CN102558159A - 4-subsittution m sulfonylurea amide aniline-quinazoline derivate and preparation method and application thereof - Google Patents
4-subsittution m sulfonylurea amide aniline-quinazoline derivate and preparation method and application thereof Download PDFInfo
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- CN102558159A CN102558159A CN2010105955701A CN201010595570A CN102558159A CN 102558159 A CN102558159 A CN 102558159A CN 2010105955701 A CN2010105955701 A CN 2010105955701A CN 201010595570 A CN201010595570 A CN 201010595570A CN 102558159 A CN102558159 A CN 102558159A
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- 0 CS(Nc(cc(cc1)Nc(c2c3)ncnc2ccc3-c2ccc(C*)[o]2)c1OCc1cccc(*)c1)(=O)=O Chemical compound CS(Nc(cc(cc1)Nc(c2c3)ncnc2ccc3-c2ccc(C*)[o]2)c1OCc1cccc(*)c1)(=O)=O 0.000 description 1
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a quinazoline derivate with a general formula (I) as well as the preparation method and the application thereof, wherein both R1 and R2 have meanings defined in an instruction. The invention also relates to the preparation method of the derivative. The derivative and inorganic and organic acid or alkali form salt which is acceptable physiologically, and drug combinations containing the derivative. The compound has valuable pharmacological properties and especially plays a role in restraining signal transduction aroused by tyrosine kinase; and particularly, a mutant EGFR (Epidermal Growth Factor Receptor) (L858R/T790M) and HER 2 have higher inhibitory activity. The invention also relates to a method for treating diseases, in particular to diseases characterized in abnormal erbB PTK (protein tyrosine kinase) activity. The general formula (I) is as follows.
Description
Technical field
The present invention relates to Toluidrin anilino-quinazoline derivatives or its pharmacy acceptable salt between the 4-replacement, these compounds have anti-tumor activity.The invention still further relates to method, the pharmaceutical composition that contains these verivates and their application in antitumor drug of Toluidrin anilino-quinazoline derivatives between the said 4-replacement of preparation.
Background technology
Tyrosine SU11752 (Tyrosine Kinase Inhibitor), mainly act on the epithelial cell growth factor receptor 2 body (Epidermal Growth Factor Receptor, EGFR).EGFR has significant effects and control dependence to the growth of cancer cells.If the acceptor over-expresses or the overactivity of cancer cells, cancer cells will raised growths, thereby increase the probability of curing degree of difficulty and sending out again jointly.The EGFR acceptor can be divided into four kinds of human epithelial growth factor acceptors (Human Epidermal Receptor).First type is commonly referred to EGFR, and second type then is called HER2, and other have the 3rd and the 4th type in addition.
Known human epidermal growth factor acceptor-2 (ErbB-2, HER-2) is present understanding human carcinomas gene comparatively clearly in close relations with mammary cancer, and its high expression level in mammary cancer is often indicating and is prone to have nodus lymphoideus transferring rate and tumour poor differentiation.Go deep into along with what HER-2 was studied, it has become one of target molecule of mammary cancer specific treatment.
The biological action of the PTK of ErbB family and tie up to for example USP 5773476 with the pass of various diseases; International Patent Application WO 99/35146; M.C.Hung etc., Seminarsin oncology, 26:4, Suppl.12,1999,51-59; Ullrich etc., Cell, 61:203-212,20,1990; Modjtahedi etc., Int ' l.J.of Oncology, 13:335-342,1998; And J.R.Wooburn, Pharmacol.Ther., 82:2-3,241-250, the existing discussion in 1999.
Many synthetic compounds have the activity of inhibition epidermal growth factor recipient tyrosine kinase (EGFR-PTK); Especially the most deep with quinazoline compounds research; Wherein lapatinibditosylate was got permission listing treatment mammary cancer in 2007 in the U.S., and obtained the approval with good conditionsi of European medicine administrative organ in December.Lapatinibditosylate (Lapatinib) is the two target spot target therapeutic agents to EGFR and HER2.
