CN103896836A - N-benzyl-6-[(7-chloroquinoline-4-oxo) phenolic ether]-2-naphthamide and preparation method thereof - Google Patents
N-benzyl-6-[(7-chloroquinoline-4-oxo) phenolic ether]-2-naphthamide and preparation method thereof Download PDFInfo
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- CN103896836A CN103896836A CN201410104919.5A CN201410104919A CN103896836A CN 103896836 A CN103896836 A CN 103896836A CN 201410104919 A CN201410104919 A CN 201410104919A CN 103896836 A CN103896836 A CN 103896836A
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- XMWDOKRLGHSKQJ-UHFFFAOYSA-N CCOC(c1ccc(cc(cc2)Oc3c(ccc(Cl)c4)c4ncc3)c2c1)=O Chemical compound CCOC(c1ccc(cc(cc2)Oc3c(ccc(Cl)c4)c4ncc3)c2c1)=O XMWDOKRLGHSKQJ-UHFFFAOYSA-N 0.000 description 1
- 0 O=C(c1ccc(cc(*c2ccnc3c2ccc(Cl)c3)cc2)c2c1)Nc1ccccc1 Chemical compound O=C(c1ccc(cc(*c2ccnc3c2ccc(Cl)c3)cc2)c2c1)Nc1ccccc1 0.000 description 1
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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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
Abstract
The invention provides N-benzyl-6-[(7-chloroquinoline-4-oxo) phenolic ether]-2-naphthamide and a preparation method thereof. The N-benzyl-6-[(7-chloroquinoline-4-oxo) phenolic ether]-2-naphthamide can be used as a protein kinase inhibitor and a histone deacetylase inhibitor for treating diseases caused by dysregulation of protein kinase. The N-benzyl-6-[(7-chloroquinoline-4-oxo) phenolic ether]-2-naphthamide provided by the invention can effectively treat diseases caused by dysregulation of protein kinase, has the advantages of high bioavailability, remarkable antitumor activity and low toxicity, and is low in cost of preparation and reaction, high in yield, simple and easy to control the reaction process and suitable for industrialized production.
Description
[technical field]
The present invention relates to a kind of phenyl-6-[(7-of the N-as kinases inhibitor and NSC 630176 chloroquinoline-4-oxygen base) phenolic ether]-2-naphthoamide and preparation method thereof.
[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 to be ratified for cancer therapy by FDA, 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 uses; 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; be to provide a kind of N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-2-naphthoamide; can be used as kinases inhibitor and NSC 630176; 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 N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-2-naphthoamide, described N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether] structural formula of-2-naphthoamide is as shown in the formula I:
Two of the technical problem to be solved in the present invention, be to provide a kind of N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether] preparation method of-2-naphthoamide, there is preparation feedback cost low, productive rate is higher, 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 N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether] preparation method of-2-naphthoamide, described preparation method's step is as follows:
A) compound ii of 1.0 equivalents is dissolved in 40 milliliters of ethanol, add 4 vitriol oils, reflux 4-5 hour at 78-85 ℃, underpressure distillation removes desolventizing and adds ethyl acetate, wash respectively 2～3 times with saturated sodium bicarbonate and saturated sodium-chloride again, merge organic phase, underpressure distillation, except desolventizing, obtains compound III;
Reaction equation is as follows:
Wherein, described compound ii is 6-hydroxyl-2-naphthoic acid, and described compound III is 6-Hydroxy-2-naphthoic acid ethyl ester;
B) the compound III of 1.0 equivalents is dissolved in 5 milliliters of DMF, under ice bath, stir, 10 milliliters of the DMF solution that slowly dropping contains 2.5 equivalent NaH again, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, 10 milliliters of DMF solution that slowly splash into the compounds Ⅳ that contains 1.2 equivalents and 0.2 equivalent KI, stir half an hour, react 8-10 hour at 110 ℃, obtain compound V
Reaction equation is as follows:
Wherein, described compounds Ⅳ is 4,7-dichloroquinoline, and described compound V is 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester;
C) 1.0 equivalent compound V are dissolved in 10 milliliters of ethanol, under ice bath, stir, 5 milliliters of the ethanolic solns that slowly dropping contains 2.5 equivalent NaOEt, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, slowly splash into 10 milliliters of ethanolic solns that contain 1.0 equivalent compound VI, stir half an hour, react 6-10 hour at 45-55 ℃, obtain Compound I
Reaction equation is as follows:
Wherein, described compound is that compound VI is aniline.
