WO2016184310A1 - 4-甲基-1h-二芳基吡唑衍生物及其作为药物的用途 - Google Patents

4-甲基-1h-二芳基吡唑衍生物及其作为药物的用途 Download PDF

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WO2016184310A1
WO2016184310A1 PCT/CN2016/081091 CN2016081091W WO2016184310A1 WO 2016184310 A1 WO2016184310 A1 WO 2016184310A1 CN 2016081091 W CN2016081091 W CN 2016081091W WO 2016184310 A1 WO2016184310 A1 WO 2016184310A1
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group
methyl
dichlorophenyl
chlorophenyl
pyrazol
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PCT/CN2016/081091
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English (en)
French (fr)
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李松
郑志兵
陶晓璇
王莉莉
周辛波
陈伟
钟武
肖军海
谢云德
李行舟
王晓奎
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中国人民解放军军事医学科学院毒物药物研究所
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Publication of WO2016184310A1 publication Critical patent/WO2016184310A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicine, and in particular to 4-methyl-1H-diarylpyrazole derivatives and stereoisomers, solvates or pharmaceutically acceptable salts thereof, processes for preparing the same, pharmaceutical compositions containing the same, and
  • the compound is used as a cannabinoid type I (CB1) receptor inhibitor in the brain for the preparation of a medicament for preventing, treating or slowing down diseases or symptoms associated with excessive activity of the CB1 receptor such as obesity, memory or cognitive impairment, craving, and the like. use.
  • CBD1 cannabinoid type I
  • Marijuana (Canabis) has been used in BC and is the most used drug of abuse in Western society. It is also the longest-used drug of abuse in human history. Cannabis can change perception or make people excited, relaxed, or depressed, panic-stricken. These effects are mainly caused by tetrahydrocannabinol contained in cannabis. In 1964, the main active ingredient of cannabis was purified for the first time - tetrahydrocannabis. Phenol (delta9tetrahydrocannabinol, ⁇ 9 -THC) and clarified its chemical structure (Nakamura PE, et al. The pharmacology of SR141716A: A Review [J]. CNS Drug Reviews, 1999, 5(1): 43-58). Tetrahydrocannabinol is an aromatic quinone which also has various pharmacological effects such as analgesic, sedative, antispasmodic, anti-vomiting, anti-glaucoma and antihypertensive.
  • the cannabinoid (CB) receptor refers to a receptor that responds to cannabinoids such as ⁇ 9 -THC and belongs to a G protein coupled receptor.
  • the cannabinoid receptor mainly has CB1 (Mechoulam R, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors [J]. Biochem Pharmacol, 1995, 50(1): 83-90.
  • CB2 (Munro S, et al. Molecular characterization of a peripheral receptor for cannabinoids [J].
  • the CB1 receptor is mainly expressed in the central nervous system
  • the system also known as the central cannabinoid receptor
  • the CB2 receptor is mainly found in peripheral neurons, also known as peripheral cannabinoid receptors, and is expressed in a small amount in the central nervous system.
  • One of the functions is to prevent the release of neurotransmitters. Their main differences are in amino acid sequence, signal transduction mechanism, organ distribution and sensitivity to certain agonists and inhibitors.
  • 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.
  • the CB1 receptor is considered to be the most widely expressed G protein-coupled receptor in the brain, consisting of 473 amino acids and 7 transmembrane domains.
  • the N-terminal extracellular region of the CB1 receptor contains 116 amino acid residues.
  • CB1 receptor This structure is decisive for the biological properties of the CB1 receptor and the expression of membranes in plasma.
  • the N-terminus of CB1 regulates ligand specificity and cell surface.
  • the receptor has an important role in the affinity of the ligand drug. Studies have shown that endocrine ligands of the cannabinoid receptor type I have dual regulatory effects on food intake and energy expenditure, thereby achieving weight control (ACHowlett, et al. Pharmacol. Rev., 2002, 54, 161-202). .
  • the first cannabinoid receptor antagonist, rimonabant is a diarylpyrazole.
  • Rimonabant is a selective CB1 receptor antagonist developed by the French company Sanofi-Aventis. It can treat obesity and can be used as a Smoking cessation drugs, approved for marketing in the UK in July 2006, but rimonabant has central side effects that can increase serious mental side effects, namely depression and anxiety (Christensen R, et al.Efficacy and safety of the weight- Loss drug rimonabant: a meta-analysis of randomized trials [J]. Lancet, 2007, 370 (9600): 1706-1713.). Therefore, it is necessary to find new peripherally selective CB1 receptor antagonists.
  • One object of the present invention is to find a novel small molecule antagonist which inhibits the CB1 receptor; another object of the present invention is to find a diarylpyrazole small molecule which does not easily penetrate the blood brain barrier and mainly acts on the peripheral CB1 receptor. Antagonist.
  • a compound having the following formula I has an action of inhibiting the CB1 receptor, and thus can be used for preventing, treating or slowing down diseases or symptoms associated with excessive activity of the CB1 receptor, such as obesity, craving, memory and Cognitive impairment, mental illness, and adverse chemotherapy response to cancer Wait.
  • One aspect of the invention relates to a compound of formula I, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof,
  • R is selected from C 1 -C 15 alkyl (e.g., C 1 -C 8 alkyl), C 3 -C 10 cycloalkyl, C 1 -C 8 alkoxy, aryl, benzyl, benzyloxy An aryloxy group, an N-containing heterocyclic group, and an N-containing heterocyclic group-C 1-6 alkyl group; wherein said C 1 -C 15 alkyl group, C 3 -C 10 cycloalkyl group, C 1 -C 8 Alkoxy, aryl, benzyl, benzyloxy, aryloxy, N-containing heterocyclic, N-heterocyclyl-C 1-6 alkyl are unsubstituted or are each independently selected from the group consisting of Substituent substitution: C 1 -C 8 alkyl, aryl-C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, cyano, sulfhydry
  • M is selected from O and NR 1 ;
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, aryl or N-containing heterocyclic groups (eg, quinoline, pyridine, piperidine, piperazine, morpholine, imidazole, Pyrazole or thiazole); optionally wherein the C 1 -C 8 alkyl group, C 3 -C 10 cycloalkyl group, aryl group or N-containing heterocyclic group is unsubstituted or each independently selected from the group consisting of Substituted substituents: C 1 -C 8 alkyl, aryl C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, cyano, sulfhydryl, formyl, hydroxy, sulfonate, Nitro and nitroso.
  • C 1 -C 8 alkyl C 3 -C 10 cycloalkyl, aryl or N-
  • the number of said substituents is one or more, for example 1, 2, 3 or 4.
  • R is selected from C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 8 alkoxy, aryl, benzyl, benzyloxy, N heterocyclic group, N-containing heterocyclic group-C 1-6 alkyl group; wherein the C 1 -C 8 alkyl group, C 3 -C 10 cycloalkyl group, C 1 -C 8 alkoxy group, aryl group, Benzyl, benzyloxy, N-containing heterocyclyl, N-containing heterocyclyl-C 1-6 alkyl are unsubstituted or each independently selected from one or more (eg 1, 2, 3 or 4) The substituents described below are substituted: C 1 -C 8 alkyl, C 1 -C 8 alkoxy and halogen.
  • R is selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, phenyl, benzyl, benzyloxy, five a mono or hexavalent N-containing heteroaryl, 5- or 6-membered N-heterocycloalkyl, 5- or 6-membered N heteroaryl-C 1-4 alkyl group; wherein said C 1 -C 4 alkyl group , C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, phenyl, benzyl, benzyloxy, 5- or 6-membered N heteroaryl, 5- or 6-membered N-heterocycloalkane
  • the hexa, five or six membered N heteroaryl-C 1-4 alkyl group is unsubstituted or each independently substituted with one or more (eg 1, 2, 3 or 4) substituents selected from the group consisting of
  • R is selected from the group consisting of isopropyl, cyclopropyl, methoxy, phenyl, piperidine, piperazine, morpholine, thiazole, pyridine, benzyl, benzyloxy, pyridine
  • isopropyl, cyclopropyl, methoxy, phenyl, piperidine, piperazine, morpholine, thiazole, pyridine, benzyl, benzyloxy, pyridylmethyl groups are unsubstituted or independently Substituted by one or more (e.g., one or two) substituents selected from the group consisting of methyl, methoxy, bromo and iodo.
  • R is selected from the group consisting of a six-membered N-containing heteroaryl group, a six-membered N-containing heterocycloalkyl group, a benzyl group, and a benzyloxy group; wherein the six-membered N-containing heteroaryl group, six-membered
  • the N-containing heterocycloalkyl group, the benzyl group and the benzyloxy group are unsubstituted or each independently substituted with one or more (for example one) substituents selected from C 1 -C 4 alkyl and C 1 - C 4 alkoxy.
  • R is selected from the group consisting of 2-methoxypyridin-5-yl, piperidinyl, morpholin-4-yl, 5-methylpyridin-2-yl, benzyl, and benzyloxy
  • R is selected from the group consisting of piperidinyl and benzyloxy.
