CN103288728A - Naphthoyl amine derivative, and preparation method and application thereof - Google Patents
Naphthoyl amine derivative, and preparation method and application thereof Download PDFInfo
- Publication number
- CN103288728A CN103288728A CN2013101854423A CN201310185442A CN103288728A CN 103288728 A CN103288728 A CN 103288728A CN 2013101854423 A CN2013101854423 A CN 2013101854423A CN 201310185442 A CN201310185442 A CN 201310185442A CN 103288728 A CN103288728 A CN 103288728A
- Authority
- CN
- China
- Prior art keywords
- naphthoamide
- compound
- preparation
- derivative
- ice bath
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- WLJMCRWYIXLKQL-UHFFFAOYSA-N CCOC(c1ccc(cc(cc2)O)c2c1)=O Chemical compound CCOC(c1ccc(cc(cc2)O)c2c1)=O WLJMCRWYIXLKQL-UHFFFAOYSA-N 0.000 description 1
- KAUQJMHLAFIZDU-UHFFFAOYSA-N OC(c1ccc(cc(cc2)O)c2c1)=O Chemical compound OC(c1ccc(cc(cc2)O)c2c1)=O KAUQJMHLAFIZDU-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a naphthoyl amine derivative, and a preparation method and an application of the same. The naphthoyl amine derivative is N-(3- trifluoromethyl phenyl)-6-[(7- chloroquinoline-4-oxo) phenolic ether]-2- naphthoyl amine; the N-(3- trifluoromethyl phenyl)-6-[(7- chloroquinoline-4-oxo) phenolic ether]-2- naphthoyl amine can be used as protein kinase inhibitor and histone deacetylase inhibitor, and can be used for treating diseases caused by protein kinase dysregulation. The naphthoyl amine derivative can effectively treat the diseases caused by protein kinase dysregulation, and has the advantages of high bioavailability, obvious antitumor activity and low toxicity; moreover, the naphthoyl amine derivative is low in preparation reaction cost and higher in yield, the reaction process is simple and easy to control, so that the naphthoyl amine derivative is suitable for industrial production.
Description
[technical field]
The present invention relates to a kind of naphthoamide derivative, its preparation method and application.
[background technology]
Protein kinase is the phosphorylation on specific tyrosine, Serine and the threonine residues in the class of enzymes of catalytic protein phosphorylation, particularly catalytic protein.Protein kinase all plays a key effect in regulating many cell physiological processes, comprises metabolism, cell proliferation, cytodifferentiation, cell survival, immunne response and vasculogenesis.Numerous disease is all relevant with the unusual cell response that has the protein kinase adjusting to cause.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.eaal.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 seek the kinases inhibitor that can treat these diseases effectively always.
Protein kinase is divided into two classes usually, i.e. protein tyrosine kinase (PTKs) and serine-threonine (STKs).Wherein protein tyrosine kinase can be divided into two classes again, namely non-ly strides the film Tyrosylprotein kinase and strides film and give birth to tyrosine kinase receptor.At least determine 19 kinds of different subtribes of RTKs at present, 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 seek always and have protein kinase inhibiting activity and can treat and the micromolecular compound of the unusual relative disease of protein kinase activity.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) that replaces of pyrazolyl amido etc., wherein there are several kinases inhibitors to be used for cancer therapy by the FDA approval, as Glivec, Sutent and Sorafenib.Clinical effectiveness shows, compares with traditional chemotherapy, and these medicines are with the obvious advantage.Excite people to improve methods for the treatment of based on mechanism thus, optimize the compound molecule skeleton, the new compound of find to have the bioavailability height, antitumour activity is obvious and toxicity is low.
International monopoly WO2010139180A1 discloses structure and the synthetic method of the naphthalene amino acid derivative 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 uses, expensive, and toxicity is bigger, and is big 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 naphthoamide derivative, can effectively treat the part disease that the protein kinase dysregulation causes, and has bioavailability height, antitumour activity is obvious and toxicity is low advantage.
