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WO2017181974A1 - 五元杂环类化合物及其制备方法、药物组合物和用途 - Google Patents

五元杂环类化合物及其制备方法、药物组合物和用途 Download PDF

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WO2017181974A1
WO2017181974A1 PCT/CN2017/081294 CN2017081294W WO2017181974A1 WO 2017181974 A1 WO2017181974 A1 WO 2017181974A1 CN 2017081294 W CN2017081294 W CN 2017081294W WO 2017181974 A1 WO2017181974 A1 WO 2017181974A1
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group
compound
formula
substituted
cells
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PCT/CN2017/081294
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English (en)
French (fr)
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罗成
姚志艺
乔刚
蒋华良
周宇
陈丽敏
刘静秋
丁宏
Original Assignee
苏州苏领生物医药有限公司
中国科学院上海药物研究所
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Priority claimed from CN201610880829.4A external-priority patent/CN107304202A/zh
Application filed by 苏州苏领生物医药有限公司, 中国科学院上海药物研究所 filed Critical 苏州苏领生物医药有限公司
Priority to CN201780024845.6A priority Critical patent/CN109476650B/zh
Publication of WO2017181974A1 publication Critical patent/WO2017181974A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim 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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of biomedicine, in particular to a multi-substituted five-membered heterocyclic compound, a preparation method thereof, a pharmaceutical composition and use thereof.
  • Microtubules are composed of tubulin, which are found in the cytoplasm of all eukaryotes. They play an important cytoskeleton role in cells, maintain cell morphology, assist intracellular transport, and assemble into spindles, granules, and other proteins. Central granules, flagella, ciliated neural tube and other structures. Microtubule-associated proteins bind to microtubules and regulate microtubule function, including MAP1, MAP12, MAP4, tau, and the like. Microtubules play a key role in cell mitosis and chromosome segregation and can affect tumor cell proliferation as a target for antitumor drugs. Tubulin inhibitors can effectively prevent mitosis of tumor cells and cause cells to enter apoptotic phase, thereby inhibiting tumor growth.
  • tubulin and microtubule-associated proteins have been shown to be closely associated with key proteins in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Therefore, there is an urgent need in the art to develop novel tubulin modulators.
  • a use of a compound of formula (I), an isomer, a racemate, a pharmaceutically acceptable salt, a crystalline hydrate, a solvate or a mixture thereof characterized in that In order to (a) prepare a drug for treating or preventing a mammalian disease associated with abnormality of tubulin; (b) inhibit microtubule polymerization activity; (c) inhibit tumor cell growth:
  • X 1 is selected from N or CR 1 (when R1 is H, denoted as C);
  • X 2 is selected from NR 1 , O or S;
  • R 1 is selected from the group consisting of hydrogen, hydrazine, halogen, amino, hydroxy, nitro, cyano, carboxy, C 2-6 ester, C 1-6 amide, unsubstituted or halogenated C 1-12 alkane Or cycloalkyl, -CH 2 -Y-(C 1-12 alkyl or cycloalkyl) (wherein Y is O or NH or S), C 1-12 aryl or heteroaryl, -CH 2 - (C 1-12 aryl or heteroaryl);
  • the Ar 1 group is a substituted or unsubstituted C 1-18 aryl or heteroaryl group, a substituted or unsubstituted -CH 2 -(C 1-12 aryl or heteroaryl), substituted or unsubstituted C 1 -18 heterocyclic group, substituted or unsubstituted -CH 2 -(C 1-12 heterocyclic group);
  • the Ar 2 group is hydrogen, substituted or unsubstituted C 1-12 alkyl or cycloalkyl, substituted or unsubstituted -CH 2 -Y-(C 1-12 alkyl or cycloalkyl) (where Y is O or NH or S), substituted or unsubstituted C 1-12 aryl or heteroaryl, substituted or unsubstituted -CH 2 -(C 1-12 aryl or heteroaryl), substituted or unsubstituted C 1-12 heterocyclic group;
  • n is selected from 0, 1, 2, 3, 4, 5, 6;
  • n is selected from 0, 1, 2, 3, 4, 5, 6;
  • the R 1 is selected from the group consisting of hydrogen, hydrazine, halogen, amino, hydroxy, nitro, cyano, carboxy, ester, amide, unsubstituted C 1-6 alkyl or cycloalkyl, (1 3) fluoro C 1-6 alkyl or cycloalkyl, (1-3) C 1-6 amine substituted C 1-6 alkyl or cycloalkyl, (1-3) C 1-6 alkoxy Substituted C 1-6 alkyl or cycloalkyl, -CH 2 -Y-(C 1-6 alkyl), C 1-12 aryl or heteroaryl, -CH 2 -(C 1-12 aryl or Heteroaryl).
  • the C 5-12 aryl or heteroaryl group is selected from the group consisting of:
  • n 0, 1, 2, 3, 4, 5;
  • n 0, 1, 2, 3, 4, 5.
  • X 1 , X 2 , X 3 , R 1 , Ar 1 , Ar 2 , m and n are each independently a corresponding group corresponding to the compound 1-630.
  • the Ar 1 is selected from the group consisting of C 1-8 heteroaryl and C 2-10 heteroaryl, C 4-8 heteroaryl and C 2-10 heterocyclic.
  • the C 1-8 heteroaryl contains 1-3 nitrogen atoms.
  • the C 1-8 heteroaryl group is a six-membered ring.
  • the C 2-10 heteroaryl or C 2-10 heterocyclic group contains 1-3 nitrogen atoms.
  • the C 2-10 heteroaryl or C 2-10 heterocyclic group is a six-membered ring.
  • the heterocyclic group is a saturated or partially unsaturated heterocyclic group, and the heterocyclic group is a non-aromatic group.
  • the compound is Compound 1 to Compound 630.
  • the mammalian disease associated with dysregulation of microtubule-associated proteins is a disease selected from the group consisting of cancer, neurodegenerative diseases, malaria, AIDS, gout, diabetes.
  • the cancer is selected from the group consisting of colon cancer, cervical cancer, breast cancer, liver cancer, stomach cancer, kidney cancer, Lung cancer, fibrosarcoma, epidermal squamous cell carcinoma, prostate cancer, leukemia, pancreatic cancer, oral cancer, glioblastoma, neuroblastoma.
  • the tumor cell is a tumor cell selected from the group consisting of colon cancer cells, cervical cancer cells, breast cancer cells, liver cancer cells, gastric cancer cells, kidney cancer cells, lung cancer cells, and fibrosarcoma cells.
  • the tumor cells are selected from the group consisting of HCT116, Hela, MCF-7, LM3, NCI-N87, Caki-1, A549, HT1080, A431, PC3, HL60, Panc-1, KB. , U87-MG, K562, Kasumi-1, THP-1, Jurkat, REH, Raji, RNK-16, KMS-1, P39, U118-MG, H4, SK-N-SH, SH-SY5Y, A549/Taxol , KB/VCR, K562/Adr.
  • the mammalian disease associated with dysregulation of microtubule-associated proteins is a disease selected from the group consisting of lymphoma, lung cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, brain tumor, and Cervical cancer.
  • X 1 , X 2 , X 3 , R 1 , Ar 1 , Ar 2 , m and n are as defined in the first aspect of the invention
  • the method comprises the steps of:
  • X is a halogen
  • U is selected from the group consisting of halogen, OMs, OTs, boric acid, and pinacol borate
  • Q is O, S or NR 1
  • P is selected from the group consisting of p-methoxybenzyl, benzyl. , tert-butoxycarbonyl;
  • R 1 is halogen (fluorine, chlorine, bromine or iodine)
  • X 1 , X 2 , X 3 , R 1 , Ar 1 , Ar 2 , m and n are as defined in the first aspect of the invention
  • the method comprises the steps of:
  • the ring closure reaction is carried out by inorganic salt catalysis
  • V is halogen, OMs, or OTs; the remaining groups are as defined in the first aspect of the invention, but R 1 is a non-halogen group.
  • a compound which is a compound of any one of compound 1 to compound 630.
  • Figure 1 is a schematic representation of the concentration of neutrophil in compound 492 in a concentration-dependently inhibited urate sodium salt-induced peritonitis in mice.
  • a compound having the structure of the formula (I) has an effect of inhibiting the activity of tubulin, and can be used for preparing or treating breast milk associated with abnormality of tubulin regulation.
  • a drug for animal diseases A drug for animal diseases.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, amino, hydroxy, nitro, cyano, trifluoromethyl.
  • C 1-12 alkyl refers to a straight or branched alkyl group having from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. , tert-butyl, or the like.
  • C 1-12 cycloalkyl refers to a cycloalkyl group having from 1 to 12, preferably from 3 to 12 (ie C 3-12 ) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, Cycloheptyl, or a similar group.
  • C 1-12 alkoxy refers to a straight or branched alkoxy group having from 1 to 12 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, or the like.
