CN107304203A - Five-membered heterocycles and preparation method thereof, pharmaceutical composition and purposes - Google Patents

Five-membered heterocycles and preparation method thereof, pharmaceutical composition and purposes Download PDF

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Publication number
CN107304203A
CN107304203A CN201610880966.8A CN201610880966A CN107304203A CN 107304203 A CN107304203 A CN 107304203A CN 201610880966 A CN201610880966 A CN 201610880966A CN 107304203 A CN107304203 A CN 107304203A
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formula
group
compound
alkyl
unsubstituted
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罗成
姚志艺
乔刚
陈丽敏
刘静秋
丁宏
蒋华良
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Suzhou Suplead Life Sciences Co ltd
Shanghai Institute of Materia Medica of CAS
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Suzhou Suplead Life Sciences Co ltd
Shanghai Institute of Materia Medica of CAS
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Priority to CN201780024801.3A priority Critical patent/CN109476649B/en
Priority to PCT/CN2017/081293 priority patent/WO2017181973A1/en
Publication of CN107304203A publication Critical patent/CN107304203A/en
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    • 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
    • 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
    • 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

Abstract

The invention provides class five-membered heterocycles and preparation method thereof, pharmaceutical composition and purposes, specifically, there is such as following formula (I) compound the invention provides a class, wherein, the definition of each group is as noted in the discussion.Described compound of formula I has the effect for suppressing tubulin activity, can be used for preparing the medicine for treating or preventing the mammalian diseases related to tubulin dysregulation.

Description

Five-membered heterocycles and preparation method thereof, pharmaceutical composition and purposes
Technical field
The present invention relates to biomedicine field, and in particular to a kind of polysubstituted five-membered heterocycles, its preparation side Method, medical composition and its use.
Background technology
Micro-pipe is made up of tubulin, is almost present in all Eukaryotic cytoplasm, is risen in cell important Cytoskeleton is acted on, and maintains to transport in cellular morphology, auxiliary cell, spindle, basal granule, center are assembled into jointly with other albumen Grain, flagellum, the structure such as ciliary pipe.Microtubule associated protein is combined with micro-pipe and can adjust micro-pipe function, and it includes MAP1, MAP12, MAP4, Protein tau etc..Micro-pipe plays a crucial role in cell mitogen and chromosome separation, and can influence tumour Cell is bred, and is the target spot of antineoplastic.Antitubulin can effectively prevent the mitosis of tumour cell from causing carefully Born of the same parents enter the apoptosis phase, so as to suppress the growth of tumour.
In nervous system, the stability of microtubule system is also to maintain the basis that nutrition is transported between cell space and projection.Have proven to The close phase of key protein of the nerve degenerative diseases such as tubulin and microtubule associated protein and Parkinson's, Alzheimer disease Close.Therefore, this area is in the urgent need to developing new tubulin modulating agents.
The content of the invention
It is an object of the invention to provide a kind of new tubulin modulating agents.
The first aspect of the present invention is there is provided a kind of formula (I) compound, or its isomers, racemic modification, can pharmaceutically connect Salt, crystalline hydrate, the solvate received：
Wherein：
X1Selected from N or C-R1(when R1 is H, being expressed as C)；
X2Selected from N-R1, O or S；
X3It is selected from the group：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- or-(C=NH)-S-；
R1It is selected from the group：Hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano group, carboxyl, C2-6Ester group, C1-6Amide groups, does not take Generation or the C of halo1-12Alkyl or cycloalkyl ,-CH2-Y-(C1-12Alkyl or cycloalkyl) (wherein Y is O or NH or S), C1-12Aryl Or heteroaryl ,-CH2-(C1-12Aryl or heteroaryl)；
Ar1Group is substituted or unsubstituted C1-18Aryl or heteroaryl, substituted or unsubstituted-CH2-(C1-12Aryl or Heteroaryl), substituted or unsubstituted C1-18Heterocyclic radical, substituted or unsubstituted-CH2-(C1-12Heterocyclic radical)；Wherein, it is described Ar1For bicyclic radicals, and at least there is a C1-12Alkyl or cycloalkyl substituent；
Ar2Group is substituted or unsubstituted C1-12Alkyl or cycloalkyl, substituted or unsubstituted-CH2-Y-(C1-12Alkyl Or cycloalkyl) (wherein Y is O or NH or S), substituted or unsubstituted C1-12Aryl or heteroaryl, substituted or unsubstituted-CH2- (C1-12Aryl or heteroaryl), substituted or unsubstituted C1-12Heterocyclic radical；Wherein, described at least one alkoxy of Ar2 groups Substituent；
And work as Ar2For C1-12During aryl, described Ar1Also at least there is a halogenic substituent；
M is selected from 0,1,2,3,4,5,6；
N is selected from 0,1,2,3,4,5,6；
Wherein, described substitution is that the one or more substituents for being selected from the following group are replaced：Halogen, amino, hydroxyl, nitre Base, cyano group, trifluoromethyl, C1-12Alkyl or cycloalkyl, C1-12It is alkoxy, oxygen atom (i.e.=O), unsubstituted or by C1-4Alkylamino radical Substituted C1-12Alkylamino radical, C2-6Ester group, C2-6Acyl group, C1-6Amide groups, thio C1-12It is alkyl, carboxyl, unsubstituted or by 1-5 halogen Element, amino, hydroxyl, nitro, cyano group, the C of trifluoromethyl substitution1-12Aryl or heteroaryl, or it is unsubstituted or by 1-5 halogen, Amino, hydroxyl, nitro, cyano group, the C of trifluoromethyl substitution1-12(containing 1-5, preferably 1-3 are selected from N, O or S to heterocyclic radical Hetero atom).
In another preference, the X3It is selected from the group：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-；
The R1It is selected from the group：Hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano group, carboxyl, ester group, amide groups is unsubstituted C1-6Alkyl or cycloalkyl, (1-3) fluoro C1-6Alkyl or cycloalkyl, (1-3) C1-6Amido replaces C1-6Alkyl or cycloalkyl, (1-3)C1-6Alkoxy replaces C1-6Alkyl or cycloalkyl ,-CH2-Y-(C1-6Alkyl), C1-12Aryl or heteroaryl ,-CH2-(C1-12 Aryl or heteroaryl).
