CN101180279A - Tyrosine kinase restrainer for application of antineoplastic medicament and method for preparing the same - Google Patents

Tyrosine kinase restrainer for application of antineoplastic medicament and method for preparing the same Download PDF

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Publication number
CN101180279A
CN101180279A CNA200580049762XA CN200580049762A CN101180279A CN 101180279 A CN101180279 A CN 101180279A CN A200580049762X A CNA200580049762X A CN A200580049762XA CN 200580049762 A CN200580049762 A CN 200580049762A CN 101180279 A CN101180279 A CN 101180279A
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compound
methyl
alkyl
salt preparation
protective embankment
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黄文林
周晓虹
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HUANG WENLIN ZHOU XIAOHONG
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HUANG WENLIN ZHOU XIAOHONG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

Provided are quinazoline derivatives of the compound (I), and its preparation process and application as a medicine of inhibit tumor growth. The group X, Y, Z, R1, R2, R3, R4 of compound (I) are defined in the description. Compounds of the invention can selectively inhibit the phosphorylation of tyrosine kinase, and block the signal transduction path of tyrosine kinase, specially inhibit tyrosine kinase activity, thus to have the effect of inhibit the tumor vascularization, achieve the purpose of treating malignant tumor.

Description

A kind of tyrosine kinase inhibitor applied as antineoplastic and preparation method thereof
Technical field
The invention belongs to the field of chemical synthesis, it is related to tyrosine kinase inhibitor of the new tool antitumor action of a class and preparation method thereof, specifically, the present invention relates to the preparation method of quinazoline derivant and as the application for preparing treatment tumor disease medicine.
Background technology
The conventional method radiotherapy of current treating cancer, chemotherapy, the method that can use electrotherapy for some local entities's knurls, these conventional methods have certain curative effect, but the secondary work of its poison is quite big, and during treatment, great pain is brought to patient.
In tumor disease, entity tumor accounts for the overwhelming majority, and the generation of entity tumor, development and Preventive depend on tumor neovasculature formation.Tumor Angiongesis is the necessary requirement of implanted solid tumor growth and transfer.Suppress Tumor angiogenesis, block the tumour " hunger cure " of tumor tissues blood supply, it is considered to be one for the treatment of most promising new method of solid tumor.
Normal structure is built and the maintenance of function is the transcription and regulation and control that gene is carried out by the cell membrane signal transduction of the multi-step of cell body environment to nucleus.Cancer is abnormal cell behavior caused by a kind of signal transduction pathway due to imbalance, such as cell growth, survival, the change of function and loses differentiation capability and forms tumour.Tumour growth depends on the ability of parasitic host, produces new vessels to utilize the nutrition of host and oxygen part.A kind of growth factor that the development of entity tumor is produced dependent on tumour, stimulation of host endothelial cell signal reaction simultaneously extends tumor vasculature from the blood vessel deposited（Angiogenesis）, the speed of manhood angiogenesis is relatively slow, and only endometrium has normal proliferation activity.Therefore it is a kind of effective treatment means that pathologic vessels in tumor tissues are generated using this approach with targeting blocking angiogenesis.
VEGF (Vascular Endothelial Growth Factor, vascular endothelial growth factor）It is a kind of angiogenesis factor during Tumor Angiongesis, is the hormone regulator of endothelial cell differentiation, the development of solid tumor is with VEGF expression in closely related.Existing research discovery, a variety of diseases including malignant tumour Disease all with associated angiogenesis（Fan, et al, 1995, Trends Pharmacol. Sci. 16,57-66；Folkman, 1995, Nature Medicinel, 27-31).The change of vasopermeability is considered as all playing a role in normal and lesion physiology course（Cullinan-Bove, et al, 1993, Endocrinology 133,829-837；Senger, et al, 1993, Cancer and Metastasis Reviews. 12,303-324).VEGF is the important stimulus factor that normal and the angiogenesis of lesion and vascular permeability are sexually revised（Jakeman, et al, 1993, Endocrinology 133,848-859；Kolch, et al, 1995, Breast Cancer Research and Treatment, 36,139-155；The VEGF antagonisms that Connolly, et al, 1989, J. Biol. Chem. 264,20017-20024 are chelated and produced with VEGF multivalence using antibody can suppress tumour growth（Kim, 1993, Nature 362,841-844).
VEGF expression increase is the result that a variety of factors are stimulated, activation and hypoxemia including proto-oncogene, because tumour patient unsuitable perfusion can caused by solid tumor hypoxemia, VEGF is in addition to the effect for promoting new vessels generation, also promote the permeability of vascular wall, tumour is exchanged acceleration with the nutrition and metabolism of adjacent tissue, and reduce the natural cover of vascular wall and tumour is carried out DISTANT METASTASES IN.
