HK1000599B - Substituted n-piperidino 3-pyrazolecarboxamide - Google Patents
Substituted n-piperidino 3-pyrazolecarboxamide Download PDFInfo
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- HK1000599B HK1000599B HK97102149.0A HK97102149A HK1000599B HK 1000599 B HK1000599 B HK 1000599B HK 97102149 A HK97102149 A HK 97102149A HK 1000599 B HK1000599 B HK 1000599B
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Description
The present invention relates to a new derivative of pyrazole and its salts, a process for its preparation and pharmaceutical formulations containing it.
Many pyrazole derivatives have been described in the literature; in particular, EP-A-268554 and DE-A-3910248 claim pyrazoles with herbicidal properties, EP-A-430186 and JP-A-3031840 claim compounds useful for photography and EP-A-418845 claims pyrazoles with anti-inflammatory, analgesic and antithrombotic activity.
EP-A-477 049 describes pyrazole derivatives capable of binding to the neurotensin receptor substituted at pyrazole position 3 by a group
wherein R is the hydrogen or a (C1-C4) alkyl; n is 0 to 3; X and X' are linked with the carbon atom to form a piperidinyl-4 group, possibly N-substituted by a benzyl group; and Z is a hydroxy, a (C1-C6) alcoxy or an -OPg group (Pg = protective group of carboxylic acids).
It has now been found that an N-pipéridino-3-pyrazole carboxamide has a very good affinity for the cannabinoid receptor and is useful in therapeutic areas where cannabis is known to intervene.
Δ9-THC is the main active constituent extracted from Cannabis sativa (Tuner, 1985; In Marijuana 84, ed.
The effects of cannabinoids are due to interaction with specific high affinity receptors at the central (Devane et al., Molecular Pharmacology, 1988, 34, 605-613) and peripheral (Nye et al., The Journal of Pharmacology and Experimental Therapeutics, 1985, 234, 784-791; Kaminski et al., 1992, Molecular Pharmacology, 42, 736-742; Munro et al., Nature, 1993, 365, 61-65).
Characterisation of this receptor has been made possible by the development of specific synthetic ligands such as the agonists WIN 55212-2 (J. Pharmacol. Exp. Ther., 1993, 264, 1352-1363) or CP 55,940 (J. Pharmacol. Exp. Ther., 1988, 247, 1046-1051).
As an aspect, the present invention relates to N-pipéridino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide formula: its pharmaceutically acceptable salts and their solvates.
The pharmaceutically acceptable salts of the compound of formula (I) include the salts of addition of acids such as hydrochloride, bromohydrate, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulfonate, methyl sulphate, oxalate, maleate, fumarate, 2-naphthalesulfonate, glyconate, gluconate, citrate, isethionate, paratoluenesulfonate.
In another respect, the present invention relates to a process for the preparation of the above compound (I), its salts and their solvates, characterized by the treatment of a functional derivative of 5- (i) 4-chlorophenyl)-1- (ii) 2-chlorophenyl) -4-methylpyrazole-3-carboxylic acid with the formula:
with 1-aminopiperidine in an organic solvent and in the presence of a base, and possibly transforming the resulting compound into one of its salts or solvates.
As a functional derivative of acid (II), acid chloride, anhydride, a mixed anhydride, an alkyl ester in C1-C4 in which the alkyl is straight or branched, an activated ester, e.g. p-nitrophenyl ester, or the appropriately activated free acid, e.g. with N,N-dicyclohexylcarbodiimide or with benzotriazol-N-oxotris dimethylamino) phosphonium (BOP) hexafluorophosphate, may be used.
Thus, in the process according to the invention, the chloride of 5-(4-chlorophenyl) -1-(2,4-dichlorophenyl) -4-methylpyrazole-3-carboxylic acid, obtained by reaction of thionyl chloride on acid of formula (II), with 1-aminopiperidine, can be reacted in a solvent such as dichloromethane, under an inert atmosphere, at a temperature between 0°C and room temperature, in the presence of a base such as triethylamine.
A variant of the method is to prepare the mixed anhydride of formula (II) acid by reaction of ethyl chloroformate with formula (II) acid in the presence of a base such as triethylamine and to react it with 1-aminopiperidine in a solvent such as dichloromethane under an inert atmosphere at room temperature in the presence of a base such as triethylamine.
The resulting compound of formula (I) is isolated as a free base or as a salt or solvate by conventional techniques.