The present invention realizes one of above-mentioned technical problem like this:
A kind of naphthoamide derivative, described naphthoamide derivative are N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, its molecular formula is C
27H
16ClCF
3O
2, 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 naphthoamide derivative, and it is low to have a preparation feedback cost, 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 kind of preparation method of naphthoamide derivative, described preparation method is as follows:
Step 10, compound I I is dissolved in the ethanol, drip the vitriol oil then, at 78-85 ℃ of following reflux 4-5 hour, add ethyl acetate after the underpressure distillation desolventizing, wash 2-3 time respectively with saturated sodium bicarbonate and saturated sodium-chloride again, merge organic phase, the underpressure distillation desolventizing, obtain compound III, reaction equation is as follows:
Wherein, compound I I is 6-hydroxyl-2-naphthoic acid, and compound III is 6-hydroxyl-2-naphthoic acid;
Step 20, the compound III that obtains is dissolved among the DMF, stir under the ice bath, slowly drip the DMF solution that contains NaH, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, slowly splash into the DMF solution that contains compound IV and KI, stir half an hour, 110 ℃ were reacted 8-10 hour down, obtain compound V, reaction equation is as follows:
Wherein, compound IV is 4,7-dichloroquinoline, and compound V is 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester;
Step 30, the compound V that obtains is dissolved in the ethanol, stir under the ice bath, slowly drip the ethanolic soln that contains NaOEt, ice bath stirs half an hour, remove ice bath, treat that temperature returns to room temperature, slowly splash into the ethanolic soln that contains the compound VI 3-Aminotrifluorotoluene, stir half an hour, 45-55 ℃ was reacted 6-10 hour down, obtain the target product compound I, i.e. naphthoamide derivative, reaction equation is as follows:
Wherein, compound VI is 3-Aminotrifluorotoluene, and compound I is N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide.
Further, described ethanol is dehydrated alcohol.
Further, the concentration of the described vitriol oil is 98%.
Further, described room temperature is 25 ℃.
Further, described DMF refers to analytically pure N, dinethylformamide.
Further, described NaH refers to analytically pure sodium hydride.
Further, described KI refers to analytically pure potassiumiodide.
Further, described ice bath refers to that temperature is down to 0 ℃.
Further, described NaOEt refers to analytically pure sodium ethylate.
Three of the technical problem to be solved in the present invention is to provide a kind of application of naphthoamide derivative, can effectively treat the part disease that the protein kinase dysregulation causes, and has bioavailability height, antitumour activity is obvious and toxicity is low advantage.
The present invention realizes three of above-mentioned technical problem like this:
A kind of application of naphthoamide derivative; described naphthoamide derivative is N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, described N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide can be used as kinases inhibitor and NSC 630176.
The present invention has following advantage:
The present invention becomes ether with 4,7-dichloroquinoline after the 6-hydroxynaphthoic acid is become ester again, preparation N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, reduce reaction cost greatly, productive rate is higher, and reaction process is simple and easy to control, is applicable to suitability for industrialized production.
In addition, N-of the present invention (3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide can effectively treat cardiovascular disorder, metabolic disease, allergy, cancer and and hormone-related diseases, have bioavailability height, antitumour activity is obvious and toxicity is low advantage.The present invention is to N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-anti-tumor activity of 2-naphthoamide carried out test of many times, measure with mtt assay, find that it has tangible 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.
[description of drawings]
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]
See also illustrated in figures 1 and 2ly, embodiments of the invention are described in detail.
The present invention relates to a kind of naphthoamide derivative, described naphthoamide derivative is N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, its molecular formula is C
27H
16ClCF
3O
2, its structural formula is as shown in the formula I:
Described N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide can be used as kinases inhibitor and NSC 630176, and be used for the treatment of protein kinase and regulate the disease that causes.
