FR2789078A1 - New compound N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-3-pyrazole carboxamide useful as a cannabinoid receptor antagonist, e.g. for treating eating disorders, obesity, amnesia and cognitive disorders - Google Patents

Abstract

N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-3-pyrazole carboxamide (I) is new. N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-3-pyrazo lecarboxamide of formula (I) and its salts and solvates are new: An Independent claim is also included for a process for preparing (I).

Description

The present invention relates to a new pyrazole derivative, its salts and

  their solvates, a process for their preparation and pharmaceutical compositions containing them. Patent applications EP-A-576,357, EP-A658,546 and WO-97/19063 describe derivatives of pyrazole having an affinity for the cannabinoid receptors. More particularly, patent application EP-A-656,354 describes the

  N-piperidino-5- (4-chlorophenyl) - 1- (2,4-dichlorophenyl) -4-methylpyrazole3-

  carboxamide, also known as SR 141 716, and its pharmaceutically acceptable salts which have a very good affinity for receptors for

central cannabinoids.

  The effects of cannabinoids are due to an interaction with specific high affinity receptors present at the central (Devane et al., Mol. Pharmacol., 1988, 34, 605-613) and peripheral (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).

  The characterization of the receptors was made possible by the development of synthetic ligands specific for the cannabinoid receptors such as the agonists WIN 55212-2 (J. Pharmacol. Exp. Ther., 1993, 264, 1352-1363) or the CP , 940 (J. Pharmacol. Exp. Ther., 1988, 247, 1046-1051). The pharmacology of the CB 1 and CB2 subtypes of the cannabinoid receptors is set out in Pharmacol.

Ther., 1997, 74, 129-130.

  We have now found a new derivative of N-piperidino-3-pyrazole carboxamide which has a very good affinity for the CB1 cannabinoid receptor subtype (CB1 receptors) and which is useful in the therapeutic fields.

  o cannabis is known to intervene.

  According to one of its aspects, the present invention relates to N-piperidino5- (4-

  bromophenyl) -i- (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide of formula:

H 5C2,

H5C2CCO-NH- N

NcN Br Ci

K-: 2 (I)

Cl

  its pharmaceutically acceptable salts and their solvates.

  According to another of its aspects, the present invention relates to a process for the preparation of the above compound (I), its salts and their solvates, characterized in that

  that a functional derivative of 5- (4-bromophenyl) - 1- (2,4-

  dichlorophenyl) -4-ethylpyrazole-3-carboxylic of formula:

CH3CH2 COOH

3 2 EN <N Br N Cl

()

  C1 with 1-aminopiperidine, in an organic solvent and in the presence of a base; and optionally transforming the compound thus obtained into one of its salts or one of

their solvates.

  The reaction is carried out in basic medium, for example in the presence of

  triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran.

  As functional derivative of acid (II), acid chloride, anhydride, a mixed anhydride, a C1-C4 alkyl ester in which the alkyl is straight or branched, an activated ester can be used, for example p-nitrophenyl ester, or free acid suitably activated, for example, with N, N-dicyclohexylcarbodiimide or with

  benzotriazol hexafluorophosphate-N- oxotris (dimethylamino) phosphonium (BOP).

  Thus by the process according to the invention, the acid chloride of formula (II) obtained by reaction of thionyl chloride with the acid of formula (II) can be reacted in an inert solvent, such as benzene or toluene, or 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 the

solvent reflux temperature.

  A variant of the procedure consists in preparing the mixed anhydride of the acid of formula (II) by reaction of ethyl chloroformate with the acid of formula (II),

  presence of a base such as triethylamine.

  The acid of formula (II) can be prepared according to the reaction scheme described above.

  after which: LiHMDS: lithium salt of hexamethyldisilazane NBS: N-bromosuccinimide

DIAGRAM 1

  Br I O 1) LiHMDS -OLi + Br 80 Br -And 2) (CO2Et) 2 NH-NH2 i trCHII) CH3 CO2Et U N AcOH 1 0Br- NiH Cl Br CI CH3 CO2Et (IV) (I)

CCI4

N t Me2CuLi N (VI KOH / MeOH

H20

  = Br N Cl (VII) The first step is carried out according to J. Heterocyclic. Chem., 1989, 26, 1389. In the penultimate stage, the transformation of the 4-brornomethyl substituent of pyrazole

  in 4-ethyl is carried out according to J. Am. Chem. Soc., 1968, 90. 5615.

  The other reagent used for the process of the present invention, 1-

  aminopiperidine, is a commercial product.

  The compound of formula (I) obtained by the process according to the invention is isolated, under

  free base form or salt or solvate, according to conventional techniques.

