WO2007121687A1 - 4-methyl-1h-diaryl pyrazole derivatives and their uses as medicament - Google Patents

4-methyl-1h-diaryl pyrazole derivatives and their uses as medicament 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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French (fr)
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/en

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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

Abstract

The present application discloses 4-methyl-1H-diaryl pyrazole derivatives of formula (I), their preparation methods, pharmaceutical compositions containing the same which are used as cannabinoid receptors type I(CB1) inhibitors in brain especially useful of treatment of obesity,ameliorating memory or stopping smoking.

Description

4一甲基 -1 H-二芳基吡唑衍生物及其作为药物的用途 发明领域  4-monomethyl-1H-diarylpyrazole derivatives and their use as medicaments
本发明涉及通式 I 的 4 -曱基 -1H-二芳基吡唑衍生物及其药 用盐， 其制备方法， 含它们的药用组合物及通式 I化合物作为脑 内大麻素 I型（CB1 )受体抑制剂在治疗与 CB1受有关疾病或症状 如肥胖、 改善记忆、 戒烟方面的用途。 背景技术  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) Use of a receptor inhibitor for the treatment of a disease or condition associated with CB1 such as obesity, improvement of memory, and cessation of smoking. Background technique
大麻类物盾是最早被人类认识的成瘾性物质之一， 大约有一 千年的药用 历史， 其主要活性成分是 Δ 9-四氢大麻酚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 Δ 9 -tetrahydrocannabinol.
( de l ta-9-tetrahydro-cannabinol , Δ -THC ) 。 大麻类物质具 有止痛、 镇静、 抗痉挛、 抗呕吐、 抗青光眼及抗高血压等多种药 理作用，但易产生耐受性和成瘾性， 限制了它们的使用 (R. K. Razden, Pharmacol. Rew.， 1986, 38, 75-149)。 ( de l ta-9-tetrahydro-cannabinol, Δ -THC ). 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).
大麻素（ cannab inoid, CB )受体是指对大麻类物质如 Δ 9-THC 有应答的受体。 90 年代初， 大麻素的两种受体亚型被成功克隆： CB1 (R. Mechoulam, et a l. , Biochem. Pharmacol. , 1995, 50， 83-90)和 CB2 (S. Munro, et a l. , Na ture, 1993, 365, 61-65)。 它们都属于 G蛋白偶联受体的视紫质样家族 A纲。 基因克隆研究 发现这两种受体完整的氨基酸序列有 44 %的同源性，跨膜区氨基 酸序列有 68 %的同源性 （L. A. Mat suda, et a l. , Nature, 1990, 346, 561-564 ) 。 氨基酸序列的分析显示， 它们的结构中都包括 七次亲酯跨膜 α螺旋结构。 两种大麻素受体可以激活多重细胞内 信号转导通路，包括通过抑制腺苷酸环化酶、抑制钙通道、激活钾 通道、激活 MAP激酶通道来抑制 cAMP的生成。且都对百日咳毒素 ( pertussis toxin)敏感， 表明两种受体主要为 Gi/o型 G蛋白 偶联受体 （ P.H.Reggio, Curr. Pharm. Des. , 2003, 9， 1607-1633 )。 CB1受体主要存在于中枢神经系统， 又名中枢型大 麻素受体； CB2 受体主要存在于外周神经元， 又名外周型大麻素 受体； 功能之一都是阻止神经递质的释放。 它们的主要区别在于 其氨基酸序列、 信号转导机制、 器官分布及对某些激动剂和抑制 剂敏感度的不同。 The cannab inoid (CB) receptor is a receptor that responds to cannabinoids such as Δ 9 -THC. In the early 1990s, two receptor subtypes of cannabinoids were successfully cloned: CB1 (R. Mechoulam, et al., Biochem. Pharmacol., 1995, 50, 83-90) and 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. Gene cloning studies revealed a 44% homology between the complete amino acid sequence of the two receptors and a 68% homology to the amino acid sequence of the transmembrane region (LA Mat suda, et al., Nature, 1990, 346, 561 -564). Analysis of the amino acid sequences revealed that their structure includes seven para-ester transmembrane alpha helices. Two cannabinoid receptors activate multiple intracellular signal transduction pathways, including inhibition of cAMP production by inhibiting adenylate cyclase, inhibiting calcium channels, activating potassium channels, and activating MAP kinase channels. Pertussis toxin (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.
CB1受体是利用氚标记的 CP55940,通过放射自显影技术和放 射配体结合研究方法确证的受体。 它包含 473 个氨基酸， 由 17 个跨膜区组成，该受体在进化中有着高度保守性和重要性。人类与 大鼠的 CB1受体氨基酸序列有 97.3%同源， 分子量大约为 52800 左右。 CB1 受体主要位于脑、 脊髓与外周神经系统中， 脑内 CB1 受体主要分布于基底神经节（黑质、 苍白球、 外侧紋状体）、 海马 CA锥体细胞层， 小脑和大脑皮层。 CB1受体的这种分布可能与大 麻素对记忆、 认知、 运动控制的调节有关。  The CB1 receptor is a receptor confirmed by 放射-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.
研究证实， 大麻素受体 I型的内源性配体对食物摄取和能量 消耗有双重调控作用， 从而达到控制体重的目的（A.C.Howlett, et al. Pharmacol. Rev. , 2002， 54， 161-202)。  Studies have shown that the endogenous ligand of the cannabinoid receptor type I has dual regulation of food intake and energy expenditure to achieve weight control (ACHowlett, et al. Pharmacol. Rev., 2002, 54, 161- 202).
大麻素受体激动剂大多没有特异性， 均可以同时与两种大麻 素受体结合。 与激动剂不同的是， 目前人工合成的几种大麻素受 体抑制剂都表现出非常高的受体特异性。 其中， 大麻素受体 I型 抑制剂直接作用于中枢神经系统， 表现出多种多样的活性。 如抗 肥胖、 戒烟、 改善记忆和认知障碍、 治疗精神疾病和肿瘤化疗等。 二芳基吡唑类化合物是最受瞩目的 CB1受体抑制剂之一， 它可高 效选择性的与 CB1受体结合， 迅速的阻断或逆转 CB1受体的调节 作用， 降低信号转导通路的活性（M. Rinaldi- Carmona, et al. , FEBS Let t, 1994, 350, 240 244 ) 。 因此， 寻找结构新颖的具有 CBl抑制活性的二芳基吡唑类化合物是十分必要的。 发明内容 Most 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
本发明的目的在于寻找并开发作用于 CB1受体的新的二芳基 吡唑类小分子抑制剂.  The purpose of the present invention is to find and develop a novel diarylpyrazole small molecule inhibitor acting on the CB1 receptor.
本发明人经过研究发现， 具有下面通式（ I )的化合物具有抑 制 CB1受体的作用， 因此可以用于治疗与 CB1受体有关的疾病或 症状， 如用于治疗肥胖、 戒烟、 改善记忆和认知障碍、 治疗精神 疾病和肿瘤化疗等各种疾病或症状。  The present inventors have found through research that 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.
本发明第一方面涉及通式（ I )的化合物或其可药用的盐或水 合物，  A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof,
Figure imgf000005_0001
其中： R是 H， d-C 烷基， 尤其是 d-C8的直链或支链烷基， C3-7环烷基， 或是 C6-C15的取代或未取代的芳香基， 代表性芳香基 如苯基、 萘基、 蒽基、 芴基， 或含 N杂环如喹啉、 吡咯、 哌啶、 哌嗪、 吗啉、 咪唑、 吡唑、 吗啉或其他杂环如噻唑、 呋喃等； 取 代基选自 ! ¾素、 氰基、 硫氢基、 甲酰基、 羟基、 磺酸酯、 硝基、 亚硝基、 -( 8取代或未取代烷氨基、 d-6烷硫基、 d- 烷氧基、 d - C15烷基、 尤其是 d- C8直链、 支链或环状烷基。
Figure imgf000005_0001
Wherein: 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. 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.
根据本发明， 优选的 R是任意一取代或二取代的苯、 芴、 吡 啶， 取代基选自 iS素、 氨基、 曱酰基、 d-6烷氧基、 ； R亦可以是 哌啶、 吗啉、 呋喃、 咪唑， 取代基选自 ¾素、 d-6烷基、 氨基； R 亦可以是 d-8直链、 支链或环状烷基。 According to the invention, preferred 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.
本发明所用术语 "d-Cu烷基" 或 "d-C8烷基" 是指含 1-15 个或 1-8个碳原子的直链、 支链或环状烷基， 包括但并不局限于 曱基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 异丁基、 叔丁 基、 戊基、 新戊基、 己基、 庚基、 辛基、 壬基、 癸基、 十一烷基、 十二烷基、 环丙基、 环丁基、 环戊基、 环己基、 环庚基、 环辛基 等。 The term "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.
本发明所用术语 " ¾素" 是指由元素氟、 氯、 溴、 碘所衍生 的原子团  The term "3⁄4" as used in the present invention means an atomic group derived from the elements fluorine, chlorine, bromine or iodine.
本发明所用术语 "环烷基"是指含有 3-7个碳原子的环烷基， 包括但是并不局限于环丙基、 环戊基、 环己基等。  The term "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.
