CN106995452B - Double target spot inhibitor of a kind of thieno [3,2 d] miazines EGFR/ErbB2 and its production and use - Google Patents

Double target spot inhibitor of a kind of thieno [3,2 d] miazines EGFR/ErbB2 and its production and use Download PDF

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CN106995452B
CN106995452B CN201611199866.5A CN201611199866A CN106995452B CN 106995452 B CN106995452 B CN 106995452B CN 201611199866 A CN201611199866 A CN 201611199866A CN 106995452 B CN106995452 B CN 106995452B
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compound
formula
pharmaceutically acceptable
pharmaceutical composition
salt
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CN106995452A (en
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宋新建
马小平
王东华
谭小红
杨平
董兴高
段正超
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Wuhan Cherman Biotechnology Co.,Ltd.
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Hubei University for Nationalities
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract

The present invention relates to the compound shown in a kind of formula (1) or its pharmaceutically acceptable salt, wherein, R1Selected from C1‑6Alkyl, aryl, C1‑6Alkylaryl；R2It is identical or different, optionally from H, halogen, C1‑6Alkyl, C1‑6Alkoxy, halo C1‑6Alkyl, halo C1‑6Alkoxy, C2‑6Alkenyl, C2‑6Alkynyl, nitro, amino, or two adjacent R2With forming 38 yuan of rings together with the carbon connected, n is 0 to 5 integer.The invention further relates to the preparation method of above-claimed cpd and purposes, the compound has inhibitory activity to EGFR and/or ErbB2 protein tyrosine kinases.

Description

A kind of double target spot inhibitor of thieno [3,2-d] miazines EGFR/ErbB2 and its system Preparation Method and purposes
Technical field
The present invention relates to pharmaceutical technology field, in particular it relates to which a kind of thieno [3,2-d] miazines EGFR/ErbB2 is double Target spot inhibitor and preparation method thereof.Thieno [3,2-d] pyrimidines provided by the invention are to EGFR and ErbB2 albumen EGFR-TK is respectively provided with obvious inhibitory action, can be used as antineoplastic or lead compound.
Background technology
Cancer is one of main disease of serious threat human life and health, and it is always highly visible grind to capture cancer Study carefully problem.Since over half a century, cancer chemotherapy achieves significant progress, and wherein cytotoxicity class medicine is to some type of Tumors display goes out good efficacy, and classical cytotoxic medicine will be cancer within one considerably long at present and in the future period The main body of disease chemotherapeutics.However, there is toxic side effect is big, poor selectivity, to be also easy to produce drug resistance etc. main for cytotoxic drug Defect is wanted to cause the effect of it is to most of tumor types still difficult satisfactory.Therefore, it is clinically efficient, low there is an urgent need to find The good antineoplastic of poison, specificity.
With the rapid development of oncobiology and related discipline, people gradually recognize that the essence of cell carcinogenesis is cell The imbalance of signal transduction pathway causes the unlimited hyperplasia of cell, bring therewith antineoplastic research and development theory great change, just from Classical cytotoxic class medicine develops in the new drug direction of numerous links to during for tumor development, is especially targeted medicine Thing can be directed to the difference between normal cell and tumour cell, reach the selective strong, therapeutic effect of high-efficiency low-toxicity, so as to overcome The poor selectivity of classical cytotoxic medicine, toxic side effect is strong, is also easy to produce the shortcomings of drug resistance, malignant tumour is entered " targeting Treatment " the New Times.In recent years, carried out with protein tyrosine kinase (Protein Tyrosine Kinases, PTKs) for target spot Medicament research and development has turned into the focus of international antineoplastic research, wherein, EGF-R ELISA (Epidermal Growth Factor Receptor, EGFR) family is a kind of main protein tyrosine kinase, including EGFR (ErbB1), ErbB2, Four members such as ErbB3, ErbB4, its intracellular region have ATP-binding site, and EGFR classes inhibitor can competitive and ATP bound sites Point is combined, and so as to suppress EGFR Phosphorylation events, blocks the conduction of downstream signal, so suppress tumour cell growth, Differentiation and transfer.EGFR is progressively being illustrated as the biochemical process of anti-tumor target, its crystal structure and active site It is clearer, as the Gefitinib (Gefitinib), Erlotinib (Erlotinib) and Lapatinib of target spot Etc. (Lapatinib) aryl amine quinazoline ditosylate salt medicine is applied to clinic, and the research of EGFR class inhibitor is in the ascendant.