Through to before lapatinibditosylate clinical and the analysis and the contrast of clinical data, patent situation etc.; Establishment is a lead compound with it; Then according to reporting compound and biological activity test data; Utilize the means of CAD, autotelic structure to lapatinibditosylate designs, synthetic and screening, finds novel structure, high special, active better novel targeted antineoplastic compound with it.
Summary of the invention
The purpose of this invention is to provide one type of quinazoline derivant, and this compounds in antitumor drug as the purposes of activeconstituents.
The present invention be quinazoline derivant shown in general formula (I):
General formula (I)
Wherein:
R
1Expression:
R wherein
4Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, methylol, hydroxyethyl.R
1Preferably from morpholinyl, 4-methylol-piperidyl, N-methyl-piperazinyl and
R
2Expression: hydrogen, C
1-4Alkane, C
1-4Alcoxyl hydrocarbon, halogen, R
2Preferably from hydrogen and fluorine.
Below be the preparation method of The compounds of this invention, wherein initial compounds (II) and compound (VI) can be purchased.
Compound (II) obtains compound (III) with benzyl halogen prepared in reaction, and compound (III) obtains compound (VIII) through reactions such as sulfonylation, reduction, amination, couplings, and compound (VIII) obtains formula (I) target compound with different amine reactions again.
R wherein
1And R
2As above define.
The pharmacy acceptable salt of formula according to the invention (I) compound can contain carboxyl or amido according to different verivates, and carboxyl can react with alkaline matter (like oxyhydroxide, carbonate and the supercarbonate of basic metal or earth alkali metal); They include, but are not limited to: sodium hydroxide, Pottasium Hydroxide; Calcium hydroxide; Yellow soda ash etc. form pharmacy acceptable salt, like corresponding sodium salts, and sylvite or calcium salt or the like.Also can adopt nontoxic organic bases such as methylamine, triethylamine, meglumine etc. to generate salt; Amido can react with acidic substance (example hydrochloric acid, Hydrogen bromide, sulfuric acid etc.), and they include, but are not limited to: hydrochloric acid, and Hydrogen bromide, sulfuric acid, phosphoric acid etc. form pharmacy acceptable salt, also can adopt organic acid such as acetate, oxalic acid, Hydrocerol A etc. to generate salt.The compound of formula (I) and the form of salt thereof have anti-tumor activity,
Formula according to the invention (I) compound or its pharmacy acceptable salt can be processed pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be processed formulations such as solid orally ingestible, liquid oral medicine, injection.
Said solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, oral cavity disintegration tablet, capsule, syrup, granule, oral solution.Can adopt lactose or starch carrier as said solid orally ingestible; Use gelatin, methylcellulose gum, hypromellose, Vinylpyrrolidone polymer, starch slurry etc. are as tackiness agent; Use starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, PVPP, Microcrystalline Cellulose as disintegrating agent; Use talcum powder, little part of silica gel, stearin, calcium stearate or magnesium etc. are as antiadhesives and lubricant.The preparation method of said solid orally ingestible may further comprise the steps: with activeconstituents and carrier and optionally with a disintegration additive composition mixture; Make the aqs soln of this mixture and tackiness agent then; Alcohol property or aqueous alcohol property solution carry out wet method or dry granulation in suitable device; Dried particles, the disintegrating agent, lubricant and the antisticking agent that add other are subsequently processed appropriate formulations.
Said injection comprises: little pin, freeze-dried powder and infusion solutions etc.The preparation method of said injection may further comprise the steps: get water for injection, the auxiliary material that takes by weighing recipe quantity stirs and makes dissolving, adds the sample stirring and dissolving; Adjust pH is to proper range; After adding the charcoal absorption certain hour of 0.1%-0.5%, decarburization, filtration, packing or freeze-drying again.
The present invention shows through external HTRF homogeneous fluorescent test: the quinazoline derivant with general formula I structure has very strong enzyme inhibition to EGFR (L858R/T790M) and HER2.