  • R is selected from the group consisting of C 1 -C 4 alkoxy, five-membered N-heteroaryl, and phenyl; wherein said C 1 -C 4 alkoxy, five-membered N-containing an aryl group, and phenyl is unsubstituted or independently substituted with one or more (e.g. two) substituents selected from: C 1 -C 4 alkyl and halo.
  • R is selected from the group consisting of methoxy, thiazol-2-yl and 4-iodo-2-methylphenyl.
  • M is selected from the group consisting of O, NR 1 ;
  • R 1 is selected from hydrogen or a substituted or unsubstituted C 1 -C 8 alkyl group.
  • M is selected from the group consisting of O and NR 1 ; wherein R 1 is selected from C 1 -C 4 alkyl (preferably methyl).
  • M is O.
  • the compound of formula I is selected from
  • a second aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a compound of Formula I, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof may be used alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the form is used in the form of a composition.
  • an effective amount of a compound of formula I of the present invention, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents are usually employed.
  • the agents are combined to form a suitable administration form or dosage form.
  • 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 phosphate, 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, Carboxymethylcellulose hooks, polyacrylates, beeswax, wool vinegar, etc.
  • the amount of the carrier in the pharmaceutical composition may be from 1% by weight to 98% by weight, usually about 80% by weight.
  • the local anesthetic, preservative, buffer, etc. may be directly dissolved in the carrier.
  • the pharmaceutically acceptable excipient contained in the pharmaceutical composition of the present invention refers to an additive other than the main drug in the pharmaceutical preparation, which is stable in nature, has no compatibility contraindication with the main drug, does not cause side effects, and does not affect the therapeutic effect, at normal temperature. It is not easy to be deformed, cracked, mildewed, insects, harmless to the human body, has no physiological effects, does not produce chemical or physical effects with the main drug, and does not affect the determination of the content of the main drug.
  • the pharmaceutical composition of the present invention can be administered in the following manners: oral, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, Intrathecal, intraventricular, intrasternal or intracranial injection or input, or by means of an explanted reservoir.
  • oral administration, intramuscular, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present invention can be formulated into orally acceptable preparations such as oral tablets and capsules.
  • Excipients may be included in the oral preparation.
  • a binder such as syrup, gum arabic, sorbitol, tragacanth or polyvinylpyrrolidone
  • a filler such as lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine
  • a lubricant such as magnesium stearate , talc, polyethylene glycol or silica
  • disintegrants such as potato starch
  • humectants such as sodium lauryl sulfate.
  • the tablets may be coated by methods known in the art of pharmacy.
  • the pharmaceutical composition of the present invention in the form of an oral liquid may be a suspension of water and oil, a solution, an emulsion, a syrup or an elixir, or may be made into a dry product, supplemented with water or other suitable medium before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Oil; emulsifier, such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous carrier (may contain edible oils), such as almond oil, oils such as glycerin, ethylene glycol, or ethanol; preservatives, Such as methyl or propyl paraben, sorbic acid. Flavoring or coloring agents may also be added as needed.
  • suspending agents such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Oil
  • emulsifier such as lecithin, sorbitan monooleate, gum arabic
  • non-aqueous carrier may contain edible oils), such
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • a sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the liquid dosage form is usually made up of the compound and at least one sterile or sterile carrier, the carrier being preferably water.
  • the carrier being preferably water.
  • the compound can be dissolved in the carrier or in a suspension solution. The compound is dissolved in water before being prepared for injection, filtered and sterilized, and then placed in a sealed bottle or ampoule.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion, or cream, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers in which ointment preparations can be used include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents and creams may 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.
  • a suitable therapeutic dose for an adult for example, may be from 100 to 3000 mg per day, for example 1,500 mg per day, depending on the route of administration and the frequency of administration.
  • the optimal dosage and interval of administration of a compound of formula I is determined by the severity of the disease or condition, the nature of the compound, and such conditions as the form, route and location of administration, and the particular mammal being treated. This optimal dosage can be determined by the clinician.
  • the present invention relates to a pharmaceutically acceptable salt 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 such as hydrochloric acid, sulfuric acid, phosphoric acid, a salt of phosphoric 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, p-toluenesulfonic acid, palm a salt formed by an acid or the like.
  • a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, a salt of phosphoric acid, hydrobromic acid and nitric acid
  • various organic acids such as maleic acid, malic acid, fumaric acid, succinic acid, tartaric acid, citric acid, acetic acid, lactic acid,
  • the present invention relates to a solvate of a compound of the formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed.
  • the invention includes those stoichiometric solvations
  • the substance e.g., hydrate
  • the stereoisomer of the compound of the formula I of the present invention means that a part of the compound of the present invention may exist in the form of an optical isomer, such as a cis-trans isomer, an enantiomer or a conformational isomer.
  • the invention includes all forms of its optical isomers, especially optically pure forms.
  • the different isomers 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 compound of the formula I has a purity of at least 60%, preferably more than 75%, more preferably more than 85%, more preferably more than 98% (% by weight).
  • Another aspect of the invention relates to a process for the preparation of a compound of formula I.
  • the compounds of formula I can be prepared from known or commercially available compounds by artificial synthesis.
  • R, M are as defined in the first aspect of the invention.
  • the present invention also relates to a compound of the present invention, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, which is related to the preparation of a prophylactic, therapeutic or ameliorating activity associated with CB1 receptor overactivity.
  • a compound of the present invention or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, which is related to the preparation of a prophylactic, therapeutic or ameliorating activity associated with CB1 receptor overactivity.
  • Use in medicines for diseases or symptoms such as obesity, memory and cognitive disorders, mental illness, cancer chemotherapy adverse reactions, smoking addiction.
  • the invention further relates to the use of a compound according to the invention, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention, treatment or alleviation of obesity, improvement of memory, smoking cessation.
  • the invention further relates to the use of a compound of the invention, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, for the manufacture of a medicament as a CB1 receptor antagonist or a cannabinoid receptor antagonist.
  • the present invention also relates to a method of preventing, treating or ameliorating diseases associated with excessive activity of CB1 receptors, such as obesity, memory and cognitive disorders, psychiatric diseases, adverse reactions to cancer chemotherapy, cravings, including the treatment of need
  • the test subject is administered an effective amount of a compound of the invention, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.
  • the invention also relates to a method of preventing, treating or ameliorating obesity, improving memory, and quitting smoking, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a stereoisomer or solvate thereof Or a step of a pharmaceutically acceptable salt.
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate An animal of the type; wherein a particularly preferred subject is a human.
  • the invention also relates to a method of inhibiting CB1 receptor or cannabinoid receptor activity in a cell comprising administering to said cell an effective amount of a compound of the invention, or a stereoisomer, solvate thereof or pharmaceutically acceptable thereof Accepted salt.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • the cell is a cell line, or a cell from a subject.
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate An animal of the type; wherein a particularly preferred subject is a human.
  • the invention also relates to a compound of the invention, or a stereoisomer, solvate thereof or A pharmaceutically acceptable salt for use in preventing, treating or ameliorating a disease or condition associated with excessive activity of a CB1 receptor (eg, obesity, memory and cognitive disorders, psychiatric disorders, tumor chemotherapy adverse reactions, cravings).
  • a disease or condition associated with excessive activity of a CB1 receptor eg, obesity, memory and cognitive disorders, psychiatric disorders, tumor chemotherapy adverse reactions, cravings.
  • the invention further relates to a compound of the invention, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of obesity, in improving memory or smoking cessation.
  • the invention further relates to a compound of the invention, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, as a CB1 receptor antagonist or a cannabinoid receptor antagonist.
  • C 1 -C 15 alkyl as used herein means a straight or branched alkyl group having 1 to 15 carbon atoms, such as a C 1 -C 8 alkyl group, a C 1 -C 6 alkyl group. C 1 -C 4 alkyl, C 1 -C 3 alkyl.
  • C 3 -C 10 cycloalkyl as used herein means a cycloalkyl group having 3 to 10 (for example, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms.
  • a C 3 -C 6 cycloalkyl group or the like include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • aryl means a functional group or a substituent derived from an aromatic ring, preferably a phenyl group or a naphthyl group.
  • C 1 -C 8 alkoxy means C 1 -C 8 alkyl-O-, wherein C 1 -C 8 alkyl is as defined above, for example C 1 -C 6 alkane An oxy group or a C 1 -C 4 alkoxy group or the like.
  • aryloxy means aryl-O-, wherein the aryl group is as defined above.
  • N-containing heterocyclic group means a monocyclic or polycyclic heterocycloalkyl group or heteroaryl group containing a N atom, for example, containing 3 to 10 (for example, 3 to 8 or 5 to 10).
  • a ring-containing N-containing heterocyclic group for example, a C 3 -C 8 heterocycloalkyl group (for example, a heterocycloalkyl group having 3, 4, 5, 6, 7, or 8 ring members), C 5 -C 10 heteroaryl (e.g. comprising 8, 9 or 10 ring member heteroaryl), and the like.