Tumorigenic reason and mechanism are extremely complex, often relate to the change of multiple protein 26S Proteasome Structure and Function, it is intended to logical Cross single target drug and block some acceptor to block tumour cell signal transduction not comprehensive, curative effect is often also not optimistic enough, has Drug resistance may be caused.Therefore, research and development Mutiple Targets antineoplastic is an effective way for solving " targeted therapy " problems Footpath.Mutiple Targets medicine can act on multiple molecular targets of a certain disease correlation pathogen simultaneously, and now clinically conventional Cytotoxic drug is compared, and Mutiple Targets medicine has the advantages that efficient, low toxicity, specificity are high and are not likely to produce drug resistance.With The progressively announcement of elaboration of tumour mechanism, " more targetings " will open up a piece of new world for oncotherapy.
The content of the invention
The present invention provides a kind of thieno [3,2-d] pyrimidines and its production and use, the compound There is inhibitory activity to EGFR and/or ErbB2 protein tyrosine kinases.
Technical scheme is as follows：
Compound and its pharmaceutically acceptable salt shown in a kind of formula (1)：
Wherein,
R1Selected from C1-6Alkyl, aryl, C1-6Alkylaryl；
R2It is identical or different, selected from H, halogen, C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, nitro, amino, or two adjacent R2With forming 3-8 yuan of rings together with the carbon connected,
N is 0 to 5 integer.
According to the present invention, the alkyl refers to the straight or branched alkyl with 1-6 carbon atom, and the example of preferably alkyl is Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl.
According to the present invention, the alkenyl refers to the straight or branched alkenyl with 2-6 carbon atom, and the example of preferably alkenyl is Vinyl, acrylic or isopropenyl.
According to the present invention, the alkynyl refers to the straight or branched alkynyl with 2-6 carbon atom, and the example of preferably alkynyl is Acetenyl, propinyl, butynyl.
According to the present invention, the alkoxy refers to the straight or branched alkoxyl with 1-6 carbon atom, preferably methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy.
According to the present invention, the halogen is fluorine, chlorine, bromine, preferably iodine, fluorine, chlorine, bromine.
According to the present invention, the aryl refers to the monocyclic or polycyclic aromatic base with 6-20 (preferably 6-14) carbon atoms Group, representational aryl are selected from：Phenyl, naphthyl, anthryl etc..
According to the present invention, described two adjacent R2Can be carbocyclic ring or miscellaneous with the ring formed together with the carbon connected Ring, the hetero atom of the heterocycle can be N, O, S.
According to the preferred technical solution of the present invention, R1Selected from C1-3Alkyl, aryl, C1-3Alkylaryl；R2Selected from H, halogen, C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy, C2-3Alkenyl, C2-3Alkynyl, two adjacent R2With institute The carbon of connection forms 3-6 yuan of rings together；N is 1,2,3.
According to the preferred technical scheme of the present invention, R1For phenyl；R2For H, F, Cl, Br, methoxyl group, trifluoromethyl, acetylene Base, or two adjacent R2With forming dioxolane together with the carbon connected.
Preferably, formula (1) compound is selected from following particular compound：
According to the present invention, formula (1) compound can form pharmaceutically acceptable salt with pharmaceutically acceptable acid.Its Middle term " pharmaceutically acceptable salt " includes but is not limited to the salt formed with inorganic acid, such as hydrochloride, phosphate, diphosphonic acid Salt, hydrobromate, sulfate, sulfinate, nitrate and its similar salt；Also the salt formed with organic acid, such as lactic acid are included Salt, oxalates, malate, maleate, fumarate, tartrate, succinate, citrate, salicylate, acetic acid Salt, and its similar salt.
