CN107501279B - Furoquinoline cyclohexadione compounds and its medical usage - Google Patents
Furoquinoline cyclohexadione compounds and its medical usage Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Abstract
The application belongs to field of medicinal chemistry, is related to furoquinoline cyclohexadione compounds and its medical usage.Specifically, this application involves formula (I) compound, its prodrug, stereoisomer or pharmaceutically acceptable salt, pharmaceutical composition, preparation method and its medical usages.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to furoquinoline cyclohexadione compounds and its medical usage.
Background technique
STAT3 is signal transduction and activating transcription factor (Signal Transducer and Activator of
Transcription, STAT) family an important member.STAT3 has extensive function, its adjustable and cell week
Phase, survival and the relevant gene expression of immune response, the deterioration and progress with kinds of tumors are closely related.STAT3 two important
The phosphorylation in site is related with STAT3 activation, i.e. the 705th tyrosine and the 727th serine.Various tyrosine kinase entities
(such as EGFR, VEGFR and PDGF), non-tyrosine kinase (such as Arc and Abl) activate related cytokine receptor with JAK
Make STAT3 705 site tyrosine (Tyr705) phosphorylation Deng when activating.And various serine kinases (such as MAPK, ERK,
JNK, PKC and mTOR) etc. activation when make 727 site serine of STAT3 (Ser727) phosphorylation (Kamran MZ et
al.BioMed Res Intern 2013Article ID 421821).The STAT3 of phosphorylation forms dimer and is transferred to nucleus
In become one activation transcription factor, with the promoter region of its target gene ining conjunction with, regulation downstream and anti-apoptotic, blood vessel life
At, invasion and migration related gene expression.In about 70% human body solid tumor STAT3 constitutively activated.(Steffanie L et
al.ACS Chem Biol.11：308–318,2016；Yu H.et al.Nat Rev Cancer 14,736–746,2014).
In recent years the study found that STAT3 and tumor stem cell versatility maintain closely related (Wei W.et al.Stem
Cells 32:2571-2582,2014；Marotta LLC.J Clin Invest.121:2723-2735,2011).
STAT3 is the important target spot of antineoplastic.Multiple STAT3 inhibitor include OPB-51602, AZD9150, OPB-
31121, WP1066 and BBI608 comes into clinical investigation phase.BBI608 (Napabucasin) is that a kind of take orally has
The cancer cell versatility inhibitor of STAT3 inhibitory activity is dry thin by the stem cell gene expression and cancer of lowering STAT3 driving
Born of the same parents' performance realizes the self-renewing for effectively inhibiting highly-versatile cancer cell.In tumor model, tumour can be significantly inhibited
Transfer and recurrence (LiY., et al.PNAS 112:1839-1844,2015).
Summary of the invention
Inventor is had found by numerous studies, as formula (I) compound represented has STAT3 inhibitory activity；Such as its energy
Enough inhibit the expression of STAT3 in kinds of tumor cells；Such as it can inhibit the phosphorylation of STAT3 to inhibit STAT3's
Activation is (for example, the phosphorylation of STAT3705 tyrosine；For example, the phosphorylation of 727 serines of STAT3)；Therefore, described
Compound can be used as STAT3 inhibitor and play a role.For example, the compound can be used for preventing or treating relevant to STAT3
Disease (for example, tumour).
Also, formula (I) compound, its prodrug, stereoisomer or pharmaceutically acceptable salt can inhibit tumour cell
Proliferation, such as inhibit the proliferation of the cancer cell of colon cancer, breast cancer, colorectal cancer and lung cancer.Formula (I) compound of the present invention, before it
Medicine, stereoisomer or pharmaceutically acceptable salt can be used for preparing prevention and/or treatment tumour (such as colon cancer, breast cancer,
Colorectal cancer, lung cancer) drug.
Therefore, the one aspect of the application is related to formula (I) compound, its prodrug, stereoisomer or pharmaceutically may be used
The salt of receiving,
Wherein,
A, B, D and E atom are each independently selected from C atom and N atom, and at least one (such as 1,2,3 or 4) is N
Atom；
R1Selected from hydrogen, halogen, nitro, cyano, C1-C6Alkyl, C1-C6Alkoxy, C2-C6Alkenyl, C2-C6Alkynyl, 6-14 member
Aryl and 5-14 unit's heteroaryl；Wherein, the C1-C6Alkyl, C1-C6Alkoxy, C2-C6Alkenyl, C2-C6Alkynyl, 6-14 member aryl
It is unsubstituted or be selected from following substituent groups by one or more (such as 1,2,3 or 4) and replace with 5-14 unit's heteroaryl：Halogen
Element, hydroxyl, amino, cyano, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylamino, C1-C6Alkylthio group and C1-C6
Alkyl sulphonyl；
R2Selected from C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 6-14 member aryl and 5-14 member heteroaryl
Base；Wherein, the C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, C3-C6Methyl cycloalkyl, 6-14 member aryl
It is unsubstituted or be selected from following substituent groups by one or more (such as 1,2,3 or 4) and replace with 5-14 unit's heteroaryl：Halogen
Element, hydroxyl, amino, cyano, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, C1-C6Alkoxy, C1-C6Alkylamino, C1-C6Alkane
Sulfenyl and C1-C6Alkyl sulphonyl；
R3Selected from hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl and C3-C6Naphthenic base；Wherein, the C1-C6Alkyl,
C2-C6Alkenyl, C2-C6Alkynyl and C3-C6Naphthenic base is unsubstituted or is selected from by one or more (such as 1,2,3 or 4) following
Substituent group replace：Halogen, hydroxyl, amino, cyano, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylamino, C1-
C6Alkylthio group and C1-C6Alkyl sulphonyl.
In the certain preferred embodiments of the application, A, B, D and E atom are each independently selected from C atom and N atom,
And having one in A, B, D and E is N atom；R1Selected from hydrogen, halogen, nitro, cyano, C1-C6Alkyl, C1-C6Alkoxy, aryl and
Heteroaryl, wherein the C1-C6Alkyl, C1-C6Alkoxy, aryl and heteroaryl it is unsubstituted or by it is one or more (such as
1,2,3 or 4) replace selected from following substituent groups：Halogen, hydroxyl, amino and cyano；R2For C1-C6Alkyl or aryl；R3For
Hydrogen or C1-C6Alkyl.
In the certain preferred embodiments of the application, R1Selected from hydrogen, halogen, nitro, cyano, C1-C6Alkyl, C1-C6Alkane
Oxygroup, 6-14 member aryl and 5-6 unit's heteroaryl；Wherein, the C1-C6Alkyl, C1-C6Alkoxy, 6-14 member aryl and 5-6 member
Heteroaryl is unsubstituted or is replaced by one or more (such as 1,2,3 or 4) selected from following substituent groups：Halogen, hydroxyl, ammonia
Base, cyano, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Alkylthio group and C1-C4Alkyl sulphonyl.
In the certain preferred embodiments of the application, R1Selected from hydrogen, halogen, nitro, cyano, C1-C6Alkyl, C1-C6Alkane
Oxygroup, phenyl and 5-6 unit's heteroaryl；Wherein, the C1-C6Alkyl, C1-C6Alkoxy, phenyl and 5-6 unit's heteroaryl are not taken
In generation, is replaced by one or more (such as 1,2,3 or 4) selected from following substituent groups：Halogen, hydroxyl, amino and cyano.
In the certain preferred embodiments of the application, R1Selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C4Alkane
Base, C1-C4Alkoxy, phenyl and 5-6 unit's heteroaryl；Wherein, the 5-6 unit's heteroaryl be selected from furans, thiophene, pyrroles, pyrimidine,
Pyrazine, pyridazine and pyrimidine.
In the certain preferred embodiments of the application, R1Selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C4Alkane
Base, C1-C4Alkoxy, phenyl, furans, thiophene, pyrroles, pyrimidine, pyrazine, pyridazine and pyrimidine.
In the certain preferred embodiments of the application, R1For C1-C6Alkyl.
In the certain preferred embodiments of the application, R1For C1-C4Alkyl.
In the certain preferred embodiments of the application, R1For methyl.
In the certain preferred embodiments of the application, R1For methyl or ethyl.
In the certain preferred embodiments of the application, R1For methyl, ethyl or propyl.
In the certain preferred embodiments of the application, R1Selected from hydrogen, fluorine, chlorine, nitro, cyano, trifluoromethyl, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl group, methoxyl group, ethyoxyl, phenyl, furans and thiophene.
In the certain preferred embodiments of the application, R1Selected from halogen, nitro, cyano, C1-C6Alkyl, C1-C6Alcoxyl
Base, aryl and heteroaryl；Wherein, the C1-C6Alkyl, C1-C6Alkoxy, aryl and heteroaryl are unsubstituted.
In the certain preferred embodiments of the application, R1Selected from halogen, nitro, cyano, C1-C6Alkyl, C1-C6Alcoxyl
Base, phenyl and 5-6 unit's heteroaryl；Wherein, the C1-C6Alkyl, C1-C6Alkoxy, phenyl and 5-6 unit's heteroaryl are unsubstituted.
