CN105017149A - Substance with protein kinase inhibiting activity and preparation method therefor and application thereof - Google Patents
Substance with protein kinase inhibiting activity and preparation method therefor and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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Abstract
The present invention discloses a substance with protein kinase inhibiting activity and a preparation method therefor and an application thereof. The substance is a benzamide derivative and is specifically N-(2,4-dimethylphenyl)-4-[(7-chlorine-4-quinoline)amino]benzamide. The compound can be used as a protein kinase inhibitor and a histone deacetylase inhibitor, and used for treating a tumor; and a preparation reaction of the substance is low in cost and high in yield, and a reaction process is simple and easy to control, so that the preparation method is applicable to industrial production.
Description
Technical field
The invention belongs to field of medicaments, relate to a class new compound, the application in the preparation method being specifically related to a class benzamide derivatives (formula I) and this compound and the part disease medicament caused at preparation treatment protein kinase dysregulation thereof.
Background technology
Protein kinase is the phosphorylation in the class of enzymes of catalytic protein phosphorylation, particularly catalytic protein in specific tyrosine, Serine and threonine residues.Protein kinase all plays a key effect in the many cellular physiological processes of adjustment, comprises metabolism, cell proliferation, cytodifferentiation, cell survival, immunne response and vasculogenesis.
Protein kinase is divided into two classes usually, i.e. protein tyrosine kinase (PTKs) and serine-threonine kinase (STKs).Wherein protein tyrosine kinase can be divided into two classes again, i.e. non-transmembrane tyrosine kinase and the raw tyrosine kinase receptor of cross-film.At least determine at present 19 kinds of protein tyrosine kinase different subtribes, as EGF-R ELISA (EGFR), vascular endothelial growth factor receptor (VEGFR), Thr6 PDGF BB (PDGFR) and fibroblast growth factor receptor (FGFR).
Current research shows, numerous disease all regulates the cell response of the exception caused 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 related condition (Tan, S-L, 2006, J.Immunol, 176:2872-2879; A.et al.2006, J.Immunol.177:1886-1893; Salek-Ardakani, S.et al.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 effectively can treating these diseases always.
International patent application WO2010139180A1 discloses structure and the synthetic method of the Naphthaline amide derivative serving of a kind of kinases inhibitor and NSC 630176, in this synthetic method: 1) the first step 6-hydroxynaphthoic acid and 4, the cesium carbonate of the one-tenth ether catalysts use of 7-dichloroquinoline, expensive, and toxicity is comparatively large, large to the pollution of environment; 2) severe reaction conditions, productive rate is lower.Therefore, the compound that this preparation method obtains is unsuitable for suitability for industrialized production.
Summary of the invention
The object of the invention is the technological deficiency for existing in prior art, a kind of antitumour activity is provided significantly to have the material of protein kinase inhibiting activity---benzamide derivatives, to excavate the drug candidate of the part disease that treatment protein kinase dysregulation causes.
First aspect present invention is to provide a kind of material with protein kinase inhibiting activity, for benzamide derivatives, described benzamide derivatives is N-(2,4-3,5-dimethylphenyl)-4-[(the chloro-4-quinoline of 7-) is amino] benzamide, and structural formula is such as formula shown in I:
This material is for structural formula is such as formula the geometrical isomer of compound shown in I and pharmacy acceptable salt thereof.
Second aspect present invention is to provide a kind of pharmaceutical composition, and it contains the pharmaceutical composition of above-mentioned compound, its geometrical isomer, its pharmacy acceptable salt, its hydrate or solvated compounds and pharmaceutically acceptable carrier or vehicle.
Third aspect present invention is to provide a kind of method preparing above-claimed cpd, and reaction equation is as follows:
Step (1):
Step (2):
Step (3):
The concrete operations of step (1) are: be dissolved in Virahol by compound ii and compound III, stirring and refluxing is after 5 hours, separate out pale yellow precipitate, after question response liquid is cooled to room temperature, evaporated under reduced pressure, residual solids washed with dichloromethane 3 times, collects filter cake, dry faint yellow solid powder IV.