VEGF has tyrosine kinase activity.VEGF and its acceptor --- the combination of EGFR-TK, can activate corresponding signal transduction pathway, promote tumor neovasculature formation and propagation.Played an important role in the biochemical signal transduction path of EGFR-TK (RT s) across cell plasmalemma that VEGF is activated after being combined with its acceptor, and then influence the growth and transfer of tumour.These transmembrane molecules are characterized in that the extracellular ligand binding domain of the fragment connection intracellular tyrosine kinase domain in by plasmalemma is constituted.The combination of part and acceptor excites the tyrosine kinase activity associated with acceptor, causes the tyrosine residue phosphorylation on acceptor and other intracellular molecules.Change in these tyrosine phosphorylations starts signal chaining, produces various kinds of cell reaction.At least 19 kinds different RTK subfamilies defined according to amino acid sequence homology have been identified so far, and one of subfamily includes similar fins tyrosine kinase receptor Fit or Fltl, tyrosine kinase receptor Flt4 of the receptor KDR in domain (also referred to as Flk-1) with another similar fms is inserted containing kinases at present.Two in verified these related RTKs, Fit and KDR can be with high affinity combination VEGF (De Vries, et al, 1992, Science 255,989-991; Terman, et al, 1992, Boichem. Biophys. Res. Comm. , 1992, 187, 1579-1586).VEGF combines relevant with the change of the tyrosine phosphorylation level and calcium current of cell protein with the acceptor that these are expressed in heterogenous cell.
The studies above the sixth of the twelve Earthly Branches is verified, and VEGF is special, directly key vascular endothelial cell positivity regulatory factor, VEGF and its receptor KDR/Flk-1 paths in entity tumor new vessels forming process, is had become anti- One of major target class of tumor vessel treatment.Suppress tyrosine kinase activity, be the important channel for blocking Tumor angiogenesis.
The content of the invention：
It is an object of the invention to provide a kind of tyrosine kinase inhibitor compound（I) kinases receptors insertion domain is included as one kind --- a kind of tyrosine kinase inhibitor of endothelial cell receptor related VEGF.
It is another object of the present invention to provide the preparation method of tyrosine kinase inhibitor.
It is related to compound the invention discloses one kind（I quinazoline derivant), and preparation method thereof and be used as the medicinal application in terms of tumor growth inhibitors.
The compound provided according to the present invention（I):
X therein represents hydrogen, methyl, d-4 protective embankment bases；It is preferred that hydrogen, methyl, most preferably hydrogen.Y therein represent substituted-phenyl " " (R5)n, n is substituent number 1 or 2 or 3 or 4, and phenyl can be respectively by 14 substituent Rs5Replace simultaneously, R5It may be the same or different. R5Represent hydrogen, methyl, fluoroform, nitro, cyano group, C2-4Alkyl, C2— 4Alkoxy, N- (C2-4) alkylamine, enzyme, hydroxyl, the nitrogen of NN- tri-（- 4) alkylamine,4Alkyl sulfide, Ci-4Protective embankment base sulfonyl; R5Prioritizing selection C2-4Alkyl, nitro, cyano group, C2-4Protective embankment epoxide, N- (C2-4) protective embankment base amine, hydroxyl, -4 alkyl sulfides；More preferably C2- 4 protective embankment bases, C2- 4 protective embankment epoxides, N- (C2-4) alkylamine.
Z therein represents a C, 0, S, NH;It is preferred that one 0, S, most preferably a C ^.Expression methyl therein, d-4 alkyl；Most preferable.
R therein2Represent Q-5Alkyl-R6、 C2— 6Alkenyl-, C2_6Alkynyl-, it is 4- piperidyls or substitution 4- piperidyls, can has one or more alkynyls, enzyme, amido as substituent on alkyl, alkenyl, alkynyl and 4- piperidyls.It is preferred that-5Protective embankment base-, C2— 6Alkenyl-, it is 4- piperidyls or substitution 4- piperidyls, can has one or more alkynyls, enzyme, amido as substituent, R on alkyl, alkenyl, alkynyl and 4- piperidyls2More preferably d-5Protective embankment base-R6;R6 prioritizing selection 4- piperidyls, most preferably 4- ethyl piperidines base.
It is therein, represent hydrogen, methyl,4Alkyl, C2-6Alkenyl, C2-6Alkynyl, ring protective embankment base, Different cycloalkyl, preferably hydrogen, methyl, -4 protective embankment bases, C2— 6Alkenyl. R3Prioritizing selection Q-4Alkyl, most preferable.Prioritizing selection hydrogen.Compound（I synthesis)：
The compounds of this invention（) and its salt can be by compound I（) and compound III（IV) reaction synthesis.