  • halogen refers to F, Cl, Br and I.
  • C 1-12 alkylamino refers to a C 1-12 alkyl group substituted by an amine group, for example having "C 1-12 alkyl-NH-” or “(alkyl) 2 -N- (total number of carbon atoms) Is 1-12)", “-C 1-12 alkylene-NH 2 ", “alkyl-N-alkylene- (total number of carbon atoms 1-12)", or "(alkyl) 2 - a group of an N-alkylene-(having a total of 1-12 carbon atoms) structure, such as CH 3 NH-, C 2 H 5 NH-, C 3 H 7 NH-, (CH 3 ) 2 N-, - CH 2 NH 2 , -C 2 H 5 NH 2 , -C 3 H 7 NH 2 , -C 2 H 4 N(CH 3 ) 2 , or the like.
  • the definition of C 1-12 alkyl is as defined above.
  • C 2 -C 6 ester group refers to a substitution of a structure such as "linear or branched alkyl/cycloalkyl/aryl/heteroaryl-carbonyl-oxy-- having 1 to 5 carbon atoms".
  • a group such as an ethyl ester group, a propyl ester group, a butyl ester group, or the like.
  • C 1 -C 6 amido refers to a substitution of a structure such as "linear or branched alkyl/cycloalkyl/aryl/heteroaryl-carbonyl-amino-" having 0 to 5 carbon atoms.
  • a group such as an acetamide group, a propionamide group, a butanamide group, or the like.
  • C 1 -C 12 aryl refers to an aryl group having 1 to 12 (preferably 6 to 10, ie C 6-10 ) carbon atoms, such as phenyl, naphthyl, etc., said aryl group being Is replaced or unsubstituted.
  • C 1 -C 12 heteroaryl refers to a heteroaryl group having 1 to 12 carbon atoms and one or more (preferably 1 to 3) heteroatoms selected from O, S and/or N, preferably 5 -8-membered heteroaryl.
  • the heteroaryl group can be substituted or unsubstituted.
  • C 1 -C 12 heterocyclyl refers to a non-aromatic cyclic group having from 1 to 12 carbon atoms and one or more (preferably one to three) heteroatoms selected from O, S and/or N.
  • the group is preferably a 5- to 8-membered heterocyclic group.
  • the heterocyclic group may be substituted or unsubstituted.
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compound of the invention refers to a compound of formula I.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the present invention provides a compound of the formula:
  • X 1 , X 2 , X 3 , R 1 , Ar 1 , Ar 2 , m and n are as defined above.
  • a preferred compound is any one of compounds 1-630.
  • the compound can be prepared by the following preparation method:
  • the method comprises the steps of:
  • X is a halogen
  • U is selected from the group consisting of halogen, OMs, OTs, boric acid, and pinacol borate
  • Q is O, S or NR 1
  • P is selected from the group consisting of p-methoxybenzyl, benzyl. , tert-butoxycarbonyl;
  • R 1 is halogen (fluorine, chlorine, bromine or iodine).
  • the compounds can also be prepared by the following steps:
  • the ring closure reaction is carried out by inorganic salt catalysis
  • V is halogen, OMs, or OTs; the remaining groups are as defined above, but R 1 is a non-halogen group.
  • the respective inert solvents are not particularly limited and may be selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), and Methyl sulfoxide (DMSO), ethylene glycol dimethyl ether, 1,2-dichloroethane, dimethyl phthalate (DMP), N-methylpyrrolidone (NMP), methanol, ethanol, n-butyl A solvent for alcohol, isopropanol, petroleum ether, ethyl acetate, n-hexane or diethyl ether.
  • the necessary base may be selected from, for example, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, calcium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium t-butoxide, tert-butanol.
  • the acid may be selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid or p-toluenesulfonic acid and the like.
  • the necessary inorganic salts may be selected from sodium fluoride (NaF), potassium fluoride (KF), cesium chloride, aluminum chloride and the like.
  • a catalyst may optionally be employed in each step of the above preparation process, and the catalyst may be selected from the group consisting of tetrakistriphenylphosphorus palladium (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAC) 2 ), dichloro Palladium (PdCl 2 ) palladium carbon, ditriphenylphosphine palladium dichloride (PdCl 2 (PPh) 2 ), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (PdCl 2 (dppf) 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), iodine (or bromine or chlorine) cuprous, iodine (or bromine or chlorine) copper, copper powder, etc.
  • Pd(PPh 3 ) 4 tetrakistriphenylphosphorus palladium
  • the necessary catalytic ligand may be selected from the group consisting of triphenylphosphine, 2-biscyclohexylphosphine-2', 4',6'-triisopropylbiphenyl (Xphos) and 2-dicyclohexyl. Phosphine-2',6'-dimethoxybiphenyl (Sphos) and the like.
  • the organometallic reagent may be n-butyllithium, sodium borohydride, lithium borohydride or sodium triacetylborohydride or the like.
  • the halogenating agent may be phosphorus tribromide, phosphorus oxychloride, bromine, iodine, nitrogen chloride (or bromine or iodine) succinimide (NCS, NBS or NIS) or phenyl trimethyl three. Ammonium bromide.
  • the oxidizing agent may be a Dess-Martin oxidizing agent, a Swern oxidizing agent, m-chloroperoxybenzoic acid, chlorodichromic acid pyridine (PDC) or chlorochromic acid pyridine (PCC).
  • PDC chlorodichromic acid pyridine
  • PCC chlorochromic acid pyridine
  • the compound of the present invention has excellent inhibitory activity against tubulin, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are mainly
  • the pharmaceutical composition of the active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with tubulin activity or expression levels, particularly for diseases in which tubulin activity or expression levels are all related.
  • the compounds of the invention are useful in the treatment of diseases such as cancer, neurodegenerative diseases, malaria, AIDS, gout, diabetes and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening Agents, flavors and fragrances.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • a novel structure of a compound having a tubulin inhibitory activity is provided.
  • the nuclear magnetic resonance spectrum was recorded using a Bruker AMX-400 type, a Gemini-300 type or an AMX-600 type nuclear magnetic resonance apparatus, and the unit of the chemical shift ⁇ was ppm. All solvents are analytically pure reagents. Color development was carried out by iodine or ultraviolet fluorescence. The organic solvent was distilled off under reduced pressure in a rotary evaporator. The starting reactants used in the present invention are commercially available unless otherwise specified.
  • the conventional post-treatment method is: after the reaction is completed, an appropriate amount of an organic solvent and water are added to the reaction liquid, the organic phase and the aqueous phase are separated, the organic phase is combined, and dried using NaSO 4 . After filtration, it was evaporated to dryness under reduced pressure to give a crude material, which was purified by column chromatography to give the final product.
  • Example 2-55 The compound of Example 2-55 was prepared in the same manner as in Example 1 except that the compound b or d was different.
  • the cesium fluoride (679 mg, 2 eq) was dissolved in 15 mL of tetrahydrofuran, and protected with nitrogen.
  • Pd2(dba)3 (205 mg, 0.1 eq) and tri-tert-butylphosphonate (90 mg, 0.2 eq) were added, and the reaction was refluxed for 10 hours, and the reaction was completed. Directly evaporating the solvent column to give 5-(4-methoxyanilino)-3-(2-methylimidazolium [1,2-a]pyrimidin-3-)furan (107 mg);
  • Example 56-59 and 61-238 are the same as those of Example 60 except that the compounds b or d are different.
  • Example 239-500, 502-618 and Examples 624-630 were the same as those of Example 501 except that the compounds a or b were different, as shown in the following table.
  • Example 620-621 The preparation of Examples 620-621 was the same as Example 619 except that Compound a was different, see the table below.
  • the compound (200 mg, 1 eq) was dissolved in acetonitrile / water (4 mL / 1 mL), and then trifluoroiodomethane (157.6 mg, 1.5 eq), sodium sulphate (93.4 mg, 1 eq) and sodium bicarbonate (45 mg) ), reacted at room temperature for 12 hours, and the reaction was completed. After adding 20 mL of water and ethyl acetate (10 mL ⁇ 3), the organic layer was dried over sodium sulfate and evaporated to dryness.
  • Microtubules are multimers of tubulin. Tubulin ⁇ and ⁇ are joined end to end to form a heterodimer, which is then multi-polymerized into microtubule fibrils. The microtubules are composed of 13 fibrils, and each micrometer long microtubule is composed of 1,650 heterodimers.
  • tubulin can be polymerized. The effect of the compound on tubulin polymerization was examined using a Tubulin polymerization assay kit (BK011P, Cytoskeleton, Inc.). The kit contains specific reporter fluorescence, which is inserted into the microtube during microtubule polymerization, and the polymerization of the microtube can be monitored according to the intensity of the fluorescence.