Embodiment
Following embodiment can make those skilled in the art more comprehensively understand the present invention, but does not limit the present invention in any way.
The preparation of embodiment 1 2-benzyloxy-5-N-methyl-p-nitroaniline
With 2-amino-4-nitrophenols 4g (25.97mmol), bromobenzyl 4.9g (28.65mmol), salt of wormwood 7.18g (52.02mmol) places the 100ml round-bottomed flask; Add 30ml acetone; 60 ℃ of back flow reaction 1.5h, re-crystallizing in ethyl acetate obtains yellow solid 2-benzyloxy-5-N-methyl-p-nitroaniline (3.8g g; 58.8%), m.p.98-99 ℃;
1H NMR (400MHz, DMSO): δ 5.23 (s, 2H, CH
2O), 6.412 (s, 2H, NH
2), 6.6756.697 (d, 1H, ArH), 7.324-7.675 (m, 7H, ArH), ESI-MS:m/z 245 [M+H]
+
The preparation of embodiment 2 1-(N-methylsulfonyl)-2-benzyloxy-5-N-methyl-p-nitroaniline
2-benzyloxy-5-N-methyl-p-nitroaniline 1g (4.10mmol) is placed the 100ml round-bottomed flask, add 16mlDMF, stir.System is placed ice bath, add 0.4g hydrogen sodium (16.67mmol) in batches.Stirring at room 30min under nitrogen protection.Measure Methanesulfonyl chloride 1.42g (12.40mmol), slowly add system.Stirred overnight at room temperature.In system, add 30ml water, deposition in a large number occurs.Filter, washing obtains the faint yellow solid powder.It is dissolved among the DMF, transfers pH=9-10 with the 3N aqueous sodium hydroxide solution.90 ℃ are reacted 6h down, naturally cool to room temperature.Transfer pH=1-2 with 5N hydrochloric acid, a large amount of depositions appear in system, filter, and washing obtains pale yellow powder solid 1-(N-methylsulfonyl)-2-benzyloxy-5-N-methyl-p-nitroaniline (0.9g, 65.9%), m.p.112-113 ℃;
1H NMR (400MHz DMSO): δ 3.111 (s, 3H, CH
3), 5.333 (s, 2H, CH
2O), 7.325-7.899 (m, 8H, ArH), 9.566 (s, 1H, NH), ESI-MS:m/z 323 [M+H]
+
The preparation of embodiment 3 N-(5-amino-2-(benzyloxy) phenyl) Toluidrin
With 1-(N-methylsulfonyl)-2-benzyloxy-5-N-methyl-p-nitroaniline 0.2g (0.62mmol), FeCl
36H
2O 0.67g (2.48mmol) places the 50ml round-bottomed flask, adds 7ml DMF and H again
2O (6: 1), stirring at room 30min.Take by weighing 0.4g Zn powder (6.13mmol), slowly add system, stirring at room 3h, stopped reaction.With reacting liquid filtering, get filtrating, with 1-2 times of water gaging dilution, use ethyl acetate extraction again, add HCl/ ETHYLE ACETATE, deposition in a large number appears, filters.It is soluble in water, and transferring pH is alkalescence, uses ethyl acetate extraction, and evaporated under reduced pressure obtains N-(5-amino-2-(benzyloxy) phenyl) Toluidrin (0.16g, 92.3%), m.p.103-104 ℃;
1H NMR (400MHz DMSO): δ 2.734 (s, 3H, CH
3), 5.024 (s, 2H, NH
2), 5.154 (s, 2H, CH
2O), 6.094-7.524 (m, 8H, ArH), 8.46 (s, 1H, NH), ESI-MS:m/z 293 [M+H]
+
The preparation of embodiment 4 N-(2-(benzyloxy)-5-((6-iodine quinazoline-4-yl) amino) phenyl) Toluidrin
With N-(5-amino-2-(benzyloxy) phenyl) Toluidrin 0.2g (0.68mmol), 4-chloro-6-iodine quinazoline 0.2g (0.69mmol) places the 50ml round-bottomed flask, adds 8ml i-PrOH, heats 80 ℃ of reaction 5h.With reacting liquid filtering, filter cake is got in washing, gets yellow-green colour N-(2-(benzyloxy)-5-((6-iodine quinazoline-4-yl) amino) phenyl) Toluidrin (0.1g, 22.6%), m.p.153-154 ℃;