Wherein, R2、 R3、 、 Z、 L1And X and Y are described as follows respectively：
X represent hydrogen, methyl ,-4Alkyl；
Υ represents substituted-phenyl → Q^ ~ (R5)n, n is 14, and phenyl can be respectively by 14 substituent Rs5Replace simultaneously, R5It may be the same or different. R5Represent hydrogen, methyl, fluoroform protective embankment, nitro, cyano group, C2- 4 alkyl, C2-4Protective embankment epoxide, N- (C2- 4) alkylamine, enzyme, hydroxyl, the nitrogen of NN- tri-（ -4) protective embankment base amine ,-4Protective embankment base sulphur,4Protective embankment base sulfonyl；
Z represents 0, NH, one or S;
Expression methyl, Ci-4Alkyl；
R2Represent Q-5Alkyl-R6、 C2— 6Alkenyl-, C2- 6Alkynyl-R6, R6It is 4- piperidyls or substitution 4- piperidyls, can has one or more alkynyls, enzyme, amido as substituent on protective embankment base, alkenyl, alkynyl and 4- piperidyls；
R3, R4 represent hydrogen, methyl, -4 protective embankment bases, C2- 6 alkenyls, C2-6Alkynyl, ring protective embankment base, different ring baked base；
L1Represent a group that can easily replace, such as halogen group, sulfonyloxy.
The presence of alkali has the completion beneficial to this reaction.Alkali can be organic amino bases（Such as pyridine, 2,6 lutidines, collidine, DMAP, triithylamine, morphine, N- methylmorphines or diaza-bicyclo (5,4,0) 11 carbon -7- alkene or alkali metal, the carbonate or hydroxide of alkaline-earth metal（Such as sodium carbonate s potassium carbonate, calcium carbonate, NaOH, KOH) o is in addition, alkali can also be the hydride of alkali metal（Such as sodium hydride）Or the amino-compound of alkali metal, alkaline-earth metal（Such as Sodamide, double（Trimethyl silicane）Acid amides sodium）, preferably 2,6 lutidines. The reaction can be completed preferably in the presence of atent solvent or dilution, such as alkylol or ester（Such as methanol, ' ethanol, isopropanol or ethyl acetate）, halogenated hydrocarbons（Such as dichloromethane, three chloromethane protective embankments, carbon tetrachloride), ether（As tetrahydrofuran, 1,4- bis- dislike protective embankment）, aromatic hydrocarbons（Such as toluene）, non-polar solven with dipole moment（Such as Ν, Ν-dimethylformamide, Ν, Ν-acetic acid dimethylamide, Ν-methylpyrrole -2- ketone or dimethyl sulfoxide）, prioritizing selection ethyl acetate.
10 ~ 150 °C (particularly 20 80 °C), the temperature of more preferably 50 °C of selection is conducive to the completion of the reaction.This course of reaction can produce the free alkali or its salt of the invention compound（With H-L1Acid, wherein L1See above）.When it is desirable that gaining freedom alkali from salt, its salt can conventionally be handled with alkali mentioned above.
The compounds of this invention（) or its salt can also be synthesized with known chemical synthesis process and step I.For example, those methods illustrated in the European patent of Publication No. 0520722,0566226,0602851 and 0635498 and Publication No. W097122596, W097 I 30035, W097 I 32856 and W098 I 133541 international patent application.These methods are as will be explained hereinafter, are this patent further features.Required initiation material can be synthesized according to standard organic chemical program, and the synthetic method of these initiation materials is by described in subsequent example（Unrestrictedly）.Other required initiation materials can be synthesized according to the similar method and step described in organic chemistry handbook.
The synthesis of intermediate product：
Change
4,
It may be the same or different. R5Represent hydrogen, methyl, fluoroform, nitre
Base, cyano group, C2-4Alkyl, C2-4Alkoxy, N- (C2-4) alkylamine, enzyme, hydroxyl, the nitrogen of NN- tri- (Q-4) protective embankment base amine, -4 alkyl sulfides, d -4Alkyl sulphonyl；
Z therein represents 0, NH, a C or S;
Ri therein represent methyl ,-4Alkyl；
R therein2Represent baked base-R6、 C2-6Alkenyl-, C2— 6Alkynyl-Re;Wherein it is 4- piperidyls or substitution 4- piperidyls, can has one or more alkynyls, enzyme, amido as substituent on alkyl, alkenyl, alkynyl and 4- piperidyls；
R therein3, represent hydrogen, methyl, -4 protective embankment bases, C2— 6Alkenyl, C2— 6Alkynyl, cycloalkyl, Different ring protective embankment base；
P therein1Represent phenolic hydroxyl protecting group
A kind of atent solvent or dilution（Such as halogenated solvent dichloromethane protective embankment, chloroform or carbon tetrachloride, or aromatic solvent benzene, toluene）Presence have completion beneficial to halogenation.Certain temperature range, such as 10 150 °C (particularly 40 100 °C) are conducive to the completion of the reaction.