  • quinoline pyridine, piperidine, piperazine, morpholine, thiomorpholine, imidazole, pyrazole, thiazole, pyrrole, tetrahydropyrrole, oxazolyl, isoxazole, hydrazine, pyridazine, Pyrimidine, pyrazine, isoquinoline, indole or other heterocyclic group.
  • benzyloxy means benzyl-O-.
  • heterocyclic group and the C 1-6 alkyl group in the term "N-heterocyclic group-C 1-6 alkyl group" as used above is as defined above.
  • the melting point of the compound was determined by capillary method using a RY-1 melting point apparatus, and the temperature was not corrected; 1 H-NMR spectrum was determined by JNM-ECA-400 type nuclear magnetic resonance spectrometer; ESI-MS spectrum was determined by API 3000 triple quadrupole mass spectrometer Determination.
  • Step 3 Preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbamate (4)
  • Step 4 Preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-amino-4-methyl-1H-pyrazole (5)
  • Step 5 Preparation of phenyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbamate (6)
  • Example 12 1-(4-Bromophenyl)-3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole- 3-based urea (compound 12)
  • the solid product was filtered, and 15 mL of water was added, and extracted with dichloromethane (15 mL ⁇ 3). The organic layer was washed with water (10 mL ⁇ 2), 15 mL of saturated sodium hydrogen carbonate solution and 15 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. A white solid was obtained in a yield: 70.1%.
  • the solid product was filtered, and 15 mL of water was added, and extracted with dichloromethane (15 mL ⁇ 3).
  • the organic layer was sequentially water (10 mL ⁇ 2) and saturated sodium hydrogen carbonate solution 15 mL It was washed with 15 mL of a saturated sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate.
  • the product was a white solid, yield: 52.4%.
  • CB1 receptor inhibitors were screened on an EGFP-CB1_U2OS cell model that specifically expressed the CB1 receptor and the EGFP reporter system.
  • U2OS cells stably obtained by expressing EGFP-CB1 fusion protein (purchased from BioImage Division, Thermo Company, USA) were cultured in DMEM (high glucose) medium containing 0.5 mg/ml G418 and 10% FBS at 37 ° C 5% CO 2 . According to the cells, 0.7 ⁇ 10 4 /100 ⁇ l/well was seeded in a 96-well culture plate capable of fluorescence detection, and cultured at 37 ° C, 5% CO 2 for 46-48 h.
  • the cells were washed twice with 100 ⁇ l/well of the assay medium (containing 10 mM HEPES, 1% FBS), and 100 ⁇ l/well of the assay medium was added, and 50 ⁇ l/well of 4 ⁇ compound was added (4 ⁇ refers to a final concentration of 4 times.
  • the final concentration is five to seven concentrations in 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000 nM. After incubating for 1 h at 37 ° C 5% CO 2 , 50 ⁇ l / well 4 ⁇ is added.
  • the agonist, 4 ⁇ M WIN55, 212-2 (purchased from Sigma, formulated into 10 mM stock in DMSO, final concentration 1 ⁇ M) was incubated for 1 h at 37 ° C 5% CO 2 and assayed on an IN Cell Analyzer 1000 live cell imaging system.
  • the experiment was performed with a positive drug control group (rimonabant group), a single medium, and a single agonist control, and each concentration was repeated in parallel for 3 wells.
  • Inhibition rate (%) (number of particles per cell in the agonist-treated group - per cell in the compound-treated group) Number of grains) / (Number of particles per cell in the agonist-treated group - Number of particles per cell in the solvent control treatment group) ⁇ 100%
  • the IC 50 value was calculated from the obtained inhibition rate.
  • SR CB1 receptor selective antagonist rimonabant
  • SR inhibited the activity of the CB1 receptor agonist WIN55, 212-2 (1 ⁇ M) in the EGFP-CB1_U2OS cell model: 0.1 ⁇ M and 1 ⁇ M.
  • the screening compounds were more than 50% except that the compound 9 had an inhibitory activity of less than 50% at 1 ⁇ M.
  • a dose-effect relationship study was performed on a compound having an inhibitory activity of greater than 50% at a concentration of 1 ⁇ M.
  • IC 50 values of Compound 4, Compound 7, Compound 8, Compound 11, Compound 13, and Compound 15 ranged from 5 nM to 10 nM, wherein IC of Compound 7 6nM 50 values, the IC 15 values of compound 50 in 4nM, indicating that these compounds have an antagonistic activity to the receptor CB1, which in Example 15 strong activity.
  • Example 23 Steady state cerebral blood distribution of a compound
  • the rat brain blood flow distribution model was used to evaluate the blood-brain barrier permeability test for compounds with high CB1 inhibition activity.
  • the model uses the continuous intravenous infusion of the tail vein to achieve the steady-state plasma.
  • the plasma and brain tissue samples are taken at steady state, and the brain tissue drug concentration and plasma concentration are obtained.
  • the Kp value is calculated by Equation 1. To indicate the drug's ability to penetrate the blood-brain barrier and distribute in brain tissue, Kp values greater than 0.5 are readily permeable compounds.
  • the infusion method was as follows: a rapid bolus injection of 0.3 ml at a rate of 75 ml/h, followed by a constant bolus injection of 40 ml at a rate of 2.5 ml/h.
  • the drug concentration of the compound 10, the compound 12, the compound 15, the compound 16, the compound 21, the compound 19, and the compound 20 is 0.25 mg/ml; the drug concentration of the compound 7 and the compound 8 is 0.3 mg/ml; the drug concentration of the compound 9 Is: 0.1 mg/ml.
  • the plasma concentration of the highly active compound reached steady state at 20-30 min of infusion, and blood and brain tissue were taken at 40 min to determine the steady state concentration.
  • the steady-state plasma and brain tissue concentrations of the compounds of the present invention are shown in Tables 2 and 3, respectively, and the Kp values thus obtained are shown in Table 4.
