WO2007121687A1 - Dérivés du 4-méthyl-1h-diaryl pyrazole et leur utilisation comme médicaments - Google Patents

Dérivés du 4-méthyl-1h-diaryl pyrazole et leur utilisation comme médicaments Download PDF

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WO2007121687A1
WO2007121687A1 PCT/CN2007/001404 CN2007001404W WO2007121687A1 WO 2007121687 A1 WO2007121687 A1 WO 2007121687A1 CN 2007001404 W CN2007001404 W CN 2007001404W WO 2007121687 A1 WO2007121687 A1 WO 2007121687A1
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dichlorophenyl
chlorophenyl
pyrazole
methyl
pharmaceutical composition
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PCT/CN2007/001404
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English (en)
Chinese (zh)
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Song Li
Mengjia Liu
Zhibing Zheng
Lili Wang
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Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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Publication of WO2007121687A1 publication Critical patent/WO2007121687A1/fr

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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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a 4-mercapto-1H-diarylpyrazole derivative of the formula I, and a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition containing the same, and a compound of the formula I as a cannabinoid type I in the brain (CB1)
  • CB1 cannabinoid type I in the brain
  • Cannabis Shield is one of the earliest addictive substances recognized by humans. It has a medicinal history of about a thousand years. Its main active ingredient is ⁇ 9 -tetrahydrocannabinol.
  • Cannabinoids have a variety of pharmacological effects such as analgesic, sedative, anticonvulsant, anti-vomiting, anti-glaucoma and anti-hypertension, but are prone to tolerance and addiction, limiting their use (RK Razden, Pharmacol. Rew. , 1986, 38, 75-149).
  • the cannab inoid (CB) receptor is a receptor that responds to cannabinoids such as ⁇ 9 -THC.
  • CB1 R. Mechoulam, et al., Biochem. Pharmacol., 1995, 50, 83-90
  • CB2 S. Munro, et a l. , Na ture, 1993, 365, 61-65. They all belong to the rhodopsin-like family A of the G protein-coupled receptor.
  • Pertussis toxin is sensitive, indicating that the two receptors are mainly Gi/o type G protein coupled receptors (PHReggio, Curr. Pharm. Des., 2003, 9, 1607-1633).
  • the CB1 receptor is mainly found in the central nervous system, also known as the central cannabinoid receptor; the CB2 receptor is mainly found in peripheral neurons, also known as the peripheral cannabinoid receptor; one of the functions is to prevent the release of neurotransmitters.
  • Their main difference is their amino acid sequence, signal transduction mechanism, organ distribution and sensitivity to certain agonists and inhibitors.
  • the CB1 receptor is a receptor confirmed by ⁇ -labeled CP55940 by a combination of autoradiography and radioligand. It contains 473 amino acids and consists of 17 transmembrane regions that are highly conserved and important in evolution.
  • the human and rat CB1 receptor amino acid sequence is 97.3% homologous and has a molecular weight of approximately 52,800.
  • the CB1 receptor is mainly located in the brain, spinal cord and peripheral nervous system.
  • the CB1 receptors in the brain are mainly distributed in the basal ganglia (substantia nigra, globus pallidus, lateral striatum), hippocampal CA pyramidal cell layer, cerebellum and cerebral cortex. This distribution of CB1 receptors may be related to the regulation of memory, cognition, and motor control by cannabinoids.
  • cannabinoid receptor agonists are not specific and can bind to both cannabinoid receptors at the same time. Unlike agonists, several of the currently synthesized cannabinoid receptor inhibitors exhibit very high receptor specificity. Among them, the cannabinoid receptor type I inhibitor acts directly on the central nervous system and exhibits a variety of activities. Such as anti-obesity, smoking cessation, improvement of memory and cognitive impairment, treatment of mental illness and cancer chemotherapy. Diarylpyrazoles are one of the most attractive CB1 receptor inhibitors. They bind to the CB1 receptor efficiently and selectively, rapidly block or reverse the regulation of CB1 receptors, and reduce signal transduction pathways. Activity (M. Rinaldi-Carmona, et al., FEBS Let t, 1994, 350, 240 244). Therefore, it is necessary to find a novel diarylpyrazole compound having a CB1 inhibitory activity. Summary of the invention
  • the purpose of the present invention is to find and develop a novel diarylpyrazole small molecule inhibitor acting on the CB1 receptor.