It is used as the application for preparing treatment tumor disease medicine it is a further object of the present invention to provide above-claimed cpd.The present invention（A kind of tyrosine kinase inhibitor）It is a kind of synthetics, its specific action suppresses its activity in EGFR-TK, so as to suppress two kinds of high-affinity receptor activity of the VEGF factors, and then adjusts VEGF secretion.VEGF is main angiogenesis factor in neoplasm vascularity, and tumour VEGF expression has close ties with some malignant entity tumor complication.Preclinical study data points out that the animal model of foundation with good tolerance dose after zoopery, shows obvious antitumous effect.By suppressing the secretion of the VEGF factors, the growth of tumour can be suppressed indirectly, therapeutic purposes are reached.With respect to the traditional remedies of cancer, treatment of the invention has the advantages that targeting is good, toxic side effect is small.
Have proven to tyrosine kinase receptor（RTKs it is) intracellular important signal transduction modulators, these protein are connected by an extracellular ligand binding site by cross-film primitive with intracellular tyrosine kinase site to be constituted or acceptor combines to form acceptor, aggressiveness and activates RTK sites.These enzymatic activitys are catalyzed V phosphate cluster and prevent the VEGF Regulate signals in endothelial cell by ATP is transferred to selectivity inhibitory action that the acceptor enzyme tyrosine of itself is associated with KDP.The growth for promoting entity tumor is the result that blood vessel is continuously generated, the generation of blood vessel is all implanted solid tumor growths and the necessary condition for forming metastatic tumor, in the process, VEGF plays critical actions, it is a kind of albumen inhibiting factor of KDR EGFR-TKs, for suppressing the angiogenesis driven by VEGF, so as to suppress tumour growth, for treating tumour, with extensive potential applicability in clinical practice.Brief description of the drawings：
The thing of the present invention of accompanying drawing 1 makes rat articular epiphyseal growth plate produce dose dependent.
The thing of the present invention of accompanying drawing 2 is to planting in the inhibitory action of the PC-3 human prostate tumours of nude mice
The inhibitory action that the compounds of this invention of accompanying drawing 3 grows to colon cancer cell Lovo.
Inhibitory action of the compounds of this invention of accompanying drawing 4 to tumour in colon cancer LoVo tumour model in nude mice.The present invention is described in detail with specific embodiment below in conjunction with the accompanying drawings.
Specific embodiment： Here is embodiments of the invention, and described embodiment is used to describe the present invention rather than the limitation present invention.The compound of the present invention is a kind of solid matter, white, powdered.This compound is water-soluble, slant acidity, and pH is 6.4 or so.
Embodiment 1
By compound（) and compound III（IV synthetic reaction, prepare compound) are carried out（) and its salt I.
Wherein：X is H, and Y is tolyl, and Z is that C a ^, 1^ is methyl, is 4- ethyl piperidine bases,
R3It is 11, L for methyl1For 0-+P(CH2CH2CH2CH3)3Base.
Reaction is carried out in 0.3 moL/L 2,6 lutidines solution, by the compound of equimolar number（) and compound III（IV) add in reaction solution, containing the 0.05 moL/L ethyl acetates for accounting for overall reaction liquid product 10% in reaction solution, after mixing in 70 water-baths heating response, produced precipitation is separated by filtration after 30 minutes, is dried, as product.Product is white powdered, water-soluble, and pH is 6.4.
Embodiment 2
By compound（) and compound III（IV synthetic reaction, prepare compound) are carried out（) and its salt I.Wherein：X is methyl, and Y is ethylbenzene, and Z is a C, is ethyl, R2For 4- vinylpiperidines, R3It is methyl, L for H1For 0-+P( ^> )3Base.
Reaction is carried out in 0.2 moL/L NaOH solution, by the compound of equimolar number（) and compound III
(IV) add in reaction solution, containing the chloromethane protective embankments of 0.05 moL/L tri- for accounting for overall reaction liquid product 8% in reaction solution, after mixing in 50 water-baths heating response, produced precipitation is separated by filtration after 30 minutes, is dried, as product.Product is white powdered, water-soluble, and pH is 6.4.