The concrete operations of step (2) are: be dissolved in by compounds Ⅳ in dry methylene dichloride, stir, slowly drip sulfur oxychloride, dropwise rear backflow 4 hours in ice bath downhill reaction system, and underpressure distillation removing sulfur oxychloride, obtains compound V.
The concrete operations of step (3) are: be dissolved in by compound V in dry methylene dichloride, add compound VI, stir, the dry methylene chloride solution containing triethylamine is dripped under ice bath, 6-8 hour is reacted at 45 DEG C, TLC detects, after reacting completely, suction filtration removes most of salt, underpressure distillation, solid matter ethyl acetate/distilled water extracting and washing 3 times, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography is separated (eluent is methylene dichloride: methyl alcohol=200:1), obtains target product I.
Described Virahol, sulfur oxychloride, triethylamine, ethyl acetate, anhydrous sodium sulphate, methyl alcohol Analysis about Selection are pure, and methylene dichloride Analysis about Selection is pure and dry anhydrous, and room temperature is 25 DEG C, and ice bath is 0-4 DEG C.
Fourth aspect present invention is to provide above-claimed cpd or aforementioned pharmaceutical compositions preparing the application in kinases inhibitor medicine and/or NSC 630176 medicine.
The disease that the purposes of arrestin kinases and/or histon deacetylase (HDAC) causes for treatment protein kinase dysregulation, the disease that described protein kinase dysregulation causes includes but not limited to cardiovascular disorder, metabolic disease, allergy, cancer and the disease relevant to hormone.
Compound of the present invention can the effect of effective arrestin kinase activity, thus has the part disease activity that potential treatment protein kinase dysregulation causes, can be used as the medicine of the part disease that protein kinase dysregulation causes.
First aspect of the present invention relates to the compound with protein kinase inhibiting activity, and the preparation method of this compound; Next relates to it and is preparing the application in the medicine for the treatment of the part disease that protein kinase dysregulation causes.
Compound anti-cancering activity of the present invention is obvious, and preparation method's cost is low, productive rate is higher, reaction process is simple and easy to control, is applicable to suitability for industrialized production.Compound of the present invention can be used for as Cardiovarscular, metabolic disease, allergy, cancer and the medicine with hormone related condition, particularly there is obvious anti-tumor activity, comprise human esophagus cancer ECA-109 cell, human lung cancer cell A549's cell, HeLa Cells and human liver cancer cells Hep G2 cell.
Embodiment
For many years, people be devoted to find always have protein kinase inhibiting activity and can treat and protein kinase activity exception relative disease micromolecular compound.The compound that bibliographical information is crossed has ring compound (US Patent No. 7,151,096), double-ring compound (US Patent No. 7,189,721), three ring compounds (US Patent No. 7,132,533), (2-oxyindole base-3-methylene radical) acetogenin (US Patent No. 7,179,910), the quinazoline compound (US Patent No. 7,098,330) etc. of pyrazolyl amido replacement, several kinases inhibitor is wherein had to be ratified for cancer therapy, as Glivec, Sutent and Sorafenib by FDA.Clinical effectiveness shows, compared with traditional chemotherapy, these medicines are with the obvious advantage.Excite people to improve methods for the treatment of based on the mechanism of these medicines thus, optimize compound molecule skeleton, find that there is the new compound that bioavailability is high, antitumour activity is obvious and toxicity is low.
The present invention's research synthesizes the material with protein kinase inhibiting activity---a kind of benzamide derivatives, this benzamide derivatives is N-(2,4-3,5-dimethylphenyl)-4-[(the chloro-4-quinoline of 7-) is amino] benzamide, its molecular formula is C
24h
20clN
3o, its structural formula is as shown in the formula I:
The compound of above formula structure can be used as kinases inhibitor and NSC 630176, is used for the treatment of the disease that protein kinase dysregulation causes.