  • microtubule polymerization inhibitory activity indicates a method: + represents 1-10 ⁇ M; ++ represents 0.1-1 ⁇ M; and +++ represents ⁇ 0.1 ⁇ M.
  • the IC 50 in the above table refers to the inhibitor concentration (50% inhibitory concentration) when the microtubule polymerization is inhibited by half.
  • the above compounds also significantly inhibited the polymerization of tubulin as compared with the positive control vincristine (VCR).
  • Colon cancer cells HCT116 were cultured in modified 5A medium containing 10% fetal bovine serum and trypsinized for passage. After about 70% of cell fusion, trypsinization was performed to prepare a cell suspension, and the cells were counted under a microscope, and then seeded in a 96-well plate at 5 ⁇ 10 3 cells per well. After the overnight culture, the above compound was administered. Changes in cell proliferation after 72 hours of administration were observed by MTT method.
  • IC 50 The specific inhibition rates are shown in Tables 2 and 3, wherein the inhibition of cell proliferation activity (IC 50 ) indicates the method: + means 1-10 ⁇ M; ++ means 0.1-1 ⁇ M; +++ means 0.01-0.1 ⁇ M; ++++ means 0.01-0.001 ⁇ M; +++++ means ⁇ 0.001 ⁇ M; "-" means no activity.
  • IC 50 represents the concentration of 50% growth inhibition required for cell growth inhibition.
  • cancer cell lines used are Hela (human cervical cancer cells), MCF-7 (human breast cancer cells), LM3 (human liver cancer cells), NCI-N87 (human gastric cancer cells), and Caki-1 (human kidney cancer cells). ), A549 (human lung cancer cells), HT1080 (human fibrosarcoma cells), A431 (human epidermal squamous cell carcinoma cells), PC3 (human prostate cancer cells), HL60 (human leukemia cells), Panc-1 (human pancreatic cancer) Cells), KB (human oral cancer cells), U87-MG (human glioma cells), K562 (human chronic granulocyte leukemia cells), Kasumi-1 (human leukemia cells), THP-1 (human leukemia cells) ), Jurkat (human T lymphocytic leukemia cells), REH (human B lymphocyte leukemia cells), Raji (human Burkitt cell leukemia cells), RNK-16 (human NK cell leukemia cells), KMS-1 (human multiple bone marrow) Tumor cells), P
  • the compounds of the present invention have inhibitory activities against the growth of different types of tumor cells, suggesting that the compounds of the present invention have a broad spectrum of antitumor activity.
  • the compounds of the present invention are useful for various types of blood cancer cells (acute myeloid leukemia cells, acute or chronic lymphocytic leukemia cells, multiple myeloma cells, myelodysplastic syndrome cells).
  • the growth of both has an inhibitory activity, suggesting that the compounds of the present invention have a broad spectrum of activity for inhibiting the growth of blood cancer cells.
  • the compound of the present invention has an inhibitory activity on the growth of brain tumor cells (glioma cells and neuroblastoma cells), suggesting that the compound of the present invention is suitable for inhibiting the growth of brain tumor cells. active.
  • the above compounds have significant inhibition of the listed cancer cells compared with the positive controls of vincristine (VCR), paclitaxel (Taxol) and adriamycin (Adrmycin, Adr).
  • VCR vincristine
  • Taxol paclitaxel
  • Adrmycin Adrmycin
  • Compound 492 inhibits neutrophils to relieve gout symptoms
  • Tubulin inhibitors are widely used, in addition to their use as anti-neoplastic agents, in the treatment of gout, as well as antifungal agents and broad-spectrum anthelmintics.
  • mice 1 mg of sodium urate was dissolved in 0.5 ml of endotoxin-free phosphate buffer solution to prepare a solution.
  • C57BL/6 mice were intraperitoneally injected with sodium urate solution to establish a model of peritonitis.
  • mice On days 1-4 after injection of sodium urate solution, mice were treated with different concentrations of compound 492 (0, 0.25, 0.5, and 1 mg/kg) daily, and compound 492 was found to significantly inhibit the gout model in mice.
  • the neutrophil flow ( Figure 1) inhibits inflammation and relieves gout in mice.
  • the compound 492 inhibited the neutrophil flow in the peritonitis mice induced by sodium urate salt crystal in a concentration-dependent manner, suggesting that the compound exhibited an effect of relieving the ventilation condition in the mouse in vivo experiment.

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Abstract

本发明提供了一类五元杂环类化合物及其制备方法、药物组合物和用途，具体地，本发明提供了一类具有如下式（I）化合物，其中，各基团的定义如说明书中所述。所述的式I化合物具有抑制微管蛋白活性的效果，可以用于制备治疗或预防与微管蛋白调节异常相关的哺乳动物疾病的药物。

Description

五元杂环类化合物及其制备方法、药物组合物和用途 技术领域
本发明涉及生物医药领域，具体涉及一种多取代的五元杂环类化合物、其制备方法、药物组合物及其用途。
背景技术