In the certain preferred embodiments of the application, R1Selected from halogen, nitro, cyano, trifluoromethyl, C1-C4Alkyl,
C1-C4Alkoxy, phenyl, furans, thiophene, pyrroles, pyrimidine, pyrazine, pyridazine and pyrimidine.
In the certain preferred embodiments of the application, R1Selected from fluorine, chlorine, nitro, cyano, trifluoromethyl, methyl, second
Base, propyl, isopropyl, butyl, isobutyl group, methoxyl group, ethyoxyl, phenyl, furans and thiophene.
In the certain preferred embodiments of the application, R2For C1-C6Alkyl or aryl；Wherein, the C1-C6Alkyl and virtue
Base is unsubstituted or is replaced by one or more (such as 1,2,3 or 4) selected from following substituent groups：Halogen, hydroxyl, amino,
Cyano, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Naphthenic base, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Alkylthio group and C1-C4Alkane
Base sulfonyl.
In the certain preferred embodiments of the application, R2For C1-C4Alkyl or phenyl.
In the certain preferred embodiments of the application, R2Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group
And phenyl.
In the certain preferred embodiments of the application, R2For C1-C6Alkyl.
In the certain preferred embodiments of the application, R2For C1-C4Alkyl.
In the certain preferred embodiments of the application, R2For methyl.
In the certain preferred embodiments of the application, R2For methyl or ethyl.
In the certain preferred embodiments of the application, R2For methyl, ethyl or propyl.
In the certain preferred embodiments of the application, R3Selected from hydrogen or C1-C6Alkyl；Wherein, the C1-C6Alkyl not by
Replace or following substituent groups is selected from by one or more (such as 1,2,3 or 4) and replaces：Halogen, hydroxyl, amino, cyano,
C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Alkylthio group and C1-C4Alkyl sulphonyl；
In the certain preferred embodiments of the application, R3Selected from hydrogen and C1-C4Alkyl.
In the certain preferred embodiments of the application, R3For hydrogen or methyl.
In the certain preferred embodiments of the application, R3For hydrogen.
In the certain preferred embodiments of the application, R3For methyl.
In the certain preferred embodiments of the application, the compound has structure shown in formula (II)：
Wherein, R1、R2、R3Definition as described in the application formula (I) compound.
In the certain preferred embodiments of the application, R in formula (II)1Positioned at the meta or para position of N atom.
In the certain preferred embodiments of the application, R in formula (II)1Positioned at the meta position of N atom.
In the certain preferred embodiments of the application, R in formula (II)1Positioned at the contraposition of N atom.
In the certain preferred embodiments of the application, R in formula (II)1Selected from hydrogen, methyl, ethyl, propyl, isopropyl,
Fluorine, chlorine, bromine, nitro, cyano, methoxyl group, furyl, thienyl and phenyl.
In the certain preferred embodiments of the application, R in formula (II)1Selected from hydrogen, fluorine, chlorine, nitro, cyano, methyl, second
Base, isopropyl, methoxyl group, phenyl, furans and thiophene.
In the certain preferred embodiments of the application, R in formula (II)1Selected from hydrogen, methyl, ethyl and furyl.
In the certain preferred embodiments of the application, R in formula (II)1Selected from methyl, ethyl, propyl, isopropyl, fluorine,
Chlorine, bromine, nitro, cyano, methoxyl group, furans, thiophene and phenyl.
In the certain preferred embodiments of the application, R in formula (II)1For C1-C6Alkyl.
In the certain preferred embodiments of the application, R in formula (II)1For C1-C4Alkyl.
In the certain preferred embodiments of the application, R in formula (II)1For methyl.
In the certain preferred embodiments of the application, R in formula (II)1For methyl, ethyl or propyl.
In the certain preferred embodiments of the application, R in formula (II)1For methyl or ethyl.
In the certain preferred embodiments of the application, R in formula (II)2For C1-C6Alkyl.
In the certain preferred embodiments of the application, R in formula (II)2For C1-C4Alkyl.
In the certain preferred embodiments of the application, R in formula (II)2Selected from methyl, ethyl, isopropyl and phenyl.
In the certain preferred embodiments of the application, R in formula (II)2For methyl.
In the certain preferred embodiments of the application, R in formula (II)2For methyl or ethyl.
In the certain preferred embodiments of the application, R in formula (II)2For methyl, ethyl or propyl.
In the certain preferred embodiments of the application, R in formula (II)3For hydrogen or methyl.
In the certain preferred embodiments of the application, R in formula (II)3For hydrogen.
In the certain preferred embodiments of the application, R in formula (II)3For methyl.
In the certain preferred embodiments of the application, the compound has structure shown in formula (III)：
Wherein, R1、R2、R3Definition as described in the application formula (I) compound.
In the certain preferred embodiments of the application, R in formula (III)1Positioned at the meta or para position of N atom.
In the certain preferred embodiments of the application, R in formula (III)1Positioned at the meta position of N atom.
In the certain preferred embodiments of the application, R in formula (III)1Positioned at the contraposition of N atom.
In the certain preferred embodiments of the application, R in formula (III)1Selected from hydrogen, methyl, methoxyl group, fluorine, chlorine nitro
And cyano.
In the certain preferred embodiments of the application, R in formula (III)1Selected from hydrogen, fluorine, chlorine, nitro, cyano, methyl,
Ethyl, isopropyl, methoxyl group, phenyl, furyl and thienyl.
In the certain preferred embodiments of the application, R in formula (III)1Selected from fluorine, chlorine, nitro, cyano, methyl, second
Base, isopropyl, methoxyl group, phenyl, furyl and thienyl.
In the certain preferred embodiments of the application, R in formula (III)1For methyl or ethyl.
In the certain preferred embodiments of the application, R in formula (III)1For hydrogen.
In the certain preferred embodiments of the application, R in formula (III)2Selected from methyl, ethyl, isopropyl and phenyl.
In the certain preferred embodiments of the application, R in formula (III)2For methyl.
In the certain preferred embodiments of the application, R in formula (III)3For hydrogen or methyl.
In the certain preferred embodiments of the application, R in formula (III)3For hydrogen.
In the certain preferred embodiments of the application, the compound has structure shown in formula (IV) or formula (V)：
Wherein, each substituent group definition is as described in the application formula (I) compound.
In the certain preferred embodiments of the application, R in the formula (IV) or formula (V)1For hydrogen.
In the certain preferred embodiments of the application, R in the formula (IV) or formula (V)2For methyl or phenyl.
In the certain preferred embodiments of the application, R in the formula (IV) or formula (V)2For phenyl.
In the certain preferred embodiments of the application, R in the formula (IV) or formula (V)2For methyl.
In the certain preferred embodiments of the application, R in the formula (IV) or formula (V)3For hydrogen.
In the certain preferred embodiments of the application, the compound has structure shown in formula (VI) or formula (VII)：
Wherein,
R1For C1-C6Alkyl；
R2For C1-C6Alkyl.
In the certain preferred embodiments of the application, R in formula (VI) or formula (VII)1For C1-C4Alkyl.
In the certain preferred embodiments of the application, R in formula (VI)1For C1-C4Alkyl.
In the certain preferred embodiments of the application, R in formula (VII)1For C1-C4Alkyl.
In the certain preferred embodiments of the application, R in formula (VI)1For methyl, ethyl or propyl.
In the certain preferred embodiments of the application, R in formula (VII)1For methyl, ethyl or propyl.
In the certain preferred embodiments of the application, R in formula (VI)1For methyl or ethyl.
In the certain preferred embodiments of the application, R in formula (VII)1For methyl or ethyl.
In the certain preferred embodiments of the application, R in formula (VI)1For methyl.
In the certain preferred embodiments of the application, R in formula (VII)1For methyl.
In the certain preferred embodiments of the application, R in formula (VI) or formula (VII)2For C1-C4Alkyl.
In the certain preferred embodiments of the application, R in formula (VI)2For C1-C4Alkyl.
In the certain preferred embodiments of the application, R in formula (VII)2For C1-C4Alkyl.
In the certain preferred embodiments of the application, R in formula (VI)2For methyl, ethyl or propyl.
In the certain preferred embodiments of the application, R in formula (VII)2For methyl, ethyl or propyl.
In the certain preferred embodiments of the application, R in formula (VI)2For methyl or ethyl.
In the certain preferred embodiments of the application, R in formula (VII)2For methyl or ethyl.
In the certain preferred embodiments of the application, R in formula (VI)2For methyl.
In the certain preferred embodiments of the application, R in formula (VII)2For methyl.
In the certain preferred embodiments of the application, the compound is selected from：
Further aspect of the application is related to pharmaceutical composition, and it includes compounds described herein, its prodrug, solid
Isomers or pharmaceutically acceptable salt and one or more pharmaceutic adjuvants.
