CN104402869A - Small molecule inhibitor compound as well as preparation method and application thereof - Google Patents

Small molecule inhibitor compound as well as preparation method and application thereof Download PDF

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Publication number
CN104402869A
CN104402869A CN201410726660.8A CN201410726660A CN104402869A CN 104402869 A CN104402869 A CN 104402869A CN 201410726660 A CN201410726660 A CN 201410726660A CN 104402869 A CN104402869 A CN 104402869A
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compound
molecule inhibitor
preparation
solvent
small molecule
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杨光
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Changzhou Velox Pharmaceutical Science & Technology Co Ltd
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Changzhou Velox Pharmaceutical Science & Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a small molecule inhibitor compound as well as a preparation method and application thereof. The compound has a structure in a formula I show in the specification. The small molecule inhibitor compound provided by the invention overcomes the defects that the conventional drug only aims at a single drug target, and for a cancer at a later period and with a complex mechanism, the activity is low, drug tolerance is easy to generate and the activity is relatively low existing in the conventional drug. The small molecule inhibitor compound provided by the invention restrains VEGFR and EGFR receptor kinase families at the same time, has efficient antitumor activity and efficient antiinflammatory activity, and can be used for preparing efficient drugs for resisting tumors, inflammation, neuroinflammation and obesity.

Description

A kind of molecule inhibitor compounds, Preparation Method And The Use
Technical field
The present invention relates to a kind of molecule inhibitor compounds, be specifically related to a kind ofly to suppress molecule inhibitor compounds of VEGFR and EGFR receptor kinase family and preparation method thereof simultaneously.
Background technology
Vascular endothelial growth factor (VEGF) is also called Vascular Permeability Factor and the vascular proliferation factor, and up to now, VEGF is identified has high special, and effective short new vessel formation effect.Research shows, VEGF dividing a word with a hyphen at the end of a line not only induction of endotheliocyte, and stimulates the degraded producing a series of protein product participation blood vessel epimatrix, and these functions make VEGF have the Main Function rising under physiology and pathological conditions and regulate angiogenesis.
VEGF selectivity directly acts on two kinds of hypotype tyrosine kinase receptor Flt-1(on endothelial cellular membrane also known as VEGFR-1) and KDR(also known as VEGFR-2), it is generally acknowledged and only have vascular endothelial cell to express this two kinds of acceptors.VEGF is attached to its tyrosine kinase receptor can bring out multiple biological activity, as cell proliferation, migration and vasculogenesis.The acceptor of this family comprises VEGFR-1, VEGFR-2, VEGFR3.VEGFR-1, VEGFR-2 and VEGFR3 express and are mainly limited to lymphangiogenesis and blood vessel.Angiogenesis is the necessary requirement of tumor growth, and large quantity research proves that VEGF plays a key effect in tumour change process.The expression of VEGF is closely related with the quantity of microvascular density in tissue and new vessel.Many experimentation on animalies have confirmed that angiogenesis inhibitor can obviously Tumor suppression growth.Most scholars thinks that this is the potential method of of therapeutic intervention in oncotherapy.The new vessel of Tumor suppression, may become a kind of effective ways for the treatment of tumour particularly noumenal tumour.
EGF-R ELISA (EGFRs) is the acceptor of Urogastron (EGF) cell proliferation and intracellular signaling.EGFRs belongs to the one of ErbB Tyrosylprotein kinase receptor family, and this family comprises EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4).EGFR is distributed widely in the cell surfaces such as mammalian epithelial cell, inoblast, spongiocyte, keratinocyte.The signal path regulated by EGFR plays an important role to physiological processs such as the growth of cell, propagation and differentiation.Research shows in many noumenal tumours, there is EGFRs high expression level or unconventionality expression.The propagation of EGFRs and tumour cell, vasculogenesis, tumor invasion, transfer and apoptotic suppression are relevant.The process LAN of EGFRs plays an important role in the evolution of malignant tumour, has the process LAN of EGFRs in the tissue such as spongiocyte, kidney, lung cancer, prostate cancer, carcinoma of the pancreas, mammary cancer.The research of glioma is found that the high expression level of EGFRs is main relevant with its gene amplification.There is mutant egf Rs to exist in many tumours, have now found that many kinds of EGFRs saltant types.The effect of mutant egf Rs may comprise: the cell continuous activation with part independent form acceptor; The destruction of receptor down-regulated mechanism is caused due to some structural domain disappearance of EGFRs; The activation of abnormal signal conduction path; Apoptotic suppression etc.The part of EGFRs has a significant impact Cellular Signaling Transduction Mediated.The part of EGFRs activates EGFRs by autocrine form and promotes cell proliferation, and their coexpression often indicates that tumor prognosis is bad.