根据本发明， 本发明涉及的通式（ I)化合物或其可药用的盐 或水合物优选下面的化合物：  According to the present invention, 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:
01 1- (2, 4 -二氯苯基） -5- (4 -氯苯基） -N- (2-9H -芴基） -4-曱基- 1H-吡唑 - 3 -曱酰胺  01 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-N-(2-9H-indenyl)-4-indolyl-1H-pyrazole-3-oxoamide
{2)_ Ν- (4-溴苯基） -1- (2， 4-二氯苯基） -5- (4 -氯 苯基） 一 4一甲基一 1H -吡唑一 3-曱酰胺  {2) _ Ν-(4-bromophenyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-tetramethyl- 1H-pyrazole- 3-indole Amide
(3) 1- （2， 4 -二氯苯基） -5- （4 -氯苯基） - 4 -甲基 -Ν - (3-吡啶基） -1Η-吡唑 - 3-甲酰胺  (3) 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-indole-(3-pyridyl)-1Η-pyrazole-3-carboxamide
(4) 1- (2, 4 -二氯苯基） -5- (4 -氯苯基） - Ν -环戊基- 4 -曱基 - 1H-吡唑 - 3-曱酰胺  (4) 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-indole-cyclopentyl-4-indolyl-1H-pyrazole-3-indoleamide
(5 1- （2， 4 -二氯苯基） -5- (4-氯苯基） -Ν- (曱基环 己基） - 4-甲基一 1H-吡唑 - 3-曱酰胺  (5 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-indole-(indenylcyclohexyl)-4-methyl-1H-pyrazole-3-indamide
(6 1- (2, 4 -二氯苯基） -5- (4 -氯苯基） - 4 -曱基 -Ν 一 （4一曱基一1-哌-秦基） 一 1H -吡唑 - 3-曱酰胺(6 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-indole One (4-mercapto-1-pipe-methyl)-1H-pyrazole-3-indoleamide
(])_ 1 - (2, 4 -二氯苯基） -5- (4 -氯苯基） -N- (2 -呋 喃-曱基） -4-甲基 - 1H-吡唑 - 3-曱酰胺 (])_ 1 - (2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(2-furan-indolyl)-4-methyl-1H-pyrazole-3- Amide
l " (2， 4-二氯苯基） -5- (4-氯苯基） -N- (4-氟 苯基） - 4-甲基 -1H-吡峻 - 3-曱酰胺  l "(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-N-(4-fluorophenyl)-4-methyl-1H-pyridin-3-indamide
{9∑ 1 - (2, 4-二氯苯基） - 5- (4-氯苯基） -N- (2-氟 苯基） 一 4一甲基一 1H-吡唑 - 3—曱酰胺  {9∑ 1 - (2, 4-dichlorophenyl)-5-(4-chlorophenyl)-N-(2-fluorophenyl)-4-methyl- 1H-pyrazole-3-oxanamide
(10) N- (4-甲氧基苯基） -1- (2， 4-二氯苯基） -5- (4 -氯苯基） -4-曱基 - 1H-吡唑- 3-曱酰胺  (10) N-(4-Methoxyphenyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-1H-pyrazole-3- Amide
(11) 1- (2， 4 -二氯苯基） -5- (4 -氯苯基） -4-甲基- N- ( 3-吡啶基-曱基） - 1H-吡唑- 3-曱酰胺  (11) 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-N-(3-pyridyl-indenyl)-1H-pyrazole-3- Amide
(12) 1- (2, 4 -二氯苯基） -5- (4 -氯苯基） -4-甲基- N- (4-吡啶基-曱基） - 1H-吡唑 - 3-甲酰胺  (12) 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-N-(4-pyridyl-indenyl)-1H-pyrazole-3- Formamide
(13) N-[3- (1- 1H-咪唑基） -丙基 ] - 1- (2， 4-二氯苯基） -5- (4-氯苯基） -4-曱基- 1H-吡峻 - 3-甲酰胺  (13) N-[3- (1- 1H-Imidazolyl)-propyl] - 1-(2, 4-dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-1H -pyridin-3-formamide
(14) 1- (2, 4-二氯苯基） -5- (4-氯苯基） - N- [4- (二 曱基氨基） 苯基] -4 -曱基 - 1H -吡唑— 3-曱酰胺  (14) 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-N-[4-(didecylamino)phenyl]-4-indolyl-1H-pyrazole — 3-anthracene
及其可药用盐或水合物。  And pharmaceutically acceptable salts or hydrates thereof.
根据本发明， 本发明涉及如通式 I所示化合物或其立体异构 体的合适的可药用盐或水合物， 其中可药用的盐包括但是并不局 限于通式 I化合物与无机酸如盐酸、 硫酸、 磷酸、 亚磷酸、 氢溴 酸和硝酸所成的盐以及与各种有机酸， 如马来酸、 苹果酸、 延胡 索酸、 琥珀酸、 酒石酸、 柠檬酸、 乙酸、 乳酸、 甲磺酸、 对甲苯 磺酸、 棕榈酸等所成的盐。 本发明中的一些化合物可能用水或各 种有机溶剂结晶或重结晶， 在这种情况下， 可能形成各种溶剂化 物。 本发明包括那些化学计量的溶剂化物， 包括水合物， 也包括 在用低压升华干燥法制备时形成的包含可变量水的化合物。 According to the present invention, 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.
根据本发明， 本发明式 I化合物的立体异构体指本发明中部 分化合物可能以光学异构体或互变异构体的形式存在， 本发明包 括其所有存在形式， 特别是纯异构体的形式。 不同的异构体形式 可以以各种常规的手段与其它形式的异构体分离或拆分开， 或者 某种异构体可以各种常规的合成方法或立体专一或不对称合成的 方法得到。 既然通式 I化合物是以药用为目的的， 可以理解它们 最好以纯的形式提供， 例如至少 60%的纯度， 更合适的 75%， 更 好的 85%, 最好至少 98%的纯度（％是指重量百分比）。 不纯化合 物的制备方法可用来用于药用组合物中更纯的形式。 这些不够纯 的产物中至少含有 1%， 更适合的 5%， 更好的至少 10%的如通式 I 所示的化合物或其可药用的衍生物。  According to the invention, 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. . Since 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.
本发明另一方面涉及制备通式 I化合物的方法。 通式 I的化 合物可以从已知的或可购得的化合物为原料， 经过人工合成的方 法制备。 如果原料不能购得， 则这里提供它们的制备方法， 或它 们可以通过文献报道的方法制备。  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.
通式（ I ) 的化合物的制备方法包括：  The preparation method of the compound of the formula (I) includes:
(i)将式 115- (4-氯苯基） -1- (2， 4-二氯苯基） -4 -曱基吡唑 - 3-曱酸和氯化亚砜反应， 得到 5- (4-氯苯基） - 1- (2， 4-二氯苯基） -4-曱基吡唑 - 3-甲酰氯。  (i) reacting the formula 115-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-mercaptopyrazole-3-decanoic acid with thionyl chloride to give 5-( 4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-mercaptopyrazole-3-ylcarbonyl chloride.
Figure imgf000008_0001
Figure imgf000008_0001
(ii)将 5- (4-氯苯基） -1- (2， 4-二氯苯基） -4 -曱 基吡唑 - 3-曱酰氯与取代胺 NHR反应得到通式 （I)化合物 (ii) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-pyrene Reaction of pyridazole-3-oxoyl chloride with substituted amine NHR to give a compound of formula (I)
Figure imgf000009_0001
其中 R的定义同如前所述。
Figure imgf000009_0001
Where R is as defined above.
式 ( Π ) 的合成方法在相关文献如 Design 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)和 The synthesis and pharmacological evaluation of the cannabinoid antago— nist SR141716A, A. K. Dutta, et al. , (Med Chem Res 1994， 5， 54-62)中已有详尽 的论述。  The synthesis method of the formula ( Π ) 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.
通式（I)化合物可以用常规方法单个合成， 亦可用组合化学 的混-分方法或平行合成的方法以库 （每个库中至少含两个， 或 5-1000个， 最好是 10-100个化合物） 为单位合成， 即可以在液 相中合成也可以用固相合成方法。  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.
关于制备通式（ I )化合物更详尽的资料见实施例  For more detailed information on the preparation of compounds of formula (I), see the examples.
本发明还涉及药物组合物， 其包括至少一种式 I化合物和至 少一种药用载体或赋形剂。 通式 I的化合物或其可药用的盐可以 单独使用， 或与可药用的载体或赋形剂一起以药物组合物的形式 使用， 当以药物组合物的形式使用时， 通常将有效剂量的本发明 通式 I化合物或其可药用盐或水合物以及一种或多种可药用载体 或稀释剂结合制成适当的施用形式或剂量形式， 这一程序包括通 过合适的方式将组分混合、 粒化、 压缩或溶解。 本发明药用组合物可以以下方面的任意方式施与： 口服、 喷 雾吸入、 直肠给药、 鼻腔给药、 阴道给药、 局部给药、 非肠道给 药如皮下、 静脉、 肌内、 腹膜内、 鞘内、 心室内、 胸骨内或颅内 注射或输入， 或借助一种外植的储器用药， 其中优选口服、 肌注、 腹膜内或静脉内用药方式。 The invention further relates to 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. The pharmaceutical 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.
本发明的药物组合物中含有的药用载体包括但不局限于： 离 子交换剂， 氧化铝， 硬脂酸铝， 卵磷脂， 血清蛋白如人血清蛋白， 緩沖物质如磷酸盐， 甘油， 山梨酸， 山梨酸钾， 饱和植物脂肪酸 的部分甘油酯混合物， 水， 盐或电解质， 如硫酸鱼精蛋白， 磷酸 氢二钠， 磷酸氢钾， 氯化钠， 锌盐， 胶态氧化硅， 三硅酸镁， 聚 乙烯吡咯烷酮， 纤维素物质， 聚乙二醇， 羧曱基纤维素钠， 聚丙 烯酸酯， 蜂蜡， 羊毛酯等。 载体在药物组合物中的含量可以是 1 重量％-98重量％， 通常大约占到 80重量％。 为方便起见， 局部麻 醉剂， 防腐剂， 緩沖剂等可直接溶于栽体中。  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. For convenience, topical anesthetics, preservatives, buffers, etc., are directly soluble in the carrier.