Embodiment 3
By compound（) and compound III（IV synthetic reaction, prepare compound) are carried out（) and its salt I.Wherein：X is methyl, and Y is tolyl, and Z is NH, is methyl, R2For 4- acetylene phenylpiperidines,
R3It is hydrogen, L for ethyl1For 0-+P (~)3Base.
Reaction is carried out in 0.1 moL/L solution of potassium carbonate, by the compound of equimolar number（III) added with compound (IV) in reaction solution, containing the 0.05 moIJL isopropanols for accounting for 15 % of overall reaction liquid product in reaction solution, Heating response, the precipitation produced by being separated by filtration after 20 minutes, as drying, product in locrc water-baths after mixing.Product is white powdered, water-soluble, and pH is 6.4.
Embodiment 4
By compound（) and compound III（IV synthetic reaction, prepare compound) are carried out（) and its salt I.Wherein：For butyl, R2For 4- vinylpiperidines, R3It is acrylic for pentynyl, X is propyl group,
Y is nitro, and Z is NH, L1For 0-+P(CH2CH2CH2CH3)3Base.
Reaction is carried out in 0.15 moL/L collidine solution, by the compound of equimolar number（) and compound III（IV) add in reaction solution, containing the 0.08 moL/L toluene for accounting for overall reaction liquid product 12% in reaction solution, after mixing in 10 °C of water-baths heating response, produced precipitation is separated by filtration after 60 minutes, is dried, as product.Product is white powdered, water-soluble, and pH is 6.4.
Embodiment 5
By compound（) and compound III（IV synthetic reaction, prepare compound) are carried out（) and its salt I.Wherein：Ri is propyl group, R2For 4- vinylpiperidines, R3It is methyl for H, X is methyl, and Y is ethylbenzene, and Z is S, L1For 0-+P(_^> )3Base.
Reaction is carried out in 0.08 moL/L 2,6 lutidines solution, by the compound of equimolar number（) and compound III（IV) add in reaction solution, containing the 0.05 moL/L tetrahydrofurans for accounting for overall reaction liquid product 6% in reaction solution, after mixing in 20 °C of water-baths heating response, produced precipitation is separated by filtration after 40 minutes, is dried, as product.Product is white powdered, water-soluble, and pH is 6.4.
Embodiment 6
By compound（) and compound III（IV synthetic reaction, prepare compound) are carried out（) and its salt I.Wherein：1^ is ethyl, R2For 4- vinylpiperidines, R3It is methyl for cyclobutenyl, X is methyl, and Y is ethylbenzene, and Z is one, L1For 0-+P(C¾CH2CH2CH3)3Base.
Reaction is carried out in 0.2 moL/L amide solution, by the compound of equimolar number（III) added with compound (IV) in reaction solution, contain the 0.15 moL/L N for accounting for overall reaction liquid product 5% in reaction solution, N- acetic acid dimethylamides, after mixing in 60 °C of water-baths heating response, produced precipitation is separated by filtration after 30 minutes, dry, as product.Product is white powdered, water-soluble, and pH is 6.4. Embodiment 7-13 is the part effect experiment of following compounds
Wherein：1^ is methyl, R2For 4- ethyl piperidines, R3It is H for methyl, X is H, and Y is tolyl, and Z is a C.Embodiment 7
Dose dependent makes rat articular epiphyseal growth plate growth experiment.
Method：Alderiey Park young female rats（4-8 week old, wostar-derived), continuous 14 days, by the 0.25 dosage subcutaneous injection thing of the present invention of mg/kg/ days.Experimental mouse leg epiphysis joint tissue domain is dyed using h and E, and epiphyseal growth plate binding site uses morphology influence analysis measurement.As a result as shown in accompanying drawing 1, the undue growth of the joint epiphyseal growth plate of rat makes the increase of zona cartilaginea dose dependent.When injection volume is 50 or 100 mg/kg/ days, the ability and internal blood vessel formation against function that thing of the present invention suppresses VEGF signals are consistent.Embodiment 8
Inhibitory action experiment to nude mice mankind's transplantable tumor.
Method：Nude mice（Male, 6 week old), PC-3 human prostate tumours are inoculated with, treat that knurl volume reaches 0.2cm2When, it is randomly divided into 5 groups, respectively control group, 100mg/kg/ days dosage groups, 50mg/kg/ days dosage groups, 25mg/kg/ days dosage groups, 12.5mg/kg/ days dosage groups, successive administration 7 days, intratumor injection thing of the present invention, observation five weeks, as a result as shown in Figure 2.
Embodiment 9
Oral thing of the present invention is to nude mice mankind's transplantable tumor inhibitory action.