  • Rat 1, 2, and 3 in the table indicate rat numbers.
  • Rat 1, 2, and 3 in the table indicate rat numbers.

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Abstract

本发明涉及4-甲基-1H-二芳基吡唑衍生物，具体涉及式Ⅰ所示的化合物及其立体异构体、溶剂合物或可药用盐。本发明还涉及所述化合物的制备方法，含它们的药用组合物，以及所述化合物作为脑内大麻素I型(CB1)受体抑制剂用于制备预防、治疗或缓解与CBl受体过度活性有关的疾病或症状如肥胖、记忆或认知障碍、烟瘾等方面的药物的用途。

Description

4-甲基-1H-二芳基吡唑衍生物及其作为药物的用途 技术领域
本发明涉及医药领域，具体涉及4-甲基-1H-二芳基吡唑衍生物及其立体异构体、溶剂合物或可药用盐，其制备方法，含有它们的药物组合物，以及所述化合物作为脑内大麻素I型(CB1)受体抑制剂用于制备预防、治疗或减缓与CBl受体过度活性有关疾病或症状如肥胖、记忆或认知障碍、烟瘾等方面的药物的用途。
背景技术
大麻(Marijuana，植物学名Cannabis)公元前已被使用，是西方社会使用最多的滥用药，也是人类历史上使用时间最长的滥用药。大麻能够改变感知或使人兴奋、轻松愉悦，或使人抑郁、惊慌失措，这些作用主要由大麻中所含四氢大麻酚所引起的，1964年首次纯化出大麻的主要活性成分-四氢大麻酚(delta9tetrahydrocannabinol，Δ9-THC)，并阐明了其化学结构(Nakamura P.E，et al.The pharmacology of SR141716A:A Review[J].CNS Drug Reviews,1999,5(1):43-58)。四氢大麻酚是一种芳香类萜，其还具有止痛、镇静、抗痉挛、抗呕吐、抗青光眼以及抗高血压等多种药理作用。
大麻素(cannabinoid，CB)受体是指对大麻类物质如Δ9-THC有应答的受体，属G蛋白偶联受体。大麻素受体主要有CB1(Mechoulam R,et al.Identification of an endogenous 2-monoglyceride,present in canine gut,that binds to cannabinoid receptors[J].Biochem Pharmacol,1995,50(1):83-90.)和CB2(Munro S,et al.Molecular characterization of a peripheral receptor for cannabinoids[J].Nature,1993,365(6441):61-65.)两种亚型，其中CB1受体主要表达于中枢神经系统，又名中枢性大麻素受体，但也表达于肺、肝脏以及肾脏等外周组织中。CB2受体主要存在于外周神经元，又名外周型大麻素受体，在中枢神经系统中仅有少量表达，功能之一都是 阻止神经递质的释放。它们的主要区别在于氨基酸序列、信号转导机制、器官分布及对某些激动剂和抑制剂敏感度不同。
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、外侧纹状体)、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。CB1受体被认为是在大脑中表达最广泛的G蛋白偶联受体，由473个氨基酸，7个跨膜结构域构成。CB1受体N端胞外区域包含116个氨基酸残基，这一结构对于CB1受体的生物学特性和血浆中薄膜的表达具有决定性作用，CB1的N端对于调节配体的特异性和细胞表面受体对配体药物的亲和力具有重要作用。研究表明，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)。
内源性大麻素系统的研究推动了CB1受体拮抗剂研究的发展。第一个大麻素受体拮抗剂利莫那班为二芳基吡唑类，利莫那班(Rimonabant)是法国Sanofi-Aventis公司开发的选择性CB1受体拮抗剂，能够治疗肥胖并可作为戒烟药物，2006年7月在英国批准上市，但是利莫那班具有中枢方面的副作用，可增加精神方面的严重不良反应，即抑郁和焦虑(Christensen R,et al.Efficacy and safety of the weight-loss drug rimonabant：a meta-analysis of randomized trials[J].Lancet，2007，370(9600)：1706-1713.)。因此，寻找新的外周选择性的CB1受体拮抗剂是十分必要的。
发明内容
本发明的一个目的在于寻找新的抑制CB1受体的小分子拮抗剂；本发明的另一个目的在于寻找不易透过血脑屏障，主要作用于外周CB1受体的二芳基吡唑类小分子拮抗剂。
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，因此可以用于预防、治疗或减缓与CB1受体过度活性有关的疾病或症状，如肥胖、烟瘾、记忆和认知障碍、精神疾病和肿瘤化疗不良反应 等。
本发明的一方面涉及式Ⅰ所示的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，
Figure PCTCN2016081091-appb-000001
其中，R选自C1-C15烷基(例如C1-C8烷基)、C3-C10环烷基、C1-C8烷氧基、芳基、苄基、苄氧基、芳基氧基、含N杂环基和含N杂环基-C1-6烷基；其中所述C1-C15烷基、C3-C10环烷基、C1-C8烷氧基、芳基、苄基、苄氧基、芳基氧基、含N杂环基、含N杂环基-C1-6烷基未被取代或各自独立地被选自下述的取代基取代：C1-C8烷基、芳基-C1-C8烷基、C1-C8烷氧基、卤素、氰基、硫氢基、甲酰基、羟基、磺酸酯、硝基和亚硝基；
M选自O和NR1；
其中R1选自氢、C1-C8烷基、C3-C10环烷基、芳基或含N杂环基(如喹啉、吡啶、哌啶、哌嗪、吗啉、咪唑、吡唑或噻唑)；任选地，其中所述C1-C8烷基、C3-C10环烷基、芳基或含N杂环基未被取代或各自独立地被选自下述的取代基取代：C1-C8烷基、芳基C1-C8烷基、C1-C8烷氧基、卤素、氰基、硫氢基、甲酰基、羟基、磺酸酯、硝基和亚硝基。
在本发明的某些实施方案中，所述取代基的个数为一个或多个，例如1、2、3或4个。
在本发明的某些实施方案中，R选自C1-C8烷基、C3-C10环烷基、C1-C8烷氧基、芳基、苄基、苄氧基、含N杂环基、含N杂环基-C1-6烷基；其中所述C1-C8烷基、C3-C10环烷基、C1-C8烷氧基、芳基、苄基、苄氧基、含N杂环基、含N杂环基-C1-6烷基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自下述的取代基取代：C1-C8烷基、C1-C8烷 氧基和卤素。
在本发明的某些实施方案中，R选自C1-C4烷基、C3-C6环烷基、C1-C4烷氧基、苯基、苄基、苄氧基、五元或六元含N杂芳基、五元或六元含N杂环烷基、五元或六元含N杂芳基-C1-4烷基；其中所述C1-C4烷基、C3-C6环烷基、C1-C4烷氧基、苯基、苄基、苄氧基、五元或六元含N杂芳基、五元或六元含N杂环烷基、五元或六元含N杂芳基-C1-4烷基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自下述的取代基取代：C1-C4烷基、C1-C4烷氧基和卤素(例如氟、氯、溴或碘)。
在本发明的某些实施方案中，R选自异丙基、环丙基、甲氧基、苯基、哌啶、哌嗪、吗啉、噻唑、吡啶、苄基、苄氧基、吡啶甲基；其中所述异丙基、环丙基、甲氧基、苯基、哌啶、哌嗪、吗啉、噻唑、吡啶、苄基、苄氧基、吡啶甲基未被取代或各自独立地被一个或多个(例如1个或2个)选自下述的取代基取代：甲基、甲氧基、溴和碘。
在本发明的某些实施方案中，R选自六元含N杂芳基、六元含N杂环烷基、苄基和苄氧基；其中所述六元含N杂芳基、六元含N杂环烷基、苄基和苄氧基未被取代或各自独立地被一个或多个(例如1个)选自下述的取代基取代：C1-C4烷基和C1-C4烷氧基。
在本发明的某些实施方案中，R选自2-甲氧基吡啶-5-基、哌啶基、吗啉-4-基、5-甲基吡啶-2-基、苄基和苄氧基；优选地，R选自哌啶基和苄氧基。
在本发明的某些实施方案中，R选自C1-C4烷氧基、五元含N杂芳基和苯基；其中所述C1-C4烷氧基、五元含N杂芳基和苯基未被取代或各自独立地被一个或多个(例如2个)选自下述的取代基取代：C1-C4烷基和卤素。
在本发明的某些实施方案中，R选自甲氧基、噻唑-2-基和4-碘-2-甲基苯基。
在本发明的某些实施方案中，M选自O，NR1；
其中R1选自氢或取代或未取代的C1-C8烷基。
在本发明的某些实施方案中，M选自O和NR1；其中R1选自C1-C4 烷基(优选甲基)。
在本发明的某些实施方案中，M为O。在本发明的实施方案中，所述式I化合物选自
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-3-基)脲(化合物1)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-3-基甲基)脲(化合物2)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(6-甲基吡啶-3-基)脲(化合物3)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(6-甲氧基吡啶-3-基)脲(化合物4)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-2-基甲基)脲(化合物5)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶基-2-基)脲(化合物6)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(哌啶-1-基)脲(化合物7)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吗啉基)脲(化合物8)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(4-甲基哌嗪-1-基)脲(化合物9)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(2-溴吡啶-5-基)脲(化合物10)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(5-甲基吡啶-2-基)脲(化合物11)；
1-(4-溴苯基)-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物12)；
1-苯甲基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物13)；
1-苯基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物14)；
1-苄氧基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物15)；
1-甲氧基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物16)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-异丙基脲(化合物17)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-环丙基脲(化合物18)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(噻唑-2-基)脲(化合物19)；
1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(4-碘-2-甲基苯基)脲(化合物20)；和
1-苯甲基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-2-甲基胍(化合物21)。
本发明第二方面涉及药物组合物，其包含本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，以及药用载体或赋形剂。
在本发明的某些实施方案中，通式Ⅰ的化合物或其立体异构体、溶剂合物或药学上可接受的盐可以单独使用，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化合物或其立体异构体、溶剂合物或药学上可接受的盐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。
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，缓冲物质如磷酸盐，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， 羧甲基纤维素钩，聚丙烯酸酯，蜂蜡，羊毛醋等。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，缓冲剂等可直接溶于载体中。
本发明的药物组合物中含有的药用赋形剂是指在药物制剂中除主药以外的附加物，其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂，等等。
