Classifications

• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• - Rj represents a fluorine, a hydroxy, a (C ⁇ ⁇ C5) alkoxy, a (C ⁇ -C5) alkylthio, a hydroxy (C ⁇ -C5) alkoxy, a group -N ⁇ lO ⁇ ll ' a cyano, a (Cj- C5) alkylksulfonyl, a (C ⁇ -C5) alkylsulfinyl;
• R2 and R3 represent a (C ⁇ -C4) alkyl or together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 10 members, unsubstituted or substituted one or more times by one (C ⁇ -C3) alkyl or by a (C ⁇ ⁇ C3) alkoxy;
• R4, R5, Rg, R7, Rg, Ro. each independently represent hydrogen, a halogen, a trifluoromethyl, and when R ⁇ represents a fluorine, R4, R5, Rg, R7, Rg and / or R9 can also represent a fluoromethyl; and provided that at least one of the substituents R4 or R7 is different from hydrogen;
• R o and Ru each independently represent hydrogen or a (C ⁇ ⁇ C5) alkyl or RJQ and RJ I together with the nitrogen atom to which they are linked constitute a heterocyclic radical chosen from pyrrolidin-1-yle, piperidin- 1-yl, morpholin-4-yl, piperazin-1-yl unsubstituted or substituted by a (C 1 -C 4 alkyl; as well as their salts and their solvates.
• (C 1 -C 3 ) alkyl (C! -C5) alkoxy, (C ⁇ -C5) alkylthio, is meant alkyl radicals or respectively C1-C3 or C1-C5 alkoxy or alkylthio radicals straight or branched.
• halogen is meant chlorine, fluorine, bromine or iodine, preferably chlorine.
• saturated or unsaturated 5 or 10-membered heterocyclic radical is meant a non-aromatic mono, di or tricyclic, condensed or bridged heterocyclic radical.
• These radicals include in particular the following radicals: pyrrolidin-1-yl, piperidin-1-yl, hexahydroazepin-1-yl, 2-azabicyclo [2.2.2] oct-5-en-2-yle, 2-azaadamant-2 -yle, 1,2,3, 6-tetrahydropyridin-1-yl, 2-azabicyclo [2.2.1] heptan-2-yl, 2-azabicyclo [2.2.2] octan-2-ylc.
• the salts of the compound of formula (I) include the addition salts of pharmaceutically acceptable acids such as the hydrochloride, the hydrobromide. sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, maleate, oxalate, fumarate, 2-naphthalcncsuIfonate, glyconate. gluconate, citrate, isethionate, paratoluenesulfonate.
• pharmaceutically acceptable acids such as the hydrochloride, the hydrobromide. sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, maleate, oxalate, fumarate, 2-naphthalcncsuIfonate, glyconate. gluconate, citrate, isethionate, paratoluenesulfonate.
• the subject of the present invention is the compounds of formula:
• R ⁇ p represents a fluorine, a methoxy or a methylthio, as well as their salts and their solvates.
• the present invention relates to a process for the preparation of the compounds of formula (I) above, their salts and their solvates; this process called Process 1 is characterized in that: a) a bromine ester of formula is treated:
• R4, R5, Rg, R7, Rg, R9 are as defined above and R represents a (C ⁇ -C4) alkyl, with a compound of formula: R'i A (III) in which R'i represents Ri as defined for (I) or a precursor of Ri and A represents a hydrogen or a cation; bl) in the ester thus obtained, R'i is optionally transformed into Ri; b2) the ester thus obtained in step a) or in step bl) is saponified, of formula: c) treating the acid thus obtained of formula:
• precursor of Ri is meant a group which can be transformed into Ri in a later step. This transformation can be carried out on the ester of formula (IV) obtained in step a) or on the compound of formula (I 1 ) obtained in step c).
• the brominated esters of formula (II) are described in European patent application EP-A-658 546. They are prepared by the action of N-bromosuccinimide in a solvent such as carbon tetrachloride, in the presence of benzoyl peroxide on a composed of formula:
• the hydrazines H2N-NR2R3 are known or prepared by known methods.
• the nitroso derivative (VIII) is obtained by reaction of a compound of formula: HNR2R3 (IX) in which R2 and R3 are as defined above for (I), with sodium nitrite in aqueous solution in the presence of an acid such as acetic acid.
• 1-aminopiperidine is commercial.
• 2-amino-2-azaadamantane is prepared from 2-azaadamantane, via the nitroso derivative.
• 2-azaadamantane is prepared according to J. Org. Chem., 1981, 4_6_, 4953.
• cation is meant an alkali or alkaline earth metal cation, or a quaternary ammonium group such as tetraethylammonium.
• an activated ester can be used, for example / 7-nitrophenyl ester, or the free acid suitably activated, for example, with N, N-dicyclohexylcarbodiimide, benzotriazol hexafluorophosphate-N-oxotris (dimethylamino) phosphonium (BOP) or silicon tetrachloride ( Commun.
