CN107903248B - N- replaces the Isatine derivatives and application in preparation of anti-tumor drugs of isatin heterozygosis quinazoline compounds synthesis - Google Patents

N- replaces the Isatine derivatives and application in preparation of anti-tumor drugs of isatin heterozygosis quinazoline compounds synthesis Download PDF

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CN107903248B
CN107903248B CN201711118862.4A CN201711118862A CN107903248B CN 107903248 B CN107903248 B CN 107903248B CN 201711118862 A CN201711118862 A CN 201711118862A CN 107903248 B CN107903248 B CN 107903248B
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base
diethyllaminoethyl
ketone
quinoline
quinazoline
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CN107903248A (en
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王伟
吕梦娇
李宝林
张娅玲
张颖
李夏冰
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Shaanxi Normal University
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

The invention discloses Isatine derivatives and application in preparation of anti-tumor drugs that a kind of N- replaces the synthesis of isatin heterozygosis quinazoline compounds, the structural formula of the derivative is

Description

N- replaces the Isatine derivatives of isatin heterozygosis quinazoline compounds synthesis and is preparing Application in anti-tumor drug
Technical field
The invention belongs to the synthesis technical fields of anti-tumor drug, and in particular to a kind of novel N- replaces isatin hydrazone heterozygosis 4- fragrant amino -6- (5- formylfuran -2- base) quinazoline synthesis Isatine derivatives and they preparing anti-tumor drug In purposes.
Background technique
Cancer is also known as malignant tumour, is one of the disease for seriously endangering human health.Traditional treatment side of malignant tumour Method has: radiotherapy, operative treatment, chemotherapy, but itself has some limitations.Anticancer drug is largely thin Born of the same parents' poison class drug, this kind of drug also have great toxic side effect while killing cancer cell, to normal human tissue cell. Therefore, the high anticancer drug of research and development synthesis of selective has become the hot spot of research field.In recent years, people, which have begun to focus on, is directed to Key gene, regulatory molecule and specific cells receptor are the research of the drug of therapy target.
Studies have shown that tyrosine kinase plays an important role in cell growth, proliferation, atomization, when it is excessively living When change, cell growth control is out of hand, and death is obstructed, and is in vegetative state always, finally results in the generation of malignant tumour.Cause This, inhibits tyrosine kinase activity, and the signal transduction path for blocking it to activate becomes one of the new way for the treatment of tumour.
EGF-R ELISA (EGFR) signal path has multiple biological action, in human tumor cell often It expresses and out of hand, it is closely related with the formation of tumour.Therefore, therapy field of the EGFR tyrosine kinase inhibitor in tumour It has been to be concerned by more and more people.EGFR tyrosine kinase inhibitor can interfere or block the expression approach of receptor protein, have The phosphorylation of the control downstream signal of effect, to inhibit the process of tumor cell proliferation, division, and then accelerates tumour cell to wither It dies, achievees the purpose that treat tumour.
Until up to now, it has been found that EGFR tyrosine kinase inhibitor have: indoles, flavones, osajin, quinoline The compounds such as oxazolines, aryl urea and miazines.Wherein, active higher, the preferable small molecule tyrosine-kinase of selectivity Enzyme inhibitor is 4- fragrant amino quinazoline compounds, the anti-tumor drug listed such as: it is Lapatinib (Lapatinib), lucky It is non-to replace Buddhist nun (Gefitinib, Iressa) and Vande Thani (Vandetanib) etc..These drugs play in the treatment of tumour Good effect, but certain side effect and drug resistance can be generated after being used for a long time, the effect for the treatment of tumour is reduced, and after being Phase treatment affects.Thus, it is found that and synthesizing the small anti-tumor drug low with drug resistance of toxic side effect as in current weight Weight.Lapatinib is 4- fragrant amino quinazoline compounds, the small molecule junket ammonia as a kind of novel reversible double target spots Acid kinase inhibitor has in terms of the treatment Several Kinds of Malignancy especially breast cancer in advanced stage and has a better effect.Isatin is one A critically important medicine intermediate and raw material, isatin and its derivative have a variety of physiological activity.C-3 replaces Isatine derivatives Physiological activity includes anticancer, antiviral, anticonvulsion etc..When C-3 is hydrazone or imines replaces, tyrosine-kinase enzyme activity can be inhibited Property.The heterozygosis of pharmacophoric group is a kind of method of effective, common discovery novel drugs, two or more bioactivity The heterozygosis of segment has complementary pharmacodynamic feature or different mechanism of action, typically exhibits the effect of collaboration.
Summary of the invention
Technical problem to be solved by the present invention lies in provide a new class of N- with anti-tumor activity to replace isatin hydrazone It is prepared by the Isatine derivatives and these compounds of heterozygosis 4- fragrant amino -6- (5- formylfuran -2- base) quinazoline synthesis Purposes in anti-tumor drug.