微管由微管蛋白组成，几乎存在于所有真核生物的细胞质中，在细胞中起重要的细胞骨架作用，维持细胞形态，辅助细胞内运输，与其他蛋白共同装配成纺锤体，基粒，中心粒，鞭毛，纤毛神经管等结构。微管相关蛋白与微管结合并可调节微管功能，其包括MAP1，MAP12，MAP4，tau蛋白等。微管在细胞有丝分裂和染色体分离中起关键作用，并能影响肿瘤细胞增殖，为抗肿瘤药物的靶点。微管蛋白抑制剂能有效阻止肿瘤细胞的有丝分裂导致细胞进入凋亡期，从而抑制肿瘤的增长。
在神经系统，微管系统的稳定性也是维持胞体和突起间营养转运的基础。已证实微管蛋白及微管相关蛋白与帕金森病、阿尔茨海默病等神经退行性疾病的关键蛋白密切相关。因此，本领域迫切需要开发新型的微管蛋白调节剂。
发明内容
本发明的目的是提供一种新型的微管蛋白调节剂。
本发明的第一方面，提供了一种式(I)化合物，其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物的用途，其特征在于，用于(a)制备治疗或预防与微管蛋白调节异常相关的哺乳动物疾病的药物；(b)抑制微管聚合活性；(c)抑制肿瘤细胞生长：
Figure PCTCN2017081294-appb-000001
其中：
X1选自N或C-R1(R1为H时，表示为C)；
X2选自N-R1，O或S；
X3选自下组：NH，O，S，C＝O，C＝S，C＝NH，-(C＝O)-NH-，-(C＝O)-O-，-(C＝O)-S-，-(C＝S)-NH-，-(C＝S)-O-，-(C＝S)-S-，-(C＝NH)-NH-，-(C＝NH)-O-或-(C＝NH)-S-；
R1选自下组：氢，氘，卤素，氨基，羟基，硝基，氰基，羧基，C2-6酯基，C1-6酰胺基，未取代或卤代的C1-12烷基或环烷基，-CH2-Y-(C1-12烷基或环烷基)(其中Y为O或NH或S)，C1-12芳基或杂芳基，-CH2-(C1-12芳基或杂芳基)；
Ar1基团为取代或未取代的C1-18芳基或杂芳基，取代或未取代的-CH2-(C1-12芳基或杂芳基)、取代或未取代的C1-18杂环基，取代或未取代的-CH2-(C1-12杂环基)；
Ar2基团为氢，取代或未取代的C1-12烷基或环烷基，取代或未取代的-CH2-Y-(C1-12烷基或环烷基)(其中Y为O或NH或S)，取代或未取代的C1-12芳基或杂芳基，取代或未取代的-CH2-(C1-12芳基或杂芳基)、取代或未取代的C1-12杂环基；
m选自0，1，2，3，4，5，6；
n选自0，1，2，3，4，5，6；
其中，所述的取代是被选自下组的一个或多个取代基所取代：卤素、氨基、羟基、硝基、氰基、三氟甲基、C1-12烷基或环烷基、C1-12烷氧基、氧原子(即＝O)、未取代或被C1-4烷胺基取代的C1-12烷胺基、C2-6酯基、C2-6酰基、C1-6酰胺基、硫代C1-12烷基、羧基、未取代或被1-5个卤素、氨基、羟基、硝基、氰基、三氟甲基取代的C1-12芳基或杂芳基，或未取代或被1-5个卤素、氨基、羟基、硝基、氰基、三氟甲基取代的C1-12杂环基(含有1-5个，优选1-3个选自N、O或S的杂原子)。
在另一优选例中，所述X3选自下组：NH，O，S，C＝O，C＝S，C＝NH，-(C＝O)-NH-，-(C＝O)-O-，-(C＝O)-S-，-(C＝S)-NH-，-(C＝S)-O-，-(C＝S)-S-；
所述R1选自下组：氢，氘，卤素，氨基，羟基，硝基，氰基，羧基，酯基，酰胺基，未取代的C1-6烷基或环烷基、(1-3)氟代C1-6烷基或环烷基、(1-3)C1-6胺基取代C1-6烷基或环烷基、(1-3)C1-6烷氧基取代C1-6烷基或环烷基，-CH2-Y-(C1-6烷基)，C1-12芳基或杂芳基，-CH2-(C1-12芳基或杂芳基)。
在另一优选例中，所述的Ar1或Ar2基团中，所述的C5-12芳基或杂芳基选自下组：
Figure PCTCN2017081294-appb-000002
m为0，1，2，3，4，5；
n为0，1，2，3，4，5。
在另一优选例中，X1、X2、X3、R1、Ar1、Ar2、m和n各自独立地为化合物1-630所对应的相应基团。
在另一优选例中，所述的Ar1选自下组：C1-8杂芳基并C2-10杂芳基、C4-8杂芳基并C2-10杂环基。
在另一优选例中，所述的C1-8杂芳基含有1-3个氮原子。
在另一优选例中，所述的C1-8杂芳基为六元环。
在另一优选例中，所述的C2-10杂芳基或C2-10杂环基含有1-3个氮原子。
在另一优选例中，所述的C2-10杂芳基或C2-10杂环基为六元环。
在另一优选例中，所述的杂环基为饱和的或部分不饱和的杂环基，且所述的杂环基为非芳香性基团。
在另一优选例中，所述的化合物为化合物1至化合物630。
在另一优选例中，所述与微管相关蛋白调节异常有关的哺乳动物疾病为选自下组的疾病：癌症、神经退行性疾病、疟疾、艾滋病、痛风、糖尿病。
在另一优选例中，所述的癌症选自下组：结肠癌、宫颈癌、乳腺癌、肝癌、胃癌、肾癌、 肺癌、纤维肉瘤、表皮鳞状细胞癌、前列腺癌、白血病、胰腺癌、口腔癌、胶质细胞瘤、神经母细胞瘤。
在另一优选例中，所述的肿瘤细胞为选自下组的肿瘤细胞：结肠癌细胞，宫颈癌细胞，乳腺癌细胞，肝癌细胞，胃癌细胞，肾癌细胞，肺癌细胞，纤维肉瘤细胞，表皮鳞状细胞癌细胞，前列腺癌细胞，白血病细胞，胰腺癌细胞，口腔癌细胞，胶质细胞瘤细胞，神经母细胞瘤细胞，耐紫杉醇肺癌细胞，耐长春新碱口腔癌细胞，耐阿霉素慢性粒细胞白血病细胞。
在另一优选例中，所述的肿瘤细胞选自下组：HCT116、Hela、MCF-7、LM3、NCI-N87、Caki-1、A549、HT1080、A431、PC3、HL60、Panc-1、KB、U87-MG、K562、Kasumi-1、THP-1、Jurkat、REH、Raji、RNK-16、KMS-1、P39、U118-MG、H4、SK-N-SH、SH-SY5Y、A549/Taxol、KB/VCR、K562/Adr。
在另一优选例中，所述与微管相关蛋白调节异常有关的哺乳动物疾病为选自下组的疾病：淋巴瘤、肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、白血病、脑瘤和宫颈癌。
本发明的第二方面，提供了一种式(I)所示的化合物的制备方法：
Figure PCTCN2017081294-appb-000003
其中，X1、X2、X3、R1、Ar1、Ar2、m和n的定义如本发明第一方面中所述；
其特征在于，所述方法包括以下步骤：
Figure PCTCN2017081294-appb-000004
(i-a)在惰性溶剂中，用式a化合物与式b化合物反应，得到式c化合物；
(ii-a)在惰性溶剂中，用式c化合物与式d化合物反应，得到式e化合物；
且当Q＝N-R1时，还包括如下任选的步骤：(iii-a)在惰性溶剂中，用式e化合物脱保护基，得到式f化合物；
其中，X为卤素；U选自下组：卤素、OMs、OTs、硼酸、硼酸频那醇酯；Q为O，S或N-R1；P选自下组：对甲氧基苄基、苄基、叔丁氧羰基；
或所述方法包括以下步骤：
Figure PCTCN2017081294-appb-000005
(i-b)在惰性溶剂中，式g化合物被卤素取代，得到式h化合物；
其中，R1为卤素(氟、氯、溴或碘)
其余各基团的定义同本发明第一方面。
本发明的第三方面，提供了一种式(I)所示的化合物的制备方法：
Figure PCTCN2017081294-appb-000006
其中，X1、X2、X3、R1、Ar1、Ar2、m和n的定义如本发明第一方面中所述；
其特征在于，所述方法包括以下步骤：
Figure PCTCN2017081294-appb-000007
(i-c)在惰性溶剂中，式a化合物与式b化合物进行关环反应，得到式c化合物；
优选地，所述的关环反应通过无机盐催化进行；
其中，V为卤素、OMs，或OTs；其余各基团的定义同本发明第一方面所述，但R1为非卤素的基团。
本发明的第四方面，提供了一种化合物，所述的化合物为化合物1至化合物630中任一化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为化合物492浓度依赖地抑制尿酸钠盐结晶诱导的腹膜炎小鼠体内的中性粒细胞流示意图。
具体实施方式
本发明人经过长期而深入的研究，发现了一类具有如式(I)所示结构的化合物具有抑制微管蛋白活性的效果，可以用于制备治疗或预防与微管蛋白调节异常相关的哺乳动物疾病的药物。基于上述发现，发明人完成了本发明。
术语
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、氨基、羟基、硝基、氰基、三氟甲基、C1-12烷基或环烷基、C1-12烷氧基、氧原子(即＝O)、未取代或被C1-4烷胺基取代的C1-12烷胺基、C2-6酯基、C2-6酰基、C2-6酰胺基、硫代C1-12烷基、羧基、C5-12芳基或杂芳基、C5-12杂环基(含有1-5个，优选1-3个选自N、O或S的杂原子)。
术语“C1-12烷基”指具有1～12个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“C1-12环烷基”指具有1-12个，优选为3～12个(即C3-12)碳原子的环烷基，例如环丙基、环丁基、环戊基、环庚基、或类似基团。
术语“C1-12烷氧基”指具有1-12个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“卤素”指F、Cl、Br和I。
术语“C1-12烷胺基”指被胺基取代的C1-12烷基，例如具有“C1-12烷基-NH-”或“(烷基)2-N-(碳原子总数为1-12)”、“-C1-12亚烷基-NH2”、“烷基-N-亚烷基-(碳原子总数为1-12)”、或“(烷基)2-N-亚烷基-(碳原子总数为1-12)”结构的基团，例如CH3NH-、C2H5NH-、C3H7NH-、(CH3)2N-、-CH2NH2、-C2H5NH2、-C3H7NH2、-C2H4N(CH3)2，或类似基团。其中，C1-12烷基的定义如前所述。
术语“C2-C6酯基”指形如“具有1-5个碳原子的直链或支链烷基/环烷基/芳基/杂芳基-羰基-氧基-”结构的取代基，如乙酯基、丙酯基、丁酯基，或类似基团。
术语“C1-C6酰胺基”指形如“具有0-5个碳原子的直链或支链烷基/环烷基/芳基/杂芳基-羰基-胺基-”结构的取代基，如乙酰胺基、丙酰胺基、丁酰胺基，或类似基团。
术语“C1-C12芳基”指具有1-12个(优选为6-10个，即C6-10)碳原子的芳基，例如苯基、萘基等，所述的芳基可以是取代或未取代的。
术语“C1-C12杂芳基”指具有1-12个碳原子和一个或多个(优选1-3个)选自O、S和/或N的杂原子的杂芳基，优选5-8元杂芳基。所述的杂芳基可以是取代或未取代的。
术语“C1-C12杂环基”指具有1-12个碳原子和一个或多个(优选1-3个)选自O、S和/或N的杂原子的非芳香性环状基团，优选5-8元杂环基。所述的杂环基可以是取代或未取代的。
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
式(I)化合物的制备
本发明提供了一种如下式所示的化合物：