The compound of formula (I) may be isolated as one of its salts, e.g. hydrochloride or oxalate, in which case the free base may be prepared by neutralizing the salt with a mineral or organic base, such as sodium or ammonium hydroxide, triethylamine or an alkaline carbonate or bicarbonate such as carbonate or sodium or potassium bicarbonate, and transformed into another salt such as methanesulfonate, fumarate or 2-naphthalesulfonate.
When the compound (I) is obtained as a free base, salification is carried out by treatment with the selected 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, the corresponding salt is obtained which is isolated according to the conventional techniques.
The acid of formula (II) used as starting compound for the process of the present invention may be prepared by conventional methods, some of which are described in detail below in the PREPARATIONS.
Preparations 1 and 2 are adjacent and are carried out according to the reaction pattern described below (Way 1).
The first step is performed according to J. Heterocyclic. Chem., 1989, 26, 1389.
Preparation 3 is carried out according to the following scheme (track 2).
The first step is based on E.S. SCHWEIZER, J. Org. Chem. 1987, 52, 1324-1332.
The other reagent used in the process of the present invention, 1-aminopiperidine, is a commercial product.
The compound of formula (I) has very good in vitro affinity for central cannabinoid receptors under the experimental conditions described by Devane et al., Molecular Pharmacology, 1988, 34, 605-613.
In particular, the compound of the present invention, on its own or as one of its pharmaceutically acceptable salts, is a potent and selective antagonist of the central cannabinoid receptors, with a Ki of approximately 2 nM. It is 500-1000 times more active at the central receptor than at the peripheral receptor, is orally active and crosses the blood-brain barrier.
The good penetration of the compound of the present invention into the central nervous system and its antagonistic nature are confirmed by the results in the model of antagonism of cannabinoid receptor agonist induced hypothermia. In particular, the compound of the present invention antagonizes WIN 55212-2 induced hypothermia in mice with a DE50 of 0.3 mg/kg i.p. and 0.4 mg/kg per bone; in this test (Pertwee R.G. in Marijuana 84, Ed. Harvey, D.Y., Oxford IRL Press, 1985, 263-277), the compound showed an action duration of 8 to 10 hours after oral administration of a dose of 3 mg/kg.
In addition, the compound (I) administered alone, by subcutaneous route, improved the rat's mnemonic abilities in the central memory test (A. Pério et al., Psychopharmacology, 1989, 97, 262-268).
Due to its remarkable properties, including its high affinity, selectivity for the central receptor and ability to penetrate the blood-brain barrier, compound (I), either as such or possibly in the form of pharmaceutically acceptable salts or solvates, can be used as an active ingredient in medicinal products to combat diseases of the central nervous system of mammals.
The toxicity of the compound (I) is compatible with its use as a psychotropic drug, including for the treatment of thyroid disorders, anxiety disorders, mood disorders, vomiting, mnemonic disorders, cognitive disorders, neuropathies, migraine, stress, psychosomatic diseases, epilepsy, dyskinesias or Parkinson's disease.
The compound (I) of the invention may also be used as a drug for the treatment of appetite disorders, including as an anorexigen, for the treatment of schizophrenia, delusional disorders, psychotic disorders in general, and psychotropic substance use disorders.
The use of the compound of the invention as a drug for the treatment of appetite disorders, anxiety disorders, mood disorders, schizophrenia, psychotic disorders, memory disorders, cognitive disorders and dyskinesias, and its use in anticancer chemotherapy, is a further aspect of the present invention.
The compound of the invention is generally administered in unit doses.
These dosage units are preferably formulated in pharmaceutical formulations in which the active substance is mixed with a pharmaceutical excipient.
Thus, in another aspect, the present invention relates to pharmaceutical compositions containing, as an active ingredient, a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates.
The compound of formula (I) above and its pharmaceutically acceptable salts may be used at daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg/kg. In humans the dose may be preferably between 0.5 and 4000 mg per day, in particular between 2.5 and 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
In the pharmaceutical formulations of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active substance may be administered as a unit dose in combination with conventional pharmaceutical media to animals and humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral dosage forms, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular dosage forms and reculatory dosage forms.
In the pharmaceutical formulations of the present invention, the active substance is generally formulated in dosage units containing 0.5 to 1000 mg, preferably 1 to 500 mg, preferably 2 to 200 mg of the active substance per dosage unit for daily administration.