The present invention also provides one kind and prepares formula (1) compound and its preparation method of pharmaceutically acceptable salt, including：
Wherein, R1、R2, n is as described above, R3For C1-6Alkoxy；
1) formula (4) compound and formula (6) compound are reacted, obtains formula (5) compound；
2) formula obtained in step 1) (5) compound is reacted in the basic conditions, obtains formula (1) compound；
3) compound that optionally, step (2) is obtained further is formed with pharmaceutically acceptable acid and can pharmaceutically connect The salt received.
According to the present invention, for step 1), the reaction is carried out in acid condition, such as glacial acetic acid.The reaction temperature Degree is preferably 50-150 DEG C, more preferably 60-120 DEG C.Preferably, mode of heating can be that common heating or microwave heat.
According to the present invention, for step 2), the alkali can be inorganic base, such as lithium hydroxide, sodium hydroxide etc., described Reaction is carried out under solvent, such as in alcohols solvent (such as ethanol).The reaction temperature is preferably 50-150 DEG C, more preferably 60-120℃。
According to the present invention, formula (4) compound can be prepared via a method which that methods described includes：
Wherein, R1As described above, R3For C1-6Alkoxy.
The present invention also provides a kind of pharmaceutical composition, and it includes compound described in above-mentioned formula (1) or it pharmaceutically may be used The salt of receiving.
According to the present invention, described pharmaceutical composition also includes at least one pharmaceutically acceptable, inert, nontoxic tax Shape agent or carrier or diluent；Preferably further comprising it is one or more selected from filler, disintegrant, lubricant, glidant, Effervescent agent, flavouring, the pharmaceutically acceptable auxiliary material of preservative and coating material.
According to the present invention, described pharmaceutical composition can be made into dosage form, such as solid orally ingestible, liquid oral medicine Or injection etc..
According to the present invention, described preparation can be tablet, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, particle Agent, oral solution, injection liquid drugs injection, injection freeze-dried powder, big transfusion or primary infusion.
The present invention also provides a kind of above-mentioned formula (1) compound or its pharmaceutically acceptable salt and prepared for suppressing Application in EGFR and/or ErbB2 protein tyrosine kinase medicines.
Present invention also offers a kind of above-mentioned formula (1) compound or its pharmaceutically acceptable salt to prepare for anti-swollen Application in knurl or cancer drug.
Thieno [3,2-d] pyrimidines synthetic route of the present invention is short, preparation method is simple, raw material sources Conveniently, it is easily achieved industrialization.These compounds are respectively provided with obvious suppression to EGFR and/or ErbB2 protein tyrosine kinases Effect, it is suitable with the double target spot antineoplastic BIBW2992 of commercialization activity.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.Furthermore, it is to be understood that after described content of the invention has been read, this area skill Art personnel can make various changes or modifications to the present invention, and these equivalent form of values equally fall within limited range of the present invention.With In lower embodiment,1H NMR and13C NMR are tested using the type NMR spectrometer with superconducting magnet of BRUKER Avance 400.
