CN103724260A - Benzamide derivative and preparation method and application thereof - Google Patents
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Abstract
The invention provides a benzamide derivative and a preparation method and application thereof. The benzamide derivative is N-(3,4-dimethoxy phenyl)-4-[(7-chlorine-4-quinoline) amino] benzamide; the N-(3,4-dimethoxy phenyl)-4-[(7-chlorine-4-quinoline) amino] benzamide can be used as a protein kinase inhibitor and a histone deacetylase inhibitor for treating diseases caused by dysregulation of protein kinase. The benzamide derivative can effectively treat the diseases caused by dysregulation of protein kinase, has the advantages of high bioavailability, obvious antitumor activity and low toxicity, is low in preparation reaction cost, has high yield, has a simple and easily-controlled reaction process and is suitable for industrial production.
Description
[technical field]
The present invention relates to a kind of benzamide derivatives and its preparation method and application.
[background technology]
Protein kinase is the phosphorylation in specific tyrosine, Serine and threonine residues in the class of enzymes of catalytic protein phosphorylation, particularly catalytic protein.Protein kinase all plays a key effect in the many cell physiological processes of adjusting, comprises metabolism, cell proliferation, cytodifferentiation, cell survival, immunne response and vasculogenesis.Numerous disease all regulates the abnormal cell response causing relevant with there being protein kinase.These diseases comprise inflammation, autoimmune disease, cancer, nervous system disorders and neurodegenerative disorders, cardiovascular disorder, metabolic disease, allergy, asthma and with hormone relative disease (Tan, S-L, 2006, J.Immunol, 176:2872-2879; A.ea al.2006, J.Immunol.177:1886-1893; Salek-Ardakani, S.etal.2005, J.Immunol.175:7635-7641; Kim, J.et al.2004, J.Clin.Invest., 114:823-827).Therefore, people are devoted to find the kinases inhibitor that can effectively treat these diseases always.
Protein kinase is divided into two classes conventionally, i.e. protein tyrosine kinase (PTKs) and serine-threonine (STKs).Wherein protein tyrosine kinase can be divided into again two classes, i.e. the raw tyrosine kinase receptor of non-cross-film Tyrosylprotein kinase and cross-film.At least determine at present 19 kinds of different subtribes of RTKs, as EGF-R ELISA (EGFR), vascular endothelial growth factor receptor (VEGFR), Thr6 PDGF BB (PDGFR) and fibroblast growth factor receptor (FGFR).
For many years, people are devoted to find always and have protein kinase inhibiting activity and can treat and the micromolecular compound of the abnormal relative disease of protein kinase activity.The compound that bibliographical information is crossed has the quinazoline compound (U.S. Pat 7098330) of ring compound (U.S. Pat 7151096), double-ring compound (U.S. Pat 7189721), three ring compounds (U.S. Pat 7132533), (2-oxyindole base-3-methylene radical) acetogenin (U.S. Pat 7179910), the replacement of pyrazolyl amido etc., wherein there are several kinases inhibitors by FDA, to be ratified for cancer therapy, as Glivec, Sutent and Sorafenib.Clinical effectiveness shows, compared with traditional chemotherapy, these medicines are with the obvious advantage.Excite thus people to improve methods for the treatment of based on mechanism, optimize compound molecule skeleton, find to have the new compound that bioavailability is high, antitumour activity is obvious and toxicity is low.
International monopoly WO2010139180A1 discloses structure and the synthetic method of the Naphthaline amide derivative serving of a kind of kinases inhibitor and NSC 630176; in this patent synthetic method: 1) the first step 6-hydroxynaphthoic acid and 4; the cesium carbonate that the one-tenth ether catalysts of 7-dichloroquinoline is used; expensive; and toxicity is larger, large to the pollution of environment; 2) severe reaction conditions, productive rate is lower.Therefore, the uncomfortable easily suitability for industrialized production of this preparation method.