In another preference, described Ar1Or Ar2In group, described C5-12Aryl or heteroaryl are selected from the group：
M is 0,1,2,3,4,5；
N is 0,1,2,3,4,5.
In another preference, X1、X2、X3、R1、Ar1、Ar2, m and n be each independently group shown in table 1.
In another preference, described Ar1It is selected from the group：C1-8Heteroaryl and C2-10Heteroaryl, C4-8Heteroaryl and C2-10 Heterocyclic radical.
In another preference, described C1-8Heteroaryl contains 1-3 nitrogen-atoms.
In another preference, described C1-8Heteroaryl is hexatomic ring.
In another preference, described C2-10Heteroaryl or C2-10Heterocyclic radical contains 1-3 nitrogen-atoms.
In another preference, described C2-10Heteroaryl or C2-10Heterocyclic radical is hexatomic ring.
In another preference, described heterocyclic radical for saturation or the undersaturated heterocyclic radical in part, and described heterocycle Base is nonaro-maticity group.
In another preference, described Ar1To be substituted or unsubstituted with the structure being shown below：
Wherein, dotted line is chemical bond or nothing；Each A1、A2、A3、A4、A5、A6、A7、A8And A9Be each independently O, S, N, NH, CH or CH2；
Ra is H, halogen, C1-6Alkyl, one or more halo C1-6Alkyl or cycloalkyl, C1-6Alkoxy, C1-6Alkylthio group, C1-6Alkylamino.
Rb is fluorine, chlorine, C1-6Alkyl, one or more halo C1-6Alkyl or cycloalkyl or C1-6Alkoxy or C1-6Alkylthio group Or C1-6Alkylamino, substituted or unsubstituted C5-12Aryl or aromatic heterocyclic；
And work as A8During for N, Rb is nothing；
Substituted definition is as described in first aspect present invention.
In another preference, work as A8For C (non-CH or CH2) and Ar2 be alkoxyl phenyl or alkoxy pyridines base when, Rb For Cl or F.
In another preference, work as A8For C (non-CH or CH2) and Ar2 is the hexa-atomic aromatic ring yl or heteroaromatic that alkoxy replaces During base, Rb is Cl or F.
In another preference, when X2 is NH and Ar2 is the hexa-atomic aromatic ring yl or aromatic heterocyclic of alkoxy substitution, Rb is Cl or F.
In another preference, when X2 is NH and Ar2 is the hexa-atomic aromatic ring yl or aromatic heterocyclic of alkoxy substitution, N is Cl or F.
In another preference, described Ar2To be substituted or unsubstituted with the structure being shown below：
Wherein, each B1、B2、B3、B4、B5、B6It is each independently O, S, N, NH, CH or CH2；
Rc is amino, trifluoromethyl, C1-6Alkoxy, C1-6Alkylamino, (1-3) halo C1-6Alkyl or C1-6Alkylthio.
In another preference, Rb is located on Y atoms.
In another preference, lead to formula (I) compound and be selected from compound shown in formula (Ia)：
Wherein, dotted line is chemical bond or nothing；Y=CH or N；R1, X1, X2, X3, Ar2, m and n definition such as first party of the present invention Face；Ra, Rb definition such as first aspect present invention.
In another preference, X1For C, X2During for NH, O or S, lead to formula (I) compound and be selected from shown in below formula (Ia) Compound (wherein thick horizontal line "-" sign coupling part)：
In another preference, formula (Ia) compound is selected from compound shown in formula (Ib)：
Wherein, dotted line is chemical bond or nothing；Y=CH or N；X2=NH, O or S；R1, X3 and Ar2 definition such as the present invention First aspect；Ra, Rb definition such as first aspect present invention.
In another preference, during X2=NH or O, it is (short and thick that compound shown in formula (Ib) is preferably selected from following compound Line " one " represents coupling part)：
In another preference, during X2=S, compound shown in formula (Ib) is selected from formula (Ic), (Id), (Ie) shownization Compound：
The second aspect of the present invention is used there is provided a kind of purposes of pharmaceutical composition as described in the first aspect of the invention In the pharmaceutical composition for preparing the disease that treatment or prevention are selected from the group：The lactation relevant with microtubule associated protein dysregulation is moved Thing disease；It is preferably selected from the disease of the following group：Cancer, nerve degenerative diseases, malaria, AIDS, gout, diabetes.
In another preference, described cancer is selected from the group：Colon cancer, cervical carcinoma, breast cancer, liver cancer, stomach cancer, kidney Cancer, lung cancer, fibrosarcoma, epidermis squamous cell carcinoma, prostate cancer, leukaemia, cancer of pancreas, carcinoma of mouth, spongiocytoma, nerve Blastoma.
In another preference, described tumour cell is the tumour cell being selected from the group：Colon cancer cell, cervical carcinoma is thin Born of the same parents, breast cancer cell, liver cancer cells, stomach cancer cell, kidney cancer cell, lung carcinoma cell, fibrosarcoma cell, epidermis squamous cell carcinoma Cell, prostate gland cancer cell, leukaemia, pancreatic cancer cell, cancer cell of oral cavity, glioblastoma cell, neuroblast Oncocyte, the lung carcinoma cell of resistance to taxol, the cancer cell of oral cavity of resistance to vincristine, adriamycin-resistant chronic myeloid leukemia cell. In another preference, described tumour cell is selected from the group：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。
In another preference, the mammalian diseases relevant with microtubule associated protein dysregulation are to be selected from the group Disease：Lymthoma, lung cancer, stomach cancer, cancer of pancreas, breast cancer, prostate cancer, leukaemia, brain tumor and cervical carcinoma.