Cancer therapy drug target spot known at present and path and their each self-corresponding micromolecular compounds and macromole bio-pharmaceutical mostly are for one of them single target drug of VEGFRs receptor kinase family or EGFRs receptor kinase family.The medicine that these single target spots are corresponding much has certain restraining effect as first-selected modality of cancer treatment to some early stage cancers.But these medicines of cancer for late period and complicated mechanism more or less also exist the deficiencies such as active on the low side and easy generation resistance.It should be noted that medicine evident in efficacy often has the feature of Mutiple Targets.But because research and development and stage of optimizing not for take into account multiple target spot, existing medicine does not possess the characteristic simultaneously effectively suppressing VEGFRs and EGFRs two target spots and path.Mutiple Targets research represents the up-to-date medicament research and development direction of each large transnational pharmaceuticals and research unit.The SU11248 (Sutent) that Pfizer went on the market in 2006, although be R&D direction with Mutiple Targets but lack guidance quality, also inhibits the signal of other regular path thus has higher toxic side effect while suppression relevant cancer target and signal path.Undertaken combining and screening by selecting the target spot in multiple path relevant to pathology and path and the medicine corresponding to them.Hybrid medicine is significantly improved in curative effect and resistance, but the interaction inevitably increased between the complicacy of drug absorption and metabolism and uncertain and medicine and impact.
Summary of the invention
For existing medicine only for single medicine target spot, simultaneously these medicines of cancer of late period and complicated mechanism are also existed to the lower shortcoming of the not enough activity such as active on the low side and easy generation resistance, main purpose of the present invention is that providing a kind of can suppress molecule inhibitor compounds of VEGFR and EGFR receptor kinase family and preparation method thereof, to solve the problem simultaneously.
For achieving the above object, the invention provides a kind of molecule inhibitor compounds, this compound has the structure of formula I:
。
Present invention also offers a kind of preparation method of above-mentioned molecule inhibitor compounds, this compound has the structure of formula I, is prepared by following route:
Wherein, the method comprises following concrete steps:
Step 1, with compound 1 and compound 2 for raw material, 1,8-diazabicylo 11 carbon-7-alkene is catalyzer, and dry acetonitrile is solvent, reflux 4-6 hour, through conventional aftertreatment, obtains compound 3;
Step 2, with compound 3 and compound 4 for reactant, ethanol or cellosolvo are solvent, and temperature of reaction is 150-220 DEG C, through conventional aftertreatment, obtain compound 5; This reaction also can be carried out under microwave-excitation condition, keeps 160-220 DEG C to react 5-30 minute, using pyridine hydrochloride excessive a little and ethanol or cellosolvo as solvent.
Step 3, compound 5 is sloughed amido protecting group and is obtained Compound I.
Above-mentioned method, wherein, in described step 3, the preparation method of described Compound I refers to and is dissolved in methyl alcohol by compound 5, under stirring, dropwise adds 10% wet chemical under normal temperature; Stir under reaction mixture normal temperature after spending the night, dilute with water, suction filtration is precipitated thing, obtains Compound I.
Above-mentioned method, wherein, described Compound I crude product purified by silica gel column chromatography separating purification obtains the Compound I of purifying, and wherein, post is separated the eluent methylene chloride agent that solvent is 9% methyl alcohol+1% triethylamine, with volume percent.
Present invention also offers a kind of purposes of above-mentioned formula I, this compound can suppress vascular endothelial growth factor receptor family kinase (VEGFRs) and epidermal growth factor receptor kinase (EGFRs) simultaneously, there is antitumor and anti-inflammatory activity efficiently, can for the preparation of antitumor and anti-inflammatory medicaments efficiently.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of molecule inhibitor compounds of the present invention.
Fig. 2 is the mass spectrum of molecule inhibitor compounds of the present invention.
Embodiment
Below in conjunction with accompanying drawing, by specific embodiment, the invention will be further described, and these embodiments, only for illustration of the present invention, are not limiting the scope of the invention.
Embodiment
Compound 1(0.207g, 1.54mmol), compound 2(0.229g, 1.54mmol) and 1,8-diazabicylo 11 carbon-7-alkene (DBU) (0.235ml, in dry acetonitrile solution 1.57mmol), reflux 4-6 hour, adds EtoAc – H after being spin-dried for solvent 2o, organic layer water and sodium chloride solution are washed, anhydrous Na 2sO 4drying, after solvent evaporated, purifying (e.g., methylene dichloride crosses post) obtains 0.356g compound 3.
Get compound 3(0.085g, 0.38mmol) and compound 4(0.056g, 0.38mmol) be dissolved in cellosolvo (1mL), heat 150 DEG C of stirrings and spend the night.Reaction soln is cooled to room temperature, and syringe filter is filtered, LC-MS purifying.Then the trifluoroacetate the obtained wet chemical neutralization of 10% obtains 0.016g compound 5.This compound 5 through mass spectroscopy, MS(MH+): 482 m/zc 24h 21f 3n 6o 2.In preferred embodiments more of the present invention, the reaction of synthetic compound 5 also can be carried out under microwave-excitation condition, 160-220 DEG C is kept to react 5-30 minute, using pyridine hydrochloride excessive a little and ethanol or cellosolvo as solvent, pyridine hydrochloride needs i.e. 1.5 equivalents (0.0659g, 0.57mmol).