[summary of the invention]
One of the technical problem to be solved in the present invention, is to provide a kind of benzamide derivatives, and it can effectively treat the part disease that protein kinase dysregulation causes, and has advantages of that bioavailability is high, antitumour activity is obvious and toxicity is low.
The present invention realizes one of above-mentioned technical problem like this:
A kind of benzamide derivatives, described benzamide derivatives is N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide, its molecular formula is C
24h
20clN
3o
3, its structural formula is as shown in the formula I:
Two of the technical problem to be solved in the present invention, is to provide a kind of preparation method of benzamide derivatives, has preparation feedback cost low, and productive rate is higher, and reaction process is simple and easy to control, is applicable to the advantage of suitability for industrialized production.
The present invention realizes two of above-mentioned technical problem like this:
A preparation method for benzamide derivatives, described preparation method is as follows:
Step 1, compound ii and III are dissolved in Virahol, stirring and refluxing, after 5 hours, is separated out faint yellow precipitation, and question response liquid is cooled to after room temperature, evaporated under reduced pressure, and washed with dichloromethane 2～3 times for residual solids, collects filter cake, the dry faint yellow solid powder IV that to obtain;
Reaction equation is as follows:
Wherein, compound ii is 4,7-dichloroquinoline, and compound III is para-amino benzoic acid, and compounds Ⅳ is 4-(7-chloroquinoline-4-amino) phenylformic acid;
Reaction equation is as follows:
Wherein, compound V is 4-(7-chloroquinoline-4-amino) Benzoyl chloride;
Step 3, the compound V of acquisition is dissolved in dry methylene dichloride, adds compound VI, stir, under ice bath, drip the dry methylene chloride solution that contains triethylamine, react 6-8 hour at 45 ℃, TLC detects, after reacting completely, suction filtration is removed most of salt, underpressure distillation, ethyl acetate for solid matter/distilled water extracting and washing 2～3 times, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography separates, and eluent is V
methylene dichloride: V
methyl alcohol=200:1, obtains target product I;
Reaction equation is as follows:
Wherein, compound VI is 3,4-dimethoxyaniline.
Further, described Virahol refers to analytically pure Virahol.
Further, described methylene dichloride refers to analytically pure dry anhydrous methylene chloride.
Further, described room temperature is 25 ℃.
Further, described sulfur oxychloride refers to analytically pure sulfur oxychloride.
Further, described Et
3n refers to analytically pure triethylamine.
Further, described ice bath refers to that temperature is down to 0 ℃.
Further, described ethyl acetate refers to analytically pure ethyl acetate.
Further, described Na
2sO
4refer to analytically pure anhydrous sodium sulphate.
Further, described methyl alcohol refers to analytically pure methyl alcohol.
Three of the technical problem to be solved in the present invention, is to provide a kind of application of benzamide derivatives, can effectively treat the part disease that protein kinase dysregulation causes, and has advantages of that bioavailability is high, antitumour activity is obvious and toxicity is low.
The present invention realizes three of above-mentioned technical problem like this:
A kind of application of benzamide derivatives; described benzamide derivatives is N-(3; 4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide; described N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide can be used as kinases inhibitor and NSC 630176.
Tool of the present invention has the following advantages:
Reaction cost related in the present invention is low, and productive rate is high, and reaction process is simple and easy to control, and safe non-environmental-pollution, is applicable to suitability for industrialized production.
In addition, N-(3 of the present invention, 4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) effectively Cardiovarscular, metabolic disease, allergy, cancer and the disease relevant to hormone of benzamide, have advantages of that bioavailability is high, antitumour activity is obvious and toxicity is low.The present invention is to N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) anti-tumor activity of benzamide carried out test of many times, measure with mtt assay, find that it has obvious anti-tumor activity, described tumour cell comprises human small cell lung carcinoma NCI-H446 cell, human lung cancer cell A549's cell, HeLa Cells and human liver cancer cell SMMC-7721 cell.