There is provided the preparation method of the compound shown in a kind of formula (I) for the third aspect of the present invention：
Wherein, X1、X2、X3、R1、Ar1、Ar2, m and n definition as described in first aspect present invention；
It the described method comprises the following steps：
(i-a) in atent solvent, reacted with formula a compounds and formula b compounds, obtain formula c compounds；
(ii-a) in atent solvent, reacted with formula c compounds and formula d compounds, obtain formula e compounds；
And work as Q=N-R1When, in addition to following optional step：(iii-a) it is de- with formula e compounds in atent solvent Protection group, obtains formula f compounds；
Wherein, X is halogen；U is selected from the group：Halogen, OMs, OTs, boric acid, boric acid pinacol ester；Q is O, S or N-R1；P It is selected from the group：To methoxy-benzyl, benzyl, tertbutyloxycarbonyl；
Or the described method comprises the following steps：
(i-b) in atent solvent, formula g compounds are optionally substituted by halogen, and obtain formula h compounds；
Wherein, R1For halogen (fluorine, chlorine, bromine or iodine)
The same first aspect present invention of definition of remaining each group；
Or the described method comprises the following steps：
(i-c) in atent solvent, formula a compounds carry out ring closure reaction with formula b compounds, obtain formula c compounds；
Preferably, described ring closure reaction is catalyzed by inorganic salts and carried out；
Wherein, V is halogen, OMs, or OTs；The same first aspect present invention of definition of remaining each group, but R1For non-halogen Group.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist This no longer tires out one by one states.
Brief description of the drawings
Fig. 1 suppresses the neutral grain in the peritonitis mice body of uric acid sodium salt crystal induction for the concentration dependant of compound 492 Cell flow diagram.
Embodiment
The present inventor's in-depth study by long-term a, it was found that class has the compound tool of the structure as shown in formula (I) There is the effect for suppressing tubulin activity, can be used for the preparation treatment or prevention lactation related to tubulin dysregulation and move The medicine of thing disease.Based on above-mentioned discovery, inventor completes the present invention.
Term
Herein, except special instruction part, one or more hydrogen atoms that term " substitution " refers on group are selected from down The substituent substitution of group：Halogen, amino, hydroxyl, nitro, cyano group, trifluoromethyl, C1-12Alkyl or cycloalkyl, C1-12Alkoxy, It is oxygen atom (i.e.=O), unsubstituted or by C1-4The C of alkylamino radical substitution1-12Alkylamino radical, C2-6Ester group, C2-6Acyl group, C2-6Amide groups, Thio C1-12Alkyl, carboxyl, C5-12Aryl or heteroaryl, C5-12(containing 1-5, preferably 1-3 are selected from N, O or S to heterocyclic radical Hetero atom).
Term " C1-12Alkyl " refers to the straight or branched alkyl with 1~12 carbon atom, for example methyl, ethyl, propyl group, Isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.
Term " C1-12Cycloalkyl " refers to 1-12, preferably 3~12 (i.e. C3-12) carbon atom cycloalkyl, for example Cyclopropyl, cyclobutyl, cyclopenta, suberyl or similar group.
Term " C1-12Alkoxy " refers to the straight or branched alkoxyl with 1-12 carbon atom, such as methoxyl group, ethoxy Base, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
Term " halogen " refers to F, Cl, Br and I.
Term " C1-12Alkylamino radical " refers to the C replaced by amido1-12Alkyl, such as with " C1-12Alkyl-NH- " or " (alkane Base)2- N- (the total number of carbon atoms is 1-12) ", "-C1-12Alkylidene-NH2", " alkyl-N- alkylidenes-(the total number of carbon atoms is 1- " or " (alkyl) 12)2The group of-N- alkylidenes-(the total number of carbon atoms is 1-12) " structure, such as CH3NH-、C2H5NH-、 C3H7NH-、(CH3)2N-、-CH2NH2、-C2H5NH2、-C3H7NH2、-C2H4N(CH3)2, or similar group.Wherein, C1-12Alkyl It is defined as described above.
Term " C2-C6Ester group " finger-type is as " having straight or branched alkyl/cycloalkyl/aryl/heteroaryl of 1-5 carbon atom The substituent of base-carbonyl-epoxide-" structure, such as ethoxycarbonyl, propyl ester base, butyl ester base, or similar group.
Term " C1-C6Amide groups " finger-type such as " straight or branched alkyl/cycloalkyl/aryl with 0-5 carbon atom/miscellaneous The substituent of aryl-carbonyl-amido-" structure, such as acetamido, propionamido-, amide-based small, or similar group.
Term " C1-C12It (is preferably 6-10, i.e. C that aryl ", which refers to 1-12,6-10) carbon atom aryl, such as benzene Base, naphthyl etc., described aryl can be substituted or unsubstituted.
Term " C1-C12Heteroaryl " refer to 1-12 carbon atom and one or more (preferably 1-3) selected from O, S and/ Or N heteroatomic heteroaryl, preferred 5-8 unit's heteroaryls.Described heteroaryl can be substituted or unsubstituted.
Term " C1-C12Heterocyclic radical " refer to 1-12 carbon atom and one or more (preferably 1-3) selected from O, S and/ Or N heteroatomic non-aromatic cyclic group, preferred 5-8 circle heterocycles base.Described heterocyclic radical can be substitution or unsubstituted 's.
In the present invention, term " pharmaceutically acceptable " composition refers to suitable for people and/or animal without excessive bad pair React (such as toxicity, stimulation and allergy), that is, have rational benefit/risk than material.
In the present invention, term " effective dose " refers to therapeutic agent treatment, alleviates or prevent the amount of target disease or situation, or table Reveal the amount of detectable treatment or prevention effect.Accurate effective dose for a certain object depends on the build of the object and is good for The combination of therapeutic agent and/or therapeutic agent that health situation, the nature and extent of illness and selection are given.Therefore, standard is preassigned True effective dose is useless.However, for certain given situation, the effective dose being determined with normal experiment, is faced Bed doctor can interpolate that out.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical isomer, Such as the mixture (i.e. racemic modification) of the compound of single chiral, or various different chipal compounds.All chemical combination of the present invention Among thing, each asymmetric carbon atom can be optionally R configurations or S configurations, or R configurations and S configurations mixture.
As used herein, term " the compounds of this invention " refers to the compound shown in Formulas I.The term also includes and Formulas I chemical combination Various crystalline forms, pharmaceutically acceptable salt, hydrate or the solvate of thing.
As used herein, term " pharmaceutically acceptable salt " refers to the suitable use that the compounds of this invention is formed with acid or alkali Make the salt of medicine.Pharmaceutically acceptable salt includes inorganic salts and organic salt.The preferred salt of one class is the compounds of this invention and acid The salt of formation.The acid for suitably forming salt includes but is not limited to：Hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acid such as benzene sulfonic acid；And the acidic amino acid such as aspartic acid, glutamic acid.