  The pharmaceutically acceptable salts of the compound of formula (I) include the addition salts of acids such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, Br? [LI.Br N Cl C1 CI] KOH / MeOH HzO (II) The first step is carried out according to J. Heterocyclic. Chem., 1989, 26, 1389. In the penultimate stage, the transformation of the 4-bromomethyl substituent of pyrazole

  in 4-ethyl is carried out according to J. Arn. Chem. Soc., 1968, 90, 5615.

  The other reagent used for the process of the present invention, 1 -

  aminopiperidine, is a commercial product.

  The compound of formula (I) obtained by the process according to the invention is isolated, under

  free base form or salt or solvate, according to conventional techniques.

  The pharmaceutically acceptable salts of the compound of formula (I) include the addition salts of acids such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, oxalate, maleate , fumarate, 2-naphthalenesulfonate,

  glyconate, gluconate, citrate, isethionate, paratoluenesulfonate, 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 said salt with an inorganic or organic base, such as sodium or ammonium hydroxide, triethylamine or an alkali carbonate or bicarbonate such as sodium carbonate or bicarbonate or potassium, and turned into a

  other salt such as methanesulfonate, fumarate or 2naphthalenesulfonate.

  When the compound of formula (I) is obtained in the form of a free base, the

  salification is carried out by treatment with the chosen acid in an organic solvent.

  By treatment of 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,

  obtains the corresponding salt which is isolated according to conventional techniques.

  - The compounds of formula (I) have a very good in vitro affinity for the cannabinoid receptors CB1, under the experimental conditions described by

  Devane et al., Mol. Pharmacol., 1988, 34, 605-613.

  Thus, the compound according to the invention has a very strong affinity for the human CB1 cannabinoid receptors (Ki = 5.4 nM) which compares favorably with that of SR 141716 for the same receptors, determined in the

same conditions (Ki = 34 nM).

  On the other hand, the antagonistic nature of the compound of formula (I) has been demonstrated by the results obtained in the models of the inhibition of adenylate cyclase as

  described in M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1996, 27, 871-878.

  More particularly, the compound of the present invention, as such or in the form of one of its pharmaceutically acceptable salts, is a potent antagonist and

  selective CB 1 cannabinoid receptors.

  The toxicity of the compounds (I) is compatible with their use as a medicament. According to another of its aspects, the present invention relates to the use of a compound of formula (I), or of one of its pharmaceutically acceptable salts or solvates, for the preparation of medicaments intended for treating diseases

  involving CB 1 cannabinoid receptors.

  For example and without limitation, the compound of formula (I) is useful as a psychotropic drug, in particular for the treatment of anxiety disorders, mood disorders, delusional disorders, psychotic disorders in general, for the treatment of schizophrenia, depression, as well as for treatment

2789078

  disorders linked to the use of psychotropic substances, in particular in the case of substance abuse and / or dependence on a substance, including alcohol dependence. The compound of formula (I) according to the invention can be used as a medicament for the treatment of neuropathies, migraine, stress, diseases of psychosomatic origin, epilepsy, movement disorders, in particular

  dyskinesias or Parkinson's disease.

  The compound of formula (I) according to the invention can also be used as a medicament in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well

  than in the treatment of attention or alertness disorders.

  The compound of formula (I) according to the invention can be used as a medicament in the treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or behavior food, in particular as an appetite suppressant or for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin dependent diabetes. In addition, the compound of formula (I) according to the invention can be used as a medicament in the treatment of gastrointestinal disorders, vomiting, bladder and urinary disorders, cardiovascular disorders, fertility disorders , inflammatory phenomena, infectious diseases

  as well as as a drug for cancer chemotherapy.

  According to the present invention, the compound of formula (I) is very particularly useful for the treatment of psychotic disorders, in particular schizophrenia; for the treatment of appetite disorders and obesity and for the treatment of

memory and cognitive disorders.

  According to one of its aspects, the present invention relates to the use of a compound of formula (I) of its pharmaceutically acceptable salts and their solvates

  for the treatment of the disorders and diseases indicated above.

  According to another of its aspects, the present invention also relates to the use of the compounds of formula (I), as such or in radiolabelled form as a pharmacological tool in humans or in animals, for the detection and

labeling of CB receptors 1.

  The compound according to the invention is generally administered in dosage units.

  Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient. Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of

  formula (I), one of its pharmaceutically acceptable salts or one of their solvates.

  The compound of formula (I) above and its pharmaceutically acceptable salts or solvates can be used in daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably in daily doses of 0, 1 to mg / kg. In humans, the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2 to 1000 mg per day depending on the age of the subject to be treated or the type of treatment, namely prophylactic or curative . Although these dosages are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, age, weight and response.

said patient.

  In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle can be administered in unit administration form, in admixture with carriers conventional pharmaceuticals, animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, administration forms topical, implants, subcutaneous, intramuscular administration forms,

  intravenous, intranasal or intraocular and forms of rectal administration.