The invention still further relates to a kind of preparation method of naphthoamide derivative, described preparation method is as follows:
Step 10, compound I I is dissolved in the ethanol, drip the vitriol oil then, at 78-85 ℃ of following reflux 4-5 hour, add ethyl acetate after the underpressure distillation desolventizing, wash 2-3 time respectively with saturated sodium bicarbonate and saturated sodium-chloride again, merge organic phase, the underpressure distillation desolventizing, obtain compound III, reaction equation is as follows:
Wherein, compound I I is 6-hydroxyl-2-naphthoic acid, and compound III is 6-hydroxyl-2-naphthoic acid;
Step 20, the compound III that obtains is dissolved among the DMF, stir under the ice bath, slowly drip the DMF solution that contains NaH, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, slowly splash into the DMF solution that contains compound IV and KI, stir half an hour, 110 ℃ were reacted 8-10 hour down, obtain compound V, reaction equation is as follows:
Wherein, compound IV is 4,7-dichloroquinoline, and compound V is 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester;
Step 30, the compound V that obtains is dissolved in the ethanol, stir under the ice bath, slowly drip the ethanolic soln that contains NaOEt, ice bath stirs half an hour, remove ice bath, treat that temperature returns to room temperature, slowly splash into the ethanolic soln that contains the compound VI 3-Aminotrifluorotoluene, stir half an hour, 45-55 ℃ was reacted 6-10 hour down, obtain the target product compound I, i.e. naphthoamide derivative, reaction equation is as follows:
Wherein, compound VI is 3-Aminotrifluorotoluene, and compound I is N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide.
More excellent, described ethanol is dehydrated alcohol; The concentration of the described vitriol oil is 98%; Described room temperature is 25 ℃; Described DMF refers to analytically pure N, dinethylformamide; Described NaH refers to analytically pure sodium hydride; Described KI refers to analytically pure potassiumiodide; Described ice bath refers to that temperature is down to 0 ℃; Described NaOEt refers to analytically pure sodium ethylate.
The present invention is further illustrated below in conjunction with embodiment.
Embodiment 1:
Compound 6-hydroxyl-2-naphthoic acid 1.88g (10mmol) is dissolved in 40 milliliters of ethanol, add 4 vitriol oils, 80 ℃ of following reflux 5 hours, removal of solvent under reduced pressure obtained compound 6-hydroxyl-2-naphthoic acid ethyl ester 1.98g (9.2mmol), productive rate 91.7% afterwards;
Gained compound 6-hydroxyl-2-naphthoic acid ethyl ester 1.98g (9.2mmol) is dissolved among 5 milliliters of DMF, stir under the ice bath, slowly drip 10 milliliters of the DMF solution of the NaH that contains 0.52g (21.7mmol), ice bath stirs half an hour, remove ice bath, treat that temperature returns to room temperature, slowly splash into and contain 2.19g (11.1mmol) 4, the 7-dichloroquinoline, and 10 milliliters of the DMF solution of 0.38g (1.8mmol) KI, stir half an hour, 110 ℃ were reacted 8-10 hour down, and removal of solvent under reduced pressure obtains reaction mixture afterwards, separate with silica gel column chromatography, the gradient of moving phase is: V (normal hexane): V (ethyl acetate)=4.5: 1 obtains compound 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester 2.8g (7.5mmol), productive rate 75.1%;
Compound 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester 2.8g (7.5mmol) is dissolved in 10 milliliters of ethanol, stir under the ice bath, slowly drip 5 milliliters of ethanolic solns that contain 1.78g (21.7mmol) NaOEt, ice bath stirs half an hour, remove ice bath, treat that temperature returns to room temperature, slowly splash into 10 milliliters of ethanolic solns that contain 1.4g (8.7mmol) 3-Aminotrifluorotoluene, stirring 55 ℃ of half an hour reacted 10 hours down, reaction soln is removed in decompression, obtain reaction mixture, separate with silica gel column chromatography, the gradient of moving phase is: V (normal hexane): V (ethyl acetate)=8: 1 obtains target product N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, 2.23g (4.5mmol), productive rate 52.0%.
The target product of above-mentioned acquisition is carried out nucleus magnetic resonance, and nuclear magnetic data is as follows:
Emphasis is consulted Fig. 1,
1H NMR (400MHz, DMSO-d6): δ 10.77 (s, 1H), 8.78 (d, J=5.27Hz, 1H), 8.72 (s, 1H), 8.39 (d, J=9.03Hz, 1H), and 8.32-8.27 (m, 2H), 8.14-8.09 (m, 4H), 7.93 (d, J=2.26Hz, 1H), 7.73 (dd, J=2.01HZ, 8.78Hz, 1H), and 7.64-7.61 (m, 2H), 7.49 (d, J=7.78Hz, 1H), 6.82 (d, J=5.02Hz, 1H);
Emphasis is consulted Fig. 2,
13C NMR (100MHz, DMSO-d6): δ 166.23,161.05, and 153.65,153.52,150.29,140.48,136.00,135.54,132.46,132.11,130.44,130.37,128.75,128.30,128.06,127.65,125.80,124.24,121.92,120.01,117.58,116.86,106.39ESI-MS, m/z493.09[M-H]+.