1H NMR (400MHz DMSO): δ 2.894 (s, 3H, CH
3), 5.185 (s, 2H, CH
2O), 7.245-8.127 (m, 10H, ArH), 8.608 (s, 1H, NH), 8.953-8.984 (m, 2H, ArH), 9.848 (s, 1H, NH), ESI-MS:m/z 547 [M+H]
+，
The preparation of embodiment 5 N-(2-(benzyloxy)-5-((6-(5-formyl furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin
N-(2-(benzyloxy)-5-((6-iodine quinazoline-4-yl) amino) phenyl) Toluidrin 0.67g (1.23mmol) is placed the 100ml round-bottomed flask; Add DME 12ml, 2-formylfuran-5-boric acid 0.35g (2.48mmol), Pd-C 0.33g, triethylamine 0.67ml; MeOH 6.7ml, mixing.Heated and stirred, 60 ℃ of reaction 3h.Be cooled to room temperature, filter evaporate to dryness; Acetone solution adds the water of qdx again, deposition in a large number occurs; Cross and filter N-(2-(benzyloxy)-5-((6-(5-formyl furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin (0.5g, 44.8%), m.p.167-168 ℃;
1H NMR (400MHz DMSO): δ 2.907 (s, 3H, CH
3), 5.202 (s, 2H, CH
2O), 7.274-9.004 (m, 14H, ArH), 8.592 (s, 1H, NH), 9.670 (s, 1H, CHO), 10.143 (s, 1H, NH), ESI-MS:m/z 515 [M+H]
+
The preparation of embodiment 6 N-(2-(benzyloxy)-5-((6-(5-(((2-(methylsulfonyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin (I-1)
N-(2-(benzyloxy)-5-((6-(5-formyl furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin 0.2g (0.39mmol) and 2-(methylsulfonyl)-ethylamine hydrochloride (1.25mmol) 0.2g are placed the 50ml round-bottomed flask.Add the 2ml Virahol, mixing adds 10ml THF, 0.25g DIEA and 2ml Virahol again, 35 ℃ of stirring reaction 2h.In system, add 0.41gNa (OAC) 3BH; Stirring at normal temperature 1h; Solvent evaporated; Column chromatography obtains N-(2-(benzyloxy)-5-((6-(5-(((2-(methylsulfonyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin (I-1) (0.2g, 87.2%), m.p.185-187 ℃;
1H NMR (400MHz DMSO): δ 2.067 (s, 1H, NH), 2.913 (s, 3H, CH
3), 3.043 (s, 3H, CH
3), 3.060-3.168 (m, 2H, CH
2), 3.408-3.443 (t, 2H, CH
2), 3.983-4.036 (m, 2H, CH
2), 5.207 (s, 2H, CH
2O), 6.582-8.961 (m, 14H, ArH), 8.569 (s, 1H, NH), 10.028 (s, 1H, NH), ESI-MS:m/z 622 [M+H]
+
The preparation of embodiment 7 N-(2-((3-luorobenzyl) oxygen base)-5-((6-(5-(morpholine methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin (I-2)
With reference to the operation of the foregoing description, obtain the compound of formula I-2, m.p.171-173 ℃;
1H NMR (400MHz DMSO): δ 2.913 (s, 3H, CH
3), 3.408-3.443 (m, 8H, 4 * CH
2), 3.983-4.036 (m, 2H, CH
2), 5.207 (s, 2H, CH
2O), 6.582-8.961 (m, 13H, ArH), 8.569 (s, 1H, NH), 10.028 (s, 1H, NH), ESI-MS:m/z 604 [M+H]
+
The preparation of embodiment 8 N-(2-((3-luorobenzyl) oxygen base)-5-((6-(5-(((2-(methylsulfonyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin (I-3)
With reference to the operation of the foregoing description, obtain the compound of formula I-3, m.p.165-166 ℃;
1H NMR (400MHz DMSO): δ 2.067 (s, 1H, NH), δ 2.913 (s, 3H, CH