The preparation method of the benzamide derivatives that the present invention relates to is as follows:
Following room temperature refers to 25 DEG C, and ice bath refers to 0-4 DEG C.
Step (1), by compound ii (4,7-dichloroquinoline) (5-20mmol) and compound III (para-amino benzoic acid) (5-20mmol) be dissolved in (20-50mL) in Virahol, stirring and refluxing (75-95 DEG C), after 5-7 hour, separate out pale yellow precipitate, after question response liquid is cooled to room temperature, evaporated under reduced pressure, residual solids washed with dichloromethane 3 times, collect filter cake, dry faint yellow solid powder IV (4-(7-chloroquinoline-4-is amino) phenylformic acid).
Reaction equation is as follows:
Step (2), the compounds Ⅳ that step (1) obtains is dissolved in dry methylene dichloride, stir, sulfur oxychloride (25-100mmol) is slowly dripped in ice bath downhill reaction system, dropwise rear backflow 3-5 hour, underpressure distillation removing sulfur oxychloride, obtains compound V (4-(7-chloroquinoline-4-is amino) Benzoyl chloride).
Reaction equation is as follows:
Step (3), the compound V (10-40mmol) that step (2) is obtained and compound VI (2, 4-xylidine) (5-20mmol) be dissolved in dry dichloromethane solution (10-40mL), stir, the dichloromethane solution (10-40mL) containing triethylamine (10-40mmol) is dripped under ice bath, 6-8 hour is reacted at 40-50 DEG C, TLC detects, after reacting completely, suction filtration removes most of salt, underpressure distillation obtains solid matter, use ethyl acetate/distilled water extracting and washing 3 times again, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography is separated (eluent is methylene dichloride: methyl alcohol=200:1), obtain target product I.
Reaction equation is as follows:
For ensureing the purity of productive rate and the product reacted, preferably all Analysis about Selection is pure for Virahol, sulfur oxychloride, triethylamine, ethyl acetate, anhydrous sodium sulphate, methyl alcohol, and the best Analysis about Selection of methylene dichloride is pure and dry anhydrous.
Below in conjunction with specific embodiment, further illustrate content of the present invention, and the present invention is further elaborated, but these embodiments there is any restriction to the present invention absolutely not.Those skilled in the art under the enlightenment of this specification sheets to the embodiment of the present invention in any variation of doing all will belong in the scope of claims of the present invention.
Embodiment 1:
In the round-bottomed flask of 100mL drying, add 4,7-dichloroquinoline (0.985g, 5mmol), para-amino benzoic acid (0.685g, 5mmol) and Virahol 20mL, stir and make it fully dissolve.Slowly be warming up to 85 DEG C, after stirring and refluxing 5h, reaction solution separates out pale yellow precipitate, and TLC detection reaction balances, terminates reaction.After question response liquid is cooled to room temperature, evaporated under reduced pressure, residual solids 10mL washed with dichloromethane 3 times, collects filter cake, dry faint yellow solid powder 4-(7-chloroquinoline-4-is amino) phenylformic acid 1.40g, yield 95%.
Add containing 4-(7-chloroquinoline-4-is amino) phenylformic acid (1.491g in the round-bottomed flask of 100mL drying, dichloromethane solution 10mL 5mmol), stir, sulfur oxychloride (2.974g is slowly dripped in 0 DEG C of ice bath downhill reaction system, 25mmol), dropwise rear backflow (80 DEG C) 4 hours, underpressure distillation removing sulfur oxychloride, obtain 4-(7-chloroquinoline-4-is amino) Benzoyl chloride 1.431g, yield 91%.
