added and the mixture is then refluxed for 3 hours. The reaction medium is concentrated under vacuum and then taken up in toluene.
The operation is repeated several times. 3.3 g of the
expected compound are obtained.
B) N-Piper idino -5- ( 4 -bromophenyl ) -1- (2, 4-dichloro-
phenyl ) -4 -ethy lpyrazole-3-carboxamide
A solution of 0.23 ml of N-aminopiperidine
and 0 . 2 •"> ml of tr lethylamine in 20 ml of DCM is
prepared, under nitrogen, and is cooled to a
r.empera-.ure- of between 0°C and 5°C. 0.8 g of the acid
chloride obtained in the above step in 20 ml of DCM is added. After leaving overnight at RT, the resulting mixture is poured onto ice-cold water and the phases are separated by settling. The organic phase is extracted with DCM and the:: washed with water, with 5% Na-:CO- solution and with saturated NaCl solution. The resulting solution is evaporated to cryness and the residue is then chromatographed on silica, eluting with a toluene/EtOAc mixture (80/2C; v/v). 0.52 g of the expected compound is obtained, rr.. p. = 113°C. NMR: 1.05 ppin: t: 3H; 1.25-1.65 ppm: m: 6H; 2.65 ppm: q: 2H; 2.80 ppm: m: 4H; 7.15 ppm: d: 2H; 7.50-7.80 ppm: m: 5H; 9.10 ppm: S: 1H.
EXAMPLE 2
N-Piperidino- 5 - ( 4-brornophenyl) -1- ( 2 , 4-dichlorophenyl) -
4-ethylpyrazole-3-carboxamide
A) 5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-
4-ethylpyrazole-3-carboxylic acid chloride
A mixture containing 97 g of thionyl chloride and 118 g of the compound of Preparation 4 in 1200 ml of toluene is prepared and is heated gradually to reflux and is then maintained at reflux for 3 hours. The reaction medium is concentrated.
B) N-Piperid.ino- 5 - ( 4-bromophenyl) -1- (2, 4-dichloro-
pheny1)-4-ethylpyrazole-3-carboxamide
The acid chloride formed is taken up in
380 ml of methylcyclohexane and 2.8 g of triethylamine
in 218 ml of THF are introduced. The mixture is kept at
50°C.
A solution c: ~: Q g of N-aminopiperidine and 28 g of tr i-ethy lamine in 34 ml of methylcyclohexane is prepared and cooled to 10°C, and the mixture containing the acid chloride is added slowly. After stirring for 2 hours at 10°C, the product formed is filtered off, taken up in 2000 ml of DCM and washed twice with 2000 ml of water. The product is recrystallized from 4500 ml of methylcyclohexane and then filtered off and dried. 125 g of the expected compound are obtained.
CLAIMS
L. N-Pipendino-5- (4-bromophenyl) -
--(2 ,4-dichioiophenyl) - 4-ethylpyrazole-3-carboxamide, of torrriu 1 a -
its pharmaceutically acceptable salts and the solvates thereof,
2. Process for preparing N-piperidino-5- (4-brornophenyl) -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:is tieaved with 1-aminopiperidine, in an organic solvent: and in the presence of a base; and the compound thus obrained 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
alkyl ester of 2-(1-imidazolyl)-2-oxoacetic acid on bromobutyrophenone.
6. Process according to Claim 2, for preparing an alkyl ester of 5-(4-bromophenyl)-1- ( 2 , 4-dich.l o.vopheny.1} -4 -ethylpyrazole- 3 -carboxyl ic acid from 4-bromobenzoyl-2-oxopentanoic acid by the action of a 2 , 4 - dichiorophenyIhydrazine salt, followed by eye11za 11on.
7 Compound of formula:
0 0
CO.Alk (VIII)
in which Alk represents a (C:-C6) alkyl. 8 Compound of formula
in which Alk represents a (C.-C6)alkyl.
9. Pharmaceutical composition containing,
as active principle, a compound according to Claim I.
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 excipieat.
11. Use of a compound according to Claim 1
for the preparation of medicinal products intended for
treating diseases involving the CBj 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 oi: memory and cognitive disorders; for the
treatment of: alcohol dependency and for withdrawal from
tobacco.
13 N-Piperidino-5-[4-bromophenyl]-l-[2,4-dichlorophenyl]-4-
ethylpyrazole-3-carboxamide of formula substantially as hereinbefore
described with reference to the foregoing examples.
14 Process for preparing N-Piperidino-5-[4-bromophenyl]-l-[2,4-
dichlorophenyl]-4-ethylpyrazole~3-carboxamide of formula substantially
as hereinbefore described with reference to the foregoing examples.
15 Compounds of formula substantially as hereinbefore described
with reference to the foregoing examples.
16 Pharmaceutical composition substantially as hereinbefore
described with reference to the foregoing examples.