口服制剂如口服片剂和胶嚢可以含有赋形剂如粘合剂， 如糖 浆， 阿拉伯胶， 山梨醇， 黄芪胶， 或聚乙烯吡咯烷酮， 填充剂， 如乳糖， 蔗糖， 玉米淀粉， 磷酸钙， 山梨醇， 氨基乙酸， 润滑剂， 如硬脂酸镁， 滑石， 聚乙二醇， 硅土， 崩解剂， 如马铃薯淀粉， 或可接受的增润剂， 如月桂醇钠硫酸盐。 片剂可以用制药学上公 知的方法包衣。  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.
口服液形式的本发明药物组合物可以制成水和油的悬浮液， 溶液， 乳浊液， 糖浆或酏剂， 也可以制成干品， 用前补充水或其 它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂， 山梨醇， 纤维素曱醚， 葡萄糖糖浆， 凝胶， 羟乙基纤维素， 羧曱 基纤维素， 硬脂酸铝凝胶， 氢化的食用油脂， 乳化剂， 如卵磷脂， 山梨聚醣单油酸盐， 阿拉伯树胶； 或非水载体（可能包含可食用 油） ， 如杏仁油， 油脂如甘油， 乙二醇， 或乙醇； 防腐剂， 如对 羟基苯曱酸甲酯或丙酯， 山梨酸。如需要可添加调味剂或着色剂。 The pharmaceutical 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.
栓剂可包含常规的栓剂基质， 如可可黄油或其它甘油酯。 非肠道给药， 液态剂型通常由化合物和至少一种消毒或无菌 的载体制成。 载体首选水。 依照所选载体和药物浓度的不同， 化 合物既可溶于载体中也可制成悬浮溶液， 在制成注射用溶液时先 将化合物溶于水中， 过滤消毒后装入封口瓶或安瓿中。  The suppository can comprise a conventional suppository base such as cocoa butter or other glycerides. For parenteral administration, the liquid dosage form is usually made up of the compound and at least one sterile or sterile carrier. The carrier is preferred water. Depending on the selected carrier and drug concentration, 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.
当皮肤局郜施用时， 本发明化合物可以制成适当的软膏， 洗 剂， 或霜剂的形式， 其中活性成分悬浮或溶解于一种或多种的载 体中。 其中软膏制剂可以使用的载体包括但不局限于： 矿物油， 液体凡士林， 白凡士林， 丙二醇， 聚氧化乙烯， 聚氧化丙烯， 乳 化蜡和水； 洗剂和霜剂可使用的载体包括但不限于： 矿物油， 脱 水山梨糖醇单硬脂酸酯， 吐温 60， 十六烷酯蜡， 十六碳烯芳醇， 2 -辛基十二烷醇， 苄醇和水。  When the skin is applied, 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.
依据给药方式的不同， 组合物中可以含有重量比 0. 1%, 或更 合适的重量比 10-60%的活性组分。 但组合物为单位剂型时， 每个 单位最好包含 50-500毫克活性成分。依据给药途径和给药频率的 不同，用于成人的适宜治疗剂量，举例讲可为每天 100-3000毫克， 如每天 1500毫克。 这一剂量对应于 1. 5 - 50 毫克 /公斤 /天， 合 适的剂量是 5-20毫克 /公斤 /天。  Depending on the mode of administration, the composition may contain from 0.1% by weight, or more suitably from 10% to 60% by weight of active ingredient. Where the composition is in unit dosage form, each unit preferably contains from 50 to 500 mg of active ingredient. The appropriate therapeutic dose for an adult, for example, 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.
必须认识到， 通式 I化合物的最佳给药剂量和间隔是由疾病 或症状的严重程度、 化合物性质和诸如给药的形式、 路径和部位 以及所治疗的特定哺乳动物等条件决定的， 而这一最佳给药剂量 可由临床医生来确定。  It must be recognized that 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.
本发明还涉及式 I化合物或其立体异构体或它们的药用盐或 它们的水合物在制备用于治疗与 CB1受体有关疾病或症状的药物 中的用途。 具体实施方案 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. Specific implementation
下面的具体实施例是本发明的优选实施方案， 其不应理解为 对本发明构成任何限制。 化合物的熔点由 RY- 1熔点仪测定， 温度计未较正。 质谱由 Micromass ZabSpec 高分辨率质谱仪（分辨率 1000 )测定。 ^ NMR 由 JNM-ECA-400超导 NMR仪测定， 工作频率 1匪 R 400MHzo 实 施 例 The following specific examples are preferred embodiments of the invention and are not to be construed as limiting the invention in any way. The melting point of the compound was determined by a RY-1 melting point apparatus, and the thermometer was not corrected. Mass spectra were determined by a Micromass ZabSpec high resolution mass spectrometer (resolution 1000). ^ NMR Measured by JNM-ECA-400 superconducting NMR instrument, operating frequency 1匪 R 400 MHz o Example
实施例 1 1 - ( 2， 4 -二氯苯基） - 5 - ( 4 -氯苯基） -N - ( 2 - 9H-芴基） -4-曱基- 1H-吡唑 - 3 -甲酰胺的制备。  Example 1 1 - ( 2, 4 -Dichlorophenyl) - 5 - ( 4 -chlorophenyl) -N - ( 2 - 9H-indenyl)-4-indolyl - 1H-pyrazole - 3 - A Preparation of amides.
Figure imgf000012_0001
Figure imgf000012_0001
歩骤 1 5 - ( 4 -氯苯基） - 1 - ( 2， 4 -二氯苯基） - 4 - 甲基吡唑 - 3 -曱酰氯的制备。  Step 1 5 - Preparation of ( 4 -chlorophenyl) - 1 - ( 2, 4 -dichlorophenyl) - 4 -methylpyrazole - 3 -nonanoyl chloride.
取 0.5g 5 - ( 4-氯苯基） - 1 - ( 2， 4 -二氯苯基） - 4 - 曱基吡唑- 3-曱酸， 用 10ml甲苯溶解， 加入 0.29ml氯化亚砜， 加热至回流， 4 小时后， 蒸出氯化亚砜和曱苯， 再分三次加入各 10ml曱苯， 蒸馏， 得 0.4g红棕色油状物。 直接投料下步反应。  0.5 g of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-indolylpyrazole-3-decanoic acid was dissolved in 10 ml of toluene, and 0.29 ml of thionyl chloride was added. After heating to reflux, after 4 hours, thionyl chloride and toluene were distilled off, and 10 ml of toluene was added in three portions, and distilled to give 0.4 g of a reddish brown oil. Directly feed the next step.
步骤 2 1 - （2， 4 -二氯苯基） - 5 - ( 4 -氯苯基） -N- ( 2 - 9H -芴基） -4-曱基 - 1H -吡唑 - 3 -甲酰胺的制备。 将上步所得曱酰氯用 4ml二氯甲烷溶解， 下，緩慢滴加入 0.23g 2 -氨基芴和 0.234ml三乙胺在 5ml二氯甲烷的溶液中， 室 温下反应 9小时。 用石油醚： 乙酸乙酯 =2: 1柱层析分离，得到 0.388g的 1- (2， 4-二氯苯基） -5- ( 4 -氯苯基） -N- (2 -911-芴基）-4-甲基-111-吡唑-3-甲酰胺， mp:212.9-214.5 ， 两步总收率 54.34 % , 'H-NMR (DMSO, δ ppm)： 2.32 (s, 3H) , 3.92(s,2H), 7.27 (dd, 1H), 7.36 ( t, 1H ) ， 7.48(m, 2H),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. Separation by petroleum ether: ethyl acetate = 2: 1 column chromatography gave 0.388 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N- (2 -911-芴M)-4-methyl-111-pyrazole-3-carboxamide, mp: 212.9-214.5, two-step total yield 54.34%, 'H-NMR (DMSO, δ ppm): 2.32 (s, 3H) , 3.92(s,2H), 7.27 (dd, 1H), 7.36 ( t, 1H ) , 7.48(m, 2H),
7.55 (d, 1H), 7.61(dd, 1H), 7.78-7.84 (m, 4H),7.55 (d, 1H), 7.61 (dd, 1H), 7.78-7.84 (m, 4H),
8.18 (s， 1H)， 10.25 (s， 1H) . FAB-MS (m/e)： 545.1 (M+)。 实施例 2 N- ( 4 -溴苯基） -1- (2， 4 -二氯苯基） -5 - (4-氯苯基） -4-甲基 -1H-吡唑- 3-曱酰胺的制备。 8.18 (s, 1H), 10.25 (s, 1H) . FAB-MS (m/e): 545.1 (M+). Example 2 N-(4-bromophenyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-oxoamide Preparation.
Figure imgf000013_0001
Figure imgf000013_0001
5- (4-氯苯基） -1- (2， 4-二氯苯基） -4-曱基吡峻 - 3 -曱酰氯的制备方法参见实施例 1。  For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-indolylpyrrole-3-nonanoyl chloride, see Example 1.
将所得甲酰氯用 4ml 二氯甲烷溶解， 0°C下， 緩慢滴加入 0.215g对溴苯胺和 0.234ml三乙胺在 5ml二氯曱烷的溶液中， 室 温下反应 9小时。 用石油醚： 乙酸乙酯 =2: 1柱层析分离，得到 0.327g的 N- (4-溴苯基） -1- (2， 4-二氯苯基） -5- (4 -氯苯基） -4 -曱基 - 1H-吡唑- 3-曱酰胺， mp: 157.6 - 159.3 X：，两步总收率 46.58 % H-NMR (DMSO, δ ppm): 2.29( s， 3H ), 7.26 (dd, 2H) ，7.47-7.51(m，5H)， 7.79-7.83 (m, 4H), 10.35(s，lH)。 The obtained formyl chloride was dissolved in 4 ml of dichloromethane, and 0.215 g of p-bromoaniline and 0.234 ml of triethylamine in 5 ml of dichloromethane were slowly added dropwise at 0 ° C, and reacted at room temperature for 9 hours. Separation by petroleum ether: ethyl acetate = 2: 1 column to give 0.327 g of N-(4-bromophenyl)-1-(2,4-dichlorophenyl)-5-(4-chlorobenzene -4 - mercapto- 1H-pyrazole-3-oxoamide, mp: 157.6 - 159.3 X:, two-step total yield 46.58 % H-NMR (DMSO, δ ppm): 2.29 ( s, 3H ), 7.26 (dd, 2H), 7.47-7.51 (m, 5H), 7.79-7.83 (m, 4H), 10.35 (s, lH).