When the pharmaceutic adjuvant refers to production drug and prescription being dispensed, the excipient and additives used refers to except work
Outside property ingredient, reasonable assessment is had been carried out in terms of safety, and include the substance in pharmaceutical preparation.Pharmaceutic adjuvant removes
Excipient serves as carrier, improves outside stability, also has solubilising, hydrotropy, delays the critical functions such as controlled release, is possible influence whether
Quality, the important component of safety and validity of drug.Natural goods, semisynthetic and fully synthetic can be divided into according to its source
Object.It can be divided into according to its effect with purposes：Solvent, propellant, solubilizer, cosolvent, emulsifier, colorant, binder, disintegration
Agent, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, corrigent, preservative, suspending agent, coating
Material, aromatic, anti stickness agent, antioxidant, chelating agent, penetration enhancer, pH adjusting agent, buffer, plasticizer, surface-active
Agent, foaming agent, defoaming agent, thickener, inclusion agents, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid,
Discharge retarding agent etc.；Oral, injection, mucous membrane, percutaneous or local administration, intranasal or oral cavity sucking can be divided into according to its administration route
Administration and ophthalmic administration etc..Same pharmaceutic adjuvant can be used for the pharmaceutical preparation of different way of administration, and play the role of different and use
On the way.
Various suitable dosage forms can be made in described pharmaceutical composition according to administration route.Wherein, the pharmaceutical composition
Or suitable dosage form can the compounds of this invention containing 0.01mg to 1000mg, its prodrug, stereoisomer or pharmaceutically may be used
The salt of receiving is suitable for preferably comprising 0.5-500mg containing 0.1mg to 800mg, preferably comprises 1 to 350mg, preferably 5-250mg,
It is preferred that 5-150mg, preferably 5-100mg.
When oral medication, described pharmaceutical composition can be made into and arbitrarily take orally acceptable dosage form, including but unlimited
In tablet, capsule, granule, pill, syrup, oral solution, oral suspensions and Orally taken emulsion etc..Wherein, tablet
The carrier used generally comprises lactose and cornstarch, and lubricant such as magnesium stearate in addition can also be added.Capsule uses dilute
It releases agent and generally comprises lactose and dried corn starch.Oral suspensions are then usually by active constituent and suitable emulsifier and to hang
Floating agent is used in mixed way.Optionally, some sweeteners, aromatic or colorant can also be added in the above oral dosage form.
When percutaneous or local application, described pharmaceutical composition can be made into ointment, lotion or liniment form appropriate, wherein
Active constituent is suspended or dissolved in one or more carriers.Carrier workable for ointment formulation includes but is not limited to：Mineral
Oil, Albolene, albolene, propylene glycol, polyethylene glycol oxide, polypropylene oxide, emulsifying wax and water；Lotion or liniment can make
Carrier includes but is not limited to：Mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene
Fragrant and mellow, 2- octyldodecanol, benzyl alcohol and water.
Described pharmaceutical composition can the medication in the form of injection, including injection, injection sterile powder and injection
Concentrated solution.Wherein, workable carrier and solvent include water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterilizing is non-
Volatile oil also is used as solvent or suspension media, such as monoglyceride or two glyceride.
The another aspect of the application is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or described pharmaceutical composition preparation inhibit STAT3 expression reagent in purposes.
The another aspect of the application is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or described pharmaceutical composition preparation inhibit STAT3 activation reagent in purposes.
The another aspect of the application is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or described pharmaceutical composition preparation inhibit STAT3 phosphorylation (such as inhibit 705 site tyrosine of STAT3 phosphorylation
Or the phosphorylation of 727 site serine of STAT3) reagent in purposes.
The another aspect of the application is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or described pharmaceutical composition preparing the purposes in STAT3 inhibitor.
The another aspect of the application is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Purposes in the drug of preparation prevention or relevant to the STAT3 disease for the treatment of of salt or described pharmaceutical composition.
The another aspect of the application is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or described pharmaceutical composition, it is used to prevent or treat diseases relevant to STAT3.
The another aspect of the application is related to a kind of method prevented or treat disease relevant to STAT3 comprising Xiang You
This subject needed applies a effective amount of herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
The step of salt or described pharmaceutical composition.
In the certain preferred embodiments of the application, the disease relevant to STAT3 is tumour.
In the certain preferred embodiments of the application, the tumour is entity tumor or neoplastic hematologic disorder.
In the certain preferred embodiments of the application, the entity tumor is colorectal cancer, gastric cancer, breast cancer, pancreas
Cancer or lung cancer.
In the certain preferred embodiments of the application, the neoplastic hematologic disorder is lymthoma, myeloma, the white blood of lymphocyte
Disease or acute myeloid leukemia.
The another aspect of the application is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or herein described pharmaceutical composition preparing the application in drug for inhibiting tumor cell proliferation.
In the certain preferred embodiments of the application, the tumour cell is selected from colon cancer, breast cancer, colorectal cancer and lung
The cancer cell of cancer.
In the certain preferred embodiments of the application, the tumour cell be selected from SW620, MCF7, MDA-MD-231,
LOVO, H1975 and Colon 205.
The another aspect of the application is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or herein described pharmaceutical composition preparing the purposes in drug for preventing and/or treating tumour.
In the certain preferred embodiments of the application, the tumour is selected from colon cancer, breast cancer, colorectal cancer and lung cancer.
The another aspect of the application is related to inhibiting the method for tumor cell proliferation in vivo or in vitro, including to there is demand
Subject imposes a effective amount of herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable salt or this Shen
It please described pharmaceutical composition.
In the certain preferred embodiments of the application, the tumour cell is selected from colon cancer, breast cancer, colorectal cancer and lung
The cancer cell of cancer.
In the certain preferred embodiments of the application, the tumour cell be selected from SW620, MCF7, MDA-MD-231,
LOVO, H1975 and Colon 205.
The another aspect of the application is related to preventing and/or treating the method for tumour, including give the subject of demand with
A effective amount of herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable salt or herein described drug
Composition.
In the certain preferred embodiments of the application, the tumour is selected from colon cancer, breast cancer, colorectal cancer and lung cancer.
Another aspect of the present invention is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or herein described pharmaceutical composition, are used to inhibit STAT3.
Another aspect of the present invention is related to herein described compound, its prodrug, stereoisomer or pharmaceutically acceptable
Salt or herein described pharmaceutical composition are used to inhibit tumor cell proliferation or for preventing and/or treating tumour.
In the certain preferred embodiments of the application, the tumour cell is selected from colon cancer, breast cancer, colorectal cancer and lung
The cancer cell of cancer.
In the certain preferred embodiments of the application, the tumour is selected from colon cancer, breast cancer, colorectal cancer and lung cancer.
In the certain preferred embodiments of the application, the tumour cell be selected from SW620, MCF7, MDA-MD-231,
LOVO, H1975 and Colon 205.
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology
The normally understood meaning of personnel institute.Also, cell culture used herein, Immunology Lab operating procedure are corresponding neck
Widely used conventional steps in domain.Meanwhile for a better understanding of the present invention, the definition reconciliation of relational language is provided below
It releases.
As used herein, term " stereoisomer " includes conformer and configurational isomer, wherein described
Configurational isomer mainly includes cis-trans-isomer and optical isomer.Compound of the present invention can be with the shape of stereoisomer
Formula exists, and therefore covers all possible stereoisomer form and any combination thereof or any mixture.Such as it is single right
Reflect isomers, single diastereoisomer or more than mixture.When compound of the present invention contains olefinic double bonds, remove
Non-specifically illustrate, otherwise it includes cis-isomer and transisomer and any combination thereof.
As used herein, term " pharmaceutically acceptable salt " refers to, acid present in (1) the compounds of this invention
Property functional group (such as-COOH ,-OH ,-SO3H etc.) with appropriate inorganic or organic cation (alkali) formed salt, such as this
The ammonium salt and the compounds of this invention of salt, the compounds of this invention that invention compound and alkali or alkaline earth metal are formed with it is nitrogenous
The salt that organic base is formed；And basic functionality present in (2) the compounds of this invention (such as-NH2Deng) with it is appropriate inorganic
Or the salt that organic anion (acid) is formed, such as the salt that the compounds of this invention and inorganic acid or organic carboxyl acid are formed.
Therefore, " pharmaceutically acceptable salt " of the compounds of this invention includes but is not limited to alkali metal salt, such as sodium salt, potassium
Salt, lithium salts etc.；Alkali salt, such as calcium salt, magnesium salts；Other metal salts, such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt
Deng；Inorganic base salts, such as ammonium salt；Organic alkali salt, such as t-octyl amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, the sweet ammonia of phenyl
Acid alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-
Dibenzyl ethylenediamine salt, chloroprocanine salt, procaine salt, diethanolamine salt, N- benzyl-phenethyl amine salt, piperazine salt, four
Methyl amine salt, three (methylol) aminomethane salt；Halogen acid salt, such as hydrofluoride, hydrochloride, hydrobromate, hydriodate；
Inorganic acid salt, such as nitrate, perchlorate, sulfate, phosphate；Rudimentary alkyl sulfonate, such as mesylate, trifluoromethanesulfonic acid
Salt, esilate etc.；Arylsulphonate, such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt；Acylate, as acetate, malate,
Fumarate, succinate, citrate, tartrate, oxalates, maleate etc.；Amino-acid salt, such as glycinate, three
Methylglycine salt, arginine salt, ornithine salt, glutamate, aspartate etc..