Figure PCTCN2017081294-appb-000008
其中，X1、X2、X3、R1、Ar1、Ar2、m和n的定义如上文中所述。
优选的化合物为化合物1-630中任一化合物。
所述的化合物可以通过如下的制备方法进行制备：
其特征在于，所述方法包括以下步骤：
Figure PCTCN2017081294-appb-000009
(i-a)在惰性溶剂中，用式a化合物与式b化合物反应，得到式c化合物；
(ii-a)在惰性溶剂中，用式c化合物与式d化合物反应，得到式e化合物；
且当Q＝N-R1时，还包括如下任选的步骤：(iii-a)在惰性溶剂中，用式e化合物脱保护基，得到式f化合物；
其中，X为卤素；U选自下组：卤素、OMs、OTs、硼酸、硼酸频那醇酯；Q为O，S或N-R1；P选自下组：对甲氧基苄基、苄基、叔丁氧羰基；
或所述方法包括以下步骤：
Figure PCTCN2017081294-appb-000010
(i-b)在惰性溶剂中，式g化合物被卤素取代，得到式h化合物；
其中，R1为卤素(氟、氯、溴或碘)。
所述的化合物还可以通过以下步骤制备：
Figure PCTCN2017081294-appb-000011
(i-c)在惰性溶剂中，式a化合物与式b化合物进行关环反应，得到式c化合物；
优选地，所述的关环反应通过无机盐催化进行；
其中，V为卤素、OMs，或OTs；其余各基团的定义同上文中所述，但R1为非卤素的基团。
上述的合成反应过程中，所述的各个惰性溶剂没有特别的限制，可以是选自二氯甲烷、氯仿、四氯化碳、四氢呋喃(THF)、乙腈、二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、乙二醇二甲醚、1,2-二氯乙烷、邻苯二甲酸二甲酯(DMP)、N-甲基吡咯烷酮(NMP)、甲醇、乙醇、正丁醇、异丙醇、石油醚、乙酸乙酯、正己烷或乙醚的溶剂。
在上述制备过程中，必要的碱可以选用如氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钠、碳酸钙、磷酸钾、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、二乙胺、三乙胺、N，N-二异丙基乙胺(DIPEA)或1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)等；必要的酸可以选自三氟乙酸、盐酸、硫酸、硝酸、甲磺酸或对甲苯磺酸等。
在上述制备过程中，必要的无机盐可以选用氟化钠(NaF)，氟化钾(KF)，氯化钡，氯化铝等。
在上述制备过程中的各个步骤还可以任选地采用催化剂，所述的催化剂可以选自四三苯基磷钯(Pd(PPh3)4)、醋酸钯(Pd(OAC)2)、二氯化钯(PdCl2)钯碳、二三苯基膦二氯化钯(PdCl2(PPh)2)、1,1’-双(二苯基膦基)二茂铁]二氯化钯(PdCl2(dppf)2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)、碘(或溴或氯)化亚铜、碘(或溴或氯)化铜、铜粉等。当需要使用催化配体时，必要的催化配体可以选自三苯基膦、2-双环己基膦-2’,4’,6’-三异丙基联苯(Xphos)和2-双环己基膦-2’,6’-二甲氧基联苯(Sphos)等。
所述有机金属试剂可以是正丁基锂、硼氢化钠、硼氢化锂或三乙酰基硼氢化钠等。所述卤代试剂可以是三溴化磷、三氯氧磷、溴素、碘、氮氯(或溴或碘)代丁二酰亚胺(NCS、NBS或NIS)或苯基三甲基三溴化铵。
所述的氧化剂可以是Dess-Martin氧化剂、Swern氧化剂、间氯过氧苯甲酸、氯重铬酸吡啶(PDC)或氯铬酸吡啶(PCC)。
药物组合物和施用方法
由于本发明化合物具有优异的对微管蛋白的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由微管蛋白活性或表达量相关的疾病，尤其适用于微管蛋白活性或表达量均相关的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：癌症、神经退行性疾病、疟疾、艾滋病、痛风、糖尿病等等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2017081294-appb-000012
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味 剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明的主要优点包括：
(1)提供了一类结构新颖的化合物，所述的化合物具有微管蛋白抑制活性。
(2)提供了一种具有肿瘤抑制活性的化合物，所述的化合物可以用于制备治疗肿瘤的药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
核磁共振氢谱用BrukerAMX-400型、Gemini-300型或AMX–600型核磁共振仪记录，化学位移δ的单位为ppm。所有溶剂均为分析纯试剂。采用碘、紫外荧光等方法显色。减压蒸除有机溶剂在旋转蒸发仪中进行。本发明中用到的起始反应物未经特别说明，均为商业购买。
应当说明的是，下述实施例中，常规后处理方法是：反应完成后，在反应液中加入适量的有机溶剂和水，分离有机相和水相，合并有机相，并使用NaSO4干燥，过滤之后减压旋蒸干，得到粗产物，再经过柱层析分离纯化之后得到最终产物。
制备实施例：
实施例1：化合物1的制备(参照以下反应式所示方案)
Figure PCTCN2017081294-appb-000013
步骤(i)：N-PMB-5-碘-3-氯吡咯(1g，1eq)、对甲氧基苯胺(1.06g，3eq)和磷酸钾(1.22g，2eq)溶解于1，4-二氧六环溶液30mL中，氮气保护，加入碘化亚铜(55mg，10％)，110度反应24小时反应完毕，直接蒸干溶剂柱层析得N-PMB-5-(4-甲氧基苯胺)-3-氯吡咯(532mg)；
步骤(ii)：N-PMB-5-(4-甲氧基苯胺)-3-氯吡咯(500mg，1eq)、2-噻吩硼酸(280mg，1.5eq) 和磷酸钾(619mg，2eq)溶解于5mL正丁醇中，氮气保护，加入醋酸钯(16mg，0.05eq)和xphos(70mg，0.1eq)，110度反应12小时，反应完毕。直接蒸干溶剂柱层析得N-PMB-5-(4-甲氧基苯胺基)-3-(2-噻吩基)吡咯(319mg)；
步骤(iii)：N-PMB-5-(4-甲氧基苯胺基)-3-(2-噻吩基)吡咯(100mg)溶解于20mL三氟醋酸中，室温搅拌过夜反应完毕。饱和碳酸氢钠调PH至弱碱性，乙酸乙酯萃取，有机层干燥蒸干柱层析得化合物1[5-(4-甲氧基苯胺基)-3-(2-噻吩基)吡咯](47mg)；
1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.70(dd,J＝8.5,3.1Hz,1H),7.58–7.48(m,2H),7.40(dd,J＝8.3,3.1Hz,1H),7.13(t,J＝7.9Hz,1H),7.06–6.94(m,2H),6.61(d,J＝7.9Hz,1H),5.89(d,J＝3.1Hz,1H),3.79(s,3H).
除了化合物b或d不同外，实施例2-55所示化合物制备方法同实施例1所示方法。
Figure PCTCN2017081294-appb-000014
Figure PCTCN2017081294-appb-000015
Figure PCTCN2017081294-appb-000016
Figure PCTCN2017081294-appb-000017
实施例60化合物60的制备
Figure PCTCN2017081294-appb-000018
步骤(i)：5-溴-3-氯呋喃(1g，1eq)、对甲氧基苯胺(2.04g，3eq)和磷酸钾(2.34g，2eq)溶解于N-甲基吡咯烷酮15mL中，氮气保护，加入溴化亚铜(158mg，20％)，150度反应24小时反应完毕，乙酸乙酯萃取，有机层干燥蒸干柱层析得5-(4-甲氧基苯胺)-3-氯呋喃(613mg)；
步骤(ii)：5-(4-甲氧基苯胺)-3-氯呋喃(500mg，1eq)、2-甲基咪唑骈[1，2-a]嘧啶-3-硼酸(791mg，2eq)和氟化铯(679mg，2eq)溶解于15mL四氢呋喃中，氮气保护，加入Pd2(dba)3(205mg，0.1eq)和三叔丁基磷(90mg，0.2eq)，回流反应10小时，反应完毕。直接蒸干溶剂柱层析得5-(4-甲氧基苯胺基)-3-(2-甲基咪唑骈[1，2-a]嘧啶-3-)呋喃(107mg)；
1H NMR(400MHz,CDCl3)δ9.58(dd,J＝7.9,3.0Hz,1H),8.77(dd,J＝8.0,3.0Hz,1H),7.78–7.43(m,2H),7.27(t,J＝8.2Hz,1H),7.03(ddd,J＝8.2,6.7,3.3Hz,3H),5.93(d,J＝7.0Hz,1H),3.79(s,3H),2.61(s,3H).
除了化合物b或d不同外，实施例56-59,61-238制备方法同实施例60的制备方法，见下表
Figure PCTCN2017081294-appb-000019
Figure PCTCN2017081294-appb-000020
Figure PCTCN2017081294-appb-000021
Figure PCTCN2017081294-appb-000022
Figure PCTCN2017081294-appb-000023
Figure PCTCN2017081294-appb-000024
Figure PCTCN2017081294-appb-000025
Figure PCTCN2017081294-appb-000026
Figure PCTCN2017081294-appb-000027
Figure PCTCN2017081294-appb-000028
Figure PCTCN2017081294-appb-000029
Figure PCTCN2017081294-appb-000030
实施例501化合物501的制备(参照以下反应式所示方案)
Figure PCTCN2017081294-appb-000031
在25ml三口瓶中加入对甲氧基硫脲0.1g(1eq)和杂环化合物0.215g(1eq)，向其中加入6mL甲醇和水(体积：体积＝1：1)，氮气保护下，加入催化量NaF(2.3mg，0.1eq)，室温反应1-5分钟，TLC检测反应完全，饱和碳酸氢钠溶液洗涤,二氯甲烷(10mLx3)萃取，有机层干燥蒸干柱层析分离，得到化合物501。
1H NMR(400MHz,CDCl3)δ8.95(d,J＝7.9Hz,1H),7.90(d,J＝8.1Hz,1H),7.55(d,J＝8.0Hz,2H),7.11(s,1H),7.02(d,J＝7.8Hz,2H),3.79(s,3H),2.61(s,3H),2.36(s,3H).