3), 3.043 (s, 3H, CH
3), 3.060-3.168 (m, 2H, CH
2), 3.408-3.443 (t, 2H, CH
2), 3.983-4.036 (m, 2H, CH
2), 5.207 (s, 2H, CH
2O), 6.582-8.961 (m, 13H, ArH), 8.569 (s, 1H, NH), 10.028 (s, 1H, NH), ESI-MS:m/z 640 [M+H]
+
The preparation of embodiment 9 N-(2-(benzyloxy)-5-((6-(5-(morpholine methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin (I-4)
With reference to the operation of the foregoing description, obtain the compound of formula I-4, m.p.168-171 ℃;
1H NMR (400MHz DMSO): δ 2.913 (s, 3H, CH
3), 3.408-3.443 (m, 8H, 4 * CH
2), 3.983-4.036 (m, 2H, CH
2), 5.207 (s, 2H, CH
2O), 6.582-8.961 (m, 14H, ArH), 8.569 (s, 1H, NH), 10.028 (s, 1H, NH), ESI-MS:m/z 586 [M+H]
+
Embodiment 10
Method for preparing tablet thereof is following:
Prescription consumption/sheet
I-1 100mg
Microcrystalline Cellulose 50mg
Starch 40mg
Polyvidone 8mg
Sodium starch glycolate 10mg
Magnesium Stearate qs
Technology: the activeconstituents auxiliary material is crossed 100 mesh sieves respectively, take by weighing the main ingredient and auxiliary material (half sodium starch glycolate) thorough mixing of recipe quantity, add the Vinylpyrrolidone polymer aqueous solution and make softwood in right amount; Cross 24 mesh sieves; Make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, will remain sodium starch glycolate and Magnesium Stearate and particle and mix, whole; Measure midbody content, with the shallow stamping of Φ 8mm.
Embodiment 11
The preparation of injection liquid
I-3 200mg
SODIUM PHOSPHATE, MONOBASIC 10mg
Hydrocerol A 30mg
Water for injection 50ml
Technology: get water for injection 50ml, the Hydrocerol A, the SODIUM PHOSPHATE, MONOBASIC that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, use the hydrochloric acid of 0.1mol/L or sodium hydroxide adjust pH to be 4.0-5.0, the charcoal absorption of adding 0.1% 20 minutes.Filter with 0.45 μ m filter membrane earlier, again with the smart filter of 0.22 μ m.Press 5 milliliters of cans of per ampoule, 105 ℃ of high-temperature sterilizations promptly got injection liquid in 30 minutes.
The extracorporeal anti-tumor enzymic activity test of compound I
(1) material and instrument:
1 experiment material: the test kit HTRF KinEASE-TK kit of Cisbio company (article No.: 62TKOPEB); Distilled water
2 detecting instruments: SpectraMax M5:Mplecular Devices product
(2) testing sequence:
1. the preparation of solution and reaction density
2. experimental procedure:
1) calculates all ingredients institute expense.
2) prepare the working fluid of ATP, TK Substrate-biotin.
3) ratio ATP by volume: TK Substrate-biotin: Kinase buffer=2: after getting the liquid mixing at 2: 1, get mixed solution to the BP pipe by 5 μ L/ holes.
4) add medicine, 2 μ L/ holes.No medicine hole is with 2 μ L kinase buffer polishings.Mixing.
5) prepare the working fluid of enzyme.
6) add enzyme, 3 μ L/ holes.No enzyme hole is with 3 μ L kinase buffer polishings.Mixing.
7) reaction solution is transferred in 384 orifice plates.
8) put 37 ℃ of incubation 30min.