  • a compound having the following formula (I) has an action of inhibiting the CB1 receptor, and thus can be used for treating diseases or symptoms associated with the CB1 receptor, such as for treating obesity, quitting smoking, improving memory, and Various diseases or symptoms such as cognitive disorders, treatment of mental illness and cancer chemotherapy.
  • a first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof,
  • R is H, dC alkyl, especially a linear or branched alkyl group of dC 8 , a C 3 - 7 cycloalkyl group, or a C 6 - C 15 substituted or unsubstituted aryl group, a representative aromatic Such as phenyl, naphthyl, anthracenyl, fluorenyl, or N-containing heterocyclic ring such as quinoline, pyrrole, piperidine, piperazine, morpholine, imidazole, pyrazole, morpholine or other heterocyclic ring such as thiazole, furan, etc.
  • a representative aromatic such as phenyl, naphthyl, anthracenyl, fluorenyl, or N-containing heterocyclic ring such as quinoline, pyrrole, piperidine, piperazine, morpholine, imidazole, pyrazole, morpholine or other heterocyclic ring such as thi
  • the substituent is selected from the group consisting of: 3 ⁇ 4, cyano, sulfhydryl, formyl, hydroxy, sulfonate, nitro, nitroso, -( 8- substituted or unsubstituted alkylamino, d- 6 alkylthio, d - alkoxy, d - C 15 alkyl, in particular d- C 8 linear, branched or cyclic alkyl group.
  • R is any mono- or di-substituted benzene, hydrazine, pyridyl a pyridine, the substituent is selected from the group consisting of iS, amino, decanoyl, d- 6 alkoxy, and R may also be piperidine, morpholine, furan, imidazole, and the substituent is selected from the group consisting of 3 ⁇ 4, d- 6 alkyl, amino. R may also be a d- 8 straight chain, branched or cyclic alkyl group.
  • d-Cu alkyl or "dC 8 alkyl” as used in the present invention means a straight-chain, branched or cyclic alkyl group having 1 to 15 or 1 to 8 carbon atoms, including but not limited to Sulfhydryl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, decyl, decyl , undecyl, dodecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • 3 ⁇ 4" as used in the present invention means an atomic group derived from the elements fluorine, chlorine, bromine or iodine.
  • cycloalkyl as used in the present invention means a cycloalkyl group having 3 to 7 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • the compound of the formula (I) or a pharmaceutically acceptable salt or hydrate thereof to which the present invention relates is preferably the following compound:
  • the present invention relates to a suitable pharmaceutically acceptable salt or hydrate of a compound of the formula I or a stereoisomer thereof, wherein the pharmaceutically acceptable salt includes, but is not limited to, a compound of the formula I and a mineral acid.
  • Salts such as hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid and nitric acid, and various organic acids such as maleic acid, malic acid, fumaric acid, succinic acid, tartaric acid, citric acid, acetic acid, lactic acid, methanesulfonic acid a salt formed by an acid, p-toluenesulfonic acid, palmitic acid or the like.
  • Some of the compounds in the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed.
  • the present invention includes those stoichiometric solvates, including hydrates, as well as A compound comprising a variable amount of water formed when prepared by a low pressure sublimation drying process.
  • the stereoisomers of the compounds of the formula I according to the invention mean that some of the compounds of the invention may exist in the form of optical isomers or tautomers, the invention including all their forms, in particular pure isomers form.
  • the different isomeric forms may be separated or separated from other forms of isomers by various conventional means, or an isomer may be obtained by various conventional synthetic methods or stereospecific or asymmetric synthesis methods.
  • the compounds of formula I are for pharmaceutical purposes, it is understood that they are preferably provided in pure form, for example at least 60% pure, more suitably 75%, more preferably 85%, and most preferably at least 98% pure ( % means weight percentage).
  • the preparation of the non-purified compound can be used in a more pure form of the pharmaceutical composition.
  • These less pure products contain at least 1%, more preferably 5%, more preferably at least 10% of a compound of formula I or a pharmaceutically acceptable derivative thereof.
  • Another aspect of the invention relates to a process for the preparation of a compound of formula I.
  • the compound of the formula I can be produced by a synthetic method from a known or commercially available compound. If the starting materials are not commercially available, their preparation methods are provided herein, or they can be prepared by methods reported in the literature.