When preparing a solid composition in tablet form, a wetting agent such as sodium lauryl sulphate may be added to the micronized or unmicronized active substance and mixed with a pharmaceutical vehicle such as silica, starch, lactose, magnesium stearate, talc or analogues.
A capsule preparation is obtained by mixing the active substance with a diluent such as glycol or glycerol ester and incorporating the resulting mixture into soft or hard capsules.
A preparation in the form of a syrup or elixir may contain the active substance together with a sweetener, preferably a non-caloric sweetener, methylparaben and propylparaben as antiseptic, as well as a flavouring agent and an appropriate colouring.
Water-dispersible powders or granules may contain the active substance mixed with dispersing agents, wetting agents, or suspension agents, such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.
For rectal administration, suppositories are used which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile solutions for injection containing dispersion agents and/ or pharmacologically compatible solubilisers, e. g. propylene glycol or polyethylene glycol, are used.
For example, to prepare an aqueous solution for intravenous injection, a co-solvent 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.
For transdermal administration, multi-laminated patches or tanks containing the active substance in an alcoholic solution may be used.
The active substance may also be formulated in the form of microcapsules or microspheres, possibly with one or more media or additives.
The active substance may also be presented as a complex with a cyclodextrin, e.g. α-, β- or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.
Implants are one of the long-release forms useful in the case of chronic treatments, which can be prepared as an oil suspension or as a microsphere suspension in an isotonic medium.
The following examples illustrate the invention without limiting it.
The melting or decomposition points of the products, F, were measured in capillary tubes with a Tottoli apparatus; in some cases differential calorimetric analysis (DSC) was used to measure the melting temperature.
In the preparation and in the examples, the following abbreviations are used:
The following is a list of the active substances in the active substance:
The following abbreviations are used for interpreting MRI spectra:
The following is a list of the most common types of data:
125 ml of 1M solution of lithium hexamethylsilazan salt is added to the THF at 500 ml of ether under nitrogen atmosphere. It is cooled to -78°C and a 21 g solution of 4-chloropropiophenone is added, drop by drop, to 100 ml of ether. After 45 minutes of stirring, 19.2 ml of ethyl oxalate is quickly added and stirred for 16 hours, raising the temperature to TA. The precipitate is left to form, washed with ether and vacuum-dried. 12.6 g of the expected product is obtained.
The precipitate is filtered, washed with EtOH and then ether and vacuum dried. 12.6 g of hydrazone is obtained, which is dissolved in 100 ml of AcOH. Reflux heated for 24 hours and then pour the reaction mixture into 500 ml of ice water. The AcOEt is extracted from the water, with a saturated solution of NaCl, dried on sulfate of magnesium and evaporated under vacuum. The desired product is obtained after crystallization in the ether, 124 m = 9,6 g = F, 124 ° C.
To a 9.6 g solution of ester obtained in the previous step in 70 ml of MeOH, add a 3.3 g solution of KOH in 70 ml of water and reflux heat for 3 hours. Pour the reaction mixture over 200 ml of cold water, acidify to pH = 1 by adding a 10% HCl solution, filter the precipitate formed, wash with water and vacuum dry.
Preparation 1 is improved using the operating conditions described in preparation 2 below.
In a reactor, 2008 g of lithium hexamethyldisilazane salt is added to 10.1 litres of methylcyclohexane in a nitrogen atmosphere. A solution of 1686 g of 4-chloropropiophenone is added slowly at 20 °C ± 5 °C to 4 litres of methylcyclohexane. After 4 hours 30 minutes of stirring, 1607 g of ethyl oxalate is added at 20 °C ± 5 °C in 35 minutes. The solid is filtered, washed with methylcyclohexane and dried empty (mass of product obtained: 1931 g).
1) At 20°C ± 5°C, add immediately 1493 g of 2,4-dichlorophenylhydrazine hydrochloride. Stir for 1 hour and then add 2.88 l of deionized water and maintain the stirring at 17°C ± 5°C. Filter the precipitate formed, wash with ethanol at 80% (vol/vol) and dry under vacuum (hydrazone mass obtained = 2280 g), F = 140°C.2) At nitrogen atmosphere, in a reactor, add 2267 g of hydrazone to 11.3 l of toluene.201.6 g of paratoluene sulfonic acid is added and heated at the toluene backflow for 3 hours. It is cooled to 20°C ± 5°C and the paratoluene sulfonic acid is removed by dionized water extraction. To the toluene solution, 120.75 g of benzyltriethylammonium chloride and 636 g of NaOH are added in solution in 1180 ml of dionized water. Under proper agitation, it is heated for 4 hours at 68°C ± 3°C, then the sodium hydroxide is neutralized and the reaction mixture is acidified with 1500 ml of HCl (dange = 1.19). It is cooled to 20°C ± 5°C, the filter precipitated, formed in the toluene lava, de-hydrated and vacuum-seasoned: 1585 g of toluene is obtained.F = 210°C.