Method：As described in table 1, male, the nude mice of 6 week old are taken, transplantable tumor is inoculated with different parts, knurl is planted not Inhibitory action of the oral thing of the present invention to nude mice mankind's transplantable tumor
Oral dose experiment kind knurl time medication tumour inhibiting rate significant difference transplantation tumor (mg/kg/d) number of times (d) number of times (%) (P values）
MDA-mb-231 chests 100 1 16 25 99<0.001
50 1 16 25 82 <0 precipice
25 1 16 25 64 <0.01
12.5 1 16 25 71 <0.001
SKOV-3 ovaries 100 1 18 28 100<0.001
50 1 18 28 98 <0.001
25 1 18 28 50 NS
12.5 1 18 28 30 NS
LoVo colons 100 25 14 7 99>100 <0.001
50 2 5 14〜17 77〜81 <0.01 Please 1
25 2 5 14〜17 55〜60 <0.05 Honor 1
12.5 2 5 14〜17 5〜27 NS
A549 lungs 100 1 14 25>100 <0.001
50 1 14 25 >100 <0.001
25 1 14 25 88 <0.001
12.5 1 14 25 64 <0.001
12.5 1 14 2 foretell 30 15 46 NS<0.05
A431 private parts 100 1 14 21>100 <ο.οαι
50 2 14 21〜30 83〜>100 <0.001
25 2 14 21 -30 42-80 <0.05〜<0.001
12.5 2 14 21〜30 15〜46 NS〜<0.05
NS is not notable
Embodiment 10
Suppress people's navel tire vascular endothelial cell proliferation effect of VEGF inductions.
The compounds of this invention is the people's navel tire vascular endothelial cell proliferation VEGFR tyrosine kinase inhibitors for suppressing VEGF inductions, but the basal cell that non-VEGF is induced is grown without influence.Utilize thymus gland pyridine pyridine test and appraisal people's navel tire vascular endothelial cell containing demarcation（HUVEC) point when existing or lacking VEGF, ECF or bFGF Split situation.
Specific implementation situation is：It will contain3H thymus gland pyridine pyridine（Ι Ο μ α/mL) with cell concentration be 1 X 105/ mL HUVEC is co-cultured, and treats that the thymus gland pyridine pyridine of 1H demarcation is integrated in HUVEC, by 10-1Gradient（Initial concentration 800mg/L) dilution the compounds of this invention, add and cultivated in the HUVEC after the thymus gland pyridine pyridine containing 1H is integrated, the division situation of the HUVEC when existing or lacking VEGF, EGF or bFGF is observed, 50 3nhibitory dose of the compound to HUVEC is detected.
As shown in table 2, the compounds of this invention is strong and optionally suppresses the propagation of people's navel tire vascular endothelial cell of VEGF inductions, in its 50 times of concentration on the growth of base portion endothelial cell still without influence.The analysis of this synthetic enzyme,（Inhibition level power arrangement KDR>EGFR>) and cell composition analysis FGFR1（Inhibition level power arrangement VEGF>EGF>BFGF), it is also demonstrated that this inhibitory action tool selectivity of this compound.
The compounds of this invention inductive factor ability and suppression base portion endothelial cell division
Average scholar's error
VEGF EGF FGF Basal
IC50 (MM) 0.06 ±0.02 0.16±0.03 0.8±0.06 >3
Test number (TN) 6654
EGF:Endothelial growth factors
FGF:Fibroblast cells growth factor
VEGF:VEGF
Embodiment 11
Extracorporeal suppression tumor cell division experiment.
Test thing of the present invention is in the ability of direct inhibitionin vitro growth of tumour cell, to understand fully that it is the division of direct antitumor cell or indirect neoplasm growth thought such as most people in vivo（Such as：It is anti-angiogenetic therapy or suppresses tumor vessel penetration）, by containing3The H sweet evaluation cell division of thymidine core.Specific implementation method is as follows：By containing3H thymidine core is sweet（Ι Ο μ α/mL) marked tumor cell, Ji Jianghan3After the H sweet co-cultivation with tumour cell of thymidine core, by 10'1Gradient（Initial concentration 800mg/L) dilution the compounds of this invention, add integration and contain3The sweet tumour cell of H thymidine core, detects the 50 3nhibitory dose of the compound on tumor cell.
As shown in table 3, the compounds of this invention suppresses growth of tumour cell IC5()Scope is 0.8 1.4mm (table 3), and its concentration is 13 230 times of the concentration for the HUVEC divisions for suppressing VEGF inductions（Table 3).Data above shows that the compound Anticancer effect in vivo is mainly to suppress endothelial cell VEGF signal factor, rather than directly Antitumor cell divides.