FAB-MS (m/e): 536.0 (M+)。 实施例 3 1- (2, 4 -二氯苯基） -5- (4 -氯苯基） -4 -曱基 - N- (3-吡啶基） - 1H-吡唑 - 3-曱酰胺的制备。 FAB-MS (m/e): 536.0 (M+). Example 3 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-N-(3-pyridyl)-1H-pyrazole-3-oxanamide preparation.
Figure imgf000014_0001
Figure imgf000014_0001
5- (4-氯苯基） -1- (2， 4-二氯苯基） -4-曱基吡峻 -3-甲酰氯的制备方法参见实施例 1。  For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-mercaptopyrimidine-3-carbonyl chloride, see Example 1.
将所得曱酰氯用 4ml 二氯甲烷溶解， O 下， 緩慢滴加入 0.141g对溴苯胺和 0.234ml三乙胺在 5ml二氯曱烷的溶液中， 室 温下反应 6.5小时。 用石油醚: 乙酸乙酯 =1: 3柱层析分离，得 到 0.311g的 1- (2， 4-二氯苯基） -5- (4-氯苯基） -4- 甲基- N - ( 3 -吡啶基）- 1H-吡唑 - 3-甲酰胺 mp: 162.8 - 164.1 。C , 两 步总收率 51.86 % ， ^-NMR (DMS0, δ ppm)： 2.31 ( s，3H ) , 7.27-7.38 (m, 3Η) , 7.47 (d, 2Η) , 7.60 (dd, IH)， 7.80-7.84 (m， 2H)， 8.22-8.30 (m， 2H)， 8.98 (d， IH)， 10.47 (s， IH) . FAB-MS (m/e)： 457.0 (M+)。 实施例 4 1- (2， 4-二氯苯基） -5- (4-氯苯基） - N -环戊基- 4-曱基 -1H-吡唑 - 3 -曱酰胺的制备。 The obtained 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. C, total yield of two steps of 51.86%, ^-NMR (DMS0, δ ppm): 2.31 (s, 3H), 7.27-7.38 (m, 3Η), 7.47 (d, 2Η), 7.60 (dd, IH), 7.80-7.84 (m, 2H), 8.22-8.30 (m, 2H), 8.98 (d, IH), 10.47 (s, IH) . FAB-MS (m/e): 457.0 (M + ). Example 4 Preparation of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-cyclopentyl-4-indole-1H-pyrazole-3- amide.
Figure imgf000014_0002
5- (4-氯苯基） -1- (2， 4-二氯苯基） -4-甲基吡峻 - 3 -曱酰氯的制备方法参见实施例 1。
Figure imgf000014_0002
For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyridin-3-yloyl chloride, see Example 1.
将所得甲酰氯用 4ml 二氯曱烷溶解， OX下， 緩慢滴加入 0.256g环戊胺和 0.234ml三乙胺在 5ml二氯曱烷的溶液中， 室温 下反应 5.5小时。 用石油醚: 乙酸乙酯 =8: 1柱层析分离，得到 The obtained formyl chloride was dissolved in 4 ml of dichloromethane, and 0.256 g of cyclopentylamine and 0.234 ml of triethylamine were slowly added dropwise in a solution of 5 ml of dichloromethane at OX, and the mixture was reacted at room temperature for 5.5 hours. Separated by petroleum ether: ethyl acetate = 8: 1 column chromatography
0.398g的 1- (2， 4-二氯苯基） -5 - ( 4 -氯苯基） -N-环戊 基- 4-曱基 - 1H-吡唑 - 3 -甲酰胺， mp: 146.9― 148.7°C， 两步 总 收 率 67.69 % ， ^-NMR (DMS0, δ ppm)：0.398 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-cyclopentyl-4-indolyl-1H-pyrazole-3-carbamide, mp: 146.9 ― 148.7°C, total yield of two steps of 67.69 %, ^-NMR (DMS0, δ ppm):
1.50-1.66 (m， 6H)， 1.80-1.88 (m, 2H)， 2.24 (s， 3H) , 4.20-4.24 (m, 1Η)， 7.21-7.24 (d, 2H)， 7.44-7.59 (m， 3H)， 7.74-7.76 (m， 2H)， 8.01 (d, 1H) . FAB-MS (m/e)： 448.1 (M+)。 元素分析： C22H2。 C13N30， 计算值（％ ) C58.88， H4.49， N9.36, 测定值（％ ) C58.98, H4.50， N9.49。 实施例 5 1- (2, 4 -二氯苯基） -5- (4 -氯苯基） - N - （曱基环己基） -4-甲基 -1H-吡唑 - 3-甲酰胺的制备。 1.50-1.66 (m, 6H), 1.80-1.88 (m, 2H), 2.24 (s, 3H), 4.20-4.24 (m, 1Η), 7.21-7.24 (d, 2H), 7.44-7.59 (m, 3H ), 7.74-7.76 (m, 2H), 8.01 (d, 1H) . FAB-MS (m/e): 448.1 (M + ). Elemental analysis: C 22 H 2 . C1 3 N 3 0, calculated (%) C58.88, H4.49, N9.36, found (%) C58.98, H4.50, N9.49. Example 5 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(indolylcyclohexyl)-4-methyl-1H-pyrazole-3-carboxylate preparation.
Figure imgf000015_0001
Figure imgf000015_0001
5- (4-氯苯基） -1- (2， 4-二氯苯基） -4-甲基吡唑 -3-甲酰氯的制备方法参见实施例 1。 将所得甲酰氯用 4ml二氯曱烷溶解， O 下，緩慢滴加入 0.22g 氨曱基环戊烷和 0.234ml三乙胺在 5ml二氯曱烷的溶液中， 室温 下反应 4.5小时。 用石油醚： 乙酸乙酯 = 7: 1柱层析分离，得到 0.250g的 1 - ( 2， 4 -二氯苯基） - 5 - ( 4-氯苯基） -N- (甲 基环己基） - 4 -曱基- 1H -吡唑- 3-曱酰胺， mp: 110.4 - 111.9 。C , 两 步 总 收 率 40 % , 'H-NMR (DMS0, δ ppm)： 0.87-1.68 (m， 10H)， 2.24 (s， 3H)， 3.05 (t, 1H)， 7.22 (d,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. Separation by petroleum ether: ethyl acetate = 7:1 column to give 0.250 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N- (methylcyclohexyl) ) - 4 - mercapto- 1H-pyrazole-3-oxoamide, mp: 110.4 - 111.9. C, total yield of two steps of 40%, 'H-NMR (DMS0, δ ppm): 0.87-1.68 (m, 10H), 2.24 (s, 3H), 3.05 (t, 1H), 7.22 (d,
2H)， 7.45-7.60 (m, 3H)， 7.75-7.78 (m， 2H)， 8.20 (t， 1H) · 2H), 7.45-7.60 (m, 3H), 7.75-7.78 (m, 2H), 8.20 (t, 1H)
FAB-MS (m/e)： 476· 2(Μ+)。 实施例 6 1 - ( 2, 4 -二氯苯基） - 5 - ( 4 -氯苯基） - 4 -甲基 - Ν- ( 4 -曱基 - 1 -哌豢基） - 1H-吡唑- 3-曱酰胺的 制备 FAB-MS (m/e): 476· 2 (Μ+). Example 6 1 - ( 2, 4 -Dichlorophenyl) - 5 - ( 4 -chlorophenyl) - 4 -methyl - fluorene - ( 4 - fluorenyl - 1 -piperidinyl) - 1H-pyrazole - Preparation of 3-indoleamide
Figure imgf000016_0001
Figure imgf000016_0001
5 - ( 4 -氯苯基） - 1 - ( 2, 4 -二氯苯基） - 4-甲基吡唑 - 3 -甲酰氯的制备方法参见实施例 1。  For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxycarbonyl chloride, see Example 1.
将所得曱酰氯用 ½ι二氯曱烷溶解， ox:下， 緩慢滴加入 The resulting decanoyl chloride is dissolved in 1⁄2 of dichloromethane, ox: under, slowly added dropwise
0.225g的 1 -氨基 - 4曱基哌嗪和 0.234ml三乙胺在 5ml二氯曱 烷的溶液中， 室温下反应 4.5小时。 用石油醚: 乙酸乙酯 = 7: 1 柱层析分离，得到 0.266g的 1 - ( 2， 4 -二氯苯基） - 5 - ( 4 - 氯苯基 ) - 4-曱基一 N— ( 4_曱基一 1一哌嗪基 ) - 1H-吡唑 - 3 -甲酰胺， mp: 96.7 - 98.9V,两步总收率 42.42 % , 'H-NMR (DMS0, δ ppm): 2.16-2.21 (d, 6H) , 2.50(s,4H),0.225 g of 1-amino-4-mercaptopiperazine and 0.234 ml of triethylamine were reacted in a solution of 5 ml of dichloromethane at room temperature for 4.5 hours. Separation by column chromatography using petroleum ether: ethyl acetate = 7:1 to give 0.266 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-N- (4_decyl-l-piperazinyl)-1H-pyrazole-3-carbamide, mp: 96.7 - 98.9 V, two-step total yield 42.42%, 'H-NMR (DMS0, δ ppm): 2.16-2.21 (d, 6H), 2.50(s, 4H),
2.81 (t， 4H)， 7.21 (d, 2H)， 7.44-7.48 (d, 2H)， 7.57-7.60 (dd, IH)， 7.76-7.77 (m， 2H)， 9.22 (s， IH) . FAB-MS (m/e)： 478.2 (M+)。 实施例 7 1- (2, 4-二氯苯基） -5 - (4-氯苯基） -N - (2-呋喃-曱基） -4-曱基 -1H-吡唑- 3-甲酰胺的制备。 2.81 (t, 4H), 7.21 (d, 2H), 7.44-7.48 (d, 2H), 7.57-7.60 (dd, IH), 7.76-7.77 (m, 2H), 9.22 (s, IH) . FAB- MS (m/e): 478.2 (M + ). Example 7 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-N-(2-furan-indolyl)-4-indolyl-1H-pyrazole-3-yl Preparation of amides.