除了化合物a或b不同外，实施例239-500，502-618以及实施例624-630的制备方法同实施例501的制备方法，见下表。
Figure PCTCN2017081294-appb-000032
Figure PCTCN2017081294-appb-000033
Figure PCTCN2017081294-appb-000034
Figure PCTCN2017081294-appb-000035
Figure PCTCN2017081294-appb-000036
Figure PCTCN2017081294-appb-000037
Figure PCTCN2017081294-appb-000038
Figure PCTCN2017081294-appb-000039
Figure PCTCN2017081294-appb-000040
Figure PCTCN2017081294-appb-000041
Figure PCTCN2017081294-appb-000042
Figure PCTCN2017081294-appb-000043
Figure PCTCN2017081294-appb-000044
Figure PCTCN2017081294-appb-000045
Figure PCTCN2017081294-appb-000046
Figure PCTCN2017081294-appb-000047
Figure PCTCN2017081294-appb-000048
Figure PCTCN2017081294-appb-000049
Figure PCTCN2017081294-appb-000050
Figure PCTCN2017081294-appb-000051
Figure PCTCN2017081294-appb-000052
Figure PCTCN2017081294-appb-000053
Figure PCTCN2017081294-appb-000054
Figure PCTCN2017081294-appb-000055
实施例619化合物619的制备
Figure PCTCN2017081294-appb-000056
化合物(100mg，1eq)溶解于2mL醋酸中，加入氮溴代丁二酰亚胺(54mg，1.5eq)，60度反应12小时，反应完毕。饱和碳酸氢钠淬灭，乙酸乙酯(10mLx3)萃取，有机层用硫酸钠干燥，旋蒸干，柱层析得化合物620(37mg)。1H NMR(400MHz,CDCl3)δ8.55(dd,J＝15.0,2.9Hz,1H),7.61–7.48(m,2H),7.40(dd,J＝14.9,3.0Hz,1H),7.08–6.93(m,3H),3.77(s,3H),2.59(s,3H).
除了化合物a不同外，实施例620-621的制备方法同实施例619，见下表。
Figure PCTCN2017081294-appb-000057
实施例622化合物622的制备
Figure PCTCN2017081294-appb-000058
化合物(200mg，1eq)溶解于乙腈/水(4mL/1mL)混合溶剂中，依次加入三氟碘甲烷(157.6mg，1.5eq)、连二硫酸钠(93.4mg，1eq)和碳酸氢钠(45mg)，室温反应12小时，反应完毕。加入20mL水，乙酸乙酯(10mLx3)萃取，有机层用硫酸钠干燥，旋蒸干，柱层析得化合物622(52mg)。1H NMR(400MHz,CDCl3)δ8.48(dd,J＝7.9,3.0Hz,1H),8.39(s,2H),7.33(dd,J＝7.9,3.0Hz,1H),6.96(t,J＝8.0Hz,1H),3.76(s,3H),2.52(s,3H).
实施例623化合物623的制备
Figure PCTCN2017081294-appb-000059
化合物(100mg，1eq)溶解于无水乙腈5mL中，加入SlectFluor(247mg，1.3eq)，80度反应3小时反应完毕。水10mL淬灭，乙酸乙酯(10mLx3)萃取，有机层用硫酸钠干燥，旋蒸干，柱层析得化合物623(35mg)。1H NMR(400MHz,CDCl3)δ8.56(d,J＝8.3Hz,1H),8.47(s,2H),7.41(d,J＝9.0Hz,1H),7.04(t,J＝7.9Hz,1H),3.84(s,3H),2.59(s,3H).
化合物体外生物活性测试
微管相关蛋白生化活性的测定
测定原理：微管是微管蛋白的多聚体。微管蛋白α和β首尾相接形成异源二聚体，进而多重聚合成微管原纤维。微管由13个原纤维构成，每微米长微管由1650个异源二聚体组成。在体外，微管蛋白能够发生聚合。运用Tubulin polymerization assay kit(BK011P,Cytoskeleton,Inc.)检测化合物对微管蛋白聚合的影响。该试剂盒中含特异的报告荧光，微管聚合的过程中 插入微管中，则根据荧光的强度可以监测微管的聚合反应。首先，加5μl不同浓度的上述化合物或对照化合物于96黑板中，37℃预热，再每孔中加入45μl微管聚合的混合液(243ul Buffer1，112μl Tubulin Glycerol Buffer，4.4μl GTP stock，85μl Tubulin stock)，于酶标仪中在37℃下每分钟以Ex.＝360nm和Em.＝450nm的波长检测荧光强度，检测一个小时，监测微管的聚合反应，计算化合物抑制微管蛋白聚合的IC50，测试结果见表1。表1中，微管聚合抑制活性(IC50)表示方法：+表示1-10μM；++表示0.1-1μM；+++表示<0.1μM。
表1抑制微管聚合活性测试结果
Figure PCTCN2017081294-appb-000060
检测结果与分析：
上表中IC50是指被微管聚合抑制一半时抑制剂的浓度(50％inhibitory concentration)。
从上表中结果可以看出：上述的化合物与阳性对照长春新碱(Vincristine,VCR)相比，也能显著地抑制微管蛋白的聚合。
化合物的体外抗肿瘤活性筛选
测定原理：结肠癌细胞HCT116培养在含10％胎牛血清的modified 5A培养基中，胰酶消化传代。至细胞融合70％左右后胰酶消化，制成细胞悬液后显微镜下细胞计数，然后接种于96孔板中，每孔5×103个细胞。培养过夜后给予上述化合物处理。通过MTT法观察给药72小时后细胞增殖的变化。化合物处理72小时后，每孔加10μl MTT工作溶液(5mg/ml)，37℃孵育2小时后吸出培养液，每孔加入DMSO 100μl.室温震荡15min后酶标仪于492nm波长测量OD值。计算化合物抑制HCT116细胞增殖的活性，具体抑制率见表2和3，其中抑制细胞增殖活性(IC50)表示方法：+表示1-10μM；++表示0.1-1μM；+++表示0.01-0.1μM；++++表示0.01-0.001μM；+++++表示<0.001μM；“-”表示无活性。IC50表示的是细胞50％生长抑制 所需的药物浓度(50％growth inhibition)。
细胞存活率(％)计算方法为：
存活率(％)＝(给药孔OD-空白孔OD)/(对照孔OD-空白孔OD)×100
抑制率(％)＝1-存活率(％)
其他所使用的癌细胞系为Hela(人宫颈癌细胞)，MCF-7(人乳腺癌细胞)，LM3(人肝癌细胞)，NCI-N87(人胃癌细胞)，Caki-1(人肾癌细胞)，A549(人肺癌细胞)，HT1080(人纤维肉瘤细胞)，A431(人表皮鳞状细胞癌细胞)，PC3(人前列腺癌细胞)，HL60(人白血病细胞)，Panc-1(人胰腺癌细胞)，KB(人口腔癌细胞)，U87-MG(人神经胶质细胞瘤细胞)，K562(人慢性粒细胞白血病细胞)，Kasumi-1(人白血病细胞)，THP-1(人白血病细胞)，Jurkat(人T淋巴细胞白血病细胞)，REH(人B淋巴细胞白血病细胞)，Raji(人Burkitt细胞白血病细胞)，RNK-16(人NK细胞白血病细胞)，KMS-1(人多发性骨髓瘤细胞)，P39(人骨髓增生异常综合征细胞)，U118-MG(人胶质细胞瘤细胞)，H4(人神经胶质瘤细胞)，SK-N-SH(人神经母细胞瘤细胞)，SH-SY5Y(人神经母细胞瘤细胞)，A549/Taxol(耐紫杉醇人肺癌细胞)，KB/VCR(耐长春新碱人口腔癌细胞)，K562/Adr(耐阿霉素人慢性粒细胞白血病细胞)，分别用DMEM+10％FBS培养基培养或者使用1640+10％FBS培养。
表2化合物抑制癌细胞生长广谱生物活性测试结果
Figure PCTCN2017081294-appb-000061
Figure PCTCN2017081294-appb-000062
Figure PCTCN2017081294-appb-000063
Figure PCTCN2017081294-appb-000064
Figure PCTCN2017081294-appb-000065
Figure PCTCN2017081294-appb-000066
从上述实验结果中可以看出，本发明化合物对于不同类型的肿瘤细胞的生长均具有抑制活性，提示本发明化合物具有广谱的抑瘤活性。
表3部分化合物抑制血液癌症细胞生长的活性测试结果
编号 Kasumi-1 THP-1 Jurkat REH Raji RNK-16 KMS-1 P39
VCR ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
Taxol ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
149 ++++ ++++ +++ +++ +++ +++ +++ +++
153 ++++ +++ +++ +++ +++ +++ +++ +++
167 ++++ +++ ++++ +++ ++++ +++ ++++ +++
253 +++ +++ +++ +++ +++ +++ +++ +++
257 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
272 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
275 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
285 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
305 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
325 +++++ +++ +++++ +++ +++++ +++ +++++ +++++
359 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
361 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
370 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
374 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
387 +++ +++++ +++ +++++ +++ +++++ +++ +++++
392 +++++ +++ +++ +++++ +++ +++++ +++ +++++
413 +++ +++++ +++ +++ +++ +++ +++ +++
414 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
417 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