• step c) the chloride of pyrazole-3-carboxylic acid, obtained by reaction of thionyl chloride with the acid of formula (V), can be reacted with a hydrazine H2N-NR2R3 (VI), in a solvent such as dichloromethane, under an ine ⁇ e atmosphere, at a temperature between 0 * C and room temperature, in the presence of a base such as triethylamine.
• a variant of the procedure of step c) consists in preparing the mixed anhydride of the acid of formula (V) by reaction of ethyl chloroformate with the acid of formula (V), in the presence of a base such as triethylamine, and reacting it with hydrazine, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.
• an R'iA (III) reagent is used an alkali or alkaline alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, the acid of formula (V).
• R4, R5, Rg, R7, Rg, R9 and R are as defined above by an alkali or alkaline earth metal hydroxide; f) treating the acid thus obtained of formula:
• a metallic cyanide such as sodium cyanide or a quaternary ammonium cyanide, for example tetraethylammonium cyanide; in the latter case, the nucleophilic substitution reaction of step a) or of step h) is carried out in the presence of a phase transfer catalyst.
• fluorinating agent there may be mentioned a quaternary ammonium fluoride such as tetrabutylammonium fluoride; a metal fluoride, for example potassium fluoride used in the presence of a weak base such as potassium carbonate and a complexing agent such as Kryptofix®; a hydrofluoric acid complex, for example a (HF) n-
• a compound of formula (I) is prepared in which Ri represents a fluorine and R4, R5, Rg, R7, Rg and / or R9 represents a fluoromethyl using as starting material a compound of formula (II) in which R4, R5, Rg, R7, Rg and / or R9 represents bromomethyl.
• the fluorination carried out according to one of the methods described above makes it possible to transform R4, R5, Rg, R7, Rg and / or R9 into fluoromethyl.
• the starting compound (II) is prepared by action of N- 97/19063 y PO7FR96 / 01847
• a compound of formula (I) in which R ⁇ is a group -NRIQRH, it is possible to react in step a) an amine of formula: HNRIQRH (III) -
• a non-nucleophilic base such as a metal hydride, such as sodium hydride.
• the compound of formula (I) obtained by the process according to the invention is isolated, in the form of a free base or of salt or of solvate, according to conventional techniques.
• 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 transformed into another salt such as methanesulfonate, fumarate or 2- ⁇ aphthalenesulfonate.
• 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
• the salification is carried out by treatment with the chosen acid in an organic solvent.
• an organic solvent such as diethyl ether or in acetone
• the free base dissolved for example in an ether such as diethyl ether or in acetone
• the corresponding salt is obtained which is isolated according to conventional techniques.
• the compounds of formula (I) have a very good in vitro affinity for the central cannabinoid receptors, under the experimental conditions described by Devane et al., Molecular Pharmacology, 1988, 3.4, 605-613.
• the compounds of the present invention are potent and selective antagonists of the central cannabinoid receptors, having a Ki of between 1 and 100 nM. They are between 100 and 1000 times more active on central receptors than on peripheral receptors, are active orally and pass the blood-brain barrier.
• the compounds (I), as such or possibly in the form of salts pharmaceutically acceptable or solvates, can be used as active principles of medicaments intended to combat diseases of the central nervous system of mammals.
• the toxicity of the compounds (I) is compatible with their use as psychotropic drugs, in particular for the treatment of thymic disorders, anxiety disorders, mood disorders, vomiting, memory disorders, cognitive disorders, neuropathies , migraine, stress, psychosomatic illnesses, epilepsy, dyskinesias or
• the compounds (I) according to the invention can also be used as a medicament for the treatment of appetite disorders, in particular as an appetite suppressant, for the treatment of schizophrenia, delusional disorders, psychotic disorders in general, as well as disorders related to the use of psychotic substances.
• the compounds (I) according to the invention can be used as a medicament for anticancer chemotherapy.
• the compounds (I) according to the invention can be used as pharmacological tools in humans or in animals, for the detection and labeling of central cannabinoid receptors.
• the compounds of formula (I) in which Ri is a radioactive fluorine atom such as 1 ⁇ F can be used in studies of positron emission tomography in order to visualize in vivo the location and the density of the central cannabinoid receptors and to study the pharmacokinetics and biodistribution of central cannabinoid receptor agonists or antagonists.
• irreversible ligands comprising photoactivable groups or electrophilic groups such as for example an azido, an isothiocyanato, a haloacetamido, a Michael acceptor or an aldol ester.
• Irreversible ligands can be used to isolate, purify and characterize cannabinoid receptors, and identify their active site.
• the compounds according to the invention are 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.
• the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I) or one of its pharmaceutically acceptable salts or one of their solvates.
• the compounds of formula (I) above and their pharmaceutically acceptable salts 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
• the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
• the active ingredient 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, implants, forms topical administration, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and forms of rectal administration.