Figure imgf000017_0001
Figure imgf000017_0001
5- (4 -氯苯基） -1- (2, 4 -二氯苯基） - 4 -曱基吡唑 - 3 -曱酰氯的制备方法参见实施例 1。  For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-indolylpyrazole-3-meroyl chloride, see Example 1.
将所得甲酰氯用 ½1 二氯曱烷溶解， ox:下， 緩慢滴加入 The obtained formyl chloride was dissolved in 1⁄21 dichloromethane, ox: under, slowly added dropwise
0.189g的 2 -呋喃甲基胺和 0.234ml三乙胺在 5ml二氯甲烷的溶 液中， 室温下反应 6小时。 用石油醚： 乙酸乙酯 =6: 1柱层析分 离，得到 0.415g的 1- (2， 4-二氯苯基） -5- (4-氯苯基） -N- ( 2 -呋喃 -甲基） - 4-甲基 - 1H-吡唑 - 3-甲酰胺， mp: 154.7 - 156.1 ， 两步总收率 68.75 % , ^-NMR (DMSO, δ ppm): 2.25(s,3H), 4.40(d, 2H), 6.22 (d, IH),0.189 g of 2-furylmethylamine and 0.234 ml of triethylamine were reacted in 5 ml of dichloromethane at room temperature for 6 hours. Separation by petroleum ether: ethyl acetate = 6:1 column to give 0.415 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(2-furan- Methyl) 4-methyl-1H-pyrazole-3-carboxylamide, mp: 154.7 - 156.1, two-step total yield 68.75 %, ^-NMR (DMSO, δ ppm): 2.25 (s, 3H), 4.40(d, 2H), 6.22 (d, IH),
6.38 (m， IH)， 7.23 (d, 2H)， 7.45-7.60 (m， 4H)， 7.75-7.79 (m， 2H)， 8.69 (t, IH). FAB-MS (m/e)： 462.1 (M++1)。 实施例 8 1- (2, 4 -二氯苯基） -5- (4 -氯苯基） -N - (4-氟苯基） -4-甲基- 1H-吡唑 - 3-曱酰胺的制备。 6.38 (m, IH), 7.23 (d, 2H), 7.45-7.60 (m, 4H), 7.75-7.79 (m, 2H), 8.69 (t, IH). FAB-MS (m/e): 462.1 ( M++1). Example 8 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-oxanamide Preparation.
Figure imgf000017_0002
Figure imgf000017_0002
5- (4-氯苯基） -1- (2， 4-二氯苯基） -4-曱基吡唑 - 3-甲酰氯的制备方法参见实施例 1。 For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-mercaptopyrazole-3-ylyl chloride, see Example 1.
将所得甲酰氯用 4ml二氯甲烷溶解，0"C下，緩慢滴加入 0.22g 的 4 -氟苯胺和 0.234ml三乙胺在 5ml二氯甲烷的溶液中， 室温 下反应 5小时。用石油醚：乙酸乙酯 = 7： 1柱层析分离，得到 0.398g 的 1- (2， 4-二氯苯基） -5 - (4-氯苯基） - N- (4-氟苯基） -4-曱基 -1H-吡唑- 3-曱酰胺， mp: 174.7 - 176.3°C， 两步总 收 率 63.99 % ， 'H-NMR (DMS0, δ ppm)： 2.30 (s, 3H) , 7.14-7.29 (m, 4Η)， 7.46-7.63 (m， 3H)， 7.80-7.86 (m， 4H)， 10.30 (s, 1H). FAB-MS (m/e)： 474.1 (M+)。 实施例 9 1- (2, 4-二氯苯基） -5- (4-氯苯基） - N - (2-氟苯基） - 4-曱基 -1H-吡唑 - 3-甲酰胺的制备。  The obtained formyl chloride was dissolved in 4 ml of dichloromethane, and a solution of 0.22 g of 4-fluoroaniline and 0.234 ml of triethylamine in 5 ml of dichloromethane was slowly added dropwise at 0 ° C, and reacted at room temperature for 5 hours. :ethyl acetate = 7: 1 column chromatography to give 0.398 g of 1- (2, 4-dichlorophenyl) -5 - (4-chlorophenyl) - N- (4-fluorophenyl) - 4-mercapto-1H-pyrazole-3-oxanamide, mp: 174.7 - 176.3 ° C, two-step total yield 63.99 % , 'H-NMR (DMS0, δ ppm): 2.30 (s, 3H) , 7.14 -7.29 (m, 4Η), 7.46-7.63 (m, 3H), 7.80-7.86 (m, 4H), 10.30 (s, 1H). FAB-MS (m/e): 474.1 (M+). Preparation of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(2-fluorophenyl)-4-indolyl-1H-pyrazole-3-carboxamide.
Figure imgf000018_0001
Figure imgf000018_0001
5- (4-氯苯基） -1- (2， 4-二氯苯基） -4-曱基吡唑 - 3 -曱酰氯的制备方法参见实施例 1。  For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-mercaptopyrazole-3-carboxycarbonyl chloride, see Example 1.
将所得曱酰氯用 4ml二氯曱烷溶解，0 下，緩慢滴加入 0.22g 的 2 -氟苯胺和 0.234ml三乙胺在 5ml二氯曱烷的溶液中， 室温 下反应 5小时。用石油醚：乙酸乙酯 = 7: 1柱层析分离，得到 0.438g 的 1- (2, 4-二氯苯基） -5 - (4-氯苯基） -N- (2-氟苯基） -4-曱基 - 1H-吡唑 - 3-曱酰胺， mp: 163.5 - 165. 两步总 收 率 70.42 % ， 'H-NMR (DMS0, δ pm)： 2.29 (s, 3H) , 7.20-7.31 (m， 5Η)， 7.47-7.50 (d, 2H)， 7.60-7.63 (dd, 1H)， 7.74-7.84 (m, 3H), 9.81(s,lH). FAB-MS (m/e)： 474.0 (M+)o 实施例 10 N- (4-曱氧基苯基） -1- (2， 4-二氯苯基） - 5- (4-氯苯基） -4-曱基 -1H-吡唑 - 3-甲酰胺的制备。 The obtained decanoyl chloride was dissolved in 4 ml of dichlorosilane, and 0, 0.22 g was slowly added dropwise. The 2-fluoroaniline and 0.234 ml of triethylamine were reacted in a solution of 5 ml of dichloromethane at room temperature for 5 hours. Separation by column chromatography with petroleum ether: ethyl acetate = 7:1 to give 0.438 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N- (2-fluorobenzene) -4-mercapto- 1H-pyrazole-3-oxanamide, mp: 163.5 - 165. Total yield in two steps 70.42 % , 'H-NMR (DMS0, δ pm): 2.29 (s, 3H), 7.20-7.31 (m, 5Η), 7.47-7.50 (d, 2H), 7.60-7.63 (dd, 1H), 7.74-7.84 (m, 3H), 9.81(s,lH). FAB-MS (m/e ): 474.0 (M + ) o Example 10 N-(4-decyloxyphenyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl Preparation of -1H-pyrazole-3-carboxylate.
Figure imgf000019_0001
Figure imgf000019_0001
5- (4-氯苯基） -1- (2， 4-二氯苯基） -4-曱基吡峻 - 3 -甲酰氯的制备方法参见实施例 1。  For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-indolylpyrrole-3-carboxycarbonyl chloride, see Example 1.
将所得曱酰氯用 4ml 二氯甲烷溶解， 0。C下， 緩慢滴加入 0.268g的（4-曱氧基苯基） -曱基胺和 0.234ml三乙胺在 5ml二 氯曱烷的溶液中， 室温下反应 6小时。 用石油醚： 乙酸乙酯 =6: 1柱层析分离，得到 0.405g的 N- (4-甲氧基苯基） -1- (2， 4 一二氯苯基） -5- (4一氯苯基） — 4一甲基 -1H -吡唑一 3_曱 酰胺， mp:130.8 - 132.3 ， 两步总收率 61.74%, ]H-NMR (DMS0, δ ppm)： 2.25 (s, 3H) , 3.72 (s, 3Η) , 4.34 (d, 2Η) , 6.86 (d, 2Η) , 7.23(t,4H), 7.45-7.59 (m, 3H) , 7.75-7.78 (m， 2H)， 8.75 (t, 1H). FAB-MS (m/e): 500.0 (M+)o 实施例 11 1- (2, 4-二氯苯基） -5- (4-氯苯基） -4-曱基 -N- (4-吡啶基-曱基） - 1H-吡唑- 3-曱酰胺的 制备。 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. Separation by petroleum ether: ethyl acetate = 6: 1 column to give 0.405 g of N-(4-methoxyphenyl)-1-(2,4-dichlorophenyl)-5- (4 Chlorophenyl)-4-methyl-1H-pyrazole-3-indoleamide, mp: 130.8 - 132.3, total yield in two steps 61.74%, ] H-NMR (DMS0, δ ppm): 2.25 (s, 3H ), 3.72 (s, 3Η), 4.34 (d, 2Η), 6.86 (d, 2Η), 7.23(t,4H), 7.45-7.59 (m, 3H), 7.75-7.78 (m, 2H), 8.75 ( t, 1H). FAB-MS (m/e): 500.0 (M + ) o Example 11 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-N-(4-pyridyl-indenyl)-1H-pyrazole-3- Preparation of oxime amide.