本发明的药物组合物可以以下面的方式施用：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、肌内、腹膜内或静脉注射的用药方式。
当口服用药时，本发明的化合物可制成口服可接受的制剂形式，如口服片剂和胶囊。口服制剂中可以含有赋形剂。例如含有粘合剂，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，山梨醇或氨基乙酸；润滑剂，如硬脂酸镁，滑石，聚乙二醇或硅土；崩解剂，如马铃薯淀粉；或增润剂，如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液形式的本发明药物组合物可以是水和油的悬浮液，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，纤维素甲醚，葡萄糖糖浆，凝胶，羟乙基纤维素，羧甲基纤维素，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，如对羟基苯甲酸甲酯或丙酯，山梨酸。如需要还可添加调味剂或着色剂。
本发明的化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
非肠道给药，液态剂型通常由化合物和至少一种消毒或无茵的载体制成，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。
当皮肤局部施用时，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。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。但药物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，例如可为每天100-3000毫克，例如每天1500毫克。
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。
本发明涉及通式Ⅰ所示化合物或其立体异构体的药学上可接受的盐，其中药学可接受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。
本发明涉及通式Ⅰ所示化合物、其立体异构体或其药学上可接受的盐的溶剂合物。本发明的化合物可能与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(例如水合物)，也包括在制备时(例如采用低压升华干燥法制备)形成的包含可变量溶剂(例如水)的化合物。
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以光学异构体的形式存在，例如顺反异构体、对映异构体或构象异构体等。本发明包括其所有光学异构体的存在形式，特别是光学纯的形式。不同的异构体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。在本发明的优选实施方案中，式I化合物具有至少60％的纯度，优选大于75％的纯度，更优选大于85％，更优选大于98％的纯度(％是指重量百分比)。
本发明另一方面涉及式I化合物的制备方法。式I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。
本发明的式I化合物合成方案如下所示：
Figure PCTCN2016081091-appb-000002
其中R、M的定义如本发明第一方面所述。
关于制备式I化合物更详尽的信息见具体实施方式。
本发明还涉及本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐在制备预防、治疗或缓解与CB1受体过度活性相关的 疾病或症状(例如肥胖、记忆和认知障碍、精神疾病、肿瘤化疗不良反应、烟瘾)的药物中的用途。
本发明还涉及本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐用于制备预防、治疗或缓解肥胖、改善记忆、戒烟的药物中的用途。
本发明还涉及本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐在制备作为CB1受体拮抗剂或大麻素受体拮抗剂的药物中的用途。
本发明还涉及预防、治疗或缓解与CB1受体过度活性相关的疾病(例如肥胖、记忆和认知障碍、精神疾病、肿瘤化疗不良反应、烟瘾)的方法，所述方法包括给有需要的受试者施用有效量的本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐的步骤。
本发明还涉及预防、治疗或缓解肥胖、改善记忆、戒烟的方法，所述方法包括给有需要的受试者施用有效量的本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐的步骤。
在本发明的某些实施方案中，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
本发明还涉及抑制细胞中CB1受体或大麻素受体活性的方法，其包括向所述细胞施用有效量的本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐。
在本发明的某些实施方案中，所述方法在体外进行。
在本发明的某些实施方案中，所述方法在体内进行。
在本发明的某些实施方案中，所述的细胞为细胞系，或者来自受试者的细胞。
在本发明的某些实施方案中，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
本发明还涉及本发明所述的化合物、或其立体异构体、溶剂合物或 药学上可接受的盐，其用于预防、治疗或缓解与CB1受体过度活性相关的疾病或症状(例如肥胖、记忆和认知障碍、精神疾病、肿瘤化疗不良反应、烟瘾)。
本发明还涉及本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，其用于预防和/或治疗肥胖、改善记忆或戒烟。
本发明还涉及本发明所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，其作为CB1受体拮抗剂或大麻素受体拮抗剂。
在本发明中，所用术语“C1-C15烷基”是指含1-15个碳原子的直链或支链烷基，例如C1-C8烷基、C1-C6烷基、C1-C4烷基、C1-C3烷基。包括但并不局限于甲基、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、环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中，所用术语“C3-C10环烷基”是指含有3-10个(例如3、4、5、6、7、8、9或10个)碳原子的环烷基，例如C3-C6环烷基等。包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中，所用术语“卤素”是指氟、氯、溴、碘。
在本发明中，所用术语“芳基”是指由芳香环衍生得到的官能团或取代基，优选苯基或萘基。
在本发明中，所用术语“C1-C8烷氧基”是指C1-C8烷基-O-，其中的C1-C8烷基如上所述，例如C1-C6烷氧基或C1-C4烷氧基等。
在本发明中，所用术语“芳基氧基”是指芳基-O-，其中的芳基如上所述。
在本发明中，所用术语“含N杂环基”是指含有N原子的单环或多环杂环烷基或杂芳基，例如含有3-10个(例如3-8个或5-10个)环成员的含N杂环基，再例如C3-C8杂环烷基(例如含有3、4、5、6、7或8个环成员的杂环烷基)、C5-C10杂芳基(例如含有5、6、7、8、9或10个环成员的杂芳基)等。其包括但不限于喹啉、吡啶、哌啶、哌嗪、吗啉、硫吗啉、咪唑、吡唑、噻唑、吡咯、四氢吡咯、噁唑基、异噁唑、吲哚、哒嗪、嘧啶、吡 嗪、异喹啉、嘌呤或其他杂环基。
在本发明中，所用术语“苄氧基”是指苄基-O-。
在本发明中，所用术语“含N杂环基-C1-6烷基”中的杂环基和C1-6烷基的定义如上所述。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
化合物的熔点用RY-1熔点仪采用毛细管法测定，温度未经校正；1H-NMR谱由JNM-ECA-400型核磁共振仪测定；ESI-MS谱由API 3000三重四级杆串联质谱仪测定。
实施例1：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-3-基)脲(化合物1)
Figure PCTCN2016081091-appb-000003
步骤1：5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-甲酰氯(2)的制备
将1.93g(5.06mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-甲酸溶于10mL甲苯中，然后加入10mL氯化亚砜并加热至120℃，回流4h后，迅速将其改为蒸馏装置，于110℃－130℃之间蒸干溶剂，得白色固体1.39g，收率72.1％。m.p.155-156℃，ESI-MS m/z:401.2[M+H]+。
步骤2：5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-甲酰胺(3) 的制备
将1.39g(3.67mmol)步骤1制备的酰氯溶解于10mL四氢呋喃中，后将其慢慢滴加至10mL氨水中，于10℃－20℃反应1h，TLC检测其原料反应完毕后，减压蒸除溶剂，得白色固体。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得产物1.26g，收率：89.7％。m.p.200-202℃，1H-NMR(400MHz,DMSO-d6)δppm:7.79(d,1H),7.75(d,1H),7.63(s,1H),7.59(dd,1H),7.45-7.48(m,2H),7.32(s,1H),7.23-7.26(m,2H),7.24(s,3H),ESI-MS m/z:382.2[M+H]+。
步骤3：5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸酯(4)的制备
将1.78g(33.00mmol)甲醇钠溶于40mL甲醇中，依次加入1.26g(3.30mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-甲酰胺和0.88g(4.95mmol)N-溴代丁二酰亚胺，加热回流，反应1.5h，反应完毕后减压蒸除溶剂。加入水15mL并用乙酸乙酯(15mL×3)萃取，有机层依次用水(10mL×2)以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥，经硅胶柱层析分离得产物1.16g，收率84.2％。m.p.175-177℃,1H-NMR(400MHz,DMSO-d6)δppm 9.47(s,1H),7.75(d,J＝1.6Hz,1H),7.54-7.59(m,2H),7.43-7.45(m,2H),7.19-7.21(m,2H),3.66(s,3H),1.95(s,3H),ESI-MS m/z:412.1[M+H]+。
步骤4：5-(4-氯苯基)-1-(2,4-二氯苯基)-3-氨基-4-甲基-1H-吡唑(5)的制备
将1.16g(2.83mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸酯溶解于50mL甲醇中,后加入10.00gNaOH的水溶液(15mL)，加热至70℃，回流反应12h，反应完毕后减压蒸除溶剂。加入水15mL并用乙酸乙酯((15mL×3))萃取，有机层依次用水(10mL×3)以及饱和氯化钠溶液20mL洗涤，无水硫酸钠干燥有机层，浓缩，得到黄色固体0.74g，收率92.1％，m.p.140-142℃，1H-NMR(400MHz,DMSO-d6)δppm:7.66(d,J＝2.4Hz,1H),7.37-7.46(m,4H),7.12-7.14(m,2H),4.93(s,2H), 1.90(s,3H),ESI-MS m/z:354.2[M+H]+。
步骤5：5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯(6)的制备
将0.74g(2.14mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑--3-氨基甲酸酯溶解于10mL四氢呋喃中，保持温度在-10℃，加入0.54g(6.42mmol)碳酸氢钠，搅拌，后缓慢滴加0.39g(2.52mmol)氯甲酸苯酯至反应体系中，20min后将温度升至室温，搅拌1.5h，TLC检测反应完全，减压蒸除溶剂。加入水20mL并用二氯甲烷(20mL×3)萃取,有机层依次用水(10mL×2)以及饱和氯化钠溶液20mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体0.85g，收率：84.2％。m.p.139-141℃，1H-NMR(400MHz,DMSO-d6)δppm:10.09(s,1H),7.77(d,1H),7.63(d,1H),7.55(dd,1H),7.41-7.44(m,4H),7.21-7.28(m,5H),2.01(s,3H),ESI-MS m/z:474.1[M+H]+。
步骤6：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-3-基)脲(Ia)的制备