[accompanying drawing explanation]
The present invention is further illustrated in conjunction with the embodiments with reference to the accompanying drawings.
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of naphthoamide derivative of the present invention.
Fig. 2 is the carbon-13 nmr spectra figure of naphthoamide derivative of the present invention.
[embodiment]
Refer to shown in Fig. 1 and Fig. 2, embodiments of the invention are described in detail.
The present invention relates to a kind of benzamide derivatives, described benzamide derivatives is N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide, its molecular formula is C
24h
20clN
3o
3, its structural formula is as shown in the formula I:
The invention still further relates to a kind of preparation method of benzamide derivatives, described preparation method is as follows:
Step 1, compound ii and III are dissolved in Virahol, stirring and refluxing, after 5 hours, is separated out faint yellow precipitation, and question response liquid is cooled to after room temperature, evaporated under reduced pressure, and washed with dichloromethane 2～3 times for residual solids, collects filter cake, the dry faint yellow solid powder IV that to obtain;
Reaction equation is as follows:
Wherein, compound ii is 4,7-dichloroquinoline, and compound III is para-amino benzoic acid, and compounds Ⅳ is 4-(7-chloroquinoline-4-amino) phenylformic acid;
Reaction equation is as follows:
Wherein, compound V is 4-(7-chloroquinoline-4-amino) Benzoyl chloride;
Step 3, the compound V of acquisition is dissolved in dry methylene dichloride, adds compound VI, stir, under ice bath, drip the dry methylene chloride solution that contains triethylamine, react 6-8 hour at 45 ℃, TLC detects, after reacting completely, suction filtration is removed most of salt, underpressure distillation, ethyl acetate for solid matter/distilled water extracting and washing 2～3 times, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography separates, and eluent is V
methylene dichloride: V
methyl alcohol=200:1, obtains target product I;
Reaction equation is as follows:
Wherein, compound VI is 3,4-dimethoxyaniline.
Preferably, described Virahol refers to analytically pure Virahol; Described methylene dichloride refers to analytically pure dry anhydrous methylene chloride; Described room temperature is 25 ℃; Described sulfur oxychloride refers to analytically pure sulfur oxychloride; Described Et
3n refers to analytically pure triethylamine; Described ice bath refers to that temperature is down to 0 ℃; Described ethyl acetate refers to analytically pure ethyl acetate; Described Na
2sO
4refer to analytically pure anhydrous sodium sulphate; Described methyl alcohol refers to analytically pure methyl alcohol.
The invention still further relates to the application of above-mentioned a kind of benzamide derivatives; described benzamide derivatives is N-(3; 4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide; described N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide can be used as kinases inhibitor and NSC 630176.
Below in conjunction with specific embodiment, the present invention is further illustrated.
Embodiment 1:
In the dry round-bottomed flask of 100mL, add 4,7-dichloroquinoline (0.985g, 5mmol), para-amino benzoic acid (0.685g, 5mmol) and Virahol 20mL, stir it is fully dissolved.Slowly be warming up to 85 ℃, after stirring and refluxing 5h, reaction solution is separated out faint yellow precipitation, and TLC detection reaction balance finishes reaction.Question response liquid is cooled to after room temperature, evaporated under reduced pressure, residual solids 10mL washed with dichloromethane 3 times, collect filter cake, dry faint yellow solid powder 4-(7-chloroquinoline-4-amino that to obtain) and phenylformic acid 1.40g, yield 95%.
In the dry round-bottomed flask of 100mL, add and contain 4-(7-chloroquinoline-4-amino) phenylformic acid (1.491g, dry methylene chloride solution 10mL 5mmol), stir, in 0 ℃ of ice bath downhill reaction system, slowly drip chloride containing sulfoxide (2.974g, 25mmol), dropwise rear backflow 4 hours, sulfur oxychloride is removed in underpressure distillation, obtain compound 4-(7-chloroquinoline-4-amino) Benzoyl chloride 1.431g, yield 91%.