From the above, the target product of acquisition is N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide.
Embodiment 2:
Compound 6-hydroxyl-2-naphthoic acid 3.53g (20mmol) is dissolved in 40 milliliters of ethanol, add 8 vitriol oils, 80 ℃ of following reflux 5 hours, removal of solvent under reduced pressure obtained compound 6-hydroxyl-2-naphthoic acid ethyl ester 4.01g (18.5mmol), productive rate 92.5% afterwards;
Compound 6-hydroxyl-2-naphthoic acid ethyl ester 2.01g (18.5mmol) is dissolved among 5 milliliters of DMF, stir under the ice bath, slowly drip 15 milliliters of the DMF solution of the NaH that contains 1.02g (41.7mmol), ice bath stirs half an hour, remove ice bath, treat that temperature returns to room temperature, slowly splash into and contain 3.68g (18.6mmol) 4, the 7-dichloroquinoline, and 15 milliliters of the DMF solution of 0.69g (4.16mmol) KI, stir half an hour, 110 ℃ were reacted 8-10 hour down, and removal of solvent under reduced pressure obtains reaction mixture afterwards, separate with silica gel column chromatography, the gradient of moving phase is: V (normal hexane): V (ethyl acetate)=4.5: 1 obtains compound 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester 5.58g (14.8mmol), productive rate 75.1%;
Compound 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester 5.58g (14.8mmol) is dissolved in 15 milliliters of ethanol, stir under the ice bath, slowly drip 5 milliliters of ethanolic solns that contain 2.72g (40.1mmol) NaOEt, ice bath stirs half an hour, remove ice bath, treat that temperature returns to room temperature, slowly splash into 15 milliliters of ethanolic solns that contain 2.39g (14.9mmol) 3-Aminotrifluorotoluene, stirring 55 ℃ of half an hour reacted 10 hours down, reaction soln is removed in decompression, obtain reaction mixture, separate with silica gel column chromatography, the gradient of moving phase is: V (normal hexane): V (ethyl acetate)=8: 1 obtains target product N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, 3.74g (8.9mmol), productive rate 51.8%.
Below for described N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide 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, after adding 0.25% trysinization, add the RPMI-1640 substratum that contains 10% calf serum, blow and beat into single cell suspension, adjust cell concn, be inoculated into 96 orifice plates with 4000/hole of cell count, every hole adds substratum to 200 μ L, after cell is uniformly dispersed, leave standstill and cultivate 24h, treat that cell is adherent fully after, give medicine (the 4 μ molL-1 of different concns respectively, 8 μ molL-1, the medicine of 16 μ molL-1 and 32 μ molL-1, DMSO content are 1 ‰), positive controls gives the Gefitinib of same concentrations, negative control group gives the DMSO with volume, cultivate 24h respectively, 48h and 72h, positive controls is cultivated 72h, and lucifuge adds 5mgmL-1MTT20 μ L then, after continuing to cultivate 4h, abandon nutrient solution, every hole adds 150 μ LDMSO, and concussion is fully dissolved crystallisate, with the absorbancy (A) at microplate reader detection 490nm place, calculate relative cell appreciation rate (RGR%) then.Experiment repeats 3 times.Select the antineoplastic experimental study result of part to give an example.
A) human small cell lung carcinoma NCI-H446 cell.Measure N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base with mtt assay) phenolic ether]-the anti-tumor activity result of 2-naphthoamide shows: 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 the significant concn dependency, IC50 is lower than 18 μ M behind the administration 24h.
B) human lung cancer cell A549's cell.Experimental result shows: when 14 μ molL-1 and above concentration thereof, N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide is not the significant concn dependency to human lung cancer cell A549's cell inhibiting, and IC50 is lower than 20 μ M behind the administration 24h.
C) HeLa Cells.Experimental result shows: under 32 μ molL-1M concentration, and N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide is fairly obvious to the effect of HeLa Cells inhibition of proliferation, and 24 hours IC50 of drug effect are 10 μ M.