• the active ingredient is generally formulated in dosage units containing from 0.5 to 1000 mg, advantageously from 1 to 500 mg, preferably from 2 to 200 mg of said active ingredient per dosage unit for daily administrations.
• 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, starch. , lactose, magnesium stearate, talc or the like.
• the tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
• a preparation in capsules is obtained by mixing the active principle with a diluent such as a, glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
• a diluent such as a, glycol or a glycerol ester
• 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.
• 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 taste.
• Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
• aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or polyethylene glycol.
• a cosolvent can be used: an alcohol such as ethanol, a glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as
• Tween® 80 To prepare an oily solution for injection by the intramuscular route, the active principle can be dissolved by a triglyceride or a glycerol ester.
• gels for local administration, gels, ointments or creams can be used.
• patches in multilaminate form or reservoirs in which the active principle is in alcoholic solution can be used.
• the active principle can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives.
• the active principle can also be presented in the form of a complex with a cyclodextrin, for example ⁇ -, ⁇ - or ⁇ - cyclodextrin, 2-hydroxypropyl- ⁇ - cyclodextrin or methyl- ⁇ -cyclodextrin.
• 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.
• the melting or decomposition points of the products, F are measured in a capillary tube with a Tottoli device.
• Kryptofix® 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo [8.8.8] -hexacosane
• TFA trifluoroacetic acid
• s singlet se: widened singlet d: doublet d. from d. : doublet of doublet t: triplet q: quadruple! m: multiplet or massive.
• PREPARATION 1 Methyl ester of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4- bromomethylpyrazole-3-carboxylic acid.
• A) 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxylic acid r-butyl ester A solution of 5 g of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxylic acid in 35 ml of dioxane is introduced into a 250 ml autoclave, then cooled to - 10 * C. 2 ml of concentrated SO 2 SO 4 and 70 ml of 2-methylpropene cooled to -10 ° C. are then added, the autoclave is closed, the mixture is allowed to return to RT and then heated to 40 ° C.
• PREPARA ⁇ ON 8 and 0.68 g of sodium methylthiolate in 40 ml of THF Hydrolyzed by adding 50 ml of water, the THF is concentrated in vacuo, the remaining aqueous phase is extracted with DCM, the organic phase is washed with a saturated NaCl solution, dried over MgS ⁇ 4 and the solvent evaporated under vacuum. 2.51 g of the expected product are obtained.
• N- (piperidin-1 -yl) -5- (4-chloropheny 1) - 1 - (2,4-dichlorophenyl) -4- hydroxymethylpyrazole-3-carboxamide was placed 1.75 g of the compound of PREPARA ⁇ ON 2 in 30 ml of DCM are successively added 1.53 ml of triethylamine, 0.50 ml of 1-aminopiperidine and then, at 0 ° C, 2.33 g of BOP. The mixture is left stirring at 0 ° C. for 10 minutes and then at RT for 3.5 hours.
• reaction medium is poured into 100 ml of ice water, extracted with DCM, washed with water, with a saturated NaCl solution, then dried over MgS ⁇ 4- The residue obtained is chromatographed on fine silica eluting with AcOEt / toluene
• This compound can also be prepared by following the procedure described below.

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Citations (6)

• 1995
  • 1995-11-23 FR FR9513956A patent/FR2741621B1/fr not_active Expired - Fee Related
• 1996
  • 1996-11-21 WO PCT/FR1996/001847 patent/WO1997019063A1/fr not_active Ceased
  • 1996-11-21 CA CA002238430A patent/CA2238430C/en not_active Expired - Fee Related
  • 1996-11-21 DE DE69613860T patent/DE69613860T2/de not_active Expired - Lifetime
  • 1996-11-21 PT PT96939962T patent/PT876350E/pt unknown
  • 1996-11-21 JP JP9519454A patent/JP2000500479A/ja active Pending
  • 1996-11-21 DK DK96939962T patent/DK0876350T3/da active
  • 1996-11-21 US US09/068,869 patent/US6028084A/en not_active Expired - Lifetime
  • 1996-11-21 BR BR9611618A patent/BR9611618A/pt not_active Application Discontinuation
  • 1996-11-21 ES ES96939962T patent/ES2161382T3/es not_active Expired - Lifetime
  • 1996-11-21 AU AU76985/96A patent/AU7698596A/en not_active Abandoned
  • 1996-11-21 AT AT96939962T patent/ATE203015T1/de not_active IP Right Cessation
  • 1996-11-21 EP EP96939962A patent/EP0876350B1/fr not_active Expired - Lifetime
• 1998
  • 1998-05-15 MX MX9803891A patent/MX9803891A/es unknown
  • 1998-05-22 NO NO19982330A patent/NO310508B1/no unknown
• 2001
  • 2001-10-08 GR GR20010401691T patent/GR3036830T3/el not_active IP Right Cessation

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