The influence that the compounds of this invention divides to tumor cell in vitro（n=3 )
Tumor cell line origin average（Scholar's error） IC5o (MM)
Calu-6 lungs 1.30 ± 005
MDA-MB-231 chests 6.00 ± 1.60
SKOV-3 ovaries 5.60 ± 0.10
A431 private parts 480 ± 0.10
A549 lungs 3.80 ± 0.40
PC-3 prostates 3.70 ± 1.40
LoVo colons 0.75 ± 0.20
Embodiment 12
The inhibitory action grown to colon cancer cell Lovo.
Lovo cell growth inhibition assays using mtt assay ' detected：The Lovo cells of exponential phase are put in 96 well culture plates and cultivated, experimental group adds 0 10 (^g/mL the compounds of this invention after 48 h, each concentration sets 6 multiple holes, control wells add the culture mediums of RPMI 1640 that same volume is free of the compounds of this invention, and set blank control wells (it is acellular, only containing the culture mediums of RPMI 1640）.Cultivate after 72h, 37 °C of reaction 4h of MTT (5g/L) 20 μ are added per hole, nutrient solution in hole is sucked, 15 is added and (after ^L dimethyl sulfoxides (DMSO), fully dissolving, absorbance is surveyed under 570nm（A) value, calculates inhibitory rate of cell growth.As a result as shown in Figure 3, the compounds of this invention has obvious growth inhibition effect to Lovo cells, and dose dependent is presented：During drug concentration 12.5ug/mL, growth inhibition ratio 50%；Growth inhibition ratio is up to more than 90% during 25 g/mL of drug concentration.Embodiment 13
To the inhibitory action of tumour growth in colon cancer Lovo Nude Mouse Models.
Colon cancer Lovo Nude Mouse Models are set up, nude mice is divided into Liang Zu treatment groups：100mg/kg/day groups and 50mg/kg/day groups, intraperitoneal injection, successive administration 30 days；It is another to set blank control group, 0.5 %DMSO is injected intraperitoneally, only, successive administration puts to death animal to 0.2mL/ after 30 days, calculates gross tumor volume T/C ratios, evaluation index is used as using T/C ratios；Tumour is weighed, calculate tumour inhibiting rate, as a result as shown in Figure 4, the compounds of this invention alternative suppresses KDR EGFR-TK phosphorylations, block tyrosine kinase signal Signal Transduction Pathways, thus with Antineoplastic angiogenesis effect, there is obvious inhibiting effect to the growth of tumour in colon cancer LoVo Nude Mouse Models.

Claims (1)

  1. A kind of compound of claims（I) and its salt preparation method, it is characterised in that compound（I) (quinazoline derivant) such as following chemical formula：
    X therein represent hydrogen, methyl ,-4Alkyl；
    Y therein represents substituted-phenyl Q>~ (R5)n, n is substituent number 1 or 2 or 3 or 4, and phenyl can be respectively by 14 substituent Rs5Replace simultaneously, R5It may be the same or different. R5Represent hydrogen, methyl, fluoroform, nitro, cyano group, C2-4Alkyl, C2- 4 alkoxies, N- (C2— 4) alkylamine, enzyme, hydroxyl, the nitrogen of NN- tri-（- 4) protective embankment base amine, protective embankment base sulphur ,-4Alkyl sulfonyl Z therein represents a C^^, 0, S, NH;
    Expression methyl therein, d-4Alkyl；
    R therein2Represent d-5Alkyl-R6、 C2— 6Alkenyl-, C2-6Alkynyl-, it is 4- piperidyls or substitution 4- piperidyls, can has one or more alkynyls, enzyme, amido as substituent on alkyl, alkenyl, alkynyl and 4- piperidyls；
    R therein3, R4 represent hydrogen, methyl, d-4Protective embankment base, C2-6Alkenyl, C2— 6Alkynyl, ring protective embankment base, different cycloalkyl；
    Compound（I) can be by compound（) and compound III（IV) reaction synthesis：
    X therein represents hydrogen, methyl, CH protective embankment bases； —―
    Y therein represent substituted-phenyl ~<Q^" (R5)n, n is 14, and phenyl can be respectively by 14 substituent Rs5Replace simultaneously, R5It may be the same or different. R5Represent hydrogen, methyl, fluoroform, Nitro, cyano group, C2-4Protective embankment base, C2— 4Alkoxy, N- (C2-4) alkylamine, enzyme, hydroxyl, the nitrogen of NN- tri-（d-4) alkylamine, d-4Alkyl sulfide, d-4Alkyl sulphonyl；
    Z therein represents 0, NH or S;
    Expression methyl therein, Q-4 alkyl；
    Expression d therein-5Burn base-R6、 C2-6Alkenyl-R6、 C2-6Alkynyl-, it is 4- piperidyls or substitution 4- piperidyls, can has one or more alkynyls, enzyme, amido as substituent on alkyl, alkenyl, alkynyl and 4- piperidyls；
    R therein3, represent hydrogen, methyl, Q-4Alkyl, C2-6Alkenyl, C2-6' alkynyl, ring protective embankment base, different cycloalkyl；
    L therein1Represent a group that can easily replace, such as halogen group, sulfonyloxy.