  • the preparation method of the compound of the formula (I) includes:
  • the synthesis method of the formula ( ⁇ ) is related to literature and synthesis of the CB1 selective cannabinoid antagonist AM281: A Potential Human SPECT ligand, R. Lan, Q. Lu and P. Fan, (AAPS Pharmsci 1999, 1 (3), Article 4) and The synthesis and pharmacological evaluation of the cannabinoid antago- nist SR141716A, AK Dutta, et al., (Med Chem Res 1994, 5, 54-62) have been discussed in detail.
  • the compound of the formula (I) can be synthesized individually by a conventional method, or can be a combination of a chemical chemical mixing method or a parallel synthesis method (each containing at least two, or 5-1000, preferably 10-) 100 compounds) are synthesized in units, that is, they can be synthesized in a liquid phase or a solid phase synthesis method.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the formula I and at least one pharmaceutically acceptable carrier or excipient.
  • the compound of the formula I or a pharmaceutically acceptable salt thereof may be used alone or in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier or excipient, and when used in the form of a pharmaceutical composition, an effective dose will usually be employed.
  • the compound of the formula I of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers or diluents are combined in a suitable administration form or dosage form, the procedure comprising the group comprising the appropriate means Mix, granulate, compress or dissolve.
  • composition of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, peritoneal Internal, intrathecal, intraventricular, intrasternal or intracranial injection or input, or by means of an explanted reservoir, preferably oral, intramuscular, intraperitoneal or intravenous.
  • Pharmaceutically acceptable carriers contained in the pharmaceutical compositions of the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerin, sorbic acid , potassium sorbate, a mixture of partially glycerides of saturated plant fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, trisilicate Magnesium, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin, and the like.
  • the amount of the carrier in the pharmaceutical composition may range from 1% by weight to 98% by weight, usually about 80% by weight.
  • topical anesthetics, preservatives, buffers, etc. are directly
  • Oral preparations such as oral tablets and capsules may contain excipients such as binders such as syrup, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, Sorbitol, glycine, a lubricant such as magnesium stearate, talc, polyethylene glycol, silica, a disintegrant such as potato starch, or an acceptable humectant such as sodium lauryl sulfate.
  • the tablets may be coated by methods known in the pharmacy.
  • compositions of the present invention in the form of oral liquids can be prepared as suspensions, solutions, emulsions, syrups or elixirs of water and oil, either as a dry product, before reconstitution with water or other suitable medium.
  • Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose oxime ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Oils, emulsifiers, such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous carrier (may contain edible Oil), such as almond oil, oils such as glycerin, ethylene glycol, or ethanol; preservatives such as methyl or propyl p-hydroxybenzoate, sorbic acid. Flavoring or coloring agents can be added as needed.
  • the suppository can comprise a conventional suppository base such as cocoa butter or other glycerides.
  • the liquid dosage form is usually made up of the compound and at least one sterile or sterile carrier.
  • the carrier is preferred water.
  • the compound can be dissolved in both the carrier and the suspension. The compound is dissolved in water prior to preparation into the solution for injection, filtered and sterilized and placed in a vial or ampoule.
  • the compound of the present invention can be formulated into a suitable ointment, lotion, or cream, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • the carrier in which the ointment preparation can be used includes, but is not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polyoxypropylene, emulsifying wax and water; and detergents and creams can be used, including but not limited to : mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the composition may contain from 0.1% by weight, or more suitably from 10% to 60% by weight of active ingredient.
  • each unit preferably contains from 50 to 500 mg of active ingredient.
  • the appropriate therapeutic dose for an adult may be 100-3000 mg per day, such as 1500 mg per day, depending on the route of administration and the frequency of administration. This dose corresponds to 1. 5 - 50 mg / kg / day, and the appropriate dose is 5-20 mg / kg / day.
  • the optimal dosage and interval of administration of the compound of formula I is determined by the severity of the disease or condition, the nature of the compound, and the conditions such as the form, route and location of administration, and the particular mammal being treated. This optimal dosage can be determined by the clinician.
  • the invention further relates to a compound of formula I or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a hydrate thereof for the preparation of a medicament for the treatment of a disease or condition associated with the CB1 receptor Use in.
  • Example 1 1 - ( 2, 4 -Dichlorophenyl) - 5 - ( 4 -chlorophenyl) -N - ( 2 - 9H-indenyl)-4-indolyl - 1H-pyrazole - 3 - A Preparation of amides.