The structural formula for solving Isatine derivatives used by above-mentioned technical problem is as follows:
X represents hydrogen, fluorine, chlorine, bromine, any one in iodine in formula, Ar represent the chloro- 4- fluorophenyl of 3- ethynyl phenyl, 3-, Any one in the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl, 4- (E)-acrylic phenyl.
Any one in the above-mentioned preferred following compounds A~I of Isatine derivatives:
A:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (3- 3-ethynylphenylamino) quinazoline -6- base) furan Mutter -2- base) methylene) hydrazono-) indole-2-ketone
B:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (3- 3-ethynylphenylamino) quinazoline -6- base) furan Mutter -2- base) methylene) hydrazono-) -5- fluoro indole quinoline -2- ketone
C:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (3- 3-ethynylphenylamino) quinazoline -6- base) furan Mutter -2- base) methylene) hydrazono-) -5--bromo indole quinoline -2- ketone
D:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- fluoroanilino of 3-) quinazoline -6- base) Furans -2- base) methylene) hydrazono-) indole-2-ketone
E:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- fluoroanilino of 3-) quinazoline -6- base) Furans -2- base) methylene) hydrazono-) -5- fluoro indole quinoline -2- ketone
F:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- fluoroanilino of 3-) quinazoline -6- base) Furans -2- base) methylene) hydrazono-) -5--bromo indole quinoline -2- ketone
G:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenylamino) quinoline Oxazoline -6- base) furans -2- base) methylene) hydrazono-) indole-2-ketone
H:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenylamino) quinoline Oxazoline -6- base) furans -2- base) methylene) hydrazono-) -5- fluoro indole quinoline -2- ketone
I:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenylamino) quinoline Oxazoline -6- base) furans -2- base) methylene) hydrazono-) -5--bromo indole quinoline -2- ketone
The synthetic route and synthetic method of above-mentioned Isatine derivatives are as follows:
N- shown in formula 2 is replaced into 4- fragrant amino -6- (5- formylfuran -2- base) quinoline azoles shown in isatin hydrazone and formula 1 Quinoline is condensed in the presence of acetic acid can be obtained Isatine derivatives shown in formula 3.
N- of the present invention replaces the isatin of isatin hydrazone heterozygosis 4- fragrant amino -6- (5- formylfuran -2- base) quinazoline synthesis The purposes of derivative in the preparation of antitumor drugs, routinely pharmaceutical formulation, with pharmaceutically acceptable carrier according to various The conventional fabrication process of preparation is made, and can be tablet, granule, capsule etc..
Above-mentioned tumour is people's cutaneous squamous cancer cell A431, human colon cancer cell SW480, Non-small cell lung carcinoma cell Any one in A549, human lung carcinoma cell NCI-H1975.
The synthetic method of Isatine derivatives of the present invention is simple, has good inhibiting effect to the proliferation of tumour cell, can Be used to prepare anti-tumor drug, both can medication alone, can also be used in combination with other medicines;Wherein compound A, B, E, G couple Application on human skin squamous cancer cell A431, human lung carcinoma cell NCI-H1975, human colon cancer cell SW480, Non-small cell lung carcinoma cell The proliferation of A549 all has apparent inhibiting effect, and effect is substantially better than the anti-tumor drug Lapatinib of clinical use.
Specific embodiment
Below with reference to embodiment, invention is further described in detail, but protection scope of the present invention is not limited only to these Embodiment.
4- used in following example (3- ethynylanilino) -6- (5- formylfuran -2- base) quinazoline, 4- (the chloro- 4- fluoroanilino of 3-) -6- (5- formylfuran -2- base) quinazoline bibliography [chemistry notification, 2016,79 (4): 360 ~365] the method synthesis in;4- [the chloro- 4- of 3- (3- fluorine benzyloxy) phenylamino] -6- (5- formylfuran -2- base) quinazoline Bibliography [China Medicine University's journal, 2010,41 (4): the method synthesis in 317~320];1- (diethyllaminoethyl)- 1- hydrogen indoles -2,3- diketone bibliography [Pharmaceutical Chemistry Journal, 2006,40 (11): 595~ 602] the method synthesis in;(Z) -1- (diethyllaminoethyl) -3- hydrazone indole-2-ketone referenced patent [US 20120252860] In method synthesis.Other agents useful for same are that analysis is pure.Compound structure determines nuclear magnetic resonance data used by Bruker 600 NMR spectrometer with superconducting magnet of Avance measurement, using TMS as internal standard;Ir data uses Nicolet 170SX FT- IR determination of infrared spectroscopy;Fusing point using X-6 micro melting point apparatus (Beijing Tyke Instrument Ltd.) measurement (temperature not into Row correction);Mass spectrometric data is measured with Bruker Esquire 3000plus mass spectrograph.