将0.25g(2.70mmol)3-氨基吡啶溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑--3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体0.56g，收率：65.6％。m.p.214-216℃，1H-NMR(400MHz,DMSO-d6)δppm:2.01(s,3H),7.21-7.23(m,2H),7.31-7.35(m,1H),7.46-7.48(m,2H),7.54-7.62(m,2H),7.78-7.79(d,1H),7.96-7.98(m,1H),8.21-8.22(d,1H),8.62-8.63(d,1H),9.02(s,1H),9.43(s,1H),ESI-MS m/z:472.0[M+H]+。
实施例2：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-3-基甲基)脲(化合物2)
Figure PCTCN2016081091-appb-000004
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑--3-氨基甲酸苯酯的制备见实施例1。
将0.29g(2.70mmol)3-氨甲基吡啶溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体0.56g，收率：65.6％。m.p.200-202℃，1H-NMR(400MHz,DMSO-d6)δppm:1.96(s,3H),4.38-4.40(d,2H),7.17-7.19(m,2H),7.35-7.37(m,1H),7.44-7.56(m,4H),7.68-7.75(m,2H),8.44-8.46(dd,1H),8.51-8.52(d,1H),8.84(s,1H),ESI-MS m/z:488.1[M+H]+。
实施例3：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(6-甲基吡啶-3-基)脲(化合物3)
Figure PCTCN2016081091-appb-000005
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.29g(2.70mmol)5-氨基-2-甲基吡啶溶于10mL氯仿中，并加入三 乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：53.6％。m.p.231-233℃，1H-NMR(400MHz,DMSO-d6)δppm:2.00(s,3H),2.50(s,3H),7.17-7.22(m,3H),7.46-7.48(m,2H),7.52-7.60(m,2H),7.78-7.79(d,1H),7.82-7.85(dd,1H),8.48-8.49(d,1H),8.96(s,1H),9.34(s,1H),ESI-MS m/z:488.2[M+H]+。
实施例4：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(6-甲氧基吡啶-3-基)脲(化合物4)
Figure PCTCN2016081091-appb-000006
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.33g(2.70mmol)对甲氧基氨基吡啶溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑--3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：37.6％。m.p.235-237℃，1H-NMR(400MHz,DMSO-d6)δppm:2.00(s,3H),3.71(s,3H),6.86-6.88(m,2H),7.20-7.22(m,2H),7.35-7.37(m,2H), 7.45-7.48(m,2H),7.52-7.59(m,2H),7.78-7.79(d,1H),8.84(s,1H),9.26(s,1H),ESI-MS m/z:502.1[M+H]+。
实施例5：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-2-基甲基)脲(化合物5)
Figure PCTCN2016081091-appb-000007
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.29g(2.70mmol)2-氨甲基吡啶溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得黄白色固体，收率：43.6％。m.p.180-182℃，1H-NMR(400MHz,DMSO-d6)δppm:1.98(s,3H),4.45-4.47(d,2H),7.18-7.20(m,2H),7.25-7.28(m,1H),7.32-7.34(d,1H),7.44-7.46(m,2H),7.52-7.59(m,2H),7.75-7.79(m,2H),7.80(s,1H),8.48-8.49(d,1H),8.87(s,1H),ESI-MS m/z:488.2[M+H]+。
实施例6：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶基-2-基)脲(化合物6)
Figure PCTCN2016081091-appb-000008
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.25g(2.70mmol)2-氨基吡啶溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑--3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：53.3％。m.p.196-198℃，1H-NMR(400MHz,DMSO-d6)δppm:2.01(s,3H),7.02-7.04(m,1H),7.23-7.28(m,2H),7.45-7.58(m,2H),7.54-7.64(m,3H),7.76-7.78(m,2H),8.25-8.26(m,1H),9.86(s,1H),10.22(s,1H),ESI-MS m/z:474.2[M+H]+。
实施例7：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(哌啶-1-基)脲(化合物7)
Figure PCTCN2016081091-appb-000009
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.27g(2.70mmol)N-氨基哌啶溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4- 二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：40.6％。m.p.193-195℃，1H-NMR(400MHz,CHLOROFORM-D)δppm:1.86-1.25(m,1H),1.66-1.73(m,6H),2.09(s,3H),2.35(m,1H),3.20(m,2H),5.43(s,1H),7.07-7.09(d,2H),7.25-7.29(m,4H),7.40(s,1H),8.09(s,1H),ESI-MS m/z:478.1[M+H]+。
实施例8：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吗啉-4-基)脲(化合物8)
Figure PCTCN2016081091-appb-000010
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑--3-氨基甲酸苯酯的制备见实施例1。
将0.28g(2.70mmol)N-氨基吗啉溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：52.1％。m.p.202-204℃，1H-NMR(400MHz,DMSO-d6)δppm:1.94(s,3H),2.78-2.80(m,4H),3.68(m,4H),7.17-7.19(m,2H),7.44-7.46(m,2H),7.54-7.55(m,2H),7.75-7.76(m,1H),7.86(s,1H),,8.53(s,1H),ESI-MS m/z:482.0[M+H]+。
实施例9：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(4-甲基哌嗪-1-基)脲(化合物9)
Figure PCTCN2016081091-appb-000011
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.31g(2.70mmol)1-氨基-4-甲基哌嗪溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：43.6％。m.p.203-205℃，1H-NMR(400MHz,CHLOROFORM-D)δppm:2.08(s,3H),2.35(m,5H),2.73-3.14(m,6H),5.58(s,1H),7.08-7.10(d,2H),7.24-7.30(m,4H),7.41(s,1H),8.01(s,1H),ESI-MS m/z:495.3[M+H]+。
实施例10：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(2-溴吡啶-5-基)脲(化合物10)
Figure PCTCN2016081091-appb-000012
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.47g(2.70mmol)5-氨基-2-溴吡啶溶于15mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：60.6％。m.p.212-214℃，1H-NMR(400MHz,DMSO-d6)δppm:2.01(s,3H),7.21-7.23(m,2H),7.44-7.48(m,2H),7.54-7.57(dd,1H),7.61-7.63(d,1H),7.74-7.79(m,2H),7.97-8.00(dd,1H),8.37-8.38(d,1H),9.70(s,1H),9.97(s,1H),ESI-MS m/z:552.0[M+H]+。
实施例11：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(5-甲基吡啶-2-基)脲(化合物11)
Figure PCTCN2016081091-appb-000013
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.29g(2.70mmol)2-氨基-5-甲基吡啶溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：33.6％。m.p.204-206℃，1H-NMR(400MHz,DMSO-d6)δppm:2.01(s,3H), 2.27(s,3H),7.20-7.23(m,2H),7.45-7.48(m,2H),7.54-7.56(dd,1H),7.59-7.63(m,2H),7.77-7.78(m,1H),8.08-8.09(m,1H),9.78(s,1H),10.15(s,1H),ESI-MS m/z:486.1[M+H]+。
实施例12：1-(4-溴苯基)-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物12)
Figure PCTCN2016081091-appb-000014
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.46g(2.70mmol)对溴苯胺溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，析出固体，TLC检测反应完全，过滤出固体并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。产物为白色固体，收率：65.0％。m.p.248-250℃，1H-NMR(400MHz,DMSO-d6)δppm:2.01(s,3H),7.20-7.22(m,2H),7.46-7.48(m,6H),7.53-7.61(m,2H),7.78-7.79(d,1H),8.95(s,1H),9.45(s,1H),ESI-MS m/z:551.3[M+H]+。
实施例13：1-苯甲基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物13)
Figure PCTCN2016081091-appb-000015
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.29g(2.70mmol)苄胺滴入10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，析出固体，TLC检测反应完全，过滤出固体产物并加入水15mL，用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。得白色固体，收率：70.1％。m.p.218-220℃，1H-NMR(400MHz,DMSO-d6)δppm:1.98(s,3H),4.37-4.38(d,2H),7.18-7.23(m,3H),7.28-7.32(m,4H),7.44-7.54(m,4H),7.73-7.74(m,2H),8.79(s,1H),ESI-MS m/z:487.0[M+H]+。