As used herein, term " prodrug ", also referred to as pro-drug, prodrug, forerunner's drug etc., refer to this Shen
The inactive in vitro or active smaller conversion in vivo through enzyme or non-enzymatic that compound please obtains after modifying releases work
Property drug and the compound for playing drug effect.The design principle and preparation method of prodrug are known to those skilled in the art.
As used herein, term " halogen " refers to fluorine, chlorine, bromine and iodine.
As used herein, term " C1-C6Alkyl " refers to the linear or branched alkyl group with 1-6 carbon atom, example
Such as C1-C4Alkyl, C1-C2Alkyl, C1Alkyl, C2Alkyl, C3Alkyl, C4Alkyl, C5Alkyl or C6Alkyl.Specifically example includes
But be not limited to methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, n-hexyl etc..
As used herein, term " C1-C6Alkoxy " refers to C1-C6The group that alkyl-O- mode is formed,
In " C1-C6Described in alkyl " text as defined above.Specific example includes but is not limited to methoxyl group, ethyoxyl, propoxyl group, isopropyl
Oxygroup, butoxy, 2- butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, hexyloxy etc..
As used herein, term " C1-C6Alkylamino " refers to C1-C6The group that alkyl-NH- mode is formed,
In " C1-C6Described in alkyl " text as defined above.Specific example includes but is not limited to methylamino, ethylamino, the third amino, isopropyl
Amino, fourth amino, 2- fourth amino, i-butylamino, Zhong Ding amino, tertiary fourth amino, penta amino, own amino etc..
As used herein, term " C1-C6Alkylthio group " refers to C1-C6The group that alkyl-S- mode is formed,
In " C1-C6Described in alkyl " text as defined above.Specific example includes but is not limited to methyl mercapto, ethylmercapto group, rosickyite base, isopropyl
Sulfenyl, butylthio, 2- butylthio, isobutylthio, secondary butylthio, tertiary butylthio, penta sulfenyl, own sulfenyl etc..
As used herein, term " C1-C6Alkyl sulphonyl " refers to C1-C6Alkyl-S (O)2What mode was formed
Group, wherein " C1-C6Described in alkyl " text as defined above.Specific example includes but is not limited to mesyl, ethylsulfonyl
Deng.
As used herein, term " C2-C6Alkenyl " refers to containing 2-6 carbon atom and one, two or three
The linear chain or branched chain alkyl of carbon-carbon double bond, preferably comprises the C of a carbon-carbon double bond2-C6Alkenyl.Such as C2-C4Alkenyl, C2Alkenyl,
C3Alkenyl, C4Alkenyl, C5Alkenyl or C6Alkenyl.Specific example includes but is not limited to vinyl, acrylic, 2- acrylic, butylene
Base, 2- cyclobutenyl, 2- methyl-propenyl, butadienyl, pentenyl, 2- methyl-butene base, 3- methyl-butene base, 1,3- penta
Dialkylene, 1,4- pentadienyl, hexenyl, 2- ethyl-butylene base, 3- methyl pentene base, 4- methyl pentene base, 1,3- oneself two
Alkenyl, 1,4- hexadienyl, 1,5- hexadienyl etc..
As used herein, term " C2-C6Alkynyl " refers to containing 2-6 carbon atom and one, two or three
The linear chain or branched chain alkyl of triple carbon-carbon bonds, preferably comprises the C of a triple carbon-carbon bonds2-C6Alkynyl.Such as C2-C4Alkynyl, C2Alkynyl,
C3Alkynyl, C4Alkynyl, C5Alkynyl or C6Alkynyl.Specific example includes but is not limited to acetenyl, propinyl, 2-propynyl, butine
Base, 2- butynyl, 2- methyl-propinyl, diacetylene base, pentynyl, 2- methyl-butynyl, 3- methyl-butynyl, 1,3- penta
Diynyl, 1,4- pentadiine base, hexin base, 2- ethyl-butynyl, 3- methyl-pentinylen, 4- methyl-pentinylen, 1,3- oneself two
Alkynyl, 1,4- adipic alkynyl, 1,5- adipic alkynyl etc..
As used herein, term " aryl " refers to monocycle or multi-ring alkyl with armaticity, such as 6-10 member
Aryl etc..Specific example includes but is not limited to phenyl, naphthalene, anthryl, phenanthryl etc..
As used herein, term " heteroaryl ", which refers to, is selected from the heteroatomic as before of N, O and S containing at least one
The aryl, such as C5-C6Heteroaryl.Specific example include but is not limited to furyl, thienyl, pyrrole radicals, thiazolyl,
Isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, imidazole radicals, pyrazolyl, 1,2,3- triazolyl, 1,2,4- triazolyl, 1,
2,3- oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4- oxadiazolyl, pyridyl group, 2- pyriconyl,
4- pyriconyl, pyrimidine radicals, 2H-1,2- oxazinyl, 4H-1,2- oxazinyl, 6H-1,2- oxazinyl, 4H-1,3- oxazinyl, 6H-
1,3- oxazinyl, 4H-1,4- oxazinyl, pyridazinyl, pyrazinyl, 1,2,3- triazine radical, cyanuro 1,3,5,1,2,4,5- tetrazine
Base, azepine cycloheptatriene base, 1,3- diaza cycloheptatriene base, benzofuranyl, benzisoxa furyl, benzothienyl, Yin
Diindyl base, iso-indoles, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazole base, quinolyl, 2- quinolinone, 4- quinolinone,
1- isoquinolines, isoquinolyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base,
Pteridine radicals, purine radicals, naphthyridines base, azophenlyene, phenthazine etc..
As used herein, term " C3-C6Naphthenic base " refers to the monocycle saturated alkyl containing 3-6 ring members, example
Such as 3-5 member naphthenic base, 3 yuan, 4 yuan, 5 yuan, 6 yuan of naphthenic base.Specifically example includes but is not limited to：Cyclopropyl, cyclobutyl, ring penta
Base, cyclohexyl etc..
As used herein, term " C3-C6Methyl cycloalkyl " refers to C3-C6Naphthenic base-CH2What mode was formed
Group, wherein C3-C6Described in naphthenic base text as defined above.Specifically example includes but is not limited to：Cvclopropvlmethvl, cyclobutyl
Methyl, cyclopentyl-methyl, cyclohexyl methyl etc..
Advantageous effect of the invention is at least one following：
1. in kinds of tumor cells, the compound may be used also the inventors discovered that a kind of compound as shown in formula (I)
Significantly inhibit the expression of STAT3；The compound can obviously inhibit the phosphorylation of STAT3, such as 705 junket ammonia of STAT3
The phosphorylation of acid, such as the phosphorylation of 727 serines of STAT3, to inhibit the activation of STAT3.Therefore, the application
Compound can be used as STAT3 inhibitor and play a role, to treat disease relevant to STAT3, such as tumour.
2. the increasing of the compounds of this invention, its prodrug, stereoisomer or pharmaceutically acceptable salt to tumour cell is inhibited
Grow it is active, especially inhibition colon cancer, breast cancer, colorectal cancer and lung cancer cancer cell multiplication.
3. the compounds of this invention, its prodrug, stereoisomer or pharmaceutically acceptable salt have good medicine for power
Learn property.
Detailed description of the invention
Fig. 1 shows that the compound 1 through various concentration and BBI608 processing, are detected under the conditions of different time respectively,
The results of immunoblot analysis of total STAT3 and the STAT3 of phosphorylation in SW480 cell.
Fig. 2 shows that the compound 1 through various concentration and BBI608 processing, are detected under the conditions of different time respectively,
The results of immunoblot analysis of total STAT3 and the STAT3 of phosphorylation in K562 cell.
Fig. 3 shows that the compound 2 through various concentration, compound 3 and BBI608 are handled respectively, in different time condition
The results of immunoblot analysis of total STAT3 and p-Stat3 (Tyr705) in lower detection, SW480 cell and K562 cell.
Fig. 4 shows that the compound 2 through various concentration, compound 3 and BBI608 are handled respectively, in different time condition
The results of immunoblot analysis of total STAT3 and p-Stat3 (Ser727) in lower detection, SW480 cell and K562 cell.
Fig. 5 shows that 2 oral administration of compound is in the intracorporal pharmacokinetic results of rat.