Further, described ethanol refers to dehydrated alcohol.
Further, the concentration of the described vitriol oil is 98%.
Further, described DMF refers to analytically pure DMF.
Further, described NaH refers to analytically pure sodium hydride.
Further, described room temperature refers to 25 ℃.
Further, described ice bath refers to that temperature is down to the ice bath of 0 ℃.
Further, described KI refers to analytically pure potassiumiodide.
Further, described NaOEt refers to analytically pure sodium ethylate.
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-phenyl-6-[(7-chloroquinoline-4-oxygen base of the present invention) phenolic ether]-2-naphthoamide; can be used as kinases inhibitor and NSC 630176; 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.N-phenyl-6-[(7-chloroquinoline-4-oxygen base of the present invention) phenolic ether]-2-naphthoamide has obvious anti-tumor activity, and described tumour cell comprises human lung cancer cell A549's cell and HeLa Cells etc.
[accompanying drawing explanation]
The present invention is further illustrated in conjunction with the embodiments with reference to the accompanying drawings.
Fig. 1 is N-phenyl-6-[(7-chloroquinoline-4-oxygen base of the present invention) phenolic ether] the hydrogen nuclear magnetic resonance spectrogram of-2-naphthoamide.
Fig. 2 is N-phenyl-6-[(7-chloroquinoline-4-oxygen base of the present invention) phenolic ether] the carbon-13 nmr spectra figure of-2-naphthoamide.
[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 phenyl-6-[(7-of the N-as kinases inhibitor and NSC 630176 chloroquinoline-4-oxygen base) phenolic ether]-2-naphthoamide, described N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether] structural formula of-2-naphthoamide is as shown in the formula I:
The invention still further relates to a kind of N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether] preparation method of-2-naphthoamide, described preparation method's step is as follows:
A) compound ii of 1.0 equivalents is dissolved in 40 milliliters of ethanol, add 4 vitriol oils, reflux 4-5 hour at 78-85 ℃, underpressure distillation removes desolventizing and adds ethyl acetate, wash respectively 2～3 times with saturated sodium bicarbonate and saturated sodium-chloride again, merge organic phase, underpressure distillation, except desolventizing, obtains compound III;
Reaction equation is as follows:
Wherein, described compound ii is 6-hydroxyl-2-naphthoic acid, and described compound III is 6-Hydroxy-2-naphthoic acid ethyl ester;
B) the compound III of 1.0 equivalents is dissolved in 5 milliliters of DMF, under ice bath, stir, 10 milliliters of the DMF solution that slowly dropping contains 2.5 equivalent NaH again, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, 10 milliliters of DMF solution that slowly splash into the compounds Ⅳ that contains 1.2 equivalents and 0.2 equivalent KI, stir half an hour, react 8-10 hour at 110 ℃, obtain compound V
Reaction equation is as follows:
Wherein, described compounds Ⅳ is 4,7-dichloroquinoline, and described compound V is 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester;
C) 1.0 equivalent compound V are dissolved in 10 milliliters of ethanol, under ice bath, stir, 5 milliliters of the ethanolic solns that slowly dropping contains 2.5 equivalent NaOEt, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, slowly splash into 10 milliliters of ethanolic solns that contain 1.0 equivalent compound VI, stir half an hour, react 6-10 hour at 45-55 ℃, obtain Compound I
Reaction equation is as follows:
Wherein, described compound is that compound VI is aniline.
Described ethanol refers to dehydrated alcohol; The concentration of the described vitriol oil is 98%; Described DMF refers to analytically pure DMF; Described NaH refers to analytically pure sodium hydride; Described room temperature refers to 25 ℃; Described ice bath refers to that temperature is down to the ice bath of 0 ℃; Described KI refers to analytically pure potassiumiodide; Described NaOEt refers to analytically pure sodium ethylate.