Figure imgf000020_0001
Figure imgf000020_0001
5- (4-氯苯基) -1- (2, 4-二氯苯基） -4-甲基吡唑 - 3-甲酰氯的制备方法参见实施例 1。  For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxyl chloride, see Example 1.
将所得甲酰氯用 ½Γ二氯甲烷溶解， O 下， 緩慢滴加入 0.211g的 4-氨曱基吡啶和 0.234ml三乙胺在 5ml二氯曱烷的溶 液中， 室温下反应 7小时。 用石油醚： 乙酸乙酯 =1: 1柱层析分 离，得到 0.263g的 1- (2, 4-二氯苯基） -5- ( 4 -氯苯基） 一 4-曱基 -N— (4-吡 基-甲基） 一 1H -吡唑一 3-甲酰胺， mp: 64.7 - 67.0 ， 两步总收率 42.55 % , ^-NMR (DMS0, δ ppm)： 2.25 (s, 3H)， 4.42 (d, 2H)， 7.24-7.30 (m, 4H)， 7.46 (d, 2H)， 7.59 (dd, 1H), 7.78-7.80 (m， 2H)， 8.49(m，2H)， 8.98 (t, 1H). FAB-MS (m/e)： 471·2(Μ+)。 实施例 12 N-[3- (1-lH-咪唑基） -丙基 ] -1- (2， 4 一二氯苯基） -5- (4一氯苯基） 一 4-甲基— 1H-吡唑 - 3 -甲 酰胺的制备。  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. Separation by petroleum ether: ethyl acetate = 1 : 1 column chromatography gave 0.263 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)- 4-indolyl-N- (4-Pyridyl-methyl)- 1H-pyrazole-3-carboxamide, mp: 64.7 - 67.0, two-step total yield 42.55 %, ^-NMR (DMS0, δ ppm): 2.25 (s, 3H) , 4.42 (d, 2H), 7.24-7.30 (m, 4H), 7.46 (d, 2H), 7.59 (dd, 1H), 7.78-7.80 (m, 2H), 8.49 (m, 2H), 8.98 (t , 1H). FAB-MS (m/e): 471·2 (Μ+). Example 12 N-[3-(1-lH-imidazolyl)-propyl]-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H - Preparation of pyrazole-3-carboxyformamide.
0 ,-/~N^ 5- (4-氯苯基） -1- (2, 4-二氯苯基） -4-甲基吡唑 - 3-甲酰氯的制备方法参见实施例 1。 0 ,-/~ N ^ For the preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-yl chloride, see Example 1.
将所得曱酰氯用 4ml 二氯曱烷溶解， 下， 緩慢滴加入 0.244g 的 N- (3-氨基丙基） -咪唑和 0.23½1 三乙胺在 5ml 二氯曱烷的溶液中， 室温下反应 7小时。用氨水： 乙醇： 氯仿 = 1: 10: 200柱层析分离，得到 0.42g的 N-[3- (1-1H-咪唑基) - 丙基] -1- (2, 4—二氯苯基） -5- (4-氯苯基） -4—甲基一 1H-吡唑 - 3-甲酰胺， mp:184.5 - 186.8 ， 两步总收率 65.58 % ， ^-NMR (DMS0, δ ppm): 1.93-1.95 (m, 2H) , 2.25(s,3H), 3.21(dd, 2H), 3.96 (t,2H), 6.88(t，lH)， 7.21-7.25 (m, 3H) , 7.45(d, 2H), 7.57 (dd, 1H), 7.67 (s, 1H), 7.75-7.79 (m， 2H)， 8.43(t, 1H). FAB-MS (m/e)： 488.0 (M+)o 实施例 14 1- (2， 4-二氯苯基） -5- (4-氯苯基） -N - [4- (二甲基氨基）苯基]一4一曱基—111-吡唑- 3—甲酰 胺的制备。 The obtained 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. Ammonia: ethanol: chloroform = 1: 10: 200 column chromatography to give 0.42 g of N-[3-(1-1H-imidazolyl)-propyl]-1-(2,4-dichlorophenyl) -5-(4-Chlorophenyl)-4-methyl- 1H-pyrazole-3-carbamide, mp: 184.5 - 186.8, two-step total yield 65.58 %, ^-NMR (DMS0, δ ppm) : 1.93-1.95 (m, 2H) , 2.25(s,3H), 3.21(dd, 2H), 3.96 (t,2H), 6.88(t,lH), 7.21-7.25 (m, 3H) , 7.45(d , 2H), 7.57 (dd, 1H), 7.67 (s, 1H), 7.75-7.79 (m, 2H), 8.43(t, 1H). FAB-MS (m/e): 488.0 (M + ) o Example 14 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-N-[4-(dimethylamino)phenyl]-tetramethyl-111-pyrazole- Preparation of 3-formamide.
Figure imgf000021_0001
5- (4-氯苯基） - I- (2， 4-二氯苯基） -4-曱基吡唑 - 3 -曱酰氯的制备方法参见实施例 1。
Figure imgf000021_0001
For the preparation of 5-(4-chlorophenyl)-I-(2,4-dichlorophenyl)-4-mercaptopyrazole-3-nonanoyl chloride, see Example 1.
将所得甲酰氯用 4ml 二氯曱烷溶解， O 下， 緩慢滴加入 0.266g的 N，N-二曱基对位苯胺和 0.234ml三乙胺在 5ml二氯曱 烷的溶液中， 室温下反应 7小时。 用石油醚: 乙酸乙酯 =1: 3柱 层析分离，得到 0.443g的 1- (2， 4-二氯苯基） -5- (4-氯 苯基） -N - [4 - (二曱基氨基 )苯基]一 4—甲基一 1H—吡唑一 3 -曱酰胺， mp: 151.5 - 152.8 ，两步总收率 67.65 % ,Ή-NMR (DMS0 δ ppm)： 2.29(s，3H)， 2.86(s,6H), 6.68(d, 2H), 7.25(d, 2H), 7.46(d, 2H), 7.59 (dd, 3H) , 7.79-7.81 (m，2H)， 9.88 (s, 1H). FAB-MS (m/e)： 500. l(M+)。 实施例 15 本发明化合物对大鼠小脑 CB1受体的作用 实验方法  The obtained formyl chloride was dissolved in 4 ml of dichloromethane, and 0.266 g of N,N-dimercapto-p-aniline and 0.234 ml of triethylamine were slowly added dropwise in a solution of 5 ml of dichloromethane at room temperature. 7 hours. Separation by petroleum ether: ethyl acetate = 1: 3 column chromatography gave 0.443 g of 1- (2, 4-dichlorophenyl) -5- (4-chlorophenyl) -N - [4 - (2)曱-amino)phenyl]- 4-methyl- 1H-pyrazole-3-oxoamide, mp: 151.5 - 152.8, two-step total yield: 67.65 %, Ή-NMR (DMS0 δ ppm): 2.29 (s, 3H), 2.86(s,6H), 6.68(d, 2H), 7.25(d, 2H), 7.46(d, 2H), 7.59 (dd, 3H), 7.79-7.81 (m,2H), 9.88 (s , 1H). FAB-MS (m/e): 500. l (M+). Example 15 Effect of the compound of the present invention on CB1 receptor of rat cerebellum Experimental method
( 1 ) 大鼠小脑 CB1受体膜蛋白的制备：  (1) Preparation of CB1 receptor membrane protein in rat cerebellum:
用 Wistar大鼠， 220 ~ 260g， 雌雄不限， 断头处死后， 迅速 分离出小脑，称量后加入 10倍体积的 Tris-HCl Buffer( 50mM Tris HC1, 5mM MgC126. H20, ImM EDTA, 0.5% ( W/V ) BSA, pH7.4 ) , 用匀桨器 15000rpm/min进行勾浆， 每次 30秒， 共 5次。 句浆液 经 400 x g离心 10min，取上清液再用 39000 x g离心 lOmin, 收集 沉淀， 用原重量的 10倍体积 Tris-HCl Buffer pH7.4重新悬浮， 再用 39000 x g离心 lOmin, 取沉淀用相同緩冲液洗涤， 39000 x g 离心 lOmin, 最后将得到的沉淀用 Tris-HCl Buffer悬浮， 分装 后（整个操作过程要在 4。C进行）在- 8 (TC保存备用。 用 Folin法 测定蛋白质含量。  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. 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. .