Embodiment 1
Synthesize compound A
By 0.1018g (0.3mmol) 4- (3- ethynylanilino) -6- (5- formylfuran -2- base) quinazoline, 0.0780g (0.3mmol) (Z) -1- (diethyllaminoethyl) -3- hydrazone indole-2-ketone, 0.3mL acetic acid, 7mL ethyl alcohol and 0.1mL N,N-Dimethylformamide is added in reaction flask, and back flow reaction 6 hours at 79 DEG C are cooled to room temperature after having reacted, decompression Revolving removes solvent, and gained residue is recrystallized with MeOH/THF, obtains red solid i.e. compound A 0.1361g, yield It is 77.9%, m.p.242.0-244.4 DEG C, structural characterization data are as follows: HRMS (C35H31N7O2)m/z[M+H]+: 582.2614 (meters Calculation value 582.2617);1H NMR(600MHz,DMSO-d6)δ(ppm):10.16(s,1H),9.05(s,1H),8.74(s,1H), 8.69 (s, 1H), 8.48 (d, J=6.4Hz, 1H), 8.36 (d, J=8.2Hz, 1H), 8.09 (s, 1H), 8.03 (d, J= 7.7Hz, 1H), 7.93 (d, J=8.9Hz, 1H), 7.66-7.65 (m, 1H), 7.54-7.49 (m, 2H), 7.47 (t, J= 7.7Hz, 1H), 7.29 (d, J=7.3Hz, 1H), 7.25 (d, J=7.3Hz, 1H), 7.22-7.17 (m, 1H), 4.26 (s, 1H), 4.12(brs,2H),3.24(brs,4H),1.19(brs,6H);13C NMR(151MHz,DMSO-d6)δ(ppm):164.1, 157.7,157.0,155.0,152.3,151.0,150.0,149.2,146.0,144.4,139.4,133.5,129.6, 129.3,129.0,126.9,126.7,124.9,123.3,123.1,122.6,121.9,119.2,116.7,115.5, 110.6,109.5,83.4,80.7,48.6,46.4,34.8,8.7;IRνmax(KBr)cm-1:3448,2929,1714,1608, 1533,1384,1161,842,746,590。
Embodiment 2
Synthesize compound B
In the present embodiment, is replaced and implemented with equimolar (Z) -1- (diethyllaminoethyl) -3- hydrazone -5- fluoro indole quinoline -2- ketone (Z) -1- (diethyllaminoethyl) -3- hydrazone indole-2-ketone in example 1, other steps are same as Example 1, obtain red solid Body, that is, compound B 0.1340g, yield 74.6%, m.p.253.5-256.2 DEG C, structural characterization data are as follows: HRMS (C35H30FN7O2)m/z[M+H]+: 600.2521 (calculated values 600.2523);1H NMR(600MHz,DMSO-d6)δ(ppm): 10.11 (s, 1H), 9.08 (s, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 8.32 (d, J=8.6Hz, 1H), 8.24 (dd, J= 8.0,2.0Hz, 1H), 8.08 (s, 1H), 7.96 (d, J=8.0Hz, 1H), 7.90 (d, J=8.6Hz, 1H), 7.68 (d, J= 3.5Hz, 1H), 7.50 (d, J=3.5Hz, 1H), 7.45 (t, J=7.9Hz, 1H), 7.41 (td, J=8.7Hz, 2.7Hz, 1H), 7.29-7.28(m,2H),4.21(s,1H),4.14(brs,2H),3.41(brs,2H),3.29-3.22(m,4H),1.22(t,J =6.7Hz, 6H);13C NMR(151MHz,DMSO-d6)δ(ppm):164.0,159.0,157.8,157.4,157.3,154.1 (d,1JC-F=270Hz), 150.8,149.9,149.1,140.6,139.2,129.1,128.9,128.7,127.1,12 6.7, 125.2,123.7,123.0,121.8,119.6(d,2JC-F=23.4Hz), 119.4,117.3 (d,3JC-F=8.9Hz), 116.4 (d,2JC-F=26.1Hz), 115.5,110.8,110.7 (d,3J C-F=8.2Hz), 83.4,80.6,47.8,46.4,34.7, 8.3;IR νmax(KBr)cm-1:3490,2974,1716,1573,1533,1384,1164,1028,847,574。
Embodiment 3
Synthesize compound C