    2. the compound as described in claim 1（I) and its salt preparation method, it is characterised in that can be by compound（) and compound III（IV) reaction synthesis：
    X prioritizing selections hydrogen therein；
    Y therein is substituted-phenyl, wherein R5Prioritizing selection protective embankment base；
    Z prioritizing selections therein;
    Prioritizing selection methyl therein；
    Prioritizing selection Q-5 protective embankment bases therein
    ' R therein3The alkyl of prioritizing selection -4；
    Prioritizing selection hydrogen therein；
    L therein1Prioritizing selection bromine, sulfonyloxy methyl epoxide.
    3. the compound as described in claim 1（I) and its salt preparation method, it is characterised in that can be by compound（) and compound III（IV) reaction synthesis：
    X therein is hydrogen；
    Y therein is tolyl；
    Z therein is one；
    Therein is methyl；
    R therein2For 4- ethyl piperidine bases；
    Therein is methyl；
    Therein is hydrogen；
    L therein1For 0-+P (CH2C¾CH2C¾)3Group or 0-+P( - <Q)3Group.
    4. the compound as described in claim 1,2（I) and its salt preparation method, it is characterised in that the presence of alkali have beneficial to this reaction completion.
    5. the compound as described in claim 1,2,5（I) and its salt preparation method, it is characterised in that：Alkali can be the hydride of organic amino bases, either alkali metal, the carbonate of alkaline-earth metal or hydroxide or alkali metal, or alkali metal, alkaline-earth metal amino-compound.Such as：2,6 lutidines, collidine, DMAP, triithylamine, morphine, N- methylmorphines or diaza-bicyclo（5,4,0) 11 carbon -7- alkene, sodium carbonate, potassium carbonate, calcium carbonate, NaOH, KOH, sodium hydride, Sodamide, double（Trimethyl silicane）Acid amides sodium.
    6. the compound as described in claim 1,2,5,6（I) and its salt preparation method, it is characterised in that the lutidines of alkali prioritizing selection 2,6.
    7. the compound as described in claim 1,2（I) and its salt preparation method, it is characterised in that the reaction can be completed preferably in the presence of atent solvent or dilution.
    8. the compound as described in claim 1,2,8（I) and its salt preparation method, it is characterized in that atent solvent or dilution can be protective embankment base alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, halogenated hydrocarbons such as dichloromethane, three chloromethane protective embankments, carbon tetrachloride, ether such as tetrahydrofuran, 1,4- dioxanes, aromatic hydrocarbons such as toluene, such as Ν of the non-polar solven with dipole moment, Ν-dimethylformamide, Ν, Ν-acetic acid dimethylamide, Ν-methylpyrrole -2- ketone or dimethyl sulfoxide.
    9. the compound as described in claim 1,2,8,9（I) and its salt preparation method, it is characterised in that atent solvent or dilution prioritizing selection ethyl acetate.
    10. the compound as described in claim 1,2（I) and its salt preparation method, it is characterised in that 10 150 °C of reaction temperature is conducive to the completion of the reaction.
    11. the compound as described in claim 1,2,11（I) and its salt preparation method, it is characterised in that reaction temperature prioritizing selection 20-80.
    12. the compound as described in claim 1,2,11,12（I) and its salt preparation method, it is characterised in that reaction temperature prioritizing selection 50.
    13. the compound as described in claim 1,2（I) and its and its salt preparation method, it is characterised in that this method can produce compound（I free alkali or its salt), and can be with being obtained after well-known conventional process.
CNA200580049762XA 2005-05-12 2005-05-12 Tyrosine kinase restrainer for application of antineoplastic medicament and method for preparing the same Pending CN101180279A (en)

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GB9314893D0 (en) * 1993-07-19 1993-09-01 Zeneca Ltd Quinazoline derivatives
HUP9901155A3 (en) * 1996-02-13 2003-04-28 Astrazeneca Ab Quinazoline derivatives as vegf inhibitors
GB9603095D0 (en) * 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline derivatives
GB9718972D0 (en) * 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
CN1542004A (en) * 2003-04-30 2004-11-03 黄文林 Tyrosine kinase inhibitor, preparation method and use thereof

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