The synthetic route of the compounds of this invention is as follows：
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 1 (1-1)
1) it is in 150mL round-bottomed flasks that 11.31g (0.10mol) cyan-acetic esters and 5.61g (0.10mol) KOH is molten Solution stirs 3h in 50mL DMF (DMF) at 0~5 DEG C, and 13.52g (0.10mol) different sulphur is slowly added dropwise Phenyl-cyanate, add in 1h, continue to stir 3h under ice-water bath.Then, the DMF that 7.55g (0.10mol) chloroacetonitrile is slowly added dropwise is molten Liquid, 1h are added, and are stirred overnight at room temperature.Reaction is finished, and reaction solution is poured into 100g trash ices, is separated out a large amount of yellow solids, is taken out Filter, a small amount of methanol wash, are dry that brown solid is compound (yield 65%) shown in formula (2 '),
2) by compound shown in 2.87g (0.01mol) formulas (2 ') and 1.98g (0.03mol) second in 150mL round-bottomed flasks Sodium alkoxide is dissolved in 50mL absolute ethyl alcohols, back flow reaction 3h.Room temperature is cooled to, reaction solution is added in 100mL distilled water, it is quiet Put and separate out a large amount of yellow solids, filter, dry, absolute ethyl alcohol recrystallize yellow crystals are compound (yield shown in formula (3 ') For 60%),
3) compound and 1.19g (0.01mol) shown in 2.87g (0.01mol) formulas (3 ') are added in 100mL round-bottomed flasks DMF dimethylacetal (DMF-DMA) and 15mL anhydrous acetonitriles, back flow reaction 2h.It is concentrated under reduced pressure, anhydrous acetonitrile Recrystallize clear crystal is compound (yield 82%) shown in formula (4 '),
4) compound shown in 3.42g (0.01mol) formulas (4 ') and 0.93g (0.01mol) aniline is taken to be dissolved in 50mL ice vinegar In acid, the back flow reaction 3h (reaction conditions of replacement：Microwave heats, power 100W, 125 DEG C of temperature, reacts 30min).React Finish, be cooled to room temperature, reaction solution is added in 100mL distilled water, separates out a large amount of solids.Filter, wash, dry, DMF recrystallizations It is compound (yield 85%) shown in formula (5-1) to obtain clear crystal,
5) compound, 2.39g (0.10mol) shown in 3.90g (0.01mol) formula (5-1) are added in 150mL round-bottomed flasks 70% ethanol of lithium hydroxide and 50mL, 4h is reacted at 90 DEG C.Room temperature is cooled to, reaction solution is added in 100mL distilled water, With 10% watery hydrochloric acid regulation pH in neutrality, a large amount of solids, pillar layer separation (silica gel, solvent are separated out：VPetroleum ether:VEthyl acetate=2:1) It is compound (yield 73%) shown in formula (1-1) to obtain white solid,
1H NMR(400MHz,DMSO-d6)δ:11.22(s,1H,NH),10.81(s,1H,NH),8.71(s,1H, pyrimidyl H),7.44-7.15(m,10H,Ar-H),6.75(s,1H,thienyl H)；13C NMR(100MHz,DMSO- d6)δ:160.92,154.21,149.76,147.88,140.76,137.48,130.18,129.25,126.29,124.87, 124.56,119.70,102.95,93.77。
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 2 (1-2)
Preparation method is substantially identical with the method described in embodiment 1, unlike, replace benzene with 3- fluoroanilines in step 4) Amine, so as to which thieno [3,2-d] pyrimidines (yield of final step is 71%) shown in formula (1-2) be made,
1H NMR(400MHz,DMSO-d6)δ:11.26(s,1H,NH),10.88(s,1H,NH),8.77(s,1H, pyrimidyl H),7.46-7.18(m,9H,Ar-H),6.75(s,1H,thienyl H)；13C NMR(100MHz,DMSO-d6) δ:163.52,161.17,153.79,150.17,148.05,140.71,139.77,130.81,130.24,124.71, 119.84,119.62,112.29,110.91,103.79,93.77。
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 3 (1-3)
Preparation method is substantially identical with the method described in embodiment 1, unlike, replace benzene with 3- chloroanilines in step 4) Amine, so as to which thieno [3,2-d] pyrimidines (yield of final step is 75%) shown in formula (1-3) be made,
1H NMR(400MHz,DMSO-d6)δ:9.92(s,1H,NH),9.42(s,1H,NH),8.49(s,1H, pyrimidyl H),8.02-7.03(m,9H,Ar-H),6.64(s,1H,thienyl H)；13C NMR(100MHz,DMSO-d6) δ:162.35,155.31,154.48,153.35,142.10,141.90,133.22,130.53,130.04,122.72, 122.48,120.65,119.63,118.28,105.91,101.03。