The preparation of formula (I) compound
The invention provides a kind of compound being shown below：
Wherein, X1、X2、X3、R1、Ar1、Ar2, m and n be as defined above described in text.
It is preferred that compound it is as shown in table 1.
Described compound can be prepared by following preparation method：
Characterized in that, the described method comprises the following steps：
(i-a) in atent solvent, reacted with formula a compounds and formula b compounds, obtain formula c compounds；
(ii-a) in atent solvent, reacted with formula c compounds and formula d compounds, obtain formula e compounds；
And work as Q=N-R1When, in addition to following optional step：(iii-a) it is de- with formula e compounds in atent solvent Protection group, obtains formula f compounds；
Wherein, X is halogen；U is selected from the group：Halogen, OMs, OTs, boric acid, boric acid pinacol ester；Q is O, S or N-R1；P It is selected from the group：To methoxy-benzyl, benzyl, tertbutyloxycarbonyl；
Or the described method comprises the following steps：
(i-b) in atent solvent, formula g compounds are optionally substituted by halogen, and obtain formula h compounds；
Wherein, R1For halogen (fluorine, chlorine, bromine or iodine).
Described compound can also be prepared by following steps：
(i-c) in atent solvent, formula a compounds carry out ring closure reaction with formula b compounds, obtain formula c compounds；
Preferably, described ring closure reaction is catalyzed by inorganic salts and carried out；
Wherein, V is halogen, OMs, or OTs；Remaining each group is defined as above described in text, but R1For the base of non-halogen Group.
In above-mentioned synthetic reaction process, each described atent solvent has no particular limits, and can be selected from dichloro Methane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), second two Diethylene glycol dimethyl ether, 1,2- dichloroethanes, repefral (DMP), 1-METHYLPYRROLIDONE (NMP), methanol, ethanol, just Butanol, isopropanol, petroleum ether, ethyl acetate, the solvent of n-hexane or ether.
In above-mentioned preparation process, necessary alkali can select such as sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, carbon Sour hydrogen sodium, calcium carbonate, potassium phosphate, sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, diethylamine, triethylamine, N, N- diisopropyls Base ethamine (DIPEA) or the carbon -7- alkene (DBU) of 1,8- diazabicyclos [5.4.0] 11 etc.；Necessary acid can be selected from trifluoro second Acid, hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid or p-methyl benzenesulfonic acid etc..
In above-mentioned preparation process, necessary inorganic salts can select sodium fluoride (NaF), potassium fluoride (KF), barium chloride, chlorine Change aluminium etc..
Each step in above-mentioned preparation process can also can be selected from optionally with catalyst, described catalyst Four triphenyl phosphorus palladium (Pd (PPh3)4), palladium (Pd (OAC)2), palladium chloride (PdCl2) palladium carbon, two triphenylphosphine dichlorides Palladium (PdCl2(PPh)2), 1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (PdCl2(dppf)2), three (dibenzylidenes third Ketone) two palladium (Pd2(dba)3), iodine (or bromine or chlorine) changes cuprous, iodine (or bromine or chlorine) and changes copper, copper powder etc..Match somebody with somebody when needing to use catalysis During body, necessary catalysis part can be selected from triphenylphosphine, 2- dicyclohexyls phosphine -2 ', 4 ', 6 '-tri isopropyl biphenyl (Xphos) With 2- dicyclohexyls phosphine -2 ', 6 '-dimethoxy-biphenyl (Sphos) etc..
The organometallic reagent can be n-BuLi, sodium borohydride, lithium borohydride or Sodium triacetoxyborohydride etc.. The halogenating agent can be phosphorus tribromide, POCl3, bromine, iodine, nitrogen chlorine (or bromine or iodine) for succimide (NCS, NBS or NIS) or phenyltrimethyl-ammonium tribromide.
Described oxidant can be Dess-Martin oxidants, Swern oxidants, metachloroperbenzoic acid, chlorine weight chromium Sour pyridine (PDC) or pyridine chlorochromate (PCC).
Pharmaceutical composition and application process
Because the compounds of this invention has an excellent inhibitory activity to tubulin, therefore the compounds of this invention and its each Kind of crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and containing the compounds of this invention be main The pharmaceutical composition of active component can be used for treating, prevent and alleviating by tubulin activity or the related disease of expression quantity, Be particularly suitable for use in tubulin activity or the related disease of expression quantity.According to prior art, the compounds of this invention can be used for controlling Treat following disease：Cancer, nerve degenerative diseases, malaria, AIDS, gout, diabetes etc..
The pharmaceutical composition of the present invention comprising the compounds of this invention in the range of safe and effective amount or its be pharmacologically subjected to Salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " is referred to：The amount of compound is enough substantially Improve the state of an illness, and be unlikely to produce serious side effect.Generally, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, More preferably, containing 5-200mg the compounds of this invention/agent.It is preferred that described is " one " for a capsule or tablet.
" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solids or liquid filler or jello Matter, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity." compatibility " is referred to herein as combined In thing each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on Plain acetic acid esters of dimension etc.), gelatin, talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propane diols, glycerine, mannitol, sorbierite), emulsifying agent (such as)、 Wetting agent (such as lauryl sodium sulfate), colouring agent, flavor enhancement, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes (but being not limited to)：Orally, in knurl, rectum, parenteral (intravenous, intramuscular is subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed with least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions are mixed：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) bond Agent, for example, hydroxymethyl cellulose, alginates, gelatin, PVP, sucrose and Arabic gum；(c) NMF, example Such as, glycerine；(d) disintegrant, for example, agar, calcium carbonate, farina or tapioca, alginic acid, some composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Alcohol and glycerin monostearate；(h) adsorbent, for example, kaolin；Lubricant, for example, talcum, calcium stearate, tristearin (i) Sour magnesium, solid polyethylene glycol, lauryl sodium sulfate, or its mixture.In capsule, tablet and pill, formulation can also be included Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can using be coated and shell material prepare, such as casing and Other materials well known in the art.They can include reactive compound or compound in opacifying agent, also, this composition Release can discharge in certain part in a delayed fashion in alimentary canal.The example of adoptable embedding component is polymeric material And Wax.If necessary, reactive compound also can be with one or more formation microencapsulation forms in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture. Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this area, and such as water or other solvents increase Solvent and emulsifying agent, example knows, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3-BDO, dimethyl formyl The mixture of amine and oil, particularly cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these materials Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste Agent, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene Mixture of sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
For parenteral injection composition can comprising physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
Formulation for the local the compounds of this invention being administered includes ointment, powder, patch, propellant and inhalant. Active component aseptically with physiologically acceptable carrier and any preservative, buffer, or if necessary may need Propellant be mixed together.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable compound administering drug combinations.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment during using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when applying, for the people of 60kg body weight, day is to medicament Amount is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage be also contemplated that method of administration, patient health situation etc. because Element, within the scope of these are all skilled practitioners technical ability.