Fig. 6 shows that 3 oral administration of compound is in the intracorporal pharmacokinetic results of rat.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
The compound of the present invention can be synthesized by the following way route and be made：
Route 1：
Route 2：
Route 3：
1 2- acetyl furan of embodiment simultaneously [3,2-g] quinoline -4,9- diketone (2-acetylfuro [3,2-g]
Quinoline-4,9-dione, compound 1) preparation
Title compound can be made by aforementioned route 1：
Step 1a：1- (4,6- bis- bromo- 7- hydroxyl benzofuran -2- base) ethyl -1- ketone (1- (4,6-dibromo-7-
Hydroxybenzofuran-2-yl) ethan-1-one, compound 102-1) preparation：By 2- acetyl group -7- hydroxy benzo furan
Mutter (1.76 grams, 10 mMs, 1.0 equivalents) be dissolved in methylene chloride (100 milliliters), add alchlor (5.32 grams, 40
MM, 4.0 equivalents), by mixture in oil bath 40 degree be stirred to react 1 hour after, into reaction solution be added dropwise bromine (3.52 grams,
22 mMs, 2.2 equivalents) dichloromethane solution, kept for one hour that the reaction was continued 16 hours after being added dropwise.Into reaction flask
Be added ice water (100 milliliters), filtering washing obtain 1- (4,6- bis- bromo- 7- hydroxyl benzofuran -2- base) ethyl -1- ketone (3 grams,
Yield 89.8%).LCMS(ESI):m/z 335.0[M+1]+。
Step 1b：2- acetyl group -6- bromobenzofuran -4,7- diketone (2-acetyl-6-bromobenzofuran-4,7-
Dione, compound 103-1) preparation：By 1- (4,6- bis- bromo- 7- hydroxyl benzofuran -2- base) ethyl -1- ketone (compound
102-1) (0.334 gram, 1 mM, 1.0 equivalents) is dissolved in acetic acid (7.5 milliliters), add chromium trioxide (0.22 gram,
2.2 mMs, 2.2 equivalents), it is stirred to react at room temperature 1 hour.Into reaction solution plus water (100 milliliters) stir evenly, and add dichloro
(100 milliliters) of methane extractions separate dichloromethane layer, obtain 2- acetyl group -6- bromobenzofuran -4,7- diketone after dry concentration
(0.21 gram, yield 78%).LCMS(ESI):m/z 269.0[M+1]+。
Step 1c：(E)-N '-acrol-N, N- dimethylhydrazine ((E)-N '-allylidene-N, N-
Dimethylhydrazine, compound 105-1) preparation：By methacrylaldehyde (compound 104-1) (0.56 gram, 10 mMs,
1.0 equivalents) it is dissolved in methylene chloride (10 milliliters), add dimethylhydrazine (0.6 gram, 10 mMs, 1.0 equivalents) and acetic acid
It is stirred to react 1 hour under (1 milliliter) ice-water bath.The dry concentration of dichloromethane layer is separated into reaction solution plus after 10 milliliters of water washings
Obtain (E)-N '-acrol-N, N- dimethylhydrazine (0.8 gram, yield 81.4%).LCMS(ESI):m/z 99.2[M+1]+。
Step 1d：2- acetyl furan simultaneously [3,2-g] quinoline -4,9- diketone (2-acetylfuro [3,2-g]
Quinoline-4,9-dione, compound 1) preparation：By 2- acetyl group -6- bromobenzofuran -4,7- diketone (compound
103-1) (100 milligrams, 0.37 mM, 1.0 equivalents) are dissolved in methylene chloride (10 milliliters), add the sub- alkene of (E)-N '-
Propyl-N, N- dimethylhydrazine (compound 105-1) (36 milligrams, 0.37 mM, 1.0 equivalents) is stirred to react 30 points at room temperature
Clock.Into reaction solution plus water (20 milliliters) stir evenly, and stand, and separate dichloromethane layer, are concentrated after dry, by concentrated residue dichloro
The mixtures of eluents column of methane and methanol chromatographs to obtain 2- acetyl furan, and simultaneously (66 milligrams, receive [3,2-g] quinoline -4,9- diketone
Rate 74.1%).180-185 DEG C of fusing point；LCMS(ESI):m/z 242.1[M+1]+1；1HNMR:(600MHz,CDCl3)δ2.69
(s, 3H), 7.64 (s, 1H), 7.75 (dd, J=4.6Hz, 7.8Hz, 1H), 8.57 (dd, J=7.8Hz, 1.6Hz, 1H), 8.10
(dd, J=4.6Hz, 1.6Hz, 1H)
2 2- acetyl group -6- methylfuran of embodiment simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-6-
Methylfuro [3,2-g] quinoline-4,9-dione, compound 2) preparation
Step 2a：(E)-N, N- dimethyl-N '-(2- methallyl fork) hydrazine ((E) -1,1-dimethyl-2- (2-
Methylallylidene) hydrazine, compound 105-2) preparation：By methacrolein (compound 104-2)
(0.70 gram, 10 mMs, 1.0 equivalents) is dissolved in methylene chloride (10 milliliters), add dimethylhydrazine (0.6 gram, 10 mmoles
You, 1.0 equivalents) and acetic acid (1 milliliter) ice-water bath under be stirred to react 1 hour.It is separated into reaction solution plus after 10 milliliters of water washings
Dichloromethane layer drying is concentrated to give (E)-N, N- dimethyl-N '-(2- methallyl fork) hydrazine (0.7 gram, yield 62.5%).
Step 2b：2- acetyl group -6- methylfuran simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-6-
Methylfuro [3,2-g] quinoline-4,9-dione, compound 2) preparation：By 2- acetyl group -6- bromobenzofuran -
4,7- diketone (compound 103-1) (40 milligrams, 0.15 mM, 1.0 equivalents) are dissolved in methylene chloride (10 milliliters), then plus
Entering (E)-N, N- dimethyl-N '-(2- methallyl fork) hydrazine (compound 105-2), (18.5 milligrams, 0.16 mM, 1.0 work as
Amount) it is stirred to react at room temperature 30 minutes.Into reaction solution plus water (20 milliliters) stir evenly standing separate dichloromethane layer it is dry after it is dense
The mixtures of eluents column of concentrated residue methylene chloride and methanol is chromatographed to obtain 2- acetyl group -6- methylfuran simultaneously [3,2- by contracting
G] quinoline -4,9- diketone (29 milligrams, yield 76.3%).220-224 DEG C of fusing point；LCMS(ESI):m/z 256.3[M+1]+；1HNMR:(600MHz,CDCl3) δ 2.69 (s, 3H), 7.64 (s, 1H), 7.75 (dd, J=4.6Hz, 7.8Hz, 1H), 8.57 (dd,
J=7.8Hz, 1.6Hz, 1H), 8.10 (dd, J=4.6Hz, 1.6Hz, 1H)
3 2- acetyl group -6- ethyl furan of embodiment simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-6-
Ethylfuro [3,2-g] quinoline-4,9-dione, compound 3) preparation
Step 3a：(E)-N, N- dimethyl-N '-(2- methylene butylidene) hydrazine ((E) -1,1-dimethyl-2- (2-
Methylenebutylidene) hydrazine, compound 105-3) preparation：By 2- ethyl acrylic aldehyde (compound 104-3)
(0.186 gram, 2 mMs, 1.0 equivalents) is dissolved in methylene chloride (10 milliliters), add dimethylhydrazine (0.12 gram, 2 mmoles
You, 1.0 equivalents) and acetic acid (0.5 milliliter) ice-water bath under be stirred to react 1 hour.Divide into reaction solution plus after 10 milliliters of water washings
Dichloromethane layer drying out is concentrated to give (E)-N, N- dimethyl-N '-(2- methylene butylidene) hydrazine (0.2 gram, yield 79.3%).
Step 3b：2- acetyl group -6- ethyl furan simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-6-ethylfuro
[3,2-g] quinoline-4,9-dione, compound 3) preparation：2- acetyl group -6- bromobenzofuran -4,7- diketone (is changed
Close object 103-1) (114 milligrams, 0.42 mM, 1.0 equivalents) be dissolved in methylene chloride (10 milliliters), add (E)-N, N-
Dimethyl-N '-(2- methylene butylidene) hydrazine (compound 105-3) (54 milligrams, 0.42 mM, 1.0 equivalents) stirs at room temperature
Mix reaction 30 minutes.Into reaction solution plus water (20 milliliters) are stirred evenly after standing separates dichloromethane layer drying and are concentrated, and will be concentrated residual
The mixtures of eluents column of slag methylene chloride and methanol chromatographs to obtain 2- acetyl group -6- ethyl furan simultaneously [3,2-g] quinoline -4,9-
Diketone (50 milligrams, yield 44.2%).200-203 DEG C of fusing point；LCMS(ESI):m/z 270.1[M+1]+；1HNMR:(600MHz,
CDCl3) δ 1.37 (t, J=1.6Hz, 3H), 2.68 (s, 1H), 2.88 (dd, J=15.2Hz, 1.6Hz, 2H), 7.62 (s, 1H),
8.36 (d, J=2.2Hz, 1H), 8.91 (d, J=2.2Hz, 1H)
4 2- acetyl group -5- methylfuran of embodiment simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-5-
Methylfuro [3,2-g] quinoline-4,9-dione, compound 5) preparation
Step 4a：(E)-N '-((E) -2- butenylidene)-N, N- dimethylhydrazine ((E)-N '-((E)-but-2-en-1-
Ylidene)-N, N-dimethylhydrazine, compound 202-5) preparation：By 2- crotonaldehyde (compound 201-5)
(0.14 gram, 2 mMs, 1.0 equivalents) is dissolved in methylene chloride (10 milliliters), add dimethylhydrazine (0.12 gram, 2 mmoles
You, 1.0 equivalents) and acetic acid (0.5 milliliter) ice-water bath under be stirred to react 1 hour.Divide into reaction solution plus after 10 milliliters of water washings
Dichloromethane layer, which is dried, out is concentrated to give (E)-N '-((E) -2- butenylidene)-N, and N- dimethylhydrazine (0.158 gram, yield
69.9%).