Under a nitrogen atmosphere at 20°C ± 3°C, 13.47 g of chlorotrimethylsilane is slowly added to 12.55 g of triethylamine. The addition of reagents is continued by adding 16.86 g of 4-chloropropiophenone (endothermic mixture) and then a solution of 18.58 g of sodium iodide in 125 ml of acetonitrile while maintaining the temperature at 18°C ± 2°C. The acetonitrile is then heated for 3 hours at 40°C ± 5°C. The acetonitrile is removed at reduced pressure and added to the 150 ml of toluene solid residue. The solvent is distilled at reduced pressure at 50 ml of solvent to extract the residual acetone. The process is completed for 15 hours: with 100 ml of ice water, washed with 100 ml of ice water and removed from the acetonitrile at a pressure of 22.70 mL. The solvent is removed from the acetonitrile and the magnesium sulphate is removed at a pressure of 60 mL.
The following is a list of the most commonly used methods for the analysis of the data:
At 0°C ± 2°C, slowly add 17.0 g of anhydrous zinc chloride in 50 ml of dichloromethane. At the same temperature, add 14.5 g of the product obtained in the previous step in 1 hour 30 minutes. Bring the water to a temperature of TA and then heat it to 45°C for 4 hours. Wash the organic soil in a solution of hydrogen sulphate, sodium sulphate and sodium sulphate on the soil: 17,6 g of sulphate (magnesium sulphate) at reduced pressure.
The following is a list of the most commonly used methods for the analysis of the measurement of the noise level:
To 17.6 g of the compound obtained in the previous step, 13.3 g of 2,4-dichlorophenylhydrazine hydrochloride is added and left to simmer for 18 hours at 20 °C ± 3 °C. Without isolating the hydrazone, 0.56 g of paratoluene sulfonic acid is added and the ternary azeotrope (water, ethanol, toluene) is distilled. The toluene is held at reflux for one hour. The reaction mixture is cooled to 20 °C ± 3 °C, the insoluble is filtered and the toluene solution is washed with 2 times 100 ml of water. The solvents are removed at reduced pressure (the crude oil is used as in the next step).
After 1 hour at 25°C ± 3°C, the solvents are removed at reduced pressure. The residue is taken up again with 200 ml of water and 40 ml of toluene. The aqueous phase is heated to 60°C ± 3°C, decanted and extracted at this temperature with 3 times 40 ml of toluene. Hydrochloric acid is added to the aqueous phase until pH = 1.5. The white crystals are formed, washed with water and iso ether and vacuum dried (product mass: 9.9 g), F = 210°C.
The substance is classified in Annex I to Regulation (EC) No 396/2005 as a substance of very high concern.
To a suspension of 8.8 g of the acid obtained at step C of preparation 1 in 90 ml of toluene, add 5 ml of thionyl chloride and reflux for 3 hours. Evaporate the reaction mixture under vacuum to dry, take up the residue in 90 ml of toluene and re-evaporate under vacuum.
A solution of 2.8 ml of 1-aminopiperidine, 3.6 ml of triethylamine in 100 ml of DCM is cooled to 0°C and a solution of 8.0 g of acid chloride obtained in the previous step in 80 ml of DCM is added, drop by drop. The product is agitated for 3 hours by raising the temperature to TA and then poured over 200 ml of ice water. It is extracted from the DCM, washed with water, by a saturated solution of NaCl, dried on magnesium sulphate and evaporated under vacuum.
The compound in example 1 can also be prepared using more industrially accessible operating conditions.