In the dry round-bottomed flask of 100mL, add and contain compound 4-(7-chloroquinoline-4-amino) Benzoyl chloride (1.581g, 5mmol) and compound 3, 4-dimethoxyaniline (0.765g, dry methylene chloride solution 10mL 5mmol), stir, in 0 ℃ of ice bath downhill reaction system, slowly drip triethylamine (1.010g, 10mmol), at 45 ℃, react 6-8 hour, TLC detects, after reacting completely, suction filtration is removed most of salt, underpressure distillation, ethyl acetate for solid matter/distilled water extracting and washing 3 times, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography separates, eluent is that volume ratio is that methylene dichloride and the methyl alcohol of 200:1 (is V
methylene dichloride: V
methyl alcohol=200:1), obtain target product N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide 1.905g, yield 88%.
The target product of above-mentioned acquisition is carried out to nucleus magnetic resonance, and nuclear magnetic data is as follows:
Emphasis is consulted Fig. 1,
1h NMR (600MHz, DMSO): δ 10.03 (s, 1H), 9.35 (s, 1H), 8.59 (d, J=5.1Hz, 1H), 8.44 (d, J=9.1Hz, 1H), 8.03 (d, J=8.6Hz, 2H), 7.96 (d, J=2.0Hz, 1H), 7.63 (dd, J=9.0,2.1Hz, 1H), 7.50 (dd, J=7.9,5.5Hz, 3H), 7.36 (dd, J=8.7,2.3Hz, 1H), 7.20 (d, J=5.2Hz, 1H), 6.94 (d, J=8.8Hz, 1H), 3.76 (d, J=8.9Hz, 6H).
Emphasis is consulted Fig. 2,
13c NMR (600MHz, DMSO): δ 164.92,152.47,150.09,148.92,147.21,145.53,144.23,134.60,133.35,129.59,128.21,125.79,125.07,120.54,119.41,112.36,106.00,104.14,56.17,55.85.
High resolution data: HRMS calcd.for C
24h
20clN
3o
3[M+H]
+434.1266, found434.1261.
From the above, the target product of acquisition is N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide.
Embodiment 2:
In the dry round-bottomed flask of 100mL, add 4,7-dichloroquinoline (1.970g, 10mmol), para-amino benzoic acid (1.372g, 10mmol) and Virahol 20mL, stir it is fully dissolved.Slowly be warming up to 85 ℃, after stirring and refluxing 5h, reaction solution is separated out faint yellow precipitation, and TLC detection reaction balance finishes reaction.Question response liquid is cooled to after room temperature, evaporated under reduced pressure, residual solids 15mL washed with dichloromethane 3 times, collect filter cake, dry faint yellow solid powder 4-(7-chloroquinoline-4-amino that to obtain) and phenylformic acid 2.751g, yield 92%.
In the dry round-bottomed flask of 100mL, add and contain 4-(7-chloroquinoline-4-amino) phenylformic acid (2.982g, dry methylene chloride solution 15mL 10mmol), stir, in 0 ℃ of ice bath downhill reaction system, slowly drip chloride containing sulfoxide (5.948g, 50mmol), dropwise rear backflow 4 hours, sulfur oxychloride is removed in underpressure distillation, obtain compound 4-(7-chloroquinoline-4-amino) Benzoyl chloride 1.399g, yield 89%.
In the dry round-bottomed flask of 100mL, add and contain compound 4-(7-chloroquinoline-4-amino) Benzoyl chloride (3.162g, 10mmol) and compound 3, 4-dimethoxyaniline (1.531g, dry methylene chloride solution 15mL 10mmol), stir, in 0 ℃ of ice bath downhill reaction system, slowly drip triethylamine (2.020g, 20mmol), at 45 ℃, react 6-8 hour, TLC detects, after reacting completely, suction filtration is removed most of salt, underpressure distillation, ethyl acetate for solid matter/distilled water extracting and washing 3 times, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography separates, eluent is V
methylene dichloride: V
methyl alcohol=200:1, obtains target product N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide 3.680g, yield 85%.