  In the pharmaceutical compositions of the present invention, the active ingredient is generally formulated in dosage units containing from 0.1 to 1000 mg, advantageously from 0.5 to 500 mg, preferably from 1 to 200 mg of said active ingredient

  per dosage unit for daily administration.

  When a solid composition is prepared in the form of a tablet, a wetting agent such as sodium lauryl sulphate can be added to the active principle, micronized or not, and the whole is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, various polymers or other suitable materials or they can be treated in such a way that they have a prolonged or delayed activity and that they continuously release a quantity

predetermined active ingredient.

  A preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and incorporating the mixture obtained

in soft or hard capsules.

  A preparation in the form of a syrup or elixir may contain the active principle together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color. The water-dispersible powders or granules may contain the active principle in admixture with dispersing agents, wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with

  sweeteners or flavor correctors.

  For rectal administration, suppositories are used which are prepared with binders which melt at rectal temperature, for example cocoa butter or

polyethylene glycols.

  For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or polyethylene glycol. Thus, to prepare an aqueous solution for intravenous injection, one can use a cosolvent such as for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween 80. To prepare an oily solution injectable intramuscularly, the active principle can be dissolved by a triglyceride or an ester of

glycerol.

  For local administration, creams, ointments or gels can be used. For transdermal administration, it is possible to use patches in multilaminate or reservoir form in which the active principle can be in solution

alcoholic.

  For administration by inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant is used; one can also use a system containing the active ingredient alone or associated with an excipient, in the form of powder.

8 2789078

  The active principle can also be formulated in the form of microcapsules or

  microspheres, possibly with one or more carriers or additives.

  The active ingredient can also be presented in the form of a complex with a

  cyclodextrin, for example ct-, 5- or y-cyclodextrin, 2-hydroxypropyl53-

  cyclodextrin or methyl- [p-cyclodextrin. Among the sustained-release forms useful in the case of chronic treatments, implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.

  In the present description, the following abbreviations are used:

  DCM: dichloromethane LiHMDS: lithium salt of hexamethyldisilazane TMSCl: chlorotrimethylsilane APTS: paratoluenesulfonic acid NBS: N-bromosuccinimide TA: room temperature F: melting point NMR: nuclear magnetic resonance. NMR spectra are recorded at MHz in DMSO d6 s: singlet; d: doublet; t: triplet; m: massive or multiplet

PREPARATION 1

  5- (4-Bromophenyl) - 1 - (2,4- dichlorophenyl) -4- acid ethyl ester

  ethylpyrazole-3-carboxylic. A) Lithium salt of 4- (4-bromophenyl) -3methyl-4-oxydo-2-oxobuten-oate

ethyl.

  Under nitrogen, 21.6 g of LiHMDS are placed in 340 ml of anhydrous ether and the mixture is cooled to -60 ° C. and then 4 g of bromopropiophenone dissolved in 150 ml of anhydrous ether are added. The temperature is allowed to rise to -30 ° C. and then 17.53 ml of ethyl oxalate are added. After stirring overnight at RT, the precipitate formed is filtered and then

  rinsed with ether and dried under vacuum. 21.8 g of the expected compound are obtained.

  B) 4- (4-Bromophenyl) -2 - [(2,4- dichlorophenyl) - ethyl ethyl ester -

  hydrazono] -3-methyl-4-oxobutyric.

  16.8 g of the compound prepared in the preceding step and 12.5 g of 2,4-dichlorophenylhydrazine hydrochloride are mixed in 150 ml of ethanol and the mixture is left stirring for 2.5 hours. The precipitate formed is filtered, rinsed with ethanol and then

  vacuum dried. 16.24 g of the expected compound are obtained.

9 2789078

  C) 5- (4-Bromophenyl) - 1 - (2,4dichlorophenyl) -4- ethyl ethyl ester

  methylpyrazole-3-carboxylic. 16.24 g of the compound obtained in the preceding step are heated for 24 hours in 200 ml of acetic acid and then the reaction medium is poured onto 1 liter of ice water; the precipitate formed is filtered, rinsed with water and dried under vacuum. We obtain 12.8 g

  of the expected compound which is recrystallized from methylcyclohexane, F = 133 C.

  D) 4-Bromomethyl-5- (4-bromophenyl) - 1- (2,4-) ethyl ester

  dichlorophenyl) pyrazole-3-carboxylic. 12.8 g of ester obtained in the previous step are placed in 130 ml of carbon tetrachloride and 5.27 g of N-bromosuccinimide and then 24 mg of benzoyl peroxide are added. The mixture is heated for 4 hours at reflux, then filtered and concentrated under

  empty. The residue is chromatographed on silica, eluting with a toluene-

  ethyl acetate (97/3; v / v). 7.24 g of the expected compound are obtained, F = 116 C.