D) human liver cancer cell SMMC-7721 cell.Measure N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base with mtt assay) phenolic ether]-the anti-tumor activity result of 2-naphthoamide shows: 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 the significant concn dependency, IC50 is lower than 16 μ M behind the administration 24h.
The present invention becomes ether with 4,7-dichloroquinoline after the 6-hydroxynaphthoic acid is become ester again, preparation N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, reduce reaction cost greatly, productive rate is higher, and reaction process is simple and easy to control, is applicable to suitability for industrialized production.
In addition, N-of the present invention (3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide can effectively treat the part disease that the protein kinase dysregulation causes, and has bioavailability height, antitumour activity is obvious and toxicity is low advantage.The present invention is to N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-anti-tumor activity of 2-naphthoamide carried out test of many times, measure with mtt assay, find that it has tangible 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.
Though 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 modification and the variation of the equivalence of doing according to spirit of the present invention, all should be encompassed in the scope that claim of the present invention protects.
Claims (11)
1. naphthoamide derivative, it is characterized in that: described naphthoamide derivative is N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, its molecular formula is C
27H
16ClCF
3O
2, its structural formula is as shown in the formula I:
2. the preparation method of a naphthoamide derivative, it is characterized in that: described preparation method is as follows:
Step 10, compound I I is dissolved in the ethanol, drip the vitriol oil then, at 78-85 ℃ of following reflux 4-5 hour, add ethyl acetate after the underpressure distillation desolventizing, wash 2-3 time respectively with saturated sodium bicarbonate and saturated sodium-chloride again, merge organic phase, the underpressure distillation desolventizing, obtain compound III, reaction equation is as follows:
Wherein, compound I I is 6-hydroxyl-2-naphthoic acid, and compound III is 6-hydroxyl-2-naphthoic acid;
Step 20, the compound III that obtains is dissolved among the DMF, stir under the ice bath, slowly drip the DMF solution that contains NaH, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, slowly splash into the DMF solution that contains compound IV and KI, stir half an hour, 110 ℃ were reacted 8-10 hour down, obtain compound V, reaction equation is as follows:
Wherein, compound IV is 4,7-dichloroquinoline, and compound V is 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester;
Step 30, the compound V that obtains is dissolved in the ethanol, stir under the ice bath, slowly drip the ethanolic soln that contains NaOEt, ice bath stirs half an hour, remove ice bath, treat that temperature returns to room temperature, slowly splash into the ethanolic soln that contains the compound VI 3-Aminotrifluorotoluene, stir half an hour, 45-55 ℃ was reacted 6-10 hour down, obtain the target product compound I, i.e. naphthoamide derivative, reaction equation is as follows:
Wherein, compound VI is 3-Aminotrifluorotoluene, and compound I is N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide.
3. the preparation method of a kind of naphthoamide derivative according to claim 2, it is characterized in that: described ethanol is dehydrated alcohol.
4. the preparation method of a kind of naphthoamide derivative according to claim 2, it is characterized in that: the concentration of the described vitriol oil is 98%.
5. the preparation method of a kind of naphthoamide derivative according to claim 2, it is characterized in that: described room temperature is 25 ℃.
6. the preparation method of a kind of naphthoamide derivative according to claim 2, it is characterized in that: described DMF refers to analytically pure N, dinethylformamide.
7. the preparation method of a kind of naphthoamide derivative according to claim 2, it is characterized in that: described NaH refers to analytically pure sodium hydride.
8. the preparation method of a kind of naphthoamide derivative according to claim 2, it is characterized in that: described KI refers to analytically pure potassiumiodide.
9. the preparation method of a kind of naphthoamide derivative according to claim 2 is characterized in that: described ice bath refers to that temperature is down to 0 ℃.
10. the preparation method of a kind of naphthoamide derivative according to claim 2, it is characterized in that: described NaOEt refers to analytically pure sodium ethylate.