433 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
436 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
492 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
493 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
499 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
501 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
505 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
519 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
520 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
526 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
527 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
534 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
536 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
540 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
556 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
557 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
561 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
565 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
583 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
585 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
586 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
589 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
590 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
591 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
609 +++ +++ +++ +++ +++ +++ +++ +++
617 ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
619 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
620 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
621 +++++ +++++ +++++ +++++ +++++ +++++ +++++ +++++
从上述实验结果中可以看出，本发明化合物对于各种不同分型的血液癌症细胞(急性髓系细胞白血病细胞、急性或慢性淋巴细胞白血病细胞、多发性骨髓瘤细胞、骨髓增生异常综合征细胞)的生长均具有抑制活性的作用，提示本发明化合物具有广谱的抑制血液癌症细胞生长的活性。
表4部分化合物抑制脑癌细胞生长的活性测试结果
Figure PCTCN2017081294-appb-000067
从上述实验结果中可以看出，本发明化合物对于脑瘤细胞(神经胶质瘤细胞和神经母细胞瘤细胞)的生长均具有抑制活性的作用，提示本发明化合物适用于抑制脑瘤细胞生长的活性。
表5部分化合物对耐药癌细胞生长抑制测试结果
  KB KB/VCR A549 A549/Taxol K562 K562/Adr
VCR ++++ + ++ ++    
Taxol ++++ ++ +++ +    
Adr         +++ +
149 ++++ ++ ++ ++ +++ +++
153 ++++ ++ +++ ++ +++ +++
167 ++++ ++ +++ ++ +++ +++
253 +++ ++ ++ ++ +++ +++
257 ++++ ++++ ++++ ++++ +++++ +++++
272 +++ +++ +++ +++ ++++ ++++
275 +++ +++ +++ +++ ++++ ++++
285 ++++ ++++ ++++ ++++ +++++ +++++
305 ++++ ++++ ++++ ++++ +++++ +++++
325 ++ ++ ++ ++ +++ +++
359 +++ +++ +++ +++ ++++ ++++
361 ++++ ++++ ++++ ++++ +++++ +++++
370 ++++ ++++ ++++ ++++ +++++ +++++
374 ++++ ++++ ++++ ++++ +++++ +++++
387 ++ ++ ++ ++ +++ +++
392 ++ ++ ++ ++ +++ +++
413 ++ ++ ++ ++ +++ +++
414 +++ +++ +++ +++ ++++ ++++
417 +++ +++ +++ +++ ++++ ++++
433 ++++ ++++ ++++ ++++ +++++ +++++
436 ++++ ++++ ++++ ++++ +++++ +++++
492 ++++ ++++ ++++ ++++ +++++ +++++
493 +++ +++ +++ +++ ++++ ++++
499 +++ +++ +++ +++ ++++ ++++
501 ++++ ++++ ++++ ++++ +++++ +++++
505 ++++ ++++ ++++ ++++ +++++ +++++
519 +++ +++ +++ +++ ++++ ++++
520 +++ +++ +++ +++ ++++ ++++
526 ++++ ++++ ++++ ++++ +++++ +++++
527 ++++ ++++ ++++ ++++ +++++ +++++
534 +++ +++ +++ +++ ++++ ++++
536 +++ +++ +++ +++ ++++ ++++
540 ++++ ++++ ++++ ++++ +++++ +++++
556 ++++ ++++ ++++ ++++ +++++ +++++
557 ++++ ++++ ++++ ++++ +++++ +++++
561 ++++ ++++ ++++ ++++ +++++ +++++
565 ++++ ++++ ++++ ++++ +++++ +++++
583 +++ +++ +++ +++ ++++ ++++
585 +++ +++ +++ +++ ++++ ++++
586 +++ +++ +++ +++ ++++ ++++
589 +++ +++ +++ +++ ++++ ++++
590 +++ +++ +++ +++ ++++ ++++
591 +++ +++ +++ +++ ++++ ++++
609 ++ ++ ++ ++ +++ +++
617 +++ +++ +++ +++ ++++ ++++
619 ++++ ++++ ++++ ++++ +++++ +++++
620 ++++ ++++ ++++ ++++ +++++ +++++
621 ++++ ++++ ++++ ++++ +++++ +++++
从上表中结果可以看出：上述的化合物与阳性对照长春新碱(Vincristine，VCR)、紫杉醇(Paclitaxel，Taxol)和阿霉素(Adriamycin，Adr)相比，具有显著的抑制所列癌细胞和耐药癌细胞生长的活性，特别是对于紫杉醇、长春新碱或阿霉素耐药株具有优异的抑制活性，对慢性粒细胞白血病细胞的耐药株的生长也具有较好的抑制作用。
化合物492抑制中性粒细胞缓解痛风症状实验
Tubulin抑制剂的用途广泛，除了用作抗肿瘤药外，还被用来治疗痛风，也是抗真菌药和广谱的驱虫药。
实验内容：1mg的尿酸钠盐用0.5ml无内毒素的磷酸缓冲液溶液溶解，制成溶液。C57BL/6小鼠腹腔注射尿酸钠盐溶液，建立腹膜炎模型。在尿酸钠盐溶液注射后的第1-4天，小鼠每天给予不同浓度的化合物492(0,0.25,0.5和1mg/kg)治疗，发现化合物492能够显著地抑制小鼠痛风模型体内的中性粒细胞流(图1)，抑制炎症，缓解小鼠的痛风病情。
从图1中可以看出，化合物492能够浓度依赖地抑制尿酸钠盐结晶诱导的腹膜炎小鼠体内的中性粒细胞流，提示该化合物在小鼠体内实验中表现出缓解通风病情的效果。
应当说明的是，上述的实施例仅用于说明而不是限制本发明的技术方案，任何等同的替换或更改，均应当视为包含在本发明的范围之内。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式(I)化合物，其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物的用途，其特征在于，用于(a)制备治疗或预防与微管蛋白调节异常相关的哺乳动物疾病的药物；(b)抑制微管聚合活性；(c)抑制肿瘤细胞生长：
    Figure PCTCN2017081294-appb-100001
    其中：
    X1选自N或C-R1(R1为H时，表示为C)；
    X2选自N-R1，O或S；
    X3选自下组：NH，O，S，C＝O，C＝S，C＝NH，-(C＝O)-NH-，-(C＝O)-O-，-(C＝O)-S-，-(C＝S)-NH-，-(C＝S)-O-，-(C＝S)-S-，-(C＝NH)-NH-，-(C＝NH)-O-或-(C＝NH)-S-；
    R1选自下组：氢，氘，卤素，氨基，羟基，硝基，氰基，羧基，C2-6酯基，C1-6酰胺基，未取代或卤代的C1-12烷基或环烷基，-CH2-Y-(C1-12烷基或环烷基)(其中Y为O或NH或S)，C1-12芳基或杂芳基，-CH2-(C1-12芳基或杂芳基)；
    Ar1基团为取代或未取代的C1-18芳基或杂芳基，取代或未取代的-CH2-(C1-12芳基或杂芳基)、取代或未取代的C1-18杂环基，取代或未取代的-CH2-(C1-12杂环基)；
    Ar2基团为氢，取代或未取代的C1-12烷基或环烷基，取代或未取代的-CH2-Y-(C1-12烷基或环烷基)(其中Y为O或NH或S)，取代或未取代的C1-12芳基或杂芳基，取代或未取代的-CH2-(C1-12芳基或杂芳基)、取代或未取代的C1-12杂环基；
    m选自0，1，2，3，4，5，6；
    n选自0，1，2，3，4，5，6；
    其中，所述的取代是被选自下组的一个或多个取代基所取代：卤素、氨基、羟基、硝基、氰基、三氟甲基、C1-12烷基或环烷基、C1-12烷氧基、氧原子(即＝O)、未取代或被C1-4烷胺基取代的C1-12烷胺基、C2-6酯基、C2-6酰基、C1-6酰胺基、硫代C1-12烷基、羧基、未取代或被1-5个卤素、氨基、羟基、硝基、氰基、三氟甲基取代的C1-12芳基或杂芳基，或未取代或被1-5个卤素、氨基、羟基、硝基、氰基、三氟甲基取代的C1-12杂环基(含有1-5个，优选1-3个选自N、O或S的杂原子)。