9) working fluid of preparation Streptavidin-XL665 calculates consumption, by volume ratio Streptavidin-XL665: TK Antibody-Cryptate=1: 1 mixing.Incubation is got mixed solution by 10 μ L/ holes and is added in the reaction system after finishing, and mixing is with termination reaction.
10) room temperature is placed the 30min detection, excites in the single wavelength of ELIASA 314nm, measures 620nm and 665nm emission light, and test-results is seen table 1.
Inhibiting rate (%)=[1-(experimental group
665nm/620nm-blank control group
665nm/620nm)/(control group
665nm / 620nm-blank control group
665nm/620nm)] * 100%.
3. result
The inhibiting rate (%) of table 1. couple EGFR (L858R/T790M) and HER2
Claims (8)
1. general formula (I) quinazoline derivant or its pharmacy acceptable salt:
General formula (I)
Wherein:
R
1Expression:
R wherein
4Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, methylol, hydroxyethyl.
R
2Expression: hydrogen, C
1-4Alkane, C
1-4Alcoxyl hydrocarbon, halogen.
2. compound according to claim 1 is characterized in that R
1Preferably from morpholinyl, 4-methylol-piperidyl, N-methyl-piperazinyl and
3. compound according to claim 1 is characterized in that R
2Preferably from hydrogen and fluorine.
4. the defined compound of Formula I of claim 1 or its pharmacy acceptable salt, wherein said pharmacy acceptable salt is an alkali metal salt, alkaline earth salt or the organic amine salt of wherein carboxyl, perhaps is the organic acid salt or the inorganic acid salt of amido.
5. the defined compound of Formula I of claim 1 or its pharmacy acceptable salt, said compound or its pharmacy acceptable salt are selected from,
N-(2-(benzyloxy)-5-((6-(5-(((2-(methylsulfonyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin
N-(2-((3-luorobenzyl) oxygen base)-5-((6-(5-(((2-(methylsulfonyl) ethyl) amino) methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin
N-(2-(benzyloxy)-5-((6-(5-(morpholine methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin
N-(2-((3-luorobenzyl) oxygen base)-5-((6-(5-(morpholine methyl) furans-2-yl) quinazoline-4-yl) amino) phenyl) Toluidrin
6. being used to treat with the unusual ErbB PTK of family activity like the described arbitrary compound of claim 1-5 is the medicine of the disease of characteristic.
7. the purposes of claim 6, the wherein said ErbB PTK of family is selected from EGFR, ErbB1 (EGFR) and ErbB2 (HER2).
8. the purposes of claim 7, wherein said disease is a cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9321762B2 (en) | 2013-12-11 | 2016-04-26 | Development Center For Biotechnology | Quinazoline compounds, method for preparing the same and use thereof |
| CN106317037A (en) * | 2016-08-09 | 2017-01-11 | 浙江医药高等专科学校 | Ethoxy benzo quinazoline type tyrosine kinase inhibitor containing thiophenesulfonyl structure, preparation method and application |
| CN106432215A (en) * | 2016-08-09 | 2017-02-22 | 浙江医药高等专科学校 | Benzo-quinazoline tyrosine kinase inhibitor containing thiophene sulfamide structure and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1292788A (en) * | 1998-01-12 | 2001-04-25 | 葛兰素集团有限公司 | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
-
2010
- 2010-12-20 CN CN2010105955701A patent/CN102558159A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1292788A (en) * | 1998-01-12 | 2001-04-25 | 葛兰素集团有限公司 | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9321762B2 (en) | 2013-12-11 | 2016-04-26 | Development Center For Biotechnology | Quinazoline compounds, method for preparing the same and use thereof |
| CN106317037A (en) * | 2016-08-09 | 2017-01-11 | 浙江医药高等专科学校 | Ethoxy benzo quinazoline type tyrosine kinase inhibitor containing thiophenesulfonyl structure, preparation method and application |
| CN106432215A (en) * | 2016-08-09 | 2017-02-22 | 浙江医药高等专科学校 | Benzo-quinazoline tyrosine kinase inhibitor containing thiophene sulfamide structure and application |
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Application publication date: 20120711 |