11. the application of a naphthoamide derivative; it is characterized in that: described naphthoamide derivative is the described naphthoamide derivative of claim 1; be N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide, described N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-the 2-naphthoamide can be used as kinases inhibitor and NSC 630176.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101854423A CN103288728A (en) | 2013-05-17 | 2013-05-17 | Naphthoyl amine derivative, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101854423A CN103288728A (en) | 2013-05-17 | 2013-05-17 | Naphthoyl amine derivative, and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103288728A true CN103288728A (en) | 2013-09-11 |
Family
ID=49090320
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013101854423A Pending CN103288728A (en) | 2013-05-17 | 2013-05-17 | Naphthoyl amine derivative, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103288728A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896836A (en) * | 2014-03-20 | 2014-07-02 | 华侨大学 | N-benzyl-6-[(7-chloroquinoline-4-oxo) phenolic ether]-2-naphthamide and preparation method thereof |
| CN103923004A (en) * | 2014-04-04 | 2014-07-16 | 华侨大学 | Naphthalene formamide derivative and preparation 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 |
| CN104447534A (en) * | 2014-12-04 | 2015-03-25 | 厦门大学 | 6-[(7-chloroquinoline-4-oxyl) phenolic ether]-2-naphthamide derivative as well as preparation method and application thereof |
| CN104860885A (en) * | 2014-02-24 | 2015-08-26 | 中国科学院上海药物研究所 | Naphthylamide compound, and preparation method and use thereof |
| CN107868044A (en) * | 2016-09-27 | 2018-04-03 | 深圳微芯生物科技有限责任公司 | A kind of solvated crystalline and preparation method and application |
| US10266489B2 (en) | 2014-12-29 | 2019-04-23 | Hitgen Ltd | Pyrrolic amide compound and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101906076A (en) * | 2009-06-04 | 2010-12-08 | 深圳微芯生物科技有限责任公司 | Naphthaline amide derivative serving as protein kinase inhibitor and histone deacetylase inhibitor and preparation method and application thereof |
| CN102020638A (en) * | 2009-09-16 | 2011-04-20 | 深圳微芯生物科技有限责任公司 | 2-indolinone derivative with protein kinase inhibition activity and histone deacetylase inhibition activity and preparation method and application thereof |
| CN102260210A (en) * | 2011-05-30 | 2011-11-30 | 王立强 | Preparation method of naphthoyl amine derivatives of protein kinase inhibitor and histone deacetylase inhibitor |
| US8211901B2 (en) * | 2009-05-22 | 2012-07-03 | Shenzhen Chipscreen Biosciences Ltd. | Naphthamide derivatives as multi-target protein kinase inhibitors and histone deacetylase inhibitors |
| CN102603627A (en) * | 2011-05-31 | 2012-07-25 | 王立强 | Naphthlamide derivative used as protein kinase inhibitor and histone deacetylase inhibitor and preparation method of naphthlamide derivative |
-
2013
- 2013-05-17 CN CN2013101854423A patent/CN103288728A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8211901B2 (en) * | 2009-05-22 | 2012-07-03 | Shenzhen Chipscreen Biosciences Ltd. | Naphthamide derivatives as multi-target protein kinase inhibitors and histone deacetylase inhibitors |
| CN101906076A (en) * | 2009-06-04 | 2010-12-08 | 深圳微芯生物科技有限责任公司 | Naphthaline amide derivative serving as protein kinase inhibitor and histone deacetylase inhibitor and preparation method and application thereof |
| CN102020638A (en) * | 2009-09-16 | 2011-04-20 | 深圳微芯生物科技有限责任公司 | 2-indolinone derivative with protein kinase inhibition activity and histone deacetylase inhibition activity and preparation method and application thereof |
| CN102260210A (en) * | 2011-05-30 | 2011-11-30 | 王立强 | Preparation method of naphthoyl amine derivatives of protein kinase inhibitor and histone deacetylase inhibitor |
| CN102603627A (en) * | 2011-05-31 | 2012-07-25 | 王立强 | Naphthlamide derivative used as protein kinase inhibitor and histone deacetylase inhibitor and preparation method of naphthlamide derivative |
Non-Patent Citations (1)
| Title |
|---|
| 章思规: "《精细化学品及中间体手册(上、下卷)》", 31 January 2004, 北京：化学工业出版社 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860885A (en) * | 2014-02-24 | 2015-08-26 | 中国科学院上海药物研究所 | Naphthylamide compound, and preparation method and use thereof |