Compound 5 (0.173g, 0.36mmol) is dissolved in 5mL methyl alcohol and stirs, and dropwise adds 10% wet chemical (2.5mL, 1.81mmol) under normal temperature.Stir under reaction mixture normal temperature after spending the night, dilute with water, suction filtration is precipitated thing.Washing, vacuum-drying.(the eluent methylene chloride agent of 9% methyl alcohol+1% triethylamine of crude product purified by silica gel column chromatography, with volume percent) separation and purification obtains 0.138g end product, i.e. Compound I, in pale yellow powder, its name is called [6-(1H-indoles-5-base oxygen base)-pyrimidine-4-yl]-(4-piperazine-1-base-phenyl) amine.This Compound I is also verified through hydrogen nuclear magnetic resonance spectrum, as shown in Figure 1, 1h NMR (400 MHz, DMSO) δ11.21 (s, 1H), 9.15 (s, 1H), 8.24 (s, 1H), 7.45 (d, j=8.7 Hz, 1H), 7.40 (t, j=2.7 Hz, 1H), 7.36 (d, j=8.9 Hz, 2H), 7.32 (d, j=2.2 Hz, 1H), 6.88 (dd, j=8.7,2.3 Hz, 1H), 6.84 (d, j=9.1 Hz, 2H), 6.44 (s, 1H), 5.83 (s, 1H), 3.05-2.92 (m, 4H), 2.89-2.80 (m, 4H).This Compound I through mass spectroscopy as shown in Figure 2, MS(MH+): m/zc 22h 22n 6o 387.
Fluorescence polarization enzyme kinetic analysis
For detecting the inhibit activities of this Compound I to VEGFRs kinase families and EGFRs kinase families, we have employed a kind of kinetics Fluorescence Polarization assay (fluorescence polarization immunoassay, FP assay).Fluorescence polarization assay method is a kind of quantitative immunoassay technology, its ultimate principle is that fluorescent substance is after the blue polarized light (485nm) of single plane irradiates, absorb luminous energy and leap to excited state, return back to ground state subsequently, and send the polarizing fluorescence (525nm) of single plane.The degree of strength of polarizing fluorescence and the size of fluorescence molecule are proportionate, and the speed of rotating when being stimulated with it is inverse correlation.FP optimum detects little of medium molecule material, is usually used in the mensuration of medicine, hormone.
Fluorescence polarization immunoassay (FPIA) is usually used in measuring haptenic drug level.In reactive system except determined antigen, add simultaneously and a certain amount ofly use fluorescein-labeled small molecule antigens, make the two be combined with limited amount specific macromolecules antibody competition.When determined antigen concentration height, through competing reaction, most of antibody is combined by it, and fluorescein-labeled antigen is many in free small molecules state.Because its molecule is little, velocity of rotation is very fast in the liquid phase, and the fluorescence polarization degree measured is also lower.Otherwise if when determined antigen concentration is low, most of fluorescein-labelled antigen and antibodies, form macromolecular immune complex, and the fluorescence polarization degree now detected is also higher.Fluorescence polarization degree and determined antigen concentration are inverse relation.We are typical curve processed after measuring determined antigen standard substance.By the size of polarized light in detection reaction system, from typical curve, just accurately can learn the corresponding content of determined antigen in sample.
We have selected people source VEGFR, and EGFR, as organized enzyme, under peptide substrate saturation concentration 0.8uM, calculates the Km value (K of often kind of kinase whose ATP mvalue equals enzymatic reaction speed and reaches concentration of substrate corresponding to maximum reaction velocity one half, is one of characteristic constant of enzyme).Testing conditions for different compound concentration gradient all passes through to be optimized and checking.Enzyme dynamics shows that the inhibiting mechanism of this compound to EGFR and VEGFRs is the linear competitive inhibition for substrate A TP, i.e. the same binding site of the direct competitive zymophore of ATP and this compound.In other words, this compound and VEGFR, the same site of substrate A TP competitive binding of EGFR is to show inhibit activities, when compound of the present invention is by the preferential and VEGFR with the competition of ATP, EGFR in conjunction with time, this VEGFR, EGFR show inactivation, namely compound of the present invention all has restraining effect to VEGFR, EGFR.
IC50 is the concentration required for drug molecule arrestin enzymic activity to its normal activity half, and prevailing value is less, and restraining effect is stronger, if its activity all can not be suppressed to less than 50% by any concentration, cannot obtain this numerical value.The measuring method of IC50 value is that what to adopt is above-mentioned fluorescence polarization enzyme kinetic analysis method, uses the Analyst HT that instrument is Molecular Device company, so reagent and compound all obtain by business.Concrete operation step is: add at PBS the peptide substrate (poly (Glu that final concentration is 0.1uM 4tyr) n, purchased from Sigma) and the organized enzyme of 5nM prepare mixed solution, shift the aforesaid liquid in 9 microlitres/hole to black 96 orifice plate, every hole adds compound (the highest 100uM of 1ul different concns, three times of dilutions, 10 weaker concn points), finally adding every hole 2ul concentration is again the ATP of 300uM.Immediately check-out console is put into microplate reader after mixing and detect (lambda1-wavelength 485nm, diffraction wavelength 530nm), read once every 20 minutes.The data concentration obtained does X-coordinate, and reading value is ordinate zou, calculates IC50 by GraphPad software fitting of a curve.Through the method, the relevant IC50 value measuring compound of the present invention is as follows, IC50(VEGFR1)=3.5 nM; IC50(VEGFR2)=120 nM; IC50(VEGFR3)=18 nM; And IC50(EGFR)=120 nM.It can thus be appreciated that molecule inhibitor compounds I of the present invention has extremely strong restraining effect to VEGFRs and EGFR kinases,
Although content of the present invention has done detailed introduction by above preferred embodiment, will be appreciated that above-mentioned description should not be considered to limitation of the present invention.After those skilled in the art have read foregoing, for multiple amendment of the present invention and substitute will be all apparent.Therefore, protection scope of the present invention should be limited to the appended claims.