After heating to 83°C ± 3°C, a solution of 554.5 g thionyl chloride is added to a 1568.6 g suspension of the acid obtained at step B of preparation 2 in 14.1 litres of methylcyclohexane in a nitrogen atmosphere in 1.57 litres of methylcyclohexane. The reaction mixture is agitated for 3 hours at 83°C ± 3°C and then heated for 2 hours until the methylcyclohexane has receded while the excess thionyl chloride is removed by distillation.The organic phase is washed successively at 20°C ± 5°C by deionized water and 4% acetic acid in the water, the organic phase is washed at 70°C ± 3°C by a 1.5% NaOH solution, then by deionized water and the THF and water are drawn by azeotropic distillation at atmospheric pressure. The product is allowed to cool to 20°C ± 5°C. The expected product crystallizes. The precipitate is filtered, washed with methylhexyl and dried empty (product mass: 1627 g).
DSC: endothermic peak centred at 155.5°C.
N-Pipperidino-5-(4-Chlorophenyl)-1-(2,4-Dichlorophenyl)-4-Methylpyrazole-3-Carboxamide (solvate with ethanol) is used as a solvent.
10 g of the compound obtained in sample 1 are suspended in 60 ml of absolute ethanol and heated at low temperature until completely dissolved. They are cooled to 20 °C ± 3 °C and stirred for 2 hours. The white crystals formed are filtered, washed with ethanol and vacuum dried (product mass: 9.60 g).
DSC: endothermic peak centred at 102.7°C
- What?
| % calculés | C = 56,5 | H = 5,29 | N = 10,98 |
| % trouvés | C = 56,43 | H = 5,41 | N = 11,05 |
The substance is a hydrochloride of N-pipéridino-5- ((4-chlorophenyl)-1- ((2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide.
To a 5.9 g solution of the compound obtained in EXAMPLE 1 in 50 ml of ether, a saturated solution of gaseous HCl is added, drop by drop, in the ether until pH = 1.
N-Piperidine-5- ((4-chlorophenyl)-1- ((2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide hydrochloride (solvate with ethanol) is used as a solvent.
Suspend 40 g of the compound obtained in example 3 in 400 ml of absolute ethanol, boil until completely dissolved and stir for 20 hours, gradually cooling to 20 °C ± 3 °C. Filter the white crystals formed, wash with ethanol, vacuum dry (product mass: 29.6 g).
DSC: widely spread endothermic mass (175 to 230 °C). Thermogravimetry: loss of mass (approximately 8.2%) from 100 °C onwards.
- What?
| % calculés | C = 53,04 | H = 5,16 | N = 10,31 |
| % trouvés | C = 52,68 | H = 5,23 | N = 10,34 |
The substance is classified in Annex I to Regulation (EC) No 396/2005 as a substance of very high concern.
To a solution of 18.55 g of the compound obtained in Example 1 in 185 ml of acetone, add 3.84 g of methanesulfonic acid at 20 °C ± 3 °C and stir for 20 hours at the same temperature.
DSC: melting, recrystallization at 175°C and then melting at 191.5°C
Thermogravimetry: loss of mass (approximately 5.2%) from 90°C onwards.
- What?
| % calculés | C = 49,90 | H = 4,75 | N = 9,5 |
| % trouvés | C = 49,70 | H = 4,76 | N = 9,44 |
The substance is a mixture of N-piperidine-5- ((4-chlorophenyl)-1- ((2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide and N-piperidine-5- ((4-chlorophenyl)-1-)) -4-methylpyrazole-3-carboxamide.
To a solution of 0.30 g of the compound obtained in EXAMPLE 1 in 3 ml of acetone, add a solution of 0.038 g of fumaric acid in 6 ml of acetone, drip by drop. Filter the white crystals formed by cooling at 0 °C, wash with acetone and vacuum dry.
The substance is to be classified in Annex I to Regulation (EC) No 396/2005 as a substance of very high concern.
To a solution of 0.30 g of the compound obtained in EXAMPLE 1 in 3 ml of acetone, add 0.018 ml of concentrated sulphuric acid. Filter the white crystals formed, wash with acetone and ether and vacuum dry.
The substance is classified in Annex I to Regulation (EC) No 396/2005 as a food additive.
To a solution of 18.55 g of the compound obtained in example 1 in 185 ml of acetone, 7.61 g of paratoluene sulphonic acid is added at 20 °C ± 3 °C and stirred for 20 hours at the same temperature.
DSC: endothermic peak centered at 236.8°C
- What?
| % calculés | C = 54,76 | H = 4,60 | N = 8,72 |
| % trouvés | C = 54,11 | H = 4,71 | N = 8,69 |
The substance is a dihydrogen phosphate of N-pipéridino-5- ((4-chlorophenyl)-1- ((2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide.