Step 4b：2- acetyl group -5- methylfuran simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-5-
Methylfuro [3,2-g] quinoline-4,9-dione, compound 5) preparation：By 2- acetyl group -6- bromobenzofuran -
4,7- diketone (103-1) (80 milligrams, 0.295 mM, 1.0 equivalents) are dissolved in toluene (10 milliliters), add (E)-N '-
((E) -2- butenylidene)-N, N- dimethylhydrazine (compound 202-5) (33 milligrams, 0.295 mM, 1.0 equivalents) oil bath 100
It is stirred to react under degree 2 hours.Into reaction solution plus water (20 milliliters) are stirred evenly after standing separates toluene layer drying and are concentrated, and will be concentrated residual
Slag ethyl acetate and n-hexane mixtures of eluents column chromatograph to obtain 2- acetyl group -5- methylfuran simultaneously [3,2-g] quinoline -4,9-
Diketone (25 milligrams, yield 33.3%).233-236 DEG C of fusing point；LCMS(ESI):m/z 256.0[M+1]+；1HNMR:(600MHz,
CDCl3) δ 2.67 (s, 3H), 2.88 (s, 3H), 7.49 (d, J=4.8Hz, 1H), 7.59 (s, 1H), 8.87 (d, J=4.8Hz,
1H).
5 2- acetyl group -5- ethyl furan of embodiment simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-5-
Ethylfuro [3,2-g] quinoline-4,9-dione, compound 6) preparation
Step 5a：(E)-N, N- dimethyl-N '-((E) -2- inferior pentenyl) hydrazine ((E)-N, N-dimethyl-N '-((E) -
Pent-2-en-1-ylidene) hydrazine, compound 202-6) preparation：By 2- pentenals (compound 201-6)
(0.168 gram, 2 mMs, 1.0 equivalents) is dissolved in methylene chloride (10 milliliters), add dimethylhydrazine (0.12 gram, 2 mmoles
You, 1.0 equivalents) and acetic acid (0.5 milliliter) ice-water bath under be stirred to react 1 hour.Divide into reaction solution plus after 10 milliliters of water washings
Out dichloromethane layer it is dry be concentrated to give (E)-N, N- dimethyl-N '-((E) -2- inferior pentenyl) hydrazine (0.139 gram, yield
55.1%).
Step 5b：2- acetyl group -5- ethyl furan simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-5-ethylfuro
[3,2-g] quinoline-4,9-dione, compound 6) preparation：2- acetyl group -6- bromobenzofuran -4,7- diketone (is changed
Close object 103-1) (100 milligrams, 0.37 mM, 1.0 equivalents) be dissolved in toluene (10 milliliters), add (E)-N, N- diformazan
Under 100 degree of oil bath of base-N '-((E) -2- inferior pentenyl) hydrazine (compound 202-6) (46.6 milligrams, 0.37 mM, 1.0 equivalents)
It is stirred to react 2 hours.Into reaction solution plus water (20 milliliters) are stirred evenly after standing separates toluene layer drying and are concentrated, and concentrated residue is used
Ethyl acetate and n-hexane mixtures of eluents column chromatograph to obtain 2- acetyl group -5- ethyl furan simultaneously [3,2-g] quinoline -4,9- diketone
(22 milligrams, yield 22.1%).210-213 DEG C of fusing point；LCMS(ESI):m/z 270.1[M+1]+；1HNMR:(600MHz,
CDCl3) δ 1.33 (t, J=7.4Hz, 3H), 2.76 (s, 3H), 3.33 (dd, J=14.9Hz, J=7.4Hz, 2H), 7.53 (d, J
=4.9Hz, 1H), 7.60 (s, 1H), 8.91 (d, J=4.9Hz, 1H)
6 2- acetyl group -5- furans -2- base of embodiment-furans simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-5-
(furan-2-yl) furo [3,2-g] quinoline-4,9-dione, compound 13) preparation
Step 6a：(E)-N '-((E) -3- furans -2- base-dilute propylidene)-N, N- dimethylhydrazine ((E) -2- ((E) -3-
(furan-2-yl) allylidene) -1,1-dimethylhydrazine, compound 202-13) preparation：By 3- (2- furans
Base) methacrylaldehyde (compound 201-13) (0.224 gram, 2 mMs, 1.0 equivalents) is dissolved in methylene chloride (10 milliliters), then plus
Enter and is stirred to react 1 hour under dimethylhydrazine (0.12 gram, 2 mMs, 1.0 equivalents) and acetic acid (0.5 milliliter) ice-water bath.Toward reaction
Dichloromethane layer drying, which is separated, in liquid plus after 10 milliliters of water washings is concentrated to give (E)-N '-((E) -3- furans -2- base-dilute propylidene) -
N, N- dimethylhydrazine (0.2 gram, yield 60.9%).LCMS(ESI):m/z 165.2[M+1]+。
Step 6b：2- acetyl group -5- furans -2- base-furans simultaneously [3,2-g] quinoline -4,9- diketone (2-acetyl-5-
(furan-2-yl) furo [3,2-g] quinoline-4,9-dione, compound 13) preparation：By 2- acetyl group -6- bromobenzene
And furans -4,7- diketone (compound 103-1) (43 milligrams, 0.158 mM, 1.0 equivalents) is dissolved in toluene (10 milliliters),
Add (E)-N '-((E) -3- furans -2- base-dilute propylidene)-N, and N- dimethylhydrazine (compound 202-13) (26 milligrams, 0.158
MM, 1.0 equivalents) it is stirred to react 2 hours under 100 degree of oil bath.Into reaction solution plus water (20 milliliters) stir evenly standing and separate first
It is concentrated after benzene layer is dry, concentrated residue ethyl acetate and n-hexane mixtures of eluents column is chromatographed to obtain 2- acetyl group -5- furan
It mutters -2- base-furans simultaneously [3,2-g] quinoline -4,9- diketone (15 milligrams, yield 30.9%).LCMS(ESI):m/z 308.0[M+
1]+；1HNMR:(600MHz,CDCl3) δ 2.68 (s, 3H), 6.64 (dd, J=3.4Hz, 1.7Hz, 1H), 7.26 (d, J=
2.7Hz, 1H), 7.59 (s, 1H), 7.65 (d, J=1.0Hz, 1H), 7.90 (d, J=5.1Hz, 1H), 9.00 (d, J=5.0Hz,
1H).