Claims (6)

1. a molecule inhibitor compounds, is characterized in that, this compound has the structure of formula I:
。
2. a preparation method for molecule inhibitor compounds according to claim 1, is characterized in that, this compound has the structure of formula I, is prepared by following route:
；
Wherein, the method comprises following concrete steps:
Step 1, with compound 1 and compound 2 for raw material, 1,8-diazabicylo 11 carbon-7-alkene is catalyzer, and dry acetonitrile is solvent, reflux 4-6 hour, through conventional aftertreatment, obtains compound 3;
Step 2, with compound 3 and compound 4 for reactant, ethanol or cellosolvo are solvent, and temperature of reaction is 150-220 DEG C, through conventional aftertreatment, obtain compound 5;
Step 3, compound 5 is sloughed amido protecting group and is obtained Compound I.
3. method as claimed in claim 2, it is characterized in that, described step 2 is carried out under microwave-excitation condition, and keep 160-220 DEG C to react 5-30 minute, with excessive pyridine hydrochloride for catalyzer, ethanol or cellosolvo are as solvent.
4. method as claimed in claim 2, it is characterized in that, in described step 3, the preparation method of described Compound I refers to and is dissolved in methyl alcohol by compound 5, under stirring, dropwise adds 10% wet chemical under normal temperature; Stir under reaction mixture normal temperature after spending the night, dilute with water, suction filtration is precipitated thing, obtains Compound I.
5. method as claimed in claim 4, is characterized in that, described Compound I crude product purified by silica gel column chromatography separating purification obtains the Compound I of purifying, and wherein, post is separated the eluent methylene chloride agent that solvent is 9% methyl alcohol+1% triethylamine, with volume percent.
6. a purposes for formula I according to claim 1, is characterized in that, this compound can suppress VEGFR and EGFR receptor kinase family simultaneously, can for the preparation of antitumor, anti-inflammatory, neuroinflamation and antiobesity agents efficiently.
CN201410726660.8A 2014-12-04 2014-12-04 Small molecule inhibitor compound as well as preparation method and application thereof Pending CN104402869A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023010354A1 (en) * 2021-08-04 2023-02-09 四川大学华西医院 Small molecule compound having egfr inhibitory activity, and preparation method therefor and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101659659A (en) * 2008-08-29 2010-03-03 和记黄埔医药（上海）有限公司 Pyridine derivative and medical application thereof
WO2014183300A1 (en) * 2013-05-17 2014-11-20 Suzhou Vivotide Biotechnologies Co., Ltd. Vegfr tyrosine kinase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101659659A (en) * 2008-08-29 2010-03-03 和记黄埔医药（上海）有限公司 Pyridine derivative and medical application thereof
WO2014183300A1 (en) * 2013-05-17 2014-11-20 Suzhou Vivotide Biotechnologies Co., Ltd. Vegfr tyrosine kinase inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023010354A1 (en) * 2021-08-04 2023-02-09 四川大学华西医院 Small molecule compound having egfr inhibitory activity, and preparation method therefor and use thereof

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Application publication date: 20150311