Compared with prior art, main advantages of the present invention include：
(1) the novel compound of a class formation is provided, described compound has tubulin inhibitory activity.
(2) a kind of compound with tumors inhibition activity is provided, described compound, which can be used for preparing, treats swollen The medicine of knurl.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
Proton nmr spectra BrukerAMX-400 types, Gemini-300 types or AMX -600 types NMR record, Chemical shift δ unit is ppm.All solvents are AR.Developed the color using methods such as iodine, Ultraluminescences.Decompression is steamed Except organic solvent is carried out in Rotary Evaporators.The initial reactant used in the present invention, without special instruction, is that business is purchased Buy.
It should be noted that in following embodiments, conventional post-processing approach is：After the completion of reaction, added in reaction solution Appropriate organic solvent and water, separation organic phase and aqueous phase, merge organic phase, and use NaSO4Dry, rotation is depressurized after filtering It is evaporated, obtains crude product, then by obtaining final product after column chromatographic isolation and purification.
Prepare embodiment：
Embodiment 1：The preparation (scheme with reference to shown in formulas below) of compound 1
Step (i)：The iodo- 3- chlorine pyrroles (1g, 1eq) of N-PMB-5-, P-nethoxyaniline (1.06g, 3eq) and potassium phosphate (1.22g, 2eq) is dissolved in Isosorbide-5-Nitrae-dioxane solution 30mL, nitrogen protection, adds cuprous iodide (55mg, 10%), 110 Degree reaction reaction in 24 hours is finished, and direct solvent evaporated column chromatography obtains N-PMB-5- (4- aminoanisoles) -3- chlorine pyrroles (532mg)；
Step (ii)：N-PMB-5- (4- aminoanisoles) -3- chlorine pyrroles (500mg, 1eq), (2- methyl -5,6,7,8- Imidazolidine simultaneously [1,2-a] pyridin-3-yl) boric acid (393.8mg, 1.5eq) and potassium phosphate (619mg, 2eq) be dissolved in 5mL just In butanol, nitrogen protection adds palladium (16mg, 0.05eq) and xphos (70mg, 0.1eq), 110 degree of reactions 12 hours, instead It should finish.Direct solvent evaporated column chromatography obtains compound e (437mg)；
Step (iii)：Compound e (150mg) is dissolved in 20mL trifluoracetic acids, and the reaction that is stirred overnight at room temperature is finished.It is full Adjust PH to alkalescent with sodium acid carbonate, ethyl acetate extraction, organic layer drying is evaporated column chromatography and obtains compound 1 (71mg)；H NMR (400MHz,CDCl3)δ8.87(s,1H),7.80(s,1H),7.72–7.37(m,2H),7.20–6.85(m,2H),6.10(d,J =7.8Hz, 1H), 5.68 (d, J=7.9Hz, 1H), 3.99 (s, 1H), 3.79 (s, 3H), 2.66-2.59 (m, 5H), 2.08 (dd, J=4.9,0.8Hz, 1H), 1.87-1.76 (m, 1H)
In addition to compound b or d are different, method shown in compounds process for production thereof be the same as Example 1 shown in embodiment 2-47.
The preparation of the compound 50 of embodiment 50
Step (i)：The bromo- 3- chlorine furans (1g, 1eq) of 5-, P-nethoxyaniline (2.04g, 3eq) and potassium phosphate (2.34g, 2eq) it is dissolved in 1-METHYLPYRROLIDONE 15mL, nitrogen protection, adds cuprous bromide (158mg, 20%), 150 degree of reactions 24 Hour reaction is finished, and ethyl acetate extraction, organic layer drying is evaporated column chromatography and obtains 5- (4- aminoanisoles) -3- chlorine furans (613mg)；
Step (ii)：5- (4- aminoanisoles) -3- chlorine furans (500mg, 1eq), 2-methylimidazole parallel [1,2-a] are phonetic Pyridine -3- boric acid (791mg, 2eq) and cesium fluoride (679mg, 2eq) are dissolved in 15mL tetrahydrofurans, nitrogen protection, add Pd2 (dba) 3 (205mg, 0.1eq) and tri-tert phosphorus (90mg, 0.2eq), back flow reaction 10 hours, reaction is finished.Directly it is evaporated Solvent column chromatography obtains 5- (4- methoxybenzenes amido) -3- (2-methylimidazole a pair of horses going side by side [1,2-a] pyrimidine -3-) furans (107mg)；
1H NMR (400MHz, CDCl3) δ 9.58 (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)
In addition to compound b or d are different, embodiment 48,49, the preparation method of 51-202 preparation methods be the same as Example 50, It see the table below
The preparation (scheme with reference to shown in formulas below) of the compound 411 of embodiment 411
Added in 25ml there-necked flasks to methoxyl group thiocarbamide 0.1g (1eq) and heterocyclic compound 0.215g (1eq), thereto Add 6mL first alcohol and water (volumes：Volume=1：1), under nitrogen protection, catalytic amount NaF (2.3mg, 0.1eq) is added, room temperature is anti- Answer 1-5 minutes, TLC detection reactions are complete, saturated sodium bicarbonate solution washing, dichloromethane (10mLx3) extraction, organic layer is done It is dry to be evaporated column chromatography for separation, obtain compound 411.
1H NMR (400MHz, CDCl3) δ 8.95 (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)
In addition to compound a or b are different, the preparation method of the preparation method be the same as Example 411 shown in following table see the table below.