( 2 ) CB1受体蛋白质含量的测定： 样品 100 μ 1， 内含 BSA 5 ~ lOO g (作标准曲线用） 或待测 样品， 不足 100 μ ΐ者用 Η20补足， 加试剂曱 （①含 4%碳酸钠及 0.2%酒石酸钠 （Na2C4 H906 2H20) 的 0.2N NaOH溶液， ② 4°/。硫酸 铜 （CuS04 .5H20) 水溶液， 将①和②按 100: 1的比例混合均匀， 即为试剂曱， 配制后一天内使用） 100μ 1， 混合后放在室温反应 10分钟， 再加试剂乙 （Folin-酚试剂， 最后浓度为 1N) 20μ 1, 立即混匀， 置 水浴中， 孵温 15分钟， 取 200 μ 1用微量多道 扫描光密度计， 波长 690nm,光程 0.6cm,测光密度值，用 H20100 μ ΐ代替样品作空白对照。 (2) Determination of protein content of CB1 receptor: Sample 100 μ 1, containing BSA 5 ~ lOO g (for standard curve) or sample to be tested, less than 100 μ ΐ with Η20 to make up, plus reagent 曱 (1 with 4% sodium carbonate and 0.2% sodium tartrate (Na2C4 H906 2H20) 0.2N NaOH solution, 2 4 ° /. Copper sulfate (CuS04.5H20) aqueous solution, mix 1 and 2 in a ratio of 100:1, which is the reagent 曱, used within one day after preparation) 100μ 1, mixed After the reaction at room temperature for 10 minutes, add reagent B (Folin-phenol reagent, the final concentration is 1N) 20μ 1, mix immediately, put in a water bath, incubate for 15 minutes, take 200 μ 1 with a trace multi-channel scanning optical density Calculate, wavelength 690nm, optical path 0.6cm, photometric density value, replace the sample with H20100 μ 作 as a blank control.
( 3) CB1受体与 3H-SR141716A的饱和实验：  (3) Saturation experiments of CB1 receptor and 3H-SR141716A:
所有管中依次加 30 相同受体的蛋白量，在非特异结合管 中加入 25 μ 1 ( 10-4M) SR141716A, 在 30 反应 30分钟； 全部 试管依次加入不同的 3H-SR141716A, 用 Tris-HCl Buffer补足所 有反应管体积为 300 μ ΐ， 在 30 反应 1 小时； 然后点样于 49 型玻璃纤维滤纸上（滤纸预先用 0. lmg/ml BSA湿润） ， 经负压抽 滤，再用水冷的 Tris-HCl Buffer( 50mM Tris-HCl Buffer, pH 7.4, 1 mM EDTA, 5 mM MgCL2 ) 洗涤， 每次 2 ml, 共 10次， 抽干滤纸， 将滤纸取出烘干后， 放在闪烁瓶中， 加 1 ml 闪烁液， 用 LS6500 型液闪计数器测定放射性强度。  Add 30 molecules of the same receptor in all tubes, add 25 μl ( 10-4M) SR141716A to the non-specific binding tube, and react at 30 minutes for 30 minutes; add 3H-SR141716A to all tubes in turn, using Tris-HCl Buffer fills all reaction tubes with a volume of 300 μΐ, reacts at 30 hours for 1 hour; then samples on type 49 glass fiber filter paper (filter paper is pre-wet with 0. lmg/ml BSA), suction filtered by vacuum, and then cooled with water. Wash the 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. Add 1 ml of scintillation fluid and measure the radioactivity using a LS6500 liquid scintillation counter.
( 4 ) 药物对 CB1受体与 3H-SR141716A结合竟争实验： 在 30X的反应条件中摆放试管， 所有管中依次加入 100 受 体蛋白量， 测试管中依次加入 20 μ ΐ—定浓度的药物， 非特异结合 管中加入 50 μ 1非标配体（ACEA) , 非标配体终浓度为 lmM， 预先 反应 30分钟， 全部试管依次加入 30 μ 1 3H-SR141716A ( 16ηΜ) ， 标记配体终浓度为 2.4ηΜ，用 Buffer补足所有反应管体积为 200 μ 1, 在 30"C反应条件下反应 1小时， 然后点样于 49型玻璃纤维滤膜上， 经负压抽滤， 再用水冷的 Buffer洗涤 10次， 每次 2 ml , 抽干滤膜， 将滤膜取出烘干后， 放在闪烁瓶中， 加 lml闪烁液， 用 LS6500型液 闪计数器测定放射性强度。 (4) 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 μ ΐ-concentration is added to the test tube. Drug, non-specific binding tube was added with 50 μl 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 μl 3H-SR141716A (16ηΜ), labeled ligand The final concentration was 2.4 Μ, and all the reaction tubes were filled with Buffer to a volume of 200 μl, reacted under a reaction condition of 30"C for 1 hour, and then spotted on a Type 49 glass fiber filter. After suction filtration by vacuum, rinse with water-cooled Buffer 10 times, 2 ml each time, drain the filter, remove the filter, and place it in a scintillation vial, add 1 ml of scintillation fluid, use LS6500 liquid flash counter The radioactivity was measured.
实验结果  Experimental result
活性评价结果如下表所示：  The results of the activity evaluation are shown in the following table:
表 1  Table 1
化合物 抑制百分比 （％ )  Compound inhibition percentage (%)
lxl O"5 M 1x10— 7 M 1x10"' M lxl O "5 M 1x10- 7 M 1x10"'M
SR141716A 100. 0 100. 0 92. 2 SR141716A 100. 0 100. 0 92. 2
1实施例 1 100. 0 95. 8 84. 21 Embodiment 1 100. 0 95. 8 84. 2
2实施例 2 100. 0 69. 8 1. 52 Example 2 100. 0 69. 8 1. 5
3实施例 3 100. 0 75. 6 56. 63 embodiment 3 100. 0 75. 6 56. 6
7实施例 4 100. 0 96. 6 50. 67Example 4 100. 0 96. 6 50. 6
9实施例 5 100. 0 74. 0 40. 19th embodiment 5 100. 0 74. 0 40. 1
10实施例 6 87. 3 57. 4 27. 810 Example 6 87. 3 57. 4 27. 8
11实施例 7 100. 0 84. 2 50. 111 Example 7 100. 0 84. 2 50. 1
12实施例 8 100. 0 84. 8 30. 112 Example 8 100. 0 84. 8 30. 1
13实施例 9 100. 0 81. 2 40. 313 Example 9 100. 0 81. 2 40. 3
14实施例 10 100. 0 82. 8 24. 014 Example 10 100. 0 82. 8 24. 0
16实施例 11 100. 0 100. 0 14. 416th embodiment 11 100. 0 100. 0 14. 4
20实施例 12 100. 0 98. 9 17. 220 Example 12 100. 0 98. 9 17. 2
21实施例 13 100. 0 64. 0 31. 2 根据初筛结果， 对 CB1受体亲和力较高的化合物， 进一步测 定其 IC50 (Log M)。 SR141716为 1. 30x10— 1ϋ, 实施例 1化合物为 2. 53x10- 10。 实施例 16 本发明化合物的药代动力学性质 21 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- 1ϋ, the compound of Example 1 is 2. 53x10- 10. Example 16 Pharmacokinetic properties of the compounds of the invention
方法  Method
把所合成化合物组建一个 ISISBase数据库， *. db格式的文件， 用 Concord 4. 08程序将化合物从 2D转化到 3D, 转为 *· mol 2格式， 传入 SYBYL给化合物以相应的电荷。 在 SYBYL中组建一个数据库， *. mdb格式， 把所有分子导入， ）用 VolSurf 3. 010的 GRID程序计 算 3D分子与水、疏水和羰基 3个探针之间的相互作用场， 分别计算 Caco-2细胞吸收透膜模型、 BBB血脑屏障透过性模型和药物蛋白结 合模型的描述参数。 Combine the synthesized compounds into an ISISBase database, *.db format files, The compound was converted from 2D to 3D using the Concord 4. 08 procedure, converted to *. mol 2 format, and SYBYL was introduced to give the compound a corresponding charge. A database was constructed in SYBYL, *. mdb format, all molecules were introduced, and the interaction field between 3D molecules and water, hydrophobic and carbonyl probes was calculated using the GRS program of VolSurf 3. 010, and Caco- was calculated separately. 2 cell absorption transmembrane model, BBB blood-brain barrier permeability model and drug protein binding model description parameters.
1  1
预测结果见下表  The results are shown in the table below
化合物 BBB Caco2 蛋白结合  Compound BBB Caco2 protein binding
1实施例 1 - 0. 18 1. 17  1 embodiment 1 - 0. 18 1. 17
2实施例 2 - 0. 10 0. 77 91. 90  2 Example 2 - 0. 10 0. 77 91. 90
3实施例 3 -0. 08 0. 54 82. 29  3 embodiment 3 -0. 08 0. 54 82. 29
7实施例 4 0. 19 0. 95 86. 73  7th embodiment 4 0. 19 0. 95 86. 73
9实施例 5 0. 22 1. 02 92. 95  9 Example 5 0. 22 1. 02 92. 95
10实施例 6 -0. 05 0. 68 80. 21  10 embodiment 6 -0. 05 0. 68 80. 21
11实施例 7 0. 04 0. 77 86. 43  11th embodiment 7 0. 04 0. 77 86. 43
12实施例 8 0 0. 79 88. 40  12 embodiment 8 0 0. 79 88. 40
13实施例 9 0. 01 0. 82 87. 57  13 Embodiment 9 0. 01 0. 82 87. 57
14实施例 10 -0. 17 0. 62 89. 64  14 Examples 10 -0. 17 0. 62 89. 64
16实施例 11 -0. 17 0. 55 87. 13  16th embodiment 11 -0. 17 0. 55 87. 13
20实施例 12 0. 65 92. 00  20 embodiment 12 0. 65 92. 00
21实施例 13 -0. 05 1. 01 99. 09  21 embodiment 13 -0. 05 1. 01 99. 09
SR141716 0. 13 0. 91 上表中， BBB透过性模型的预测结果： 能穿透的为 BBB+, 不 能穿透的为 BBB-； Caco- 2模建的结果， 得分高者， 透膜性高； 蛋 白结合模型的结果， 得分者高， 蛋白结合能力强。 从表中可以看 出， 化合物实施例 4、 实施例 5在三项预测中都有良好表现， 优 于对照化合物 SR141716A, 实施例 1 的透膜性也强于阳性对照药 SR141716A.  SR141716 0. 13 0. 91 In the above table, the prediction results of the BBB permeability model: BBB+ can be penetrated, BBB- can not penetrate; Caco-2 model results, high score, transmembrane High; protein binding model results in high scorers and strong protein binding ability. As can be seen from the table, Compound Example 4 and Example 5 performed well in all three predictions, which was superior to the control compound SR141716A. The permeability of Example 1 was also stronger than that of the positive control drug SR141716A.