  • Step 1 5 Preparation of ( 4 -chlorophenyl) - 1 - ( 2, 4 -dichlorophenyl) - 4 -methylpyrazole - 3 -nonanoyl chloride.
  • Step 2 1 - (2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(2-9H-indenyl)-4-indolyl-1H-pyrazole-3-carbamide Preparation.
  • the decanoyl chloride obtained in the above step was dissolved in 4 ml of dichloromethane, and a solution of 0.23 g of 2-aminoguanidine and 0.234 ml of triethylamine in 5 ml of dichloromethane was slowly added dropwise thereto, and the mixture was reacted at room temperature for 9 hours.
  • decanoyl chloride was dissolved in 4 ml of dichloromethane, and a solution of 0.141 g of p-bromoaniline and 0.234 ml of triethylamine in 5 ml of dichloromethane was slowly added dropwise thereto, and the mixture was reacted at room temperature for 6.5 hours.
  • Separation by petroleum ether: ethyl acetate 1: 3 column chromatography gave 0.311 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-N- (3-Pyridyl)-1H-pyrazole-3-carbamide mp: 162.8 - 164.1.
  • Example 1 For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carbonyl chloride, see Example 1.
  • the obtained formyl chloride was dissolved in 4 ml of dichloromethane, and a solution of 0.22 g of aminodecylcyclopentane and 0.234 ml of triethylamine in 5 ml of dichloromethane was slowly added dropwise thereto, and the mixture was reacted at room temperature for 4.5 hours.
  • decanoyl chloride was dissolved in 4 ml of dichlorosilane, and 0, 0.22 g was slowly added dropwise.
  • the resulting decanoyl chloride was dissolved in 4 ml of dichloromethane, 0. Under C, 0.268 g of (4-methoxyphenyl)-mercaptoamine and 0.234 ml of triethylamine were slowly added dropwise in a solution of 5 ml of dichloromethane at room temperature for 6 hours.
  • the obtained formyl chloride was dissolved in 1 ⁇ 2 of dichloromethane, and 0.21 g of 4-aminopyridylpyridine and 0.234 ml of triethylamine were slowly added dropwise to a solution of 5 ml of dichloromethane in a solution of 5 ml of dichloromethane at room temperature for 7 hours.
  • decanoyl chloride was dissolved in 4 ml of dichloromethane, and 0.244 g of N-(3-aminopropyl)-imidazole and 0.231 ⁇ 21 triethylamine were slowly added dropwise in a solution of 5 ml of dichloromethane at room temperature. 7 hours.
  • Wistar rats 220 ⁇ 260g, male or female, after the decapitation, quickly cerebellum was isolated, weighed and added 10 times the volume of Tris-HCl Buffer (50mM Tris HC1, 5mM MgC126. H20, ImM EDTA, 0.5% (W/V) BSA, pH 7.4), the slurry was milled at 15000 rpm/min with a homogenizer for 30 seconds each time for 5 times. The serum was centrifuged at 400 xg for 10 min, the supernatant was centrifuged and centrifuged at 39000 xg for 10 min.
  • Tris-HCl Buffer 50mM Tris HC1, 5mM MgC126. H20, ImM EDTA, 0.5% (W/V) BSA, pH 7.4
  • the precipitate was collected, resuspended in 10 volumes of Tris-HCl Buffer pH 7.4, and centrifuged at 39000 xg for 10 min.
  • the buffer was washed, centrifuged at 39000 xg for 10 min, and finally the resulting pellet was suspended in Tris-HCl Buffer, and after dispensing (the whole process was carried out at 4 ° C) at - 8 (TC was stored for use.
  • the protein content was determined by Folin method. .
  • reagent B Feolin-phenol reagent, the final concentration is 1N
  • Tris-HCl Buffer 50 mM Tris-HCl Buffer, pH 7.4, 1 mM EDTA, 5 mM MgCL2
  • 2 ml each time, 10 times, drain the filter paper, remove the filter paper, and place it in a scintillation vial.
  • the drug competes with the CB1 receptor in combination with 3H-SR141716A.
  • the test tube is placed in a reaction condition of 30X.
  • the amount of 100 receptor protein is added to all the tubes in turn, and 20 ⁇ ⁇ -concentration is added to the test tube.