The preparation of the compound 408 of embodiment 408
Compound (100mg, 1eq) is dissolved in 2mL acetic acid, adds nitrogen bromo-succinimide (54mg, 1.5eq), 60 Degree reaction 12 hours, reaction is finished.Saturated sodium bicarbonate is quenched, and ethyl acetate (10mLx3) extraction, organic layer is dry with sodium sulphate Dry, revolving is dry, and column chromatography obtains compound 408 (37mg).1H NMR (400MHz, CDCl3) δ 8.55 (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).
In addition to compound a is different, the preparation method be the same as Example 408 of following table illustrated embodiment see the table below.
The preparation of the compound 412 of embodiment 412
Compound (100mg, 1eq) is dissolved in 5mL trifluoracetic acids, reacts at room temperature 2h, and reaction is finished.Saturated sodium bicarbonate It is quenched, ethyl acetate (10mLx3) extraction, organic layer is dried with sodium sulphate, and revolving is dry, and column chromatography obtains compound 412 (47mg).1H NMR(400MHz,CDCl3) δ 8.47 (d, J=8.0Hz, 1H), 7.53-7.46 (m, 2H), 7.35 (d, J=8.0Hz, 1H), 7.06–6.99(m,3H),3.77(s,3H),2.59(s,3H).
The preparation of the compound 432 of embodiment 432
Compound (100mg, 1eq) is dissolved in anhydrous acetonitrile 5mL, adds SlectFluor (247mg, 1.3eq), 80 degree Reaction reaction in 3 hours is finished.Water 10mL is quenched, and ethyl acetate (10mLx3) extraction, organic layer is dried with sodium sulphate, and revolving is dry, Column chromatography obtains compound 623 (35mg).1H NMR (400MHz, CDCl3) δ 8.56 (d, J=8.3Hz, 1H), 8.47 (s, 2H), (s, the 3H) of 7.41 (d, J=9.0Hz, 1H), 7.04 (t, J=7.9Hz, 1H), 3.84 (s, 3H), 2.59
In addition to compound a is different, the preparation method be the same as Example 432 of following table illustrated embodiment see the table below.
The preparation of the compound 433 of embodiment 433
Compound (200mg, 1eq) is dissolved in acetonitrile/water (4mL/1mL) in the mixed solvent, sequentially adds CF3I (157.6mg, 1.5eq), sodium dithionate (93.4mg, 1eq) and sodium acid carbonate (45mg), react at room temperature 12 hours, have reacted Finish.20mL water is added, ethyl acetate (10mLx3) extraction, organic layer is dried with sodium sulphate, and revolving is dry, and column chromatography obtains compound 622(52mg)。1H NMR (400MHz, CDCl3) δ 8.68 (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)
In addition to compound a is different, the preparation method be the same as Example 433 of following table illustrated embodiment see the table below.
Compound ira vitro biological activity test
The measure of microtubule associated protein biochemical activity
Measuring principle：Micro-pipe is the polymer of tubulin.The end to end formation heterodimers of tubulin α and β, enter And multiple polymerizations are into micro-pipe fibrillation.Micro-pipe is made up of 13 fibrillation, and every micron long micro-pipe is by 1650 heterodimer groups Into.In vitro, tubulin can polymerize.With Tubulin polymerization assay kit (BK011P, Cytoskeleton, Inc.) influence of the detection compound to tubulin polymerization.Contain special reporter fluorescence in the kit, Inserted during microtubule polymerization in micro-pipe, then the polymerisation of micro-pipe can be monitored according to the intensity of fluorescence.First, plus 5 μ l The above-claimed cpd or control compound of various concentrations add 45 μ l microtubule polymerizations in 96 blackboards in 37 DEG C of preheatings, then every hole Mixed liquor (243ul Buffer1,112 μ l Tubulin Glycerol Buffer, 4.4 μ l GTP stock, 85 μ l Tubulin stock), in ELIASA at 37 DEG C the wavelength detecting fluorescence per minute with Ex.=360nm and Em.=450nm Intensity, detects a hour, monitors the polymerisation of micro-pipe, calculates the IC50 that compound suppresses tubulin polymerization, test knot Fruit is shown in Table 1.In table 1, microtubule polymerization inhibitory activity (IC50) method for expressing：+ represent 1-10 μM；++ represent 0.1-1 μM；+++ represent <0.1μM。
Table 1 suppresses microtubule polymerization active testing result
Testing result and analysis：
IC in upper table50Refer to by the concentration (50%inhibitory of inhibitor during microtubule polymerization suppression half concentration)。
Result can be seen that from upper table：Above-mentioned compound and positive control vincristine (Vincristine, VCR) Compare, also can significantly suppress the polymerization of tubulin.
The anti tumor activity in vitro screening of compound
Measuring principle：Colon cancer cell HCT116 is cultivated in the modified 5A culture mediums containing 10% hyclone, pancreas Enzymic digestion is passed on.To the digestion of the rear pancreatin of cell fusion 70% or so, cell count under microscope, Ran Houjie are made after cell suspension Plant in 96 orifice plates, per hole 5 × 103Individual cell.Above-claimed cpd processing is given after overnight incubation.Observed and be administered by mtt assay The change that cell is bred after 72 hours.After compound is handled 72 hours, add 10 μ l MTT working solutions (5mg/ml), 37 DEG C per hole Nutrient solution is suctioned out after being incubated 2 hours, ELIASA is in 492nm wavelength measurements after every hole addition DMSO 100 μ l. room temperatures concussions 15min OD values.The activity that compound suppresses HCT116 cells propagation is calculated, specific inhibiting rate is shown in Table 2 and 3, lived wherein suppressing cell propagation Property (IC50) method for expressing：+ represent 1-10 μM；++ represent 0.1-1 μM；+++ represent 0.01-0.1 μM；++++represent 0.01- 0.001μM；+++ ++ represent<0.001μM；"-" represents inactive.IC50What is represented is the medicine needed for the growth inhibition of cell 50% Concentration (50%growth inhibition).