To a solution of 18.55 g of the compound obtained in example 1 in 185 ml of methylethyl ketone, 4.61 g of 85% phosphoric acid is added at 20 °C ± 3 °C. Water is removed by atmospheric distillation of the azeotrope methylethyl ketone-water. Gradually cooled to 20 °C ± 3 °C while agitation is maintained for 20 hours. The white crystals formed are filtered, washed with methylethyl ketone and dried under vacuum (product mass obtained: 21.0 g).
DSC: endothermic peak centered at 185.5°C
- What?
| % calculés | C = 47,04 | H = 4,31 | N = 9,97 |
| % trouvés | C = 46,96 | H = 4,62 | N = 9,98 |
Claims (11)
- N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide of the formula : its pharmaceutically acceptable acid addition salts and the solvates thereof.
- A compound according to claim 1, which is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide hydrochloride or its solvate with ethanol.
- A compound according to claim 1, which is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide methanesulfonate or its hemisolvate with acetone.
- A compound according to claim 1, which is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide hemifumarate.
- A compound according to claim 1, which is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide p-toluenesulfonate.
- A compound according to claim 1, which is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide hydrogensulfate.
- A compound according to claim 1, which is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide dihydrogenphosphate.
- A process for the preparation of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, its salts and their solvates, characterized in that a functional derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid of the formula: is treated with 1-aminopiperidine in an organic solvent in the presence of a base, and, the resulting compound is optionally converted into one of its salts or a solvate thereof.
- A pharmaceutical composition, which contains a compound according to any one of claims 1 to 7 as the active principle.
- A pharmaceutical composition according to claim 9, which is in dosage unit form, wherein the active principle is mixed with at least one pharmaceutical excipient.
- A pharmaceutical composition according to claim 10, which contains from 0.5 to 1,000 mg of active principle.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9314444 | 1993-12-02 | ||
| FR9314444A FR2713224B1 (en) | 1993-12-02 | 1993-12-02 | Substituted N-piperidino-3-pyrazolecarboxamide. |
| FR9408974A FR2713225B1 (en) | 1993-12-02 | 1994-07-20 | Substituted N-piperidino-3-pyrazolecarboxamide. |
| FR9408974 | 1994-07-20 |
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| Publication Number | Publication Date |
|---|---|
| HK1000599B true HK1000599B (en) | 1998-04-09 |
| HK1000599A1 HK1000599A1 (en) | 1998-04-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK97102149A HK1000599A1 (en) | 1993-12-02 | 1997-11-10 | Substituted n-piperidino 3-pyrazolecarboxamide |
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|---|---|
| EP (1) | EP0656354B1 (en) |
| JP (2) | JP3137222B2 (en) |
| KR (1) | KR100361051B1 (en) |
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| AT (1) | ATE154012T1 (en) |
| AU (1) | AU685518B2 (en) |
| CA (1) | CA2136893C (en) |
| CZ (1) | CZ290496B6 (en) |
| DE (2) | DE122006000034I1 (en) |
| DK (1) | DK0656354T3 (en) |
| ES (1) | ES2105575T3 (en) |
| FI (1) | FI113647B (en) |
| FR (1) | FR2713225B1 (en) |
| GR (1) | GR3024470T3 (en) |
| HK (1) | HK1000599A1 (en) |
| HU (1) | HU218277B (en) |
| IL (1) | IL111719A (en) |
| LU (1) | LU91268I2 (en) |
| NL (1) | NL300237I2 (en) |
| NO (2) | NO304596B1 (en) |
| NZ (1) | NZ270025A (en) |
| PL (1) | PL180289B1 (en) |
| RU (1) | RU2141479C1 (en) |
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Families Citing this family (156)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2714057B1 (en) * | 1993-12-17 | 1996-03-08 | Sanofi Elf | New derivatives of 3-pyrazolecarboxamide, process for their preparation and pharmaceutical compositions containing them. |
| FR2741621B1 (en) * | 1995-11-23 | 1998-02-13 | Sanofi Sa | NOVEL PYRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| FR2742148B1 (en) * | 1995-12-08 | 1999-10-22 | Sanofi Sa | NOVEL PYRAZOLE-3-CARBOXAMIDE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