| WO2015124101A1 (en) * | 2014-02-24 | 2015-08-27 | 中国科学院上海药物研究所 | Naphthylamide compound, preparation method and use thereof |
| CN104860885B (en) * | 2014-02-24 | 2017-11-17 | 中国科学院上海药物研究所 | Naphthoyl aminated compounds, preparation method and use |
| US9914707B2 (en) | 2014-02-24 | 2018-03-13 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Naphthylamide compound, preparation method and use thereof |
| RU2655607C2 (en) * | 2014-02-24 | 2018-05-29 | Шанхай Инститьют Оф Матириа Медика, Чайниз Экэдеми Оф Сайэнсиз | Naphthylamide compound, preparation method and use thereof |
| CN103896836A (en) * | 2014-03-20 | 2014-07-02 | 华侨大学 | N-benzyl-6-[(7-chloroquinoline-4-oxo) phenolic ether]-2-naphthamide and preparation method thereof |
| CN103923004A (en) * | 2014-04-04 | 2014-07-16 | 华侨大学 | Naphthalene formamide derivative and preparation 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 |
| CN104447534A (en) * | 2014-12-04 | 2015-03-25 | 厦门大学 | 6-[(7-chloroquinoline-4-oxyl) phenolic ether]-2-naphthamide derivative as well as preparation method and application thereof |
| US10266489B2 (en) | 2014-12-29 | 2019-04-23 | Hitgen Ltd | Pyrrolic amide compound and preparation method and application thereof |
| CN107868044A (en) * | 2016-09-27 | 2018-04-03 | 深圳微芯生物科技有限责任公司 | A kind of solvated crystalline and preparation method and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103288728A (en) | Naphthoyl amine derivative, and preparation method and application thereof | |
| RU2528408C2 (en) | Method for preparing dihydroindenamide compounds, pharmaceutical compositions containing these compounds and using them as protein kinase inhibitor | |
| JP6986032B2 (en) | Crystals of pyrrolopyrimidine compounds as JAK inhibitors | |
| CN103351336A (en) | Naphthalenecarboxamide derivative as inhibitors of protein kinase and histone deacetylase and preparation method thereof | |
| CN110563703B (en) | Compound for inducing PARP-1 degradation based on CRBN ligand, preparation method and application | |
| CN108191874A (en) | A kind of C-Kit inhibitor and its application | |
| Yavuz et al. | Efficient synthesis and molecular docking studies of new pyrimidine-chromeno hybrid derivatives as potential antiproliferative agents | |
| CN103288684B (en) | Biphenyl carbamide compound with antineoplastic activity and preparation method thereof | |
| CN103965118B (en) | One class pinane base-2-amino-metadiazine compound and synthetic method thereof and application | |
| RU2704125C2 (en) | Quinazoline derivatives | |
| JP7028780B2 (en) | Benzamide derivative | |
| CN103554122A (en) | Chromone structure-containing pyrazole norcantharidin derivative as well as preparation method and application thereof | |
| CN103896836A (en) | N-benzyl-6-[(7-chloroquinoline-4-oxo) phenolic ether]-2-naphthamide and preparation method thereof | |
| CN103923004A (en) | Naphthalene formamide derivative and preparation and application thereof | |
| CN102603627B (en) | Naphthlamide derivative used as protein kinase inhibitor and histone deacetylase inhibitor and preparation method of naphthlamide derivative | |
| CN110746396A (en) | Selenium-containing isoxazolidine compound and preparation method and application thereof | |
| JP7101781B2 (en) | Salt morphology as an Akt inhibitor and its crystalline morphology | |
| CN109942499B (en) | Quinazoline derivative and preparation method and application thereof | |
| CN104860866A (en) | 5-(substituted carbonylamino)-1H-indole-2-carbohydrazide derivatives as well as preparation method and application thereof | |
| CN103724260A (en) | Benzamide derivative and preparation method and application thereof | |
| CN112174958B (en) | Pyrido [2,3-d ] pyrimidine compound and preparation method and application thereof | |
| CN112209888B (en) | 4-arylmercapto quinazoline compound, preparation method and medical application | |
| Misawa et al. | Structure–activity relationships of benzhydrol derivatives based on 1′-acetoxychavicol acetate (ACA) and their inhibitory activities on multiple myeloma cell growth via inactivation of the NF-κB pathway | |
| CN112745237B (en) | 2-arylamine compound and preparation method and application thereof | |
| CN111606888B (en) | Pyrrole derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130911 |