实施例14：1-苯基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物14)
Figure PCTCN2016081091-appb-000016
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.25g(2.70mmol)苯胺滴入10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4- 二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，析出固体，TLC检测反应完毕。过滤出固体并加入水15mL，用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。产物为白色固体，收率：65.7％。m.p.239-241℃，1H-NMR(400MHz,DMSO-d6)δppm:2.01(s,3H),6.97-7.01(m,1H),7.20-7.22(m,2H),7.27-7.30(m,2H),7.45-7.48(m,4H),7.52-7.55(dd,1H),7.58-7.60(d,1H),7.79-7.80(d,1H),8.89(s,1H),9.38(s,1H),ESI-MS m/z:473.1[M+H]+。
实施例15：1-苄氧基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物15)
Figure PCTCN2016081091-appb-000017
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.43g(2.70mmol)苄氧胺盐酸盐溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得黄白色固体，收率：44.1％。m.p.198-200℃，1H-NMR(400MHz,DMSO-d6)δppm:1.90(s,3H),4.84(d,2H),7.17-7.20(m,2H),7.33-7.40(m,3H),7.44-7.48(m,4H),7.57-7.55(m,2H),7.75-7.76(m,1H),8.93(s,1H),9.65(s,1H),ESI-MS m/z:503.1[M+H]+。
实施例16：1-甲氧基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲(化合物16)
Figure PCTCN2016081091-appb-000018
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.23g(2.70mmol)甲氧胺盐酸盐溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：54.6％。m.p.181-183℃，1H-NMR(400MHz,DMSO-d6)δppm:1.95(s,3H),3.62(s,3H),7.18-7.21(m,2H),7.44-7.47(m,2H),7.53-7.58(m,2H),7.75-7.76(m,1H),8.96(s,1H),9.63(s,1H),ESI-MS m/z:427.0[M+H]+。
实施例17：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-异丙基脲(化合物17)
Figure PCTCN2016081091-appb-000019
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.16g(2.70mmol)异丙胺加入10mL氯仿中，并加入三乙胺 0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：49,2％。m.p.232-234℃，1H-NMR(400MHz,DMSO-d6)δppm:1.09-1.11(m,6H),1.96(s,3H),3.77-3.80(m,1H),7.17-7.19(m,3H),7.44-7.48(m,4H),7.77-7.78(d,1H),8.58(s,1H),ESI-MS m/z:439.4[M+H]+。
实施例18：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-环丙基脲(化合物18)
Figure PCTCN2016081091-appb-000020
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.27g(2.70mmol)环丙胺加入10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：63.6％。m.p.250-252℃，1H-NMR(400MHz,DMSO-d6)δppm:1.12-1.32(m,5H),1.49-1.63(m,3H),1.79-1.81(m,2H),1.96(s,3H),3.53-3.55(m,1H),7.17-7.19(m,2H),7.44-7.47(m,5H),7.78-7.79(d,1H),8.63(s,1H),ESI-MS  m/z:435.1[M+H]+。
实施例19：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(噻唑-2-基)脲(化合物19)
Figure PCTCN2016081091-appb-000021
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.29g(2.70mmol)2-氨基噻唑溶于10mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，TLC检测反应完全，减压蒸除溶剂。加入水15mL并用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得白色固体，收率：39.6％。m.p.220-222℃，1H-NMR(400MHz,DMSO-d6)δppm:2.01(s,3H),7.14-7.15(d,1H),7.21-7.24(m,2H),.37-7.38(d,1H),7.46-7.48(m,2H),7.54-7.56(dd,1H),7.60-7.62(d,1H),7.79-7.80(d,1H),9.28(s,1H),10.95(s,1H),ESI-MS m/z:477.9[M+H]+。
实施例20：1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(4-碘-2-甲基苯基)脲(化合物20)
Figure PCTCN2016081091-appb-000022
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的制备见实施例1。
将0.63g(2.70mmol)4-碘-2-甲基苯胺溶于15mL氯仿中，并加入三乙胺0.55g(5.40mmol)，室温下搅拌，后将0.85g(1.80mmol)5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-氨基甲酸苯酯的氯仿(15mL)溶液缓慢加至反应体系中，加热回流，反应1.5h，析出白色固体，TLC检测反应完全，过滤出固体产物并加入水15mL，用二氯甲烷(15mL×3)萃取，有机层依次用水(10mL×2)、饱和碳酸氢钠溶液15mL以及饱和氯化钠溶液15mL洗涤，有机层用无水硫酸钠干燥。产物为白色固体，收率：52.4％。m.p.275-277℃，1H-NMR(400MHz,DMSO-d6)δppm:2.03(s,3H),2.07(s,3H),7.22-7.24(m,2H),7.46-7.56(m,5H),7.64-7.66(m,1H),7.81-7.82(d,1H),7.90-7.92(d,1H),9.37(s,1H),9.60(s,1H),ESI-MS m/z:613.3[M+H]+。
实施例21：1-苯甲基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-2-甲基胍(化合物21)
Figure PCTCN2016081091-appb-000023
1-苯甲基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲的制备见实施例13。
将0.24g(0.5mmol)化合物1-苯甲基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲溶于10ml无水甲苯中，氮气保护下加入三氯氧磷5ml，加热至回流反应48h，减压蒸除溶剂。后滴加甲胺(醇溶液)10ml，回流反应8h，蒸除溶剂，加入水5ml用二氯甲烷(10mL×3)萃取，有机层依次用水(10mL×2)以及饱和氯化钠溶液10mL洗涤，有机层用无水硫酸钠干燥。经硅胶柱层析分离得黄色固体，收率31.3％。 m.p.174-176℃，1H-NMR(400MHz,DMSO-d6)δppm:1.89(s,3H),2.93(s,3H),4.60-4.61(d,2H),7.18-7.20(m,2H),7.29-7.32(m,1H),7.37-7.38(m,4H),7.46-7.48(m,2H),7.58-7.63(m,2H),7.77(m,1H),9.88(s,1H),ESI-MS m/z:498.4[M+H]+。
实施例22：活性测试
在特异性表达CB1受体和EGFP报告系统的EGFP-CB1_U2OS细胞模型上筛选CB1受体抑制剂。
实验方法：
将稳定表达EGFP-CB1融合蛋白的U2OS细胞(购自美国Thermo公司BioImage分公司)，37℃5％CO2培养于含0.5mg/ml G418和10％FBS的DMEM(高糖)培养液中，按照细胞0.7×104个/100μl/孔种于可进行荧光检测的96孔培养板，37℃5％CO2培养46-48h。细胞用100μl/孔分析培养液(含10mM HEPES、1％FBS)洗两次，加入100μl/孔分析培养液，加入50μl/孔4×化合物(4×指的是终浓度4倍浓度。化合物的终浓度是0.01、0.03、0.1、0.3、1、3、10、30、100、300、1000、3000nM中的五到七个浓度)37℃5％CO2孵育1h后，加入50μl/孔4×激动剂，即4μM WIN55,212-2(购自Sigma公司，用DMSO配成10mM母液，终浓度1μM)37℃5％CO2孵育1h，在IN Cell Analyzer 1000活细胞成像系统上进行测定。实验设阳性药物对照组(利莫那班组)、单培养基和单激动剂对照，每个浓度平行重复3孔。在IN Cell Analyzer 1000活细胞成像系统上的测定条件为：20倍物镜，激发波长Ex＝460nm，发射波长Em＝535nm，曝光300ms检测细胞核通道蓝色荧光；激发波长Ex＝475nm，发射波长Em＝535nm，曝光500ms检测细胞质通道绿色荧光EGFP，每孔5个视野连续拍照。使用GE公司IN Cell Analyzer 1000Granularity Analysis Module分析颗粒形成，以化合物抑制颗粒形成率表示化合物对CB1受体的抑制作用。每个浓度平行重复3孔，每孔5个视野，所照细胞数量平均在700个左右。
抑制率(％)＝(激动剂处理组每细胞颗粒数-化合物处理组每细胞颗 粒数)/(激动剂处理组每细胞颗粒数-溶剂对照处理组每细胞颗粒数)×100％
根据得到的抑制率计算IC50值。
实验结果：
活性评价结果如下表1所示：
表1.系列化合物体外抑制CB1活性
化合物 IC50(nM)
利莫那班 6.71±1.10
化合物1 81.99±35.51
化合物2 31.60±18.23
化合物3 25.55±5.39
化合物4 8.56±4.83
化合物5 137.47±11.09
化合物6 54.79±17.39
化合物7 5.19±3.95
化合物8 8.90±5.34
化合物9 403.44±242.33
化合物10 55.61±23.24
化合物11 7.86±3.62
化合物12 12.40±4.81
化合物13 7.37±2.14
化合物14 19.03±4.83
化合物15 3.61±1.19
化合物16 17.72±7.87
化合物17 15.45±7.42
化合物18 29.28±9.07
化合物19 13.33±6.08
化合物20 33.48±16.70
化合物21 11.29±11.56
实验结果表明，在EGFP-CB1_U2OS细胞模型上，CB1受体选择性拮 抗剂利莫那班(SR)抑制CB1受体激动剂WIN55,212-2(1μM)产生效应的活性为：0.1μM和1μM有约100％的抑制活性，利莫那班(SR)的IC50值为6.71nM。筛选化合物中除化合物9在1μM抑制活性小于50％外，其余均大于50％。将1μM浓度下抑制活性大于50％的化合物进行了量效关系研究，化合物4、化合物7、化合物8、化合物11、化合物13、化合物15的IC50值在5nM至10nM间，其中化合物7的IC50值在6nM，化合物15的IC50值在4nM，表明这些化合物对CB1受体具有拮抗活性，其中实施例15活性较强。
实施例23：化合物稳态脑血分布