Claims

权 利 要 求 Rights request
1. 通式 I 的 4-甲基 -1H-二芳基吡唑衍生物或其立体异构 体或它们的可药用的盐或它们的水合物 A 4-methyl-1H-diarylpyrazole derivative of the formula I or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a hydrate thereof
Figure imgf000026_0001
其中： R是 H， d- C15烷基， 尤其是 d-C8的直链或支链烷基， 环烷基， 或是 C6-C15的取代或未取代的芳香基， 有代表性的如苯 基、 萘基、 蒽基、 芴基， 或是含 N杂环如喹啉、 吡咯、 哌啶、 哌 嗪、 吗啉、 咪唑、 吡唑、 吗啉或其他杂环如噻唑、 呋喃等； 取代 基选自面素、 氰基、 硫氢基、 曱酰基、 羟基、 磺酸酯、 硝基、 亚 硝基、 d-C8取代或未取代烷氨基、 d-6烷硫基、 d-C8的烷氧基、 d-C15烷基、 尤其是 d-C8直链、 支链和环状结构烷基。
Figure imgf000026_0001
Wherein: R is H, d-C 15 alkyl, especially a linear or branched alkyl group of dC 8 , a cycloalkyl group, or a C 6 -C 15 substituted or unsubstituted aryl group, representative Such as phenyl, naphthyl, anthryl, 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. The substituent is selected from the group consisting of facet, cyano, sulfhydryl, decanoyl, hydroxy, sulfonate, nitro, nitroso, dC 8 substituted or unsubstituted alkylamino, d- 6 alkylthio, dC 8 Alkoxy, dC 15 alkyl, especially dC 8 linear, branched and cyclic alkyl.
2. 权利要求 1的 4 -曱基 -1H-二芳基吡唑衍生物，其选自下 列化合物： 2. The 4-mercapto-1H-diarylpyrazole derivative of claim 1 which is selected from the group consisting of the following compounds:
1 - (2, 4 -二氯苯基） - 5- (4 -氯苯基） -N- ( 2- 9H -芴基） - 4-曱基- 1H-吡唾 - 3 -甲酰胺  1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(2- 9H-indenyl)-4-yl-yl- 1H-pyrazine-3-carboxamide
N- (4 -溴苯基） -1- (2, 4 -二氯苯基） -5- (4 -氯苯 基） —4—曱基— 1H-吡唑— 3—甲酰胺  N-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-1H-pyrazole-3-carboxamide
1- (2, 4-二氯苯基） - 5- (4-氯苯基） -4-曱基 -N- ( 3 -吡啶基） -1H-吡唑 - 3-曱酰胺  1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-N-(3-pyridyl)-1H-pyrazole-3-indoleamide
1- (2, 4 -二氯苯基） -5- (4 -氯苯基） -N-环戊基 -4 -曱基- 1H-吡唑- 3-曱酰胺 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-cyclopentyl-4 -mercapto- 1H-pyrazole- 3-indoleamide
1 - ( 2， 4-二氯苯基） - 5 - ( 4 -氯苯基） -N- (曱基环 己基） — 4-曱基一 1H -吡唑 - 3—曱酰胺  1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(indolylcyclohexyl)-4-mercapto-1H-pyrazole-3-oxoamide
1 - ( 2, 4 -二氯苯基） - 5 - （4 -氯苯基） - 4 -甲基 - N - ( 4-曱基- 1 - 嗪基） - 1H -吡唑 - 3-甲酰胺  1 - ( 2, 4 -dichlorophenyl) - 5 - (4-chlorophenyl) - 4 -methyl-N - ( 4-indolyl- 1 -azinyl) - 1H -pyrazole - 3-methyl Amide
1 - ( 2, 4-二氯苯基） - 5- ( 4 -氯苯基） -N- ( 2 -呋喃 一甲基） - 4一曱基一 1H—吡唑— 3-甲酰胺  1 - ( 2, 4-dichlorophenyl) - 5-( 4 -chlorophenyl) -N-( 2 -furan monomethyl ) - 4 - fluorenyl-1H-pyrazole-3-carbamide
1 - （2， 4—二氯苯基） - 5 - ( 4-氯苯基） -N- ( 4-氟苯 基） — 4 -甲基 - 1H -吡唑一 3-甲酰胺  1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carbamide
1 - ( 2, 4-二氯苯基） - 5- (4-氯苯基） -N- ( 2-氟苯 基） - 4一曱基 - 1H -吡唑— 3-甲酰胺  1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-N-(2-fluorophenyl)-4-yl-yl- 1H-pyrazole-3-carboxyamide
N- ( 4 -曱氧基苯基） - 1 - ( 2， 4 -二氯苯基） - 5 - ( 4 -氯苯基） - 4 -曱基 - 1H-吡唑 - 3-甲酰胺  N-(4-oxophenyl)-1 - (2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-indolyl-1H-pyrazole-3-carboxamide
1 - （2, 4 -二氯苯基） - 5 - ( 4 -氯苯基） - 4 -曱基- N - ( 3-吡啶基-曱基） - 1H-吡唑 - 3-曱酰胺  1 - (2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-yl-yl-N-(3-pyridyl-indenyl)-1H-pyrazole-3-indamide
1 - ( 2, 4 -二氯苯基） - 5 - （4 -氯苯基） - 4 -曱基 - N - ( 4-吡啶基-曱基） - 1H-吡唑 - 3-曱酰胺  1 - ( 2, 4 -dichlorophenyl) - 5 - (4-chlorophenyl) - 4 -fluorenyl - N - ( 4-pyridyl-indenyl) - 1H-pyrazole - 3-indoleamide
N-[3- ( 1 - 1H-咪唑基） -丙基 ] - 1 - ( 2， 4 -二氯苯基） - 5 - ( 4-氯苯基） - 4 -曱基- 1H-吡唾 - 3-曱酰胺  N-[3- ( 1 - 1H-imidazolyl)-propyl] - 1 - ( 2, 4 -dichlorophenyl) - 5 - ( 4-chlorophenyl) - 4 -fluorenyl - 1H-pyrazole - 3-indoleamide
1 - ( 2, 4 -二氯苯基） - 5 - ( 4 -氯苯基） - N- [4- (二 甲基氨基） 苯基] - 4 -曱基 - 1H—吡唑 - 3—曱酰胺  1 - ( 2, 4 -dichlorophenyl) - 5 - ( 4 -chlorophenyl) - N- [4- (dimethylamino)phenyl] - 4 -fluorenyl-1H-pyrazole-3 Amide
3. 一种药物组合物，其包含作为活性的成分，如权利要求 1 ~ 2中任何一项所述的 4-甲基 -1H-二芳基吡唑衍生物，或其立体异 构体或它们的可药用盐， 或它们的水合物或溶剂化物及药用载体 或赋形剂。  A pharmaceutical composition comprising, as an active ingredient, the 4-methyl-1H-diarylpyrazole derivative according to any one of claims 1 to 2, or a stereoisomer thereof or Their pharmaceutically acceptable salts, or hydrates or solvates thereof, and pharmaceutically acceptable carriers or excipients.
4. 权利要求 3 的药物组合物一种用于治疗肥胖的药物组合 物。 4. The pharmaceutical composition of claim 3, a pharmaceutical combination for treating obesity Things.
5. 权利要求 3的药物组合物， 其是一种用于改善记忆的药物 组合物。  The pharmaceutical composition of claim 3 which is a pharmaceutical composition for improving memory.
6. 权利要求 3的药物组合物， 其是一种用于戒烟的药物组合 物。  6. The pharmaceutical composition of claim 3 which is a pharmaceutical composition for smoking cessation.
7. 通式 I的 4 -甲基 -1H-二芳基吡唑衍生物或其立体异构体 或它们的可药用的盐或它们的水合物在制备具有治疗肥胖、 改善 记忆、 戒烟活性的药物中的用途。  7. The 4-methyl-1H-diarylpyrazole derivative of the formula I or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a hydrate thereof is prepared for the treatment of obesity, memory improvement, smoking cessation activity Use of the drug.
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WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2009027393A3 (en) * 2007-08-27 2009-09-24 Basf Se Pyrazole compounds for controlling invertebrate pests
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2013026264A1 (en) * 2011-08-23 2013-02-28 Fan Rulin Cb1 acceptor inhibitor compound with nitrogen-containing aromatic ring having hydroxyl and use thereof
US8710056B2 (en) 2009-07-06 2014-04-29 Basf Se Pyridazine compounds for controlling invertebrate pests
US8729083B2 (en) 2008-09-24 2014-05-20 Basf Se Pyrazole compounds for controlling invertebrate pests
US8853125B2 (en) 2008-09-24 2014-10-07 Basf Se Pyrazole compounds for controlling invertebrate pests
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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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
US8642597B2 (en) 2007-08-27 2014-02-04 Basf Se Pyrazole compounds for controlling invertebrate pests
JP2010536926A (en) * 2007-08-27 2010-12-02 ビーエーエスエフ ソシエタス・ヨーロピア Pyrazole compounds for controlling invertebrate pests
WO2009027393A3 (en) * 2007-08-27 2009-09-24 Basf Se Pyrazole compounds for controlling invertebrate pests
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
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2013026264A1 (en) * 2011-08-23 2013-02-28 Fan Rulin Cb1 acceptor inhibitor compound with nitrogen-containing aromatic ring having hydroxyl and use thereof

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