Being below described N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide can be used as the experimental verification of kinases inhibitor and NSC 630176.
Embodiment 3:MTT method is measured anti-tumor activity
The cell in vegetative period of taking the logarithm, add after 0.25% trysinization, add the RPMI-1640 substratum containing 10% calf serum, blow and beat into single cell suspension, adjust cell concn, with 4000/hole of cell count, be inoculated into 96 orifice plates, every hole adds substratum to 200 μ L, after cell is uniformly dispersed, standing cultivation 24h, after cell is completely adherent, give respectively medicine (the 4 μ molL-1 of different concns, 8 μ molL-1, the medicine of 16 μ molL-1 and 32 μ molL-1, DMSO content is 1 ‰), positive controls gives the Gefitinib of same concentrations, negative control group gives the DMSO of same volume, cultivate respectively 24h, 48h and 72h, positive controls is cultivated 72h, then lucifuge adds 5mgmL-1MTT20 μ L, continue to cultivate after 4h, abandon nutrient solution, every hole adds 150 μ L DMSO, concussion is fully dissolved crystallisate, by microplate reader, detect the absorbancy (A) at 490nm place, then calculate relative cell appreciation rate (RGR%).Experiment repeats 3 times.Select the antineoplastic experimental study of part to give an example.
A) human small cell lung carcinoma NCI-H446 cell.Measure N-(3 with mtt assay, 4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide anti-tumor activity result show: this compound has remarkable restraining effect to the propagation of human small cell lung carcinoma NCI-H446 cell between 8～30 μ molL-1, and be significant concn dependency, after administration 24h, IC50 is lower than 18 μ M.
B) human lung cancer cell A549's cell.Experimental result shows: when 14 μ molL-1 and above concentration thereof, N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide is not significant concn dependency to the inhibition of human lung cancer cell A549's cell, and after administration 24h, IC50 is lower than 20 μ M.
C) human cervical carcinoma Hela cell.Experimental result shows: under 8 μ molL-1 concentration, N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide is fairly obvious to the restraining effect of HeLa Cells propagation, and 24 hours IC50 of drug effect are 3 μ M.
D) human liver cancer cell SMMC-7721 cell.Measure N-(3 with mtt assay, 4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide anti-tumor activity result show: this compound has remarkable restraining effect to the propagation of human liver cancer cell SMMC-7721 cell between 4～30 μ molL-1, and be significant concn dependency, after administration 24h, IC50 is lower than 16 μ M.
Therefore, N-(3 of the present invention, 4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide can effectively treat the part disease that protein kinase dysregulation causes, and has advantages of that bioavailability is high, antitumour activity is obvious and toxicity is low.The present invention is to N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) anti-tumor activity of benzamide carried out test of many times, measure with mtt assay, find that it has obvious anti-tumor activity, described tumour cell comprises human small cell lung carcinoma NCI-H446 cell, human lung cancer cell A549's cell, HeLa Cells and human liver cancer cell SMMC-7721 cell.
And the sharp related reaction cost of the present invention is low, and productive rate is high, and reaction process is simple and easy to control, and safe non-environmental-pollution, is applicable to suitability for industrialized production.
Although more than described the specific embodiment of the present invention; but being familiar with those skilled in the art is to be understood that; our described specific embodiment is illustrative; rather than for the restriction to scope of the present invention; those of ordinary skill in the art are in equivalent modification and the variation done according to spirit of the present invention, all should be encompassed in the scope that claim of the present invention protects.