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 4 (1-4)
Preparation method is substantially identical with the method described in embodiment 1, unlike, the chloro- 4- fluoroanilines of 3- are used in step 4) Instead of aniline, so as to thieno [3,2-d] pyrimidines for being made shown in formula (1-4), (yield of final step is 72%),
1H NMR(400MHz,DMSO-d6)δ:9.92(s,1H,NH),9.41(s,1H,NH),8.47(s,1H, pyrimidyl H),8.12-7.03(m,8H,Ar-H),6.64(s,1H,thienyl H)；13C NMR(100MHz,DMSO-d6) δ:162.27,155.27,154.43,153.34,152.04,142.11,137.57,130.01,122.83,122.69, 121.75,1119.30,118.25,117.10,105.62,101.04。
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 5 (1-5)
Preparation method is substantially identical with the method described in embodiment 1, unlike, replace benzene with 3- bromanilines in step 4) Amine, so as to which thieno [3,2-d] pyrimidines (yield of final step is 74%) shown in formula (1-5) be made,
1H NMR(400MHz,DMSO-d6)δ:9.92(s,1H,NH),9.40(s,1H,NH),8.49(s,1H, pyrimidyl H),8.14-7.03(m,9H,Ar-H),6.64(s,1H,thienyl H)；13C NMR(100MHz,DMSO-d6) δ:162.35,155.31,154.49,153.33,142.10,142.04,130.84,130.04,125.38,123.47, 122.72,121.74,120.03,118.27,105.90,101.02。
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 6 (1-6)
Preparation method is substantially identical with the method described in embodiment 1, unlike, 3- aminoanisole generations are used in step 4) For aniline, so that thieno [3,2-d] pyrimidines (yield of final step is 72%) shown in formula (1-6) are made,
1H NMR(400MHz,DMSO-d6)δ:11.21(s,1H,NH),10.78(s,1H,NH),8.73(s,1H, pyrimidyl H),7.45-6.85(m,9H,Ar-H),6.74(s,1H,thienyl H),3.78(s,3H,OCH3)；13C NMR (100MHz,DMSO-d6)δ:161.06,159.90,154.22,149.70,147.79,140.73,138.59,130.22, 130.07,124.65,119.78,116.96,111.75,110.66,102.99,93.63,55.71。
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 7 (1-7)
Preparation method is substantially identical with the method described in embodiment 1, unlike, with 3,4- methylene-dioxies in step 4) Aniline replaces aniline, and so as to thieno [3,2-d] pyrimidines for being made shown in formula (1-7), (yield of final step is 68%),
1H NMR(400MHz,DMSO-d6)δ:9.93(s,1H,NH),9.20(s,1H,NH),8.37(s,1H, pyrimidyl H),7.36-6.91(m,8H,Ar-H),6.61(s,1H,thienyl H),6.03(s,2H,OCH2O)；13C NMR(100MHz,DMSO-d6)δ:161.87,154.89,154.52,154.22,147.37,143.89,142.26,133.81, 129.97,122.43,118.01,116.27,108.24,105.46,104.86,101.51,100.88。
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 8 (1-8)
Preparation method is substantially identical with the method described in embodiment 1, unlike, 3- 5-trifluoromethylanilines are used in step 4) Instead of aniline, so as to thieno [3,2-d] pyrimidines for being made shown in formula (1-8), (yield of final step is 69%),
1H NMR(400MHz,DMSO-d6)δ:9.94(s,1H,NH),9.56(s,1H,NH),8.50(s,1H, pyrimidyl H),8.23-7.04(m,9H,Ar-H),6.65(s,1H,thienyl H)；13C NMR(100MHz,DMSO-d6) δ:162.40,155.41,154.46,153.33,142.09,141.25,130.06,130.04,129.83(q,2JF-C= 31Hz,C-CF3),126.10(q,1JF-C=270Hz,CF3),124.63,122.75,118.97,118.31,117.17, 105.97,101.02。
The preparation of thieno [3,2-d] pyrimidines shown in the formula of embodiment 9 (1-9)
Preparation method is substantially identical with the method described in embodiment 1, unlike, 3- acetylenylaniline generations are used in step 4) For aniline, so that thieno [3,2-d] pyrimidines (yield of final step is 70%) shown in formula (1-9) are made,
1H NMR(400MHz,DMSO-d6)δ:9.90(s,1H,NH),9.35(s,1H,NH),8.47(s,1H, pyrimidyl H),7.97-7.02(m,9H,Ar-H),6.63(s,1H,thienyl H),4.20(s,1H,≡CH)；13C NMR (100MHz,DMSO-d6)δ:162.27,155.18,154.53,153.51,142.13,140.49,130.03,129.37, 126.27,124.34,122.67,122.19,118.22,105.75,101.06,84.12,80.94。
Embodiment 10：Vitro kinase inhibitory activity is screened
Experimental method：
(1) experiment purpose
Experiment is using chemoluminescence method (Chemical Luminescence Assay) test the compounds of this invention sample pair The inhibiting rate of two kinds of kinases of EGFR and ErbB2, institute's test compound use serial dilutions concentration determination IC50Value, experiment are adopted Positive control drug is used as by the use of Erlotinib and BIBW2992.