  E) 5- (4-Bromophenyl) - 1- (2,4dichlorophenyl) -4- acid ethyl ester

ethylpyrazole-3-carboxylic.

  2.26 g of CuBr suspended in 100 ml of ether are introduced under argon and then a solution containing 20 ml of 1.6 M methyllithium in ether diluted in 20 ml of is added dropwise at -20 ° C. ether. After 10 minutes of stirring at -20 ° C., the suspension discolours and then becomes clear. Cooled to -78 C and added in 30 minutes 7 g of the compound prepared in the previous step, dissolved in 100 ml of ether and then allowed to rise to RT. After 2 hours with stirring, hydrolysis is carried out by adding a saturated solution of ammonium chloride. Extracted with ether, washed with water and then with a saturated NaCl solution. It is dried over MgSO4 and then evaporated to dryness. The residue is chromatographed on silica, eluting with a toluene-ethyl acetate mixture (96/4

  ; v / v). 3.7 g of the expected compound are obtained, F = 108 C.

  NMR: 1.05 ppm: t: 3H; 1.30 ppm: t 3H; 2.60 ppm: q: 2H; 4.30 ppm: q:

  2H; 7.15 ppm: d: 2H; 7.50-7.75 ppm: m: 5H.

PREPARATION 2

  5- (4-Bromophenyl) - 1- (2,4-dichlorophenyl) -4-ethylpyrazole-3- acid

carboxylic.

  3.6 g of the ester obtained in the previous step are placed in 54 ml of MeOH and a solution containing 1.08 g of KOH in 6.85 ml of water is added. The reaction medium is heated at reflux for 3 hours and then concentrated under vacuum. The residue is taken up in ice water, acidified to pH = 1 with HCI IN and then extracted with

  DCM. 3.3 g of the expected compound are obtained, F = 218 C.

  NMR: 1.10 ppm t 3H; 2.70 ppm: q: 2H; 7.25 ppm: d: 2H

7.60-7.85 ppm: m: 5H.

EXAMPLE 1

  N-piperidino-5- (4-bromophenyl) - 1 - (2,4-dichlorophenyl) -4-ethylpyrazole3-

carboxamide.

  A) 5- (4-Bromophenyl) -1- (2,4-dichlorophenyl) -4ethylpyrazole-3- acid chloride

  carboxylic. 3.2 g of the acid obtained in the previous step are placed in suspension in 32 ml of toluene, 1.6 ml of thionyl chloride are added and then the mixture is heated at reflux 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-piperidino-5- (4-bromophenyl) - 1- (2,4-dichlorophenyl) -4ethylpyrazole-3-

  carboxamide. Under nitrogen, a solution of 0.23 ml of Naminopiperidine and 0.29 ml of triethylamine in 20 ml of DCM is prepared and cooled to a temperature between 0 and 5 C. 0.8 g of the acid chloride is added obtained in the previous step in 20 ml of DCM. After a night at RT, we run on ice and decanted water. The organic phase is extracted with DCM and then washed with water, with a 5% Na2CO3 solution, with a saturated NaCl solution. Evaporated to dryness then the residue is chromatographed on silica, eluting with a toluene / AcOEt mixture (80/20; v / v). 0.52 g of

expected compound, F = 113 C.

  NMR: 1.05 ppm: 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.

Il 2789078

Claims (7)

  1. N-piperidino-5- (4-bromophenyl) -I- (2,4-dichlorophenyl) -4ethylpyrazole-3- carboxamide of formula: Hs5C2 5C O- CO-NîH - N I NN Br N Ci (I) Cl   its pharmaceutically acceptable salts and their solvates.   2. Process for the preparation of N-piperidino-5- (4-bromophenyl) - 1- (2,4-   dichlorophenyl) -4-ethylpyrazole-3-carboxamide, its salts and their solvates,   characterized in that a functional derivative of 5- (4bromophenyl) acid is treated -   1- (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxylic of formula: CH3CH2 II Ci 6OOH NOT   Br N Cl Ci with 1-aminopiperidine, in an organic solvent and in the presence of a base and optionally the compound thus obtained is converted into one of its salts or one of their solvates.   3. Pharmaceutical composition containing, as active ingredient, a compound according to claim 1.   4. Pharmaceutical composition according to claim 3, in the form of a dosage unit, in which the active principle is mixed with at least one pharmaceutical excipient. 5. Pharmaceutical composition according to claim 4, containing from 0.1 to 1000 mg of active ingredient. 12 2789078   12 / Y l 6. Use of a compound according to claim 1 for the preparation of medicaments intended to treat diseases involving receptors for cannabinoids CB 1.   7. Use of a compound according to claim 6 for the treatment of psychotic disorders, for the treatment of appetite disorders and obesity and for   treatment of memory and cognitive disorders.