Cell survival rate (%) computational methods are：
Survival rate (%)=(dosing holes OD- blank well OD)/(control wells OD- blank well OD) × 100
Inhibiting rate (%)=1- survival rates (%)
Other used cancerous cell lines are Hela (human cervical carcinoma cell), MCF-7 (human breast cancer cell), LM3 (people livers Cancer cell), NCI-N87 (gastric carcinoma cells), Caki-1 (human renal carcinoma cell), A549 (human lung carcinoma cell), HT1080 (people's fibers Sarcoma cell), A431 (people's epidermis epidermoid carcinoma cell), PC3 (Human Prostate Cancer Cells), HL60 (human leukemia cell), Panc-1 (human pancreatic cancer cell), KB (human oral cancer cell), U87-MG (neuroglia cell of human oncocyte), (people is slow by K562 Property granulocytic leukemia cell), Kasumi-1 (human leukemia cell), THP-1 (human leukemia cell), Jurkat (people's T lymphs Cell leukemia cell), REH (human B lymphocyte leukaemia), Raji (people's Burkitt's cell leukemia cell), RNK- 16 (NK cells of human beings leukaemias), KMS-1 (people's multiple myeloma cells), (people's myelodysplastic syndrome is thin by P39 Born of the same parents), U118-MG (human glial cell oncocyte), H4 (human glioma cell), (human neuroblastoma is thin by SK-N-SH Born of the same parents), SH-SY5Y (human neuroblastoma cells), A549/Taxol (human lung carcinoma cell of resistance to taxol), KB/VCR (resistance to Changchun New alkali human oral cancer cell), K562/Adr (adriamycin-resistant human chronic polymorpho nuclear leukemia cells) uses DMEM+10%FBS respectively Medium culture is cultivated using 1640+10%FBS.
The compound of table 2 suppresses growth of cancer cells broad-spectrum biological activity test result
As can be seen that the compounds of this invention has for the growth of different types of tumour cell from above-mentioned experimental result There is inhibitory activity, point out the compounds of this invention that there is the antitumor activity of wide spectrum.
The part of compounds of table 3 suppresses the active testing result of hematologic cancer cell growth
Hematologic cancer cell of the compounds of this invention for various different partings is can be seen that from above-mentioned experimental result (acute myeloid leukemia cell, acute or chronic lymphocytic leukemia cell, multiple myeloma cells, marrow increase Raw exception syndrome cell) growth be respectively provided with the effect of inhibitory activity, prompting the compounds of this invention has the suppression blood of wide spectrum The activity of liquid cancer cell growth.
The part of compounds of table 4 suppresses the active testing result of brain cancer cell growth
As can be seen that the compounds of this invention is for Tumor cells (neuroglial cytoma and god from above-mentioned experimental result Through blastoma cell) growth be respectively provided with the effect of inhibitory activity, point out the compounds of this invention to be applied to suppress Tumor cells The activity of growth.
The part of compounds of table 5 is to drug resistant cancer cells growth inhibition test result
Result can be seen that from upper table：Above-mentioned compound and positive control vincristine (Vincristine, VCR), Taxol (Paclitaxel, Taxol) and adriamycin (Adriamycin, Adr) are compared, and listed cancer cell is suppressed with significant The activity grown with drug resistant cancer cells, has excellent suppression especially for taxol, vincristine or Adriamycin resistant strain Activity, also has good inhibiting effect to the growth of the persister of chronic myeloid leukemia cell.
Compound 397 suppresses neutrophil leucocyte and alleviates the experiment of gout symptom
Tubulin inhibitor it is widely used, in addition to as antineoplastic, be also used to treat gout, be also anti-true The anthelmintic of bacterium medicine and wide spectrum.
Experiment content：The 1mg uric acid sodium salt phosphate buffered solutions of 0.5ml endotoxin-frees dissolve, and solution is made. C57BL/6 mouse peritoneal injection uric acid sodium salt solutions, set up peritonitis model.The 1-4 days after the injection of uric acid sodium salt solution, Mouse gives compound 397 (0,0.25, the 0.5 and 1mg/kg) treatment of various concentrations daily, it is found that compound 397 can be notable Ground suppresses the neutrophil leucocyte stream (Fig. 1) in mouse Gout Model body, suppresses inflammation, alleviates the gout state of an illness of mouse.
From figure 1 it appears that the peritonitis that compound 397 can suppress the induction of uric acid sodium salt crystal concentration dependant is small Neutrophil leucocyte stream in mouse body, points out the compound to show to alleviate the effect of the ventilation state of an illness in mouse experiment in vivo.
It should be noted that the technical scheme that the above embodiments are merely illustrative and not limiting of the present invention, any etc. Same replacement or change, should be considered as and be included within the scope of the present invention.
All documents referred in the present invention are all incorporated as reference in this application, independent just as each document It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited Enclose.

Claims (12)

1. a kind of formula (I) compound, or its isomers, racemic modification, pharmaceutically acceptable salt, crystalline hydrate, solvent are closed Thing：
Wherein：
X1Selected from N or C-R1(when R1 is H, being expressed as C)；
X2Selected from N-R1, O or S；
X3It is selected from the group：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- or-(C=NH)-S-；
R1It is selected from the group：Hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano group, carboxyl, C2-6Ester group, C1-6Amide groups, it is unsubstituted or The C of halo1-12Alkyl or cycloalkyl ,-CH2-Y-(C1-12Alkyl or cycloalkyl) (wherein Y is O or NH or S), C1-12Aryl is miscellaneous Aryl ,-CH2-(C1-12Aryl or heteroaryl)；
Ar1Group is substituted or unsubstituted C1-18Aryl or heteroaryl, substituted or unsubstituted-CH2-(C1-12Aryl or heteroaryl Base), substituted or unsubstituted C1-18Heterocyclic radical, substituted or unsubstituted-CH2-(C1-12Heterocyclic radical)；Wherein, described Ar1For Bicyclic radicals, and at least there is a C1-12Alkyl or cycloalkyl substituent；
Ar2Group is substituted or unsubstituted C1-12Alkyl or cycloalkyl, substituted or unsubstituted-CH2-Y-(C1-12Alkyl or ring Alkyl) (wherein Y is O or NH or S), substituted or unsubstituted C1-12Aryl or heteroaryl, substituted or unsubstituted-CH2-(C1-12 Aryl or heteroaryl), substituted or unsubstituted C1-12Heterocyclic radical；Wherein, described Ar2 groups at least one alkoxy substitution Base；
And work as Ar2For C1-12During aryl, described Ar1Also at least there is a halogenic substituent；
M is selected from 0,1,2,3,4,5,6；
N is selected from 0,1,2,3,4,5,6；
Wherein, described substitution is that the one or more substituents for being selected from the following group are replaced：Halogen, amino, hydroxyl, nitro, Cyano group, trifluoromethyl, C1-12Alkyl or cycloalkyl, C1-12It is alkoxy, oxygen atom (i.e.=O), unsubstituted or by C1-4Alkylamino radical takes The C in generation1-12Alkylamino radical, C2-6Ester group, C2-6Acyl group, C1-6Amide groups, thio C1-12It is alkyl, carboxyl, unsubstituted or by 1-5 halogen Element, amino, hydroxyl, nitro, cyano group, the C of trifluoromethyl substitution1-12Aryl or heteroaryl, or it is unsubstituted or by 1-5 halogen, Amino, hydroxyl, nitro, cyano group, the C of trifluoromethyl substitution1-12(containing 1-5, preferably 1-3 are selected from N, O or S to heterocyclic radical Hetero atom).