(2) experiment material
Experiment reagent is to purchase on the market, is shown in Table 1.
The experiment reagent of table 1
(3) laboratory apparatus and consumptive material
96 hole elisa Plates：Corning companies, platybasic type；ELIASA：BioTek companies, Synergy 2microplate Reader types；Oscillator：Jiangsu Xin Kang Medical Devices Co., Ltd.s, XK96-3 types；Low speed centrifuge：Town in Shanghai booth scientific instrument Factory, TGL-16B types；Insulating box：Tianjin tonneau Xinda instrument plant, FCD-3000 types.
(4) experimental procedure
1. sample is dissolved as to 10mM mother liquor with DMSO.During EGFR kinase assays, sample is diluted to 1mM with DMSO, Then 10 μM are diluted to the 10% DMSO aqueous solution, 5 times of gradient dilutions are then carried out to sample with the 10% DMSO aqueous solution, Totally 10 concentration；When HER2 detects, sample is diluted to 1mM with DMSO, is then diluted to the 10% DMSO aqueous solution 100 μM, 5 times of gradient dilutions are then carried out to sample with the 10% DMSO aqueous solution, totally 10 concentration；
2. prepare 1 × kinase assay buffer (kinase assay buffer：40mM Tris, pH 7.4,10mM MgCl2, 0.1mg/mL BSA, 1mM DTT)；
3. 5 μ L Poly (Glu, Tyr) (final concentration of 0.2mg/mL) is added in 96 hole elisa Plates into every hole, afterwards 5 μ L ATP solution (final concentration of 10 μM) is added per hole；
4. 30 μ L kinase assay buffer (kinase assay buffer) is then added per hole into hole, then 5 μ L Sample solution to be screened is added in every hole, and mixing 3min is carried out on microplate oscillator；
5. and then every hole adds 5 μ L kinases, then mix 3min；
6. react 30min in 30 DEG C of lucifuges；
7. the last kinases-Glo measure buffer solutions (Kinase-Glo assay buffer) that 50 μ L are added per hole, reaction 5min；
Detected 8. 96 hole elisa Plates are put into chemiluminescence detection ELIASA, numerical value substitutes into below equation：
% activity={ (Lut-Lu)/(Lut-Luc) } × 100%
Wherein, Lu：For the values of chemiluminescence in each concentration samples hole；
Lut：For the values of chemiluminescence of this bottom outlet without kinases；
Luc：For the values of chemiluminescence in the solvent control hole without sample；
9. calculate IC with Prism GraphPad softwares50Value.
Suppression IC of the compound to two kinds of kinases of EGFR and ErbB250It is shown in Table 2.Test result indicates that compound of the invention There is the activity of obvious inhibitory activity, especially compound (1-9) to EGFR and HER2 slightly better than the EGFR of commercialization Inhibitor Erlotinib, it is suitable with the double target spot antineoplastic BIBW2992 of the EGFR/ErbB2 of commercialization, therefore can be used for controlling Treat the tumour containing above-mentioned target spot.
Table 2
More than, embodiments of the present invention are illustrated.But the present invention is not limited to above-mentioned embodiment.It is all Within the thought and principle of the present invention, any modification, equivalent substitution and improvements done etc., the guarantor of the present invention should be included in Within the scope of shield.