Add containing 4-(7-chloroquinoline-4-is amino) Benzoyl chloride (1.581g in the round-bottomed flask of 100mL drying, 5mmol) and 2, 4-xylidine (0.605g, dry methylene chloride solution 10mL 5mmol), stir, slowly drip containing triethylamine (1.010g in 0 DEG C of ice bath downhill reaction system, dichloromethane solution 10mL 10mmol), react 7 hours at 45 DEG C, after TLC detection reaction is complete, suction filtration removes most of salt, underpressure distillation obtains solid matter, use ethyl acetate/distilled water extracting and washing 3 times again, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography is separated (eluent is methylene dichloride: methyl alcohol=200:1), obtain target product N-(2, 4-3,5-dimethylphenyl)-4-[(the chloro-4-quinoline of 7-) is amino] benzamide 1.764g, yield 88%.
The target product of above-mentioned acquisition is carried out nucleus magnetic resonance, and nuclear magnetic data is as follows:
Hydrogen is composed:
1h-NMR (600MHz, DMSO, ppm):
δ9.74(s,1H),9.35(s,1H),8.58(d,J＝5.14Hz,1H),8.44(d,J＝8.99Hz,1H),8.04(d,J＝8.62Hz,2H),7.96(d,J＝2.02Hz,1H),7.62(dd,J＝2.02Hz,2.20Hz,1H),7.48(d,J＝8.44Hz,2H),7.22(d,J＝8.07Hz,1H),7.20(d,J＝5.32Hz,1H),7.08(s,1H),7.02(d,J＝7.89Hz,1H),2.29(s,3H),2.21(s,3H)；
Carbon is composed:
13c-NMR (150MHz, DMSO, ppm): δ 165.11,152.54,150.14,147.23,144.20,135.40,134.57,134.42,133.99,131.28,129.56,129.23,128.24,127.03,126.95,125.80,125.09,120.64,119.40,104.14,21.02,18.33; HRMS (+): m/z 402.1366 ([M+H]
+, C
24h
20clN
3oH
+calcd:402.1368)
High resolution: HRMS (+): m/z 402.1366 ([M+H]
+, C
24h
20clN
3oH
+calcd:402.1368)
Embodiment 2:
In the round-bottomed flask of 100mL drying, add 4,7-dichloroquinoline (1.970g, 10mmol), para-amino benzoic acid (1.372g, 10mmol) and Virahol 20mL, stir and make it fully dissolve.Slowly be warming up to 85 DEG C, after stirring and refluxing 5h, reaction solution separates out pale yellow precipitate, and TLC detection reaction balances, terminates reaction.After question response liquid is cooled to room temperature, evaporated under reduced pressure, residual solids 15mL washed with dichloromethane 3 times, collects filter cake, dry faint yellow solid powder 4-(7-chloroquinoline-4-is amino) phenylformic acid 2.751g, yield 92%.
Add containing 4-(7-chloroquinoline-4-is amino) phenylformic acid (2.982g in the round-bottomed flask of 100mL drying, dry methylene chloride solution 15mL 10mmol), stir, chloride containing sulfoxide (5.948g is slowly dripped in 0 DEG C of ice bath downhill reaction system, 50mmol), dropwise rear backflow (80 DEG C) 4 hours, underpressure distillation removing sulfur oxychloride, obtain compound 4-(7-chloroquinoline-4-is amino) Benzoyl chloride 2.799g, yield 89%.
Add containing compound 4-(7-chloroquinoline-4-is amino) Benzoyl chloride (3.162g in the round-bottomed flask of 100mL drying, 10mmol) and compound 2, 4-xylidine (1.211g, dry methylene chloride solution 20mL 10mmol), stir, slowly drip containing triethylamine (2.020g in 0 DEG C of ice bath downhill reaction system, dichloromethane solution 20mL 20mmol), react 8 hours at 45 DEG C, after TLC detection reaction is complete, suction filtration removes most of salt, underpressure distillation, solid matter ethyl acetate/distilled water extracting and washing 3 times, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, silica gel column chromatography is separated (eluent is methylene dichloride: methyl alcohol=200:1), obtain target product N-(2, 4-3,5-dimethylphenyl)-4-[(the chloro-4-quinoline of 7-) is amino] benzamide 3.409g, yield 85%.