Below in conjunction with specific embodiment, the present invention is further illustrated.
Embodiment 1:
Compound 6-hydroxyl-2-naphthoic acid 1.88g (10mmol) is dissolved in 40 milliliters of ethanol, add 4 vitriol oils, reflux 5 hours at 80 ℃, removal of solvent under reduced pressure obtains compound 6-Hydroxy-2-naphthoic acid ethyl ester 1.98g(9.2mmol afterwards), productive rate 91.7%, by compound 6-Hydroxy-2-naphthoic acid ethyl ester 1.98g(9.2mmol) be dissolved in 5 milliliters of DMF, under ice bath, stir, 10 milliliters of the DMF solution of the NaH that slowly dropping 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, 7-dichloroquinoline, and 10 milliliters of the DMF solution of 0.38g (1.8mmol) KI, stir half an hour, at 110 ℃, react 8-10 hour, 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, obtain 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 3.3g (8.7mmol) is dissolved in 10 milliliters of ethanol, under ice bath, stir, 5 milliliters of the ethanolic solns that slowly dropping contains 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 0.8g (8.7mmol) aniline, stir at 55 ℃ of half an hour and react 10 hours, reaction soln is removed in decompression, obtain reaction mixture, separate with silica gel column chromatography, the gradient of moving phase is: V (sherwood oil): V (ethyl acetate)=6:1, obtain target product N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-2-naphthoamide, 2.23g (4.5mmol), productive rate 52.0%.
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 (400MHz, DMSO-d
6): δ 10.48 (s, 1H), 8.78 (d, J=5.27Hz, 1H), 8.41 (d, J=8.78Hz, 1H), 8.29 (d, J=9.03Hz, 1H), 8.15 (t, J=4.52Hz, 1.51Hz, 1H), 8.09-8.08 (m, 2H), 7.93 (d, J=2.26Hz, 1H), 7.86 (t, J=8.53Hz, 1.00Hz, 1H), 7.74 (dd, J=8.78Hz, 2.01Hz, 1H), 7.63 (dd, J=8.78Hz, 2.26Hz, 1H), 7.41 (t, 15.81Hz, 7.53Hz, 2H), 7.68 (s, 1H), 7.15 (d, J=7.28Hz, 1H), 6.82 (d, J=5.02Hz, 1H),
Emphasis is consulted Fig. 2,
13c NMR (100MHz, DMSO-d
6): δ 165.84,161.11,153.55,150.29,139.66,135.84,135.54,132.69,132.42,130.50,129.12,128.19,128.6,127.65,125.90,124.27,124.21,121.82,120.89,120.01,117.58ESI-MS, m/z424.2[M-H]
+.
From the above, the target product of acquisition is N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-2-naphthoamide.
Embodiment 2: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, 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, leaves standstill and cultivates 24h, after cell is completely adherent, give respectively medicine (the 4 μ molL of different concns
-1, 8 μ molL
-1, 16 μ molL
-1and 32 μ molL
-1medicine, DMSO content is 1 ‰), positive controls gives the Gefitinib of same concentrations, negative control group gives the DMSO of same volume, cultivates respectively 24h, 48h and 72h, positive controls cultivate 72h, then lucifuge adds 5mgmL
-1mTT20 μ L, continues to cultivate after 4h, abandons nutrient solution, and every hole adds 150 μ L DMSO, and concussion is fully dissolved crystallisate, detects the absorbancy (A) at 490nm place by microplate reader, then calculates relative cell appreciation rate (RGR%).Experiment repeats 3 times.Select the antineoplastic experimental study of part to give an example.
A) human lung cancer cell A549's cell.Experimental result shows: at 10 μ molL
-1time, N-(3-trifluoromethyl)-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-2-naphthoamide is the most obvious to the inhibition of human lung cancer cell A549's cell, IC after administration 24h
50lower than 10 μ M.