Claims (18)

1. compound or its pharmaceutically acceptable salt shown in formula (1)：
Wherein, R1Selected from C1-6Alkyl, aryl, C1-6Alkylaryl；R2It is identical or different, optionally from H, halogen, C1-6Alkyl, C1-6 Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, nitro, amino, or two adjacent R2With The carbon connected forms 3-8 yuan of rings together, and n is 0 to 5 integer；The aryl refers to monocyclic or more with 6-20 carbon atom Cyclic aromatic groups.
2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein, R1Selected from C1-3Alkyl, aryl, C1-3Alkylaryl；R2Selected from H, halogen, C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy, C2-3Alkenyl, C2-3Alkynyl, two adjacent R2With forming 3-6 yuan of rings together with the carbon connected；N is 1,2,3；The aryl refers to 6-20 The monocyclic or polycyclic aromatic group of carbon atom.
3. compound according to claim 1 or its pharmaceutically acceptable salt, wherein, R1For phenyl；R2For H, F, Cl, Br, methoxyl group, trifluoromethyl, acetenyl, or two adjacent R2With forming dioxolane together with the carbon connected.
4. compound according to claim 1 or its pharmaceutically acceptable salt, wherein, formula (1) the compound choosing From following compound：
5. compound or its pharmaceutically acceptable salt according to claim any one of 1-4, wherein, it is described pharmaceutically The salt of receiving is the salt formed with inorganic acid or the salt formed with organic acid.
6. compound according to claim 5 or its pharmaceutically acceptable salt, the inorganic acid is hydrochloride, phosphoric acid Salt, diphosphate, hydrobromate, sulfate, sulfinate, nitrate；The organic acid is lactate, oxalates, malic acid Salt, maleate, fumarate, tartrate, succinate, citrate, salicylate, acetate.
7. the preparation method of formula (1) compound or its pharmaceutically acceptable salt described in claim any one of 1-6, bag Include：
Wherein, R1、R2, n such as any one of claim 1-6 defined, R3For C1-6Alkoxy；
1) formula (4) compound and formula (6) compound are reacted, obtains formula (5) compound；
2) formula obtained in step 1) (5) compound is reacted in the basic conditions, obtains formula (1) compound；
3) compound that optionally, step 2) is obtained further forms pharmaceutically acceptable with pharmaceutically acceptable acid Salt.
8. preparation method according to claim 7, wherein, for step 1), the reaction is carried out in acid condition；Institute Reaction temperature is stated as 50-150 DEG C.
9. preparation method according to claim 7, wherein for step 2), the alkali is inorganic base, the reaction is in alcohol Carried out in class solvent；The reaction temperature is 50-150 DEG C.
10. a kind of pharmaceutical composition, it includes formula (1) compound described in claim any one of 1-6 or it pharmaceutically may be used The salt of receiving.
11. pharmaceutical composition according to claim 10, wherein, described pharmaceutical composition also includes at least one pharmaceutically Acceptable, inert, nontoxic excipient or carrier or diluent.
12. the pharmaceutical composition according to claim 10 or 11, wherein described pharmaceutical composition are also comprising one or more Selected from the pharmaceutically acceptable of filler, disintegrant, lubricant, glidant, effervescent agent, flavouring, preservative and coating material Auxiliary material.
13. the pharmaceutical composition according to claim 10 or 11, wherein, described pharmaceutical composition is dosage form.
14. pharmaceutical composition according to claim 13, wherein, described pharmaceutical composition is solid orally ingestible, liquid Oral formulations or injection.
15. pharmaceutical composition according to claim 13, wherein, described preparation is tablet, capsule, granule, oral Solution, injection liquid drugs injection, injection freeze-dried powder, big transfusion or primary infusion.
16. pharmaceutical composition according to claim 15, wherein, described preparation be dispersible tablet, enteric coatel tablets, chewable tablets, Oral disintegrating tablet.
17. formula (1) compound or its pharmaceutically acceptable salt described in claim any one of 1-6 are being prepared for suppressing Application in EGFR and/or ErbB2 protein tyrosine kinase medicines.
18. formula (1) compound or its pharmaceutically acceptable salt described in claim any one of 1-6 are being prepared for anti-swollen Application in knurl or cancer drug.
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