  • non-specific binding tube was added with 50 ⁇ l non-standard ligand (ACEA), the final concentration of non-standard ligand was lmM, pre-reacted for 30 minutes, all tubes were sequentially added with 30 ⁇ l 3H-SR141716A (16 ⁇ ), labeled ligand The final concentration was 2.4 ⁇ , and all the reaction tubes were filled with Buffer to a volume of 200 ⁇ l, reacted under a reaction condition of 30"C for 1 hour, and then spotted on a Type 49 glass fiber filter.
  • AZA non-standard ligand
  • Embodiment 1 100. 0 95. 8 84. 2
  • Example 13 100. 0 64. 0 31. 2 According to the preliminary screening results, the compound having a higher affinity for the CB1 receptor was further measured for IC50 (Log M). SR141716 is 1. 30x10- 1 ⁇ , the compound of Example 1 is 2. 53x10- 10. Example 16 Pharmacokinetic properties of the compounds of the invention
  • Embodiment 9 0. 01 0. 82 87. 57

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Abstract

L'invention porte sur des dérivés de 4-méthyl-1H-diaryl pyrazole de formule (I), sur leur procédé de préparation, sur des préparations pharmaceutiques les contenant, et servant d'inhibiteurs des récepteurs cannabinoïdes de type 1 (CB1) dans le cerveau utiles pour traiter l'obésité, améliorer la mémoire et arrêter de fumer.
PCT/CN2007/001404 2006-04-26 2007-04-26 Dérivés du 4-méthyl-1h-diaryl pyrazole et leur utilisation comme médicaments WO2007121687A1 (fr)

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WO2009027393A3 (fr) * 2007-08-27 2009-09-24 Basf Se Composés de pyrazole permettant de lutter contre les nuisibles invertébrés
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013026264A1 (fr) * 2011-08-23 2013-02-28 Fan Rulin Composé inhibiteur d'accepteur cb1 ayant un cycle aromatique contenant de l'azote portant un hydroxyle, et son utilisation
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US9029639B2 (en) 2009-07-06 2015-05-12 Basf Se Pyridazine compounds for controlling invertebrate pests
US9125414B2 (en) 2009-07-24 2015-09-08 Basf Se Pyridine derivatives compounds for controlling invertebrate pests
US9533972B2 (en) 2010-11-18 2017-01-03 Bayer Intellectual Property Gmbh Substituted sodium-1H-pyrazole-5-olate

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
US8642597B2 (en) 2007-08-27 2014-02-04 Basf Se Pyrazole compounds for controlling invertebrate pests
JP2010536926A (ja) * 2007-08-27 2010-12-02 ビーエーエスエフ ソシエタス・ヨーロピア 無脊椎動物系害虫を防除するためのピラゾール化合物
WO2009027393A3 (fr) * 2007-08-27 2009-09-24 Basf Se Composés de pyrazole permettant de lutter contre les nuisibles invertébrés
US9204647B2 (en) 2007-08-27 2015-12-08 Basf Se Pyrazole compounds for controlling invertebrate pests
AU2008292238B2 (en) * 2007-08-27 2014-06-12 Basf Se Pyrazole compounds for controlling invertebrate pests
US9375008B2 (en) 2008-09-24 2016-06-28 Basf Se Pyrazole compounds for controlling invertebrate pests
US8853125B2 (en) 2008-09-24 2014-10-07 Basf Se Pyrazole compounds for controlling invertebrate pests
US8729083B2 (en) 2008-09-24 2014-05-20 Basf Se Pyrazole compounds for controlling invertebrate pests
US9029639B2 (en) 2009-07-06 2015-05-12 Basf Se Pyridazine compounds for controlling invertebrate pests
US8710056B2 (en) 2009-07-06 2014-04-29 Basf Se Pyridazine compounds for controlling invertebrate pests
US9125414B2 (en) 2009-07-24 2015-09-08 Basf Se Pyridine derivatives compounds for controlling invertebrate pests
US9533972B2 (en) 2010-11-18 2017-01-03 Bayer Intellectual Property Gmbh Substituted sodium-1H-pyrazole-5-olate
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013026264A1 (fr) * 2011-08-23 2013-02-28 Fan Rulin Composé inhibiteur d'accepteur cb1 ayant un cycle aromatique contenant de l'azote portant un hydroxyle, et son utilisation

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