B) human cervical carcinoma Hela 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 to human cervical carcinoma Hela cell's propagation at 2-10 μ molL
-1between there is remarkable restraining effect, and be significant concn dependency, IC after administration 24h
50lower than 10 μ M.
Therefore; N-phenyl-6-[(7-chloroquinoline-4-oxygen base of the present invention) phenolic ether]-2-naphthoamide; can be used as kinases inhibitor and NSC 630176; 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.N-phenyl-6-[(7-chloroquinoline-4-oxygen base of the present invention) phenolic ether]-2-naphthoamide, measure with mtt assay, find that it has obvious anti-tumor activity, described tumour cell comprises human lung cancer cell A549's cell and HeLa Cells etc.
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 (10)
1. N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether]-2-naphthoamide, it is characterized in that: described N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether] structural formula of-2-naphthoamide is as shown in the formula I:
2. N-phenyl-6-[(7-chloroquinoline-4-oxygen base) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: described preparation method's step is as follows:
A) compound ii of 1.0 equivalents is dissolved in 40 milliliters of ethanol, add 4 vitriol oils, reflux 4-5 hour at 78-85 ℃, underpressure distillation removes desolventizing and adds ethyl acetate, wash respectively 2～3 times with saturated sodium bicarbonate and saturated sodium-chloride again, merge organic phase, underpressure distillation, except desolventizing, obtains compound III;
Reaction equation is as follows:
Wherein, described compound ii is 6-hydroxyl-2-naphthoic acid, and described compound III is 6-Hydroxy-2-naphthoic acid ethyl ester;
B) the compound III of 1.0 equivalents is dissolved in 5 milliliters of DMF, under ice bath, stir, 10 milliliters of the DMF solution that slowly dropping contains 2.5 equivalent NaH again, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, 10 milliliters of DMF solution that slowly splash into the compounds Ⅳ that contains 1.2 equivalents and 0.2 equivalent KI, stir half an hour, react 8-10 hour at 110 ℃, obtain compound V
Reaction equation is as follows:
Wherein, described compounds Ⅳ is 4,7-dichloroquinoline, and described compound V is 6-(7-chloroquinoline-4-oxygen base) phenolic ether-2-naphthoic acid ethyl ester;
C) 1.0 equivalent compound V are dissolved in 10 milliliters of ethanol, under ice bath, stir, 5 milliliters of the ethanolic solns that slowly dropping contains 2.5 equivalent NaOEt, ice bath stirs half an hour, removes ice bath, treat that temperature returns to room temperature, slowly splash into 10 milliliters of ethanolic solns that contain 1.0 equivalent compound VI, stir half an hour, react 6-10 hour at 45-55 ℃, obtain Compound I
Reaction equation is as follows:
Wherein, described compound is that compound VI is aniline.
3. N-phenyl-6-[(7-chloroquinoline-4-oxygen base according to claim 2) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: described ethanol refers to dehydrated alcohol.
4. N-phenyl-6-[(7-chloroquinoline-4-oxygen base according to claim 2) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: the concentration of the described vitriol oil is 98%.
5. N-phenyl-6-[(7-chloroquinoline-4-oxygen base according to claim 2) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: described DMF refers to analytically pure DMF.
6. N-phenyl-6-[(7-chloroquinoline-4-oxygen base according to claim 2) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: described NaH refers to analytically pure sodium hydride.
7. N-phenyl-6-[(7-chloroquinoline-4-oxygen base according to claim 2) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: described room temperature refers to 25 ℃.
8. N-phenyl-6-[(7-chloroquinoline-4-oxygen base according to claim 2) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: described ice bath refers to that temperature is down to the ice bath of 0 ℃.
9. N-phenyl-6-[(7-chloroquinoline-4-oxygen base according to claim 2) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: described KI refers to analytically pure potassiumiodide.
10. N-phenyl-6-[(7-chloroquinoline-4-oxygen base according to claim 2) phenolic ether] preparation method of-2-naphthoamide, it is characterized in that: described NaOEt refers to analytically pure sodium ethylate.
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| 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 |
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