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| US8809325B2 (en) | 2011-03-08 | 2014-08-19 | Sanofi | Benzyl-oxathiazine derivatives substituted with adamantane and noradamantane, medicaments containing said compounds and use thereof |
| EP2683700B1 (en) | 2011-03-08 | 2015-02-18 | Sanofi | Tetra-substituted oxathiazine derivatives, method for their preparation, their usage as medicament and medicament containing same and its use |
| EP2683705B1 (en) | 2011-03-08 | 2015-04-22 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| CN102206182B (en) * | 2011-04-11 | 2013-03-13 | 中国药科大学 | Method for synthesizing Rimonabant hydrochloride |
| AR087701A1 (en) | 2011-08-31 | 2014-04-09 | Japan Tobacco Inc | PIRAZOL DERIVATIVES WITH SGLT1 INHIBITING ACTIVITY |
| EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| CN103459383B (en) * | 2011-09-30 | 2016-06-22 | 财团法人国家卫生研究院 | pyrazole compound |
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| BR112018011784A2 (en) * | 2015-12-09 | 2018-12-04 | Res Triangle Inst | improved apelin receptor (apj) agonists and their uses |
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| US12054480B2 (en) | 2020-07-31 | 2024-08-06 | Makscientific, Llc | Compounds for treating cannabinoid toxicity and acute cannabinoid overdose |
| ES2947188T3 (en) | 2020-11-18 | 2023-08-02 | Fundacion Del Hospital Nac De Paraplejicos Para La Investigacion Y La Integracion Fuhnpaiin | Use of CB1 receptor antagonists and/or inverse agonists for the preparation of medicaments to treat postviral fatigue syndrome |
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| US3449350A (en) * | 1968-06-24 | 1969-06-10 | Ciba Geigy Corp | Certain pyrazole-3-carboxylic acid hydrazide derivatives |
| DE3302021A1 (en) * | 1983-01-22 | 1984-07-26 | Basf Ag, 6700 Ludwigshafen | 6-ARYL-4,5-DIHYDRO-3 (2H) -PYRIDAZINONE, THEIR PRODUCTION AND USE |
| FR2642757B1 (en) * | 1989-02-07 | 1991-05-24 | Sanofi Sa | NOVEL PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| PH27357A (en) * | 1989-09-22 | 1993-06-21 | Fujisawa Pharmaceutical Co | Pyrazole derivatives and pharmaceutical compositions comprising the same |
| CA2036307C (en) * | 1990-03-08 | 2002-07-09 | Susan Jean Ward | 3-arylcarbonyl-1-aminoalkyl-1h-indole-containing antiglaucoma compositions and method |
| FR2665898B1 (en) * | 1990-08-20 | 1994-03-11 | Sanofi | DERIVATIVES OF AMIDO-3 PYRAZOLE, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2667317B1 (en) * | 1990-10-02 | 1992-12-04 | Synthelabo | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| TW201737B (en) * | 1990-10-31 | 1993-03-11 | Mitsubishi Chemicals Co Ltd | |
| FR2692575B1 (en) * | 1992-06-23 | 1995-06-30 | Sanofi Elf | NOVEL PYRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
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1994
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- 1994-11-21 IL IL11171994A patent/IL111719A/en not_active IP Right Cessation
- 1994-11-23 AU AU78999/94A patent/AU685518B2/en not_active Ceased
- 1994-11-24 UA UA94119064A patent/UA45303C2/en unknown
- 1994-11-24 TW TW083110944A patent/TW282465B/zh not_active IP Right Cessation
- 1994-11-29 DE DE1994603614 patent/DE122006000034I1/en active Pending
- 1994-11-29 CA CA002136893A patent/CA2136893C/en not_active Expired - Fee Related
- 1994-11-29 EP EP94402717A patent/EP0656354B1/en not_active Expired - Lifetime
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- 1994-11-29 SI SI9430067T patent/SI0656354T1/en not_active IP Right Cessation
- 1994-11-29 AT AT94402717T patent/ATE154012T1/en active
- 1994-11-29 SG SG1996006363A patent/SG68570A1/en unknown
- 1994-11-29 ES ES94402717T patent/ES2105575T3/en not_active Expired - Lifetime
- 1994-11-29 DK DK94402717.6T patent/DK0656354T3/en active
- 1994-11-30 NZ NZ270025A patent/NZ270025A/en not_active IP Right Cessation
- 1994-12-01 CN CN94119030A patent/CN1047775C/en not_active Expired - Fee Related
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- 1994-12-02 CZ CZ19943016A patent/CZ290496B6/en not_active IP Right Cessation
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1997
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2000
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2006
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