7 2- acetyl furan of embodiment simultaneously [2,3-g] quinoline -4,9- diketone (2-acetylfuro [2,3-g]
Quinoline-4,9-dione, compound 20) preparation
Step 7a：2- (3- crotonylene-oxygroup) tetrahydro -2H- pyrans (2- (but-3-yn-2-yloxy) tetrahydro-
2H-pyran, compound 302) preparation：By compound p-methyl benzenesulfonic acid (0.1 gram, 0.58 mM), 3- butyne-2-alcohol
(5.0 grams, 71.4 mMs) and 3,4- dihydro -2H- pyrans (6.0 grams, 71.4 mMs) are dissolved in 50 milliliters of methylene chloride,
It is stirred overnight at room temperature.Reaction solution is quenched with water, is then extracted with ethyl acetate.Gained organic phase saturated common salt water washing
Afterwards, it is dry that anhydrous sodium sulfate is added, gained crude product is through silica gel column chromatography (eluant, eluent after reduced pressure：N-hexane) obtain colorless oil
Object, that is, target compound 2- (3- crotonylene-oxygroup) tetrahydro -2H- pyrans (4.8 grams, yield：41%).1HNMR(400MHz,
CDCl3):δ 1.47 (s, 3H), 1.53-1.63 (m, 4H), 1.71-1.87 (m, 2H), 2.38 (s, 2H), 3.52-3.55 (m,
1H), 3.79-3.85 (m, 1H), 4.52-4.58 (m, 1H), 4.94 (m, 1H)
Step 7b：2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) -4- hydroxyl benzofuran (2- (1-
(Tetrahydro-2H-pyran-2-yloxy) ethyl) benzofuran-4-ol, compound 304) preparation：Nitrogen protection
Under, by compound 2- (3- crotonylene-oxygroup) tetrahydro -2H- pyrans (compound 302) (1.7 grams, 11.0 mMs), 1,3- bis-
Hydroxyl -2- iodobenzene (compound 303) (1.3 grams, 5.5 mMs), and bis-triphenyl phosphine dichloride palladium (135 milligrams, 0.2 mmoles
You), the n,N-Dimethylformamide that cuprous iodide (56 milligrams, 0.3 mM) and triethylamine (5 milliliters) are dissolved in 5 milliliters is molten
In liquid, it is stirred overnight under 60 degree.Reaction solution is cooled to room temperature, is quenched with water, is then extracted with ethyl acetate.Gained is organic
Mutually dry with anhydrous sodium sulfate after saturated common salt water washing, is added, gained crude product is through silica gel column chromatography (elution after reduced pressure
Agent：N-hexane) obtain colorless oil, that is, target compound 2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) -4- hydroxy benzo
Furans (900 milligrams, yield：63%).1HNMR(400MHz,CDCl3):δ 1.57-1.65 (m, 7H), 1.75-1.86 (m, 2H),
3.57-3.61 (m, 1H), 3.85-3.91 (m, 1H), 4.88 (q, J=6.8Hz, 1H), 5.06-5.08 (m, 1H), 5.85 (s,
2H), 6.50 (d, J=8.0Hz, 2H), 7.12 (t, J=8.0Hz, 1H)
Step 7c：2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) benzofuran -4,7- diketone (2- (1-
(tetrahydro-2H-pyran-2-yloxy) ethyl) benzofuran-4,7-dione, compound 305) preparation：It will change
Conjunction object 2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) -4- hydroxyl benzofuran (compound 304) (800 milligrams, 3.0 mmoles
You) ethanol solution (5 milliliters) be added dropwise to KH under 0 degree Celsius2PO4(0.6M, 15 milliliters) and nitrosylsulfuric acid potassium (2.0 grams,
7.62 mMs) 10 milliliters of aqueous solutions in.Reaction solution stirs 1 hour under 0 degree Celsius, and 2 are then stirred at room temperature again
Hour, then it is extracted with ethyl acetate.After gained organic phase saturated common salt water washing, anhydrous sodium sulfate drying, decompression is added
Gained crude product is through silica gel column chromatography (eluant, eluent after concentration：N-hexane) obtain colorless oil, that is, target compound 2- (1- (tetrahydro-
2H- pyrans -2- oxygroup) ethyl) benzofuran -4,7- diketone (260 milligrams, yield：31%).
Step 7d：(E)-N'- acrol acethydrazide ((E)-N'-allylideneacetohydrazide, compound
308) preparation：By compound methacrylaldehyde (compound 306) (1.0 grams, 17.8 mMs) and acethydrazide (compound 307) (1.3
Gram, 17.8 mMs) it is dissolved in ethyl alcohol (50 milliliters) and is heated to reflux 1 hour.Reaction solution is cooled to room temperature, is quenched with water,
Then it is extracted with ethyl acetate.After gained organic phase saturated common salt water washing, anhydrous sodium sulfate drying is added, after reduced pressure
Gained crude product is through silica gel column chromatography (eluant, eluent：N-hexane/ethyl acetate=5/1) obtain colorless oil, that is, target compound (E)-
N'- acrol acethydrazide (1.8 grams, yield：90%).1HNMR(400MHz,CDCl3):δ 2.28 (s, 3H), 5.58-5.64
(m, 2H), 6.42-6.51 (m, 1H), 7.46 (d, J=9.2Hz, 1H), 9.56 (s, 1H)
Step 7e：Mixture 2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) furans simultaneously [3,2-g] quinoline -4,9- bis-
Ketone (2- (1- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) furo [3,2-g] quinoline-4,9-dione,
Compound 309) and 2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) furans simultaneously [2,3-g] quinoline -4,9- diketone (2- (1-
((tetrahydro-2H-pyran-2-yl) oxy) ethyl) furo [2,3-g] quinoline-4,9-dione, compound
309 ') preparation：By compound 2 (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) benzofuran -4,7- diketone (compound
305) (260 milligrams, 0.94 mM) and compound (E)-N'- acrol acethydrazide (compound 308) (263 milligrams, 2.36
MM) be dissolved in 25 milliliters of xylene solution, it is stirred 48 hours under 160 degrees Celsius.Reaction solution is cooled to room
Temperature is quenched with water, and is then extracted with ethyl acetate.After gained organic phase saturated common salt water washing, it is dry that anhydrous sodium sulfate is added
Dry, gained crude product is through silica gel column chromatography (eluant, eluent after reduced pressure：N-hexane/ethyl acetate=3/1) a grease is i.e. mixed
Close object 2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) furans simultaneously [3,2-g] quinoline -4,9- diketone and 2- (1- (tetrahydro -2H-
Pyrans -2- oxygroup) ethyl) furans simultaneously [2,3-g] quinoline -4,9- diketone (45 milligrams, yield：14%, two kinds of isomers).
Step 7f：Mixture 2- (1- ethoxy) furans simultaneously [3,2-g] quinoline -4,9- diketone (2- (1-
Hydroxyethyl) furo [3,2-g] quinoline-4,9-dione, compound 310) and 2- (1- ethoxy) furans simultaneously [2,
3-g] quinoline -4,9- diketone (2- (1-hydroxyethyl) furo [2,3-g] quinoline-4,9-dione, compound
310 ') preparation：By compound mixture 2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) furans simultaneously [3,2-g] quinoline -4,
9- diketone (compound 309) and 2- (1- (tetrahydro -2H- pyrans -2- oxygroup) ethyl) furans simultaneously [2,3-g] quinoline -4,9- diketone
In the hydrogen chloride/tetrahydrofuran solution for the 2N that (compound 309 ') (260 milligrams, 0.94 mM) are dissolved in 10 milliliters, room
After lower stirring 1 hour of temperature, the pH value of solution is transferred to 8-9 with saturated sodium bicarbonate solution.Then it is extracted with ethyl acetate.Gained
After organic phase saturated common salt water washing, anhydrous sodium sulfate drying is added, gained crude product is directly used in next step after reduced pressure.
Step 7g：2- acetyl furan simultaneously [2,3-g] quinoline -4,9- diketone (2-acetylfuro [2,3-g]
Quinoline-4,9-dione, compound 20) preparation：By previous step resulting crude mixture 2- (1- ethoxy) furans
And simultaneously [2,3-g] quinoline -4,9- diketone (is changed for [3,2-g] quinoline -4,9- diketone (compound 310) and 2- (1- ethoxy) furans
Close object 310 '), manganese dioxide (5.0 equivalent) is suspended in 10 milliliters of methylene chloride, is stirred 3 hours at room temperature, with diatomite mistake
Filter, gained crude product is through silica gel column chromatography (eluant, eluent after filtrate decompression concentration：N-hexane/ethyl acetate=3/1) obtain first stream
Compound (Rf=0.6) is identified and is (2- acetyl furan simultaneously [3, the 2-g] quinoline -4,9- bis- of compound 1 with standard control
Ketone) (12 milligrams).Gained second divides compound (Rf=0.58) to be (2- acetyl furan simultaneously [2, the 3-g] quinoline-of compound 20
4,9- diketone) (7 milligrams).1HNMR(400MHz,CDCl3):δ 2.68 (s, 3H), 7.70 (s, 1H), 7.75-7.78 (m, 1H),
8.61 (d, J=8.0Hz 1H), 9.10 (d, J=7.2Hz 1H)
According to the preparation method of embodiment 1-7, the application can also synthesize following compound：
8 biological activity test of embodiment
One, Cytostatic to tumor cell is tested
1. experimental method
Using CellTiter-Glo luminescent cell viability detection kit method (Promega, #G7572, Madison, WI)
The content of atriphos (ATP) is measured to assess cell viability.Tumor cell line is bought from Shanghai Fudan University IBS cellular resources
The heart and American Type Culture Collecti (ATCC).Cell is digested from Tissue Culture Dish with pancreatin, and is resuspended through DPBS culture medium
Measurement cell density is counted with Scepter automated cell calculating instrument (Millipore, #PHCC00000) afterwards.Cell is diluted to
Every milliliter of solution containing 44,000 cells.Cell experiment plate is added with every 90 μ l microlitre of hole in cell solution after adjusting density
In.Orifice plate is placed in 37 DEG C, 5%CO2The compound to be tried of various concentration is added after incubator culture 24 hours.Cell is in 10% tire
It is cultivated together with compound in the presence of cow's serum 72 hours.It usesLuminescent Cell
Viability Assay kit (see shop instruction) measures the content of ATP to assess cell growth inhibition.Briefly, often
30 μ l are added in a holeReagent, rocker 10 minutes, inducing cell lysis, with fluorescence/chemiluminescence point
Analyzer Fluoroskan Ascent FL (Thermo Scientific Fluoroskan Ascent FL) detection record fluorescence
Signal.The cell for handling 72 hours from dimethyl sulfoxide (DMSO) obtains maximum signal value.From individual culture medium (cell number
It is zero) to obtain minimum signal value to be defined as 0.Inhibiting rate %=(maximum signal level-compound signal value)/(maximum signal level-is most
Small signal value) X 100%.Use GraphPad Prism V5.0 (GraphPad Software, San Diego, CA) software
Handle data.Pass through S-shaped dose-response curve the Fitting Calculation IC50 value.