应用大鼠稳态脑血分布模型评价对抑制CB1活性较高的化合物进行血脑屏障通透性测试。该模型以尾静脉持续恒量输注给药的方式，使药物达到稳态血浆，取稳态时的血浆和脑组织样品测定，得到脑组织药物浓度和血浆浓度，由公式1计算得到Kp值，以表示药物穿透血脑屏障的、以及在脑组织中的分布能力，Kp值大于0.5为易透化合物。
Kp＝稳态脑组织浓度/稳态血浆浓度     (公式1)
实验方案:
SD雄性大鼠，实验前自由饮水和进食。实验时，采用静脉输液泵尾静脉持续衡量输注药物，输注方式为：起始以75ml/h的速度快速推注0.3ml，然后按2.5ml/h速度匀速推注40min。其中化合物10、化合物12、化合物15、化合物16、化合物21、化合物19、化合物20的药物浓度为：0.25mg/ml；化合物7、化合物8药物浓度为：0.3mg/ml；化合物9的药物浓度为：0.1mg/ml。于给药前及给药后10、15、20、25、30、35、40min各从大鼠眼角静脉丛采血250μL置于含肝素钠的抗凝管中，5000rpm离心10min，取血浆100μL置于-20℃冰箱中冻存待测。在输注40min后，立即股动脉放血处死大鼠并取脑组织，按0.2g组织/1mL生理盐水稀释脑组织并匀浆，取100μL匀浆液与血浆同法处理。以脑组织中药物浓度与血浆中药物浓度之比值(Kp值)表示药物在脑组织中的分布能力。
实验结果:
在本研究的实验条件下，高活性化合物在输注20-30min时血浆浓度达到稳态，40min时取血和脑组织，测定稳态浓度。本发明化合物的稳态血浆和脑组织浓度分别见表2和表3，由此得到的Kp值见表4。
表2.化合物的稳态血浆药物浓度(血浆浓度(ng/mL))
化合物 Rat1 Rat2 Rat3
化合物7 898.59 1010.88 1035.04
化合物8 3675.47 3271.08 4214.17
化合物10 1002.47 812.07 964.76
化合物12 23851.08 23136.63 22981.42
化合物14 8857.51 7159.52 11149.92
化合物15 1300.45 1090.93 1480.32
化合物16 1201.08 1245.09 1011.28
化合物21 1232.10 1412.51 1247.53
化合物19 1086.83 1018.27 1092.62
化合物20 10200.16 11096.21 4045.40
表中Rat1、2、3表示大鼠编号。
表3.化合物的稳态脑组织药物浓度(脑组织浓度(ng/g))
化合物 Rat1 Rat2 Rat3
化合物7 4083.52 4623.41 4728.09
化合物8 3032.35 2792.19 3530.96
化合物10 291.87 211.08 265.68
化合物12 532.18 527.46 527.17
化合物14 375.04 323.90 500.96
化合物15 1780.10 1530.20 2050.35
化合物16 3126.84 3212.59 2625.56
化合物21 663.37 784.41 701.28
化合物19 985.83 972.08 986.02
化合物20 2478.19 2675.99 958.49
表中Rat1、2、3表示大鼠编号。
表4.化合物的血脑屏障通透性(n＝3)
化合物 Kp值(mean±SD) 透脑性
化合物7 4.56±0.02 易透
化合物8 2.59±0.01 易透
化合物10 1.38±0.01 易透
化合物12 0.92±0.03 易透
化合物14 0.84±0.01 易透
化合物15 0.55±0.01 易透
化合物16 0.28±0.02 不易透
化合物21 0.24±0.00 不易透
化合物19 0.04±0.00 不易透
化合物20 0.02±0.00 不易透
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (25)

  1. 式I所示的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，
    Figure PCTCN2016081091-appb-100001
    其中，R选自C1-C15烷基(例如C1-C8烷基)、C3-C10环烷基、C1-C8烷氧基、芳基、苄基、苄氧基、芳基氧基、含N杂环基和含N杂环基-C1-6烷基；其中所述C1-C15烷基、C3-C10环烷基、C1-C8烷氧基、芳基、苄基、苄氧基、芳基氧基、含N杂环基、含N杂环基-C1-6烷基未被取代或各自独立地被选自下述的取代基取代：C1-C8烷基、芳基-C1-C8烷基、C1-C8烷氧基、卤素、氰基、硫氢基、甲酰基、羟基、磺酸酯、硝基和亚硝基；
    M选自O，NR1；
    其中R1选自氢、C1-C8烷基、C3-C10环烷基、芳基或含N杂环基(如喹啉、吡啶、哌啶、哌嗪、吗啉、咪唑、吡唑或噻唑)；任选地，其中所述C1-C8烷基、C3-C10环烷基、芳基或含N杂环基未被取代或各自独立地被选自下述的取代基取代：C1-C8烷基、芳基-C1-C8烷基、C1-C8烷氧基、卤素、氰基、硫氢基、甲酰基、羟基、磺酸酯、硝基和亚硝基。
  2. 权利要求1的化合物或其立体异构体、溶剂合物或药学上可接受的盐，其中，R选自C1-C4烷基、C3-C6环烷基、C1-C4烷氧基、苯基、苄基、苄氧基、五元或六元含N杂芳基、五元或六元含N杂环烷基、五元或六元含N杂芳基-C1-4烷基；其中所述C1-C4烷基、C3-C6环烷基、C1-C4 烷氧基、苯基、苄基、苄氧基、五元或六元含N杂芳基、五元或六元含N杂环烷基、五元或六元含N杂芳基-C1-4烷基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自下述的取代基取代：C1-C4烷基、C1-C4烷氧基和卤素(例如氟、氯、溴或碘)。
  3. 权利要求1的化合物或其立体异构体、溶剂合物或药学上可接受的盐，其中，R选自异丙基、环丙基、甲氧基、苯基、哌啶、哌嗪、吗啉、噻唑、吡啶、苄基、苄氧基、吡啶甲基；其中所述异丙基、环丙基、甲氧基、苯基、哌啶、哌嗪、吗啉、噻唑、吡啶、苄基、苄氧基、吡啶甲基未被取代或各自独立地被一个或多个(例如1个或2个)选自下述的取代基取代：甲基、甲氧基、溴和碘。
  4. 权利要求1的化合物或其立体异构体、溶剂合物或药学上可接受的盐，其中，R选自六元含N杂芳基、六元含N杂环烷基、苄基和苄氧基；其中所述六元含N杂芳基、六元含N杂环烷基、苄基和苄氧基未被取代或各自独立地被一个或多个(例如1个)选自下述的取代基取代：C1-C4烷基和C1-C4烷氧基。
  5. 权利要求4的化合物或其立体异构体、溶剂合物或药学上可接受的盐，其中，R选自2-甲氧基吡啶-5-基、哌啶基、吗啉-4-基、5-甲基吡啶-2-基、苄基和苄氧基；优选地，R选自哌啶基和苄氧基。
  6. 权利要求1的化合物或其立体异构体、溶剂合物或药学上可接受的盐，其中R选自C1-C4烷氧基、五元含N杂芳基和苯基；其中所述C1-C4烷氧基、五元含N杂芳基和苯基未被取代或各自独立地被一个或多个(例如2个)选自下述的取代基取代：C1-C4烷基和卤素。
  7. 权利要求6的化合物或其立体异构体、溶剂合物或药学上可接受的盐，其中R选自甲氧基、噻唑-2-基和4-碘-2-甲基苯基。
  8. 权利要求1的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，其中M选自O，NR1；
    其中R1选自氢或取代或未取代的C1-C8烷基。
  9. 权利要求1-8任一项的化合物或其立体异构体、溶剂合物或药学上可接受的盐，其中M选自O和NR1，R1选自C1-C4烷基(优选甲基)。
  10. 权利要求1-8任一项的化合物或其立体异构体、溶剂合物或药学上可接受的盐，其中M为O。
  11. 权利要求1的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，其选自以下化合物
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-3-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-3-基甲基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(6-甲基吡啶-3-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(6-甲氧基吡啶-3-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶-2-基甲基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吡啶基-2-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(哌啶-1-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(吗啉基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(4-甲基哌 嗪-1-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(2-溴吡啶-5-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(5-甲基吡啶-2-基)脲；
    1-(4-溴苯基)-3-(5-(4-氯苯基-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲；
    1-苯甲基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲；
    1-苯基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲；
    1-苄氧基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲；
    1-甲氧基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-异丙基脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-环丙基脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(噻唑-2-基)脲；
    1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-3-(4-碘-2-甲基苯基)脲；和
    1-苯甲基-3-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-2-甲基胍。
  12. 药物组合物，其包含权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，以及药用载体或赋形剂。
  13. 权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐在制备预防、治疗或缓解与CB1受体过度活性相关的疾病或症状(例如肥胖、记忆和认知障碍、精神疾病、肿瘤化疗不良反应、烟瘾)的药物中的用途。
  14. 权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合 物或药学上可接受的盐用于制备预防、治疗或缓解肥胖、改善记忆、戒烟的药物中的用途。
  15. 权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐在制备作为CB1受体拮抗剂或大麻素受体拮抗剂的药物中的用途。
  16. 一种预防、治疗或缓解与CB1受体过度活性相关的疾病(例如肥胖、记忆和认知障碍、精神疾病、肿瘤化疗不良反应、烟瘾)的方法，所述方法包括给有需要的受试者有效量的权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐的步骤。
  17. 一种预防、治疗或缓解肥胖、改善记忆、戒烟的方法，所述方法包括给有需要的受试者有效量的权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐的步骤。
  18. 权利要求16或17的方法，其中所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
  19. 一种抑制细胞中CB1受体或大麻素受体活性的方法，其包括向所述细胞施用有效量的权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐。
  20. 权利要求19的方法，其在体外进行。
  21. 权利要求19的方法，其在体内进行。
  22. 权利要求19的方法，所述细胞为细胞系，或者来自受试者的细 胞。
  23. 权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，其用于预防、治疗或缓解与CB1受体过度活性相关的疾病或症状(例如肥胖、记忆和认知障碍、精神疾病、肿瘤化疗不良反应、烟瘾)。
  24. 权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，其用于预防、治疗或缓解肥胖、改善记忆或戒烟。
  25. 权利要求1-11任一项所述的化合物、或其立体异构体、溶剂合物或药学上可接受的盐，其作为CB1受体拮抗剂或大麻素受体拮抗剂。
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