2. purposes as claimed in claim 1, wherein：
The X3It is selected from the group：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-；
The R1It is selected from the group：Hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano group, carboxyl, ester group, amide groups, unsubstituted C1-6 Alkyl or cycloalkyl, (1-3) fluoro C1-6Alkyl or cycloalkyl, (1-3) C1-6Amido replaces C1-6Alkyl or cycloalkyl, (1-3) C1-6Alkoxy replaces C1-6Alkyl or cycloalkyl ,-CH2-Y-(C1-6Alkyl), C1-12Aryl or heteroaryl ,-CH2-(C1-12Aryl Or heteroaryl).
3. purposes as claimed in claim 1, wherein, described Ar1Or Ar2In group, described C5-12Aryl or heteroaryl choosing From the following group：
M is 0,1,2,3,4,5；
N is 0,1,2,3,4,5.
4. compound as claimed in claim 1, it is characterised in that described Ar1Have to be substituted or unsubstituted such as following formula institute The structure shown：
Wherein, dotted line is chemical bond or nothing；Each A1、A2、A3、A4、A5、A6、A7、A8And A9Be each independently O, S, N, NH, CH or CH2；
Ra is H, halogen, C1-6Alkyl, one or more halo C1-6Alkyl or cycloalkyl, C1-6Alkoxy, C1-6Alkylthio group, C1-6 Alkylamino.
Rb is fluorine, chlorine, C1-6Alkyl, one or more halo C1-6Alkyl or cycloalkyl or C1-6Alkoxy or C1-6Alkylthio group or C1-6Alkylamino, substituted or unsubstituted C5-12Aryl or aromatic heterocyclic；
And work as A8During for N, Rb is nothing；
Substituted definition is as described in the appended claim 1.
5. compound as claimed in claim 1, it is characterised in that described Ar2Have to be substituted or unsubstituted such as following formula institute The structure shown：
Wherein, each B1、B2、B3、B4、B5、B6It is each independently O, S, N, NH, CH or CH2；
Rc is amino, trifluoromethyl, C1-6Alkoxy, C1-6Alkylamino, (1-3) halo C1-6Alkyl or C1-6Alkylthio.
6. compound as claimed in claim 1, it is characterised in that logical formula (I) compound is selected from compound shown in formula (Ia)：
Wherein, dotted line is chemical bond or nothing；Y=CH or N；R1, X1, X2, X3, Ar2, m and n definition such as claim 1；Ra、Rb Definition such as claim 4.
7. compound as claimed in claim 6, it is characterised in that X1For C, X2During for NH, O or S, lead to the choosing of formula (I) compound From compound (wherein thick horizontal line shown in below formula (Ia)Indicate coupling part)：
8. compound as claimed in claim 6, it is characterised in that formula (Ia) compound is selected from chemical combination shown in formula (Ib) Thing：
Wherein, dotted line is chemical bond or nothing；Y=CH or N；X2=NH, O or S；R1, X3 and Ar2 definition such as claim 1； Ra, Rb definition such as claim 4.
9. compound as claimed in claim 8, it is characterised in that during X2=NH or O, compound shown in formula (Ib) is preferably selected From following compound (short and thick line " one " represents coupling part)：
10. as claimed in claim 8, during X2=S, compound shown in formula (Ib) is selected from formula (Ic), (Id), (Ie) shownization Compound：
11. the purposes of pharmaceutical composition as claimed in claim 1, it is characterised in that be selected from down for preparing treatment or prevention The pharmaceutical composition of the disease of group：The mammalian diseases relevant with microtubule associated protein dysregulation；It is preferably selected from the following group Disease：Cancer, nerve degenerative diseases, malaria, AIDS, gout, diabetes.
12. a kind of preparation method of the compound shown in formula (I)：
Wherein, X1、X2、X3、R1、Ar1、Ar2, m and n definition as claim 1-10 it is any described in；
Characterized in that, the described method comprises the following steps：
(i-a) in atent solvent, reacted with formula a compounds and formula b compounds, obtain formula c compounds；
(ii-a) in atent solvent, reacted with formula c compounds and formula d compounds, obtain formula e compounds；
And work as Q=N-R1When, in addition to following optional step：(iii-a) in atent solvent, it is deprotected with formula e compounds Base, obtains formula f compounds；
Wherein, X is halogen；U is selected from the group：Halogen, OMs, OTs, boric acid, boric acid pinacol ester；Q is O, S or N-R1；P is selected from down Group：To methoxy-benzyl, benzyl, tertbutyloxycarbonyl；
Or the described method comprises the following steps：
(i-b) in atent solvent, formula g compounds are optionally substituted by halogen, and obtain formula h compounds；
Wherein, R1For halogen (fluorine, chlorine, bromine or iodine)
The definition of remaining each group is with claim 1；
Or the described method comprises the following steps：
(i-c) in atent solvent, formula a compounds carry out ring closure reaction with formula b compounds, obtain formula c compounds；
Preferably, described ring closure reaction is catalyzed by inorganic salts and carried out；
Wherein, V is halogen, OMs, or OTs；The definition of remaining each group is with claim 1, but R1For the group of non-halogen.
CN201610880966.8A 2016-04-20 2016-10-09 Five-membered heterocycles and preparation method thereof, pharmaceutical composition and purposes Pending CN107304203A (en)

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