2. experimental result
It is possessed in the detection based on cell that heretofore described representative compound 2,3,5 is listed in table 1
To the activity of 205 suppressing cell reproduction of tumour cell SW620, MCF7, MDA-MD-231, LOVO, H1975, Colon；And with
BBI608 (upper seascape face Chemical Co., Ltd., lot number:1512224) compound 1,20 and in embodiment is as a comparison.
1 compound on tumor cell Proliferation Ability result IC of table50(nM)
Remarks：" -- " indicates not detect.
Compound 5 is suitable to the inhibitory activity and compound 2 of MCF7 tumour cell.
It is above the result shows that：
The compounds of this invention has the activity of stronger anti-tumour cell proliferative to kinds of tumor cells.
The compounds of this invention anti-tumour cell proliferative activity is better than reference material BBI608.
The compounds of this invention is substantially better than compound 1,20 to the anti-tumour cell proliferative activity of kinds of tumor cells.
Two, protein immunoblot (Western Blot) is tested
1. experimental method
SW480 colon cancer cell and K562 chronic myeloid leukemia cell are grown 24 hours in 100mm culture dish culture
Afterwards, compound 1, compound 2, compound 3 or reference compound (STAT3 inhibitor BBI608 (upper seascape face chemical industry to be tried is added
Co., Ltd, lot number:1512224), Jak inhibitor INCB018424 (ChemExpress company, article No.：HY-50856 it)) trains
Support 6,12 or 24 hours, washed once with the PBS of pre-cooling, collection cell in test tube, with cell extract (Invitrogen,
Cat#FNN0011 cell) is dissolved, test tube is set 30 minutes on ice, at 4 DEG C, 14,000rpm centrifugation 30min take supernatant, and -80
DEG C storage.
Protein concentration is measured using Bradford method, 15ug albumen loading, SDS-PAGE electrophoresis are taken from each sample
(120V) protein isolate is transferred to pvdf membrane (40 minutes, 120V) using Bio-Rad ' s Tran-Blot, film closing buffering
Liquid (every 100ml TBST BSA containing 25g) closes 120min at room temperature, adds corresponding primary antibody Stat3 antibody (D3Z2G) (CST, #
12640S), Phospho-Stat3 (Tyr705) antibody (CST, #9145S), Phospho-Stat2 (Ser727) antibody (CST, #
9134S), GAPDH antibody (D16H11) (CST, #5174S) is incubated overnight at 4 DEG C, then washes film 3 × 5 minutes with TBST liquid.
Film 3x is washed with TBST liquid again after being protected from light incubation 45 minutes at room temperature with HRP-linked Anti-Rabbit lgG (CST#7074)
5 minutes.Using ECL Western Blotting Detection (Thermo, #34095), film is placed in imaging system (Cell
Biosciences chemiluminescence scanning imagery is detected on).
2. experimental result
By Fig. 1 (abbreviation that " INCB " is INCB018424 in figure) it is found that in SW480 colon cancer cell line, 1 He of compound
STAT3 inhibitor BBI608 inhibits phospho-STAT3Ser727.Meanwhile compound 1 and BBI608 reduce phospho-
STAT3 Tyr705 is horizontal, becomes apparent from 2 μM and 24 hours of high concentration effects.12-24 hours situations of high concentration and incubation time
Under, total STAT3 level is also lowered, and compound 1 is more significant in effect in 24 hours.
By Fig. 2 (abbreviation that " INCB " is INCB018424 in figure) it is found that in K562 chronic myeloid leukemia cell strain,
Compound 1 inhibit phospho-STAT3 Ser727, and STAT3 inhibitor BBI608 to phospho-STAT3 Ser727 without bright
Aobvious effect.The unobvious change phospho-STAT3 Tyr705 of the two is horizontal.
Under this experiment condition, in SW480 and K562 cell, Jak inhibitor INCB018424 does not influence STAT3 phosphorylation
It is horizontal.
Fig. 3-4 (" Veh " is Vehicle abbreviation in figure) shows compound 2, compound 3, BBI608 through various concentration
Different time is handled, total STAT3, p-Stat3 (Tyr705) and p-Stat3 (Ser727) in SW480 cell and K562 cell
Results of immunoblot analysis.
By Fig. 3-4 it is found that in SW480 colon cancer cell line, compound 2 and compound 3 can reduce after treatment
Phospho-STAT3 Tyr705 level and phospho-STAT3 Ser727 are horizontal, and high concentration (2 μM) inhibiting effect is obvious, than
Control compound BBI608 effect is stronger.
STAT3 the and β-actin level decline total after handling 24 hours in higher concentrations of compound 2 and compound 3, may
It is related with Partial tumors cell death.
In K562 chronic myeloid leukemia cell strain, compound 2 and compound 3 after 6 hours, processing in 24 hours especially
It is horizontal that phospho-STAT3 Tyr705 can be reduced under a high concentration condition；Under same experimental condition, two kinds of compounds exist
Phospho-STAT3 Ser727 level can be substantially reduced for 24 hours by handling under high concentration.It is acted on control compound BBI608
Compare, (2 μM) inhibiting effect of compound 2 and 3 is stronger under same concentrations, especially after processing 24 hours.
9 pharmacokinetics of embodiment (PK) experiment
1. experimental method
Male SD rat (Guangdong Medical Lab Animal Center), 300-350 grams of weight, overnight fast before testing.Wait try
Compound is dissolved in 30% Sulfobutyl ether β _ cyclodextrin (SBE- β-CD), with 20mg/kg gastric infusion.Respectively after administration 15
Minute, 30 minutes and 1,2,3,4,6,8 and 24 hour tail end fracture take blood, and per time point takes about 0.3ml, is placed in containing K2-EDTA
Centrifuge tube in, centrifugal treating (2,000g, 10 minutes, 4 DEG C) takes blood plasma, is stored in -80 DEG C of ultra low temperature freezer.50 μ L's
Plasma sample is mixed with 5 microlitres of internal standards (IS), is extracted with ethyl acetate.Residue is redissolved in acetonitrile after vacuum drying.It is right
Sample is filtered, and is injected into LC-MS/MS analysis.
2. experimental result
Experimental result is shown in Table 4.In table 4, TmaxRefer to peak time, CmaxRefer to maximum plasma concentration, T1/2For half-life period,
AUClastRefer to area under 0-24 hours time-concentration curves, AUCinfRefer to area under 0-Inf time-concentration curve.
4 pharmacokinetic studies result of table
For the compounds of this invention 2-3 after stomach-filling, infiltration rate is fast it can be seen from Fig. 5-6 and table 4, absorbs well,
TmaxRespectively 0.58 hour and 0.42 hour；Half-life period is respectively 12.02 hours and 8.58 hours.
Although a specific embodiment of the invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to all introductions having disclosed, those details can be carry out various modifications and be replaced, these change in guarantor of the invention
Within the scope of shield.Full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (7)
1. compound chosen from the followings, its stereoisomer or pharmaceutically acceptable salt：
2. a kind of pharmaceutical composition, it includes the compound of claim 1, its stereoisomer or pharmaceutically acceptable salt,
And one or more pharmaceutic adjuvants.
3. the pharmaceutical composition of the compound of claim 1, its stereoisomer or pharmaceutically acceptable salt or claim 2
Preparing the purposes in STAT3 inhibitor.
4. the pharmaceutical composition of the compound of claim 1, its stereoisomer or pharmaceutically acceptable salt or claim 2
Preparing the application in the drug for inhibiting tumor cell proliferation.
5. the application of claim 4, wherein the cancer that the tumour cell is selected from colon cancer, breast cancer, colorectal cancer and lung cancer is thin
Born of the same parents.
6. the pharmaceutical composition of the compound of claim 1, its stereoisomer or pharmaceutically acceptable salt or claim 2
Preparing the purposes in the drug for preventing and/or treating tumour.
7. the purposes of claim 6, wherein the tumour is selected from colon cancer, breast cancer, colorectal cancer and lung cancer.
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| CN1400969A (en) * | 2000-02-15 | 2003-03-05 | 山之内制药株式会社 | Fused imidazolium derivatives |
| CN103265559A (en) * | 2013-05-28 | 2013-08-28 | 中国人民解放军第二军医大学 | Substituted tricyclo-quinone compounds, and preparation method and application thereof |
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| CN1400969A (en) * | 2000-02-15 | 2003-03-05 | 山之内制药株式会社 | Fused imidazolium derivatives |
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