The target product of above-mentioned acquisition is carried out nucleus magnetic resonance, and nuclear magnetic data is with embodiment 1, and by analysis, target product is N-(2,4-3,5-dimethylphenyl)-4-[(the chloro-4-quinoline of 7-) is amino] benzamide.
Experimental example: adopt tetrazolium (MTT) reduction method, measures the anti-tumor activity of N-(2,4-3,5-dimethylphenyl)-4-[(the chloro-4-quinoline of 7-) is amino] benzamide.
To take the logarithm cell in vegetative period, after adding 0.25% trysinization, add the RPMI-1640 substratum containing 10% calf serum, blow and beat into single cell suspension, be inoculated into 96 orifice plates with cell count 4000/hole, every hole adds substratum to 200 μ L, after cell dispersal is even, quiescent culture 24h, after cell is completely adherent, gives medicine (4 μm of olL of different concns respectively
-1, 8 μm of olL
-1, 16 μm of olL
-1and 32 μm of olL
-1, DMSO content is 1 ‰), positive controls gives the Gefitinib of same concentrations, and negative control group gives the DMSO of same volume, cultivates 24h, 48h and 72h respectively, and positive controls cultivates 72h.Then lucifuge adds 5mgmL
-1mTT (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt) 20 μ L, after continuing to cultivate 4h, abandon nutrient solution, every hole adds 150 μ L DMSO, concussion makes crystallisate fully dissolve, detect the absorbancy (A) at 490nm place by microplate reader, then calculate versus cell appreciation rate (RGR%), experiment repetition 3 times.The last half inhibiting rate (IC calculating the compounds of this invention and positive control drug Gefitinib according to Relative cell proliferation rate
50), the results are shown in Table 1.
This compound on tumor of table 1 cell and Normocellular half inhibiting rate
Note: n=3, compare with Gefitinib, a:P<0.01, b:P<0.001, SMMC7721 is human liver cancer cell, A549 is human lung carcinoma cell, and ECA-109 is human esophagus cancer cell, and HeLa is human cervical carcinoma cell, HUVEC is human umbilical vein endothelial cell, LO2 is Human normal hepatocyte, and MRC-5 is human embryonic lung fibroblast, and HEEC is people's microgliacyte.
Visible, the compounds of this invention N-(2,4-3,5-dimethylphenyl)-4-[(7-chloro-4-quinoline) amino] benzamide all has inhibit activities to human liver cancer cell, human lung carcinoma cell, human esophagus cancer cell, human cervical carcinoma cell, human umbilical vein endothelial cell, Human normal hepatocyte, human embryonic lung fibroblast, people's microgliacyte at interior cancer cells, and inhibition or suitable with positive control Gefitinib, or on Gefitinib.Especially to human liver cancer cell (SMMC-7721 cell), human lung carcinoma cell (A549 cell), human esophagus cancer cell (ECA-109 cell) and human cervical carcinoma cell (HeLa cell), half inhibiting rate is 1/7.5,1/21,1/10 and 1/14 of Gefitinib respectively, and that is the compounds of this invention is 7 times, 21 times, 10 times and 14 times of Gefitinib respectively to the inhibition of this several cancer cells.Table 1 data show the inhibition highly significant of the compounds of this invention to this several cancer cells, effectively can treat tumour.In addition, prepare compound reaction cost low, 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.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. having a material for protein kinase inhibiting activity, is benzamide derivatives, and described benzamide derivatives is N-(2,4-3,5-dimethylphenyl)-4-[(the chloro-4-quinoline of 7-) is amino] benzamide, and structural formula is such as formula shown in I:
2. there is the material of protein kinase inhibiting activity according to claim 1, it is characterized in that, for structural formula is such as formula the geometrical isomer of compound shown in I and pharmacy acceptable salt thereof.