  2. 如权利要求1所述的用途，其中：
    所述X3选自下组：NH，O，S，C＝O，C＝S，C＝NH，-(C＝O)-NH-，-(C＝O)-O-，-(C＝O)-S-，-(C＝S)-NH-，-(C＝S)-O-，-(C＝S)-S-；
    所述R1选自下组：氢，氘，卤素，氨基，羟基，硝基，氰基，羧基，酯基，酰胺基，未取代的C1-6烷基或环烷基、(1-3)氟代C1-6烷基或环烷基、(1-3)C1-6胺基取代C1-6烷基或环烷基、(1-3)C1-6烷氧基取代C1-6烷基或环烷基，-CH2-Y-(C1-6烷基)，C1-12芳基或杂芳基，-CH2-(C1-12芳基或杂芳基)。
  3. 如权利要求1所述的用途，其中，所述的Ar1或Ar2基团中，所述的C5-12芳基或杂芳基选自下组：
    Figure PCTCN2017081294-appb-100002
    m为0，1，2，3，4，5；
    n为0，1，2，3，4，5。
  4. 如权利要求1所述的用途，其特征在于，所述的Ar1选自下组：C1-8杂芳基并C2-10杂芳基、C4-8杂芳基并C2-10杂环基。
  5. 如权利要求1所述的用途，其特征在于，所述的化合物为选自下表的化合物1至化合物630(其中粗横线
    Figure PCTCN2017081294-appb-100003
    标示连接部分)：
    表1
    Figure PCTCN2017081294-appb-100004
    Figure PCTCN2017081294-appb-100005
    Figure PCTCN2017081294-appb-100006
    Figure PCTCN2017081294-appb-100007
    Figure PCTCN2017081294-appb-100008
    Figure PCTCN2017081294-appb-100009
    Figure PCTCN2017081294-appb-100010
    Figure PCTCN2017081294-appb-100011
    Figure PCTCN2017081294-appb-100012
    Figure PCTCN2017081294-appb-100013
    Figure PCTCN2017081294-appb-100014
    Figure PCTCN2017081294-appb-100015
    Figure PCTCN2017081294-appb-100016
    Figure PCTCN2017081294-appb-100017
    Figure PCTCN2017081294-appb-100018
    Figure PCTCN2017081294-appb-100019
    Figure PCTCN2017081294-appb-100020
    Figure PCTCN2017081294-appb-100021
    Figure PCTCN2017081294-appb-100022
    Figure PCTCN2017081294-appb-100023
    Figure PCTCN2017081294-appb-100024
    Figure PCTCN2017081294-appb-100025
    Figure PCTCN2017081294-appb-100026
    Figure PCTCN2017081294-appb-100027
    Figure PCTCN2017081294-appb-100028
    Figure PCTCN2017081294-appb-100029
    Figure PCTCN2017081294-appb-100030
    Figure PCTCN2017081294-appb-100031
    Figure PCTCN2017081294-appb-100032
    Figure PCTCN2017081294-appb-100033
    Figure PCTCN2017081294-appb-100034
    Figure PCTCN2017081294-appb-100035
    Figure PCTCN2017081294-appb-100036
    Figure PCTCN2017081294-appb-100037
    Figure PCTCN2017081294-appb-100038
    Figure PCTCN2017081294-appb-100039
    Figure PCTCN2017081294-appb-100040
    Figure PCTCN2017081294-appb-100041
  6. 如权利要求1所述的药物组合物的用途，其特征在于，所述与微管相关蛋白调节异常有关的哺乳动物疾病为选自下组的疾病：癌症、神经退行性疾病、疟疾、艾滋病、痛风、糖尿病；优选地选自下组：淋巴瘤、肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、白血病、脑瘤和宫颈癌。
  7. 如权利要求1所述的用途，其特征在于，所述的肿瘤细胞为选自下组的肿瘤细胞：结肠癌细胞，宫颈癌细胞，乳腺癌细胞，肝癌细胞，胃癌细胞，肾癌细胞，肺癌细胞，纤维肉瘤细胞，表皮鳞状细胞癌细胞，前列腺癌细胞，白血病细胞，胰腺癌细胞，口腔癌细胞，胶质细胞瘤细胞，神经母细胞瘤细胞，耐紫杉醇肺癌细胞，耐长春新碱口腔癌细胞，耐阿霉素慢性粒细胞白血病细胞。
  8. 一种式(I)所示的化合物的制备方法：
    Figure PCTCN2017081294-appb-100042
    其中，X1、X2、X3、R1、Ar1、Ar2、m和n的定义如权利要求1-5任一中所述；
    其特征在于，所述方法包括以下步骤：
    Figure PCTCN2017081294-appb-100043
    (i-a)在惰性溶剂中，用式a化合物与式b化合物反应，得到式c化合物；
    (ii-a)在惰性溶剂中，用式c化合物与式d化合物反应，得到式e化合物；
    且当Q＝N-R1时，还包括如下任选的步骤：(iii-a)在惰性溶剂中，用式e化合物脱保护基，得到式f化合物；
    其中，X为卤素；U选自下组：卤素、OMs、OTs、硼酸、硼酸频那醇酯；Q为O，S或N-R1；P选自下组：对甲氧基苄基、苄基、叔丁氧羰基；
    或所述方法包括以下步骤：
    Figure PCTCN2017081294-appb-100044
    (i-b)在惰性溶剂中，式g化合物被卤素取代，得到式h化合物；
    其中，R1为卤素(氟、氯、溴或碘)
    其余各基团的定义同权利要求1。
  9. 一种式(I)所示的化合物的制备方法：
    Figure PCTCN2017081294-appb-100045
    其中，X1、X2、X3、R1、Ar1、Ar2、m和n的定义如权利要求1-5任一中所述；
    其特征在于，所述方法包括以下步骤：
    Figure PCTCN2017081294-appb-100046
    (i-c)在惰性溶剂中，式a化合物与式b化合物进行关环反应，得到式c化合物；
    优选地，所述的关环反应通过无机盐催化进行；
    其中，V为卤素、OMs，或OTs；其余各基团的定义同权利要求1，但R1为非卤素的基团。
  10. 一种如下式(I)所示的化合物，其特征在于，所述的化合物为选自下表的化合物1至化合物630(其中粗横线
    Figure PCTCN2017081294-appb-100047
    标示连接部分)：
    Figure PCTCN2017081294-appb-100048
    表1
    Figure PCTCN2017081294-appb-100049
    Figure PCTCN2017081294-appb-100050
    Figure PCTCN2017081294-appb-100051
    Figure PCTCN2017081294-appb-100052
    Figure PCTCN2017081294-appb-100053
    Figure PCTCN2017081294-appb-100054
    Figure PCTCN2017081294-appb-100055
    Figure PCTCN2017081294-appb-100056
    Figure PCTCN2017081294-appb-100057
    Figure PCTCN2017081294-appb-100058
    Figure PCTCN2017081294-appb-100059
    Figure PCTCN2017081294-appb-100060
    Figure PCTCN2017081294-appb-100061
    Figure PCTCN2017081294-appb-100062
    Figure PCTCN2017081294-appb-100063
    Figure PCTCN2017081294-appb-100064
    Figure PCTCN2017081294-appb-100065
    Figure PCTCN2017081294-appb-100066
    Figure PCTCN2017081294-appb-100067
    Figure PCTCN2017081294-appb-100068
    Figure PCTCN2017081294-appb-100069
    Figure PCTCN2017081294-appb-100070
    Figure PCTCN2017081294-appb-100071
    Figure PCTCN2017081294-appb-100072
    Figure PCTCN2017081294-appb-100073
    Figure PCTCN2017081294-appb-100074
    Figure PCTCN2017081294-appb-100075
    Figure PCTCN2017081294-appb-100076
    Figure PCTCN2017081294-appb-100077
    Figure PCTCN2017081294-appb-100078
    Figure PCTCN2017081294-appb-100079
    Figure PCTCN2017081294-appb-100080
    Figure PCTCN2017081294-appb-100081
    Figure PCTCN2017081294-appb-100082
    Figure PCTCN2017081294-appb-100083
    Figure PCTCN2017081294-appb-100084
    Figure PCTCN2017081294-appb-100085
    Figure PCTCN2017081294-appb-100086
    Figure PCTCN2017081294-appb-100087
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