Claims (12)
1. a benzamide derivatives, is characterized in that: described benzamide derivatives is N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide, its molecular formula is C
24h
20clN
3o
3, its structural formula is as shown in the formula I:
2. a preparation method for benzamide derivatives, is characterized in that: described preparation method is as follows:
Step 1, compound ii and III are dissolved in Virahol, stirring and refluxing, after 5 hours, is separated out faint yellow precipitation, and question response liquid is cooled to after room temperature, evaporated under reduced pressure, and washed with dichloromethane 2～3 times for residual solids, collects filter cake, the dry faint yellow solid powder IV that to obtain;
Reaction equation is as follows:
Wherein, compound ii is 4,7-dichloroquinoline, and compound III is para-amino benzoic acid, and compounds Ⅳ is 4-(7-chloroquinoline-4-amino) phenylformic acid;
Step 2, the compounds Ⅳ of acquisition is dissolved in dry methylene dichloride, stirs, slowly drip sulfur oxychloride in ice bath downhill reaction system, dropwise rear backflow 4 hours, sulfur oxychloride is removed in underpressure distillation, obtains compound V;
Reaction equation is as follows:
Wherein, compound V is 4-(7-chloroquinoline-4-amino) Benzoyl chloride;
Step 3, the compound V of acquisition is dissolved in dry methylene dichloride, adds compound VI, stir, under ice bath, drip the dry methylene chloride solution that contains triethylamine, react 6-8 hour at 45 ℃, TLC detects, after reacting completely, suction filtration is removed most of salt, underpressure distillation, ethyl acetate for solid matter/distilled water extracting and washing 2～3 times, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography separates, and eluent is V
methylene dichloride: V
methyl alcohol=200:1, obtains target product I;
Reaction equation is as follows:
Wherein, compound VI is 3,4-dimethoxyaniline.
3. the preparation method of a kind of benzamide derivatives according to claim 2, is characterized in that: described Virahol refers to analytically pure Virahol.
4. the preparation method of a kind of benzamide derivatives according to claim 2, is characterized in that: described methylene dichloride refers to analytically pure dry anhydrous methylene chloride.
5. the preparation method of a kind of benzamide derivatives according to claim 2, is characterized in that: described room temperature is 25 ℃.
6. the preparation method of a kind of benzamide derivatives according to claim 2, is characterized in that: described sulfur oxychloride refers to analytically pure sulfur oxychloride.
7. the preparation method of a kind of benzamide derivatives according to claim 2, is characterized in that: described Et
3n refers to analytically pure triethylamine.
8. the preparation method of a kind of benzamide derivatives according to claim 2, is characterized in that: described ice bath refers to that temperature is down to 0 ℃.
9. the preparation method of a kind of benzamide derivatives according to claim 2, is characterized in that: described ethyl acetate refers to analytically pure ethyl acetate.
10. the preparation method of a kind of benzamide derivatives according to claim 2, is characterized in that: described Na
2sO
4refer to analytically pure anhydrous sodium sulphate.
The preparation method of 11. a kind of benzamide derivatives according to claim 2, is characterized in that: described methyl alcohol refers to analytically pure methyl alcohol.
The application of 12. 1 kinds of benzamide derivatives; it is characterized in that: described benzamide derivatives is benzamide derivatives claimed in claim 1; be N-(3; 4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide; described N-(3,4-Dimethoxyphenyl)-4-(7-chloroquinoline-4-amino) benzamide can be used as kinases inhibitor and NSC 630176.
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| CN104030980A (en) * | 2014-06-10 | 2014-09-10 | 华侨大学 | N-(3-methoxyl-4-chlorphenyl)-4-[(7-chloro-4-quinoline) amino] benzamide, preparation and application thereof |
| CN105017149A (en) * | 2015-06-04 | 2015-11-04 | 中国人民解放军第三〇七医院 | Substance with protein kinase inhibiting activity and preparation method therefor and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104030980A (en) * | 2014-06-10 | 2014-09-10 | 华侨大学 | N-(3-methoxyl-4-chlorphenyl)-4-[(7-chloro-4-quinoline) amino] benzamide, preparation and application thereof |
| CN105017149A (en) * | 2015-06-04 | 2015-11-04 | 中国人民解放军第三〇七医院 | Substance with protein kinase inhibiting activity and preparation method therefor and application thereof |
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