3. pharmaceutical composition, it contains the pharmaceutical composition of compound described in claim 1 or 2, its geometrical isomer, its pharmacy acceptable salt, its hydrate or solvated compounds and pharmaceutically acceptable carrier or vehicle.
4. prepare the method for compound described in claim 1 or 2, it is characterized in that, reaction equation is as follows:
5. method according to claim 4, it is characterized in that, the concrete operations of step (1) are: be dissolved in Virahol by Compound II per and compound III, stirring and refluxing, after 5 hours, separates out pale yellow precipitate, after question response liquid is cooled to room temperature, evaporated under reduced pressure, residual solids washed with dichloromethane 3 times, collects filter cake, dry faint yellow solid powder IV.
6. method according to claim 4 or 5, it is characterized in that, the concrete operations of step (2) are: compound IV be dissolved in dry methylene dichloride, stir, slowly sulfur oxychloride is dripped in ice bath downhill reaction system, dropwise rear backflow 4 hours, underpressure distillation removing sulfur oxychloride, obtains compound V.
7. according to the arbitrary described method of claim 4-6, it is characterized in that, the concrete operations of step (3) are: be dissolved in by compound V in dry methylene dichloride, add compound VI, stir, the dry methylene chloride solution containing triethylamine is dripped under ice bath, 6-8 hour is reacted at 45 DEG C, TLC detects, after reacting completely, suction filtration removes most of salt, underpressure distillation, solid matter ethyl acetate/distilled water extracting and washing 3 times, merge organic phase, anhydrous sodium sulfate drying, underpressure distillation obtains crude product, (eluent is methylene dichloride: methyl alcohol=200 in silica gel column chromatography separation
:1) target product I, is obtained.
8. according to the arbitrary described method of claim 4-7, it is characterized in that, described Virahol, sulfur oxychloride, triethylamine, ethyl acetate, anhydrous sodium sulphate, methyl alcohol Analysis about Selection are pure, and methylene dichloride Analysis about Selection is pure and dry anhydrous, room temperature is 25 DEG C, and ice bath is 0-4 DEG C.
9. pharmaceutical composition described in compound described in claim 1 or 2 or claim 3 is preparing the application in kinases inhibitor medicine and/or NSC 630176 medicine.
10. apply according to claim 9; it is characterized in that; the disease that the purposes of arrestin kinases and/or histon deacetylase (HDAC) causes for treatment protein kinase dysregulation, the disease that described protein kinase dysregulation causes includes but not limited to cardiovascular disorder, metabolic disease, allergy, cancer and the disease relevant to hormone.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321151A (en) * | 1998-10-01 | 2001-11-07 | 阿斯特拉曾尼卡有限公司 | Chemical compounds |
| US20070072862A1 (en) * | 2005-08-15 | 2007-03-29 | Dimauro Erin F | Bis-aryl amide compounds and methods of use |
| CN102775389A (en) * | 2012-04-05 | 2012-11-14 | 华侨大学 | Preparation method of N-substituted-4-(7-chloro-quinoline -4-amino)-benzamide derivatives, and application thereof |
| CN103724260A (en) * | 2013-12-18 | 2014-04-16 | 华侨大学 | Benzamide derivative and preparation method and application thereof |
| 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 |
-
2015
- 2015-06-04 CN CN201510303407.6A patent/CN105017149A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321151A (en) * | 1998-10-01 | 2001-11-07 | 阿斯特拉曾尼卡有限公司 | Chemical compounds |
| US20070072862A1 (en) * | 2005-08-15 | 2007-03-29 | Dimauro Erin F | Bis-aryl amide compounds and methods of use |
| CN102775389A (en) * | 2012-04-05 | 2012-11-14 | 华侨大学 | Preparation method of N-substituted-4-(7-chloro-quinoline -4-amino)-benzamide derivatives, and application thereof |
| CN103724260A (en) * | 2013-12-18 | 2014-04-16 | 华侨大学 | Benzamide derivative and preparation method and application thereof |
| 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 |
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Application publication date: 20151104 |