In the present embodiment, is replaced and implemented with equimolar (Z) -1- (diethyllaminoethyl) -3- hydrazone -5--bromo indole quinoline -2- ketone (Z) -1- (diethyllaminoethyl) -3- hydrazone indole-2-ketone in example 1, other steps are same as Example 1, obtain red solid Body, that is, compound C 0.1409g, yield 76.2%, m.p.278.7-281.0 DEG C, structural characterization data are as follows: HRMS (C35H30ClN7O2)m/z[M+H]+: 616.2218 (calculated values: 616.2228);1H NMR(600MHz,DMSO-d6)δ(ppm): 10.13 (s, 1H), 9.09 (s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.55 (brs, 1H), 8.37 (d, J=8.6Hz, 1H), 8.03 (s, 1H), 7.91 (d, J=8.2Hz, 2H), 7.65 (d, J=3.1Hz, 1H), 7.61 (d, J=7.9Hz, 1H), 7.50 (d, J=3.1Hz, 1H), 7.45 (t, J=8.0Hz, 1H), 7.31-7.27 (m, 2H), 4.23 (s, 1H), 4.14 (brs, 2H),3.40(brs,2H),3.26(brs,4H),1.21-1.20(m,6H);13C NMR(151MHz,DMSO-d6)δ(ppm): 163.7,157.8,157.2,155.0,153.2,150.8,148.9,142.9,139.1,132.6,129.0,128.9, 128.6,127.1,126.6,125.4,124.3,123.1,121.8,119.6,118.0,115.4,111.2,111.1, 110.7,83.3,80.7,47.8,46.4,34.6,8.4;IR νmax(KBr)cm-1:3490,2974,1716,1573,1533, 1384,1164,1028,847,574。
Embodiment 4
Synthesize compound D
In the present embodiment, with equimolar 4- (the chloro- 4- fluoroanilino of 3-) -6- (5- formylfuran -2- base) quinazoline 4- (3- ethynylanilino) -6- (5- formylfuran -2- base) quinazoline in alternative embodiment 1, other steps and implementation Example 1 is identical, obtains red solid i.e. compound D 0.1526g, yield 83.4%, and m.p.231.5-234.1 DEG C, structure table Levy data are as follows: HRMS (C33H29ClFN7O2)m/z[M+H]+: 610.2130 (calculated values: 610.2134);1H NMR(600MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 9.01 (s, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.47 (d, J=7.4Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.20 (d, J=4.8Hz, 1H), 7.93 (d, J=7.8Hz, 2H), 7.65 (d, J= 3.2Hz, 1H), 7.55-7.47 (m, 3H), 7.27 (d, J=7.8Hz, 1H), 7.19 (t, J=7.5Hz, 1H), 4.15 (brs, 2H), 3.42 (brs, 2H), 3.29 (brs, 4H), 1.22 (t, J=6.8Hz, 6H);13C NMR(151MHz,DMSO-d6)δ (ppm):164.1,157.7,156.9,154.9,154.3,152.7,152.2,150.0(d,1JC-F=263Hz), 149.8, 144.3,136.3(d,4JC-F=1.8Hz), 133.5,129.6,129.4,128.9,126.8 (d,3JC-F=8.8Hz), 123.7, 123.3,123.0,122.5(d,3JC-F=6.8Hz), 119.1,118.9 (d,2JC-F=18.4Hz), 116.7,116.6 (d,2JC-F=21.4Hz), 115.4,110.7,109.6,47.9,46.4,34.5,8.3;IR νmax(KBr)cm-1:3456,2925, 1716,1608,1496,1191,1031,810,752,549。
Embodiment 5
Synthesize compound E
In the present embodiment, is replaced and implemented with equimolar (Z) -1- (diethyllaminoethyl) -3- hydrazone -5- fluoro indole quinoline -2- ketone (Z) -1- (diethyllaminoethyl) -3- hydrazone indole-2-ketone in example 4, other steps are same as Example 4, obtain red solid Body, that is, compound E 0.1524g, yield 81.0%, m.p.249.6-252.1 DEG C, structural characterization data are as follows: HRMS (C33H28ClFN7O2)m/z[M+H]+: 628.2036 (calculated values: 628.2039);1H NMR(600MHz,DMSO-d6)δ(ppm): 10.12 (s, 1H), 8.98 (s, 1H), 8.74 (s, 1H), 8.64 (s, 1H), 8.27 (d, J=7.5Hz, 1H), 8.23 (dd, J= 8.2,2.4Hz, 1H), 8.19 (d, J=4.8Hz, 1H), 7.90 (d, J=7.8Hz, 1H), 7.85 (d, J=8.6Hz, 1H), 7.65 (d, J=3.6Hz, 1H), 7.47-7.44 (m, 2H), 7.40 (td, J=9.0,2.7Hz, 1H), 7.28 (dd, J=8.5, 4.0Hz, 1H), 4.13 (t, J=5.3Hz, 2H), 3.30 (brs, 4H), 1.23 (t, J=7.1Hz, 6H);13C NMR(151MHz, DMSO-d6)δ(ppm):164.0,158.3(d,1JC-F=215.4Hz), 157.4,157.2,154.8,153.5 (d,1JC-F= 242.2Hz),153.3,150.9(d,4JC-F=2.2Hz), 149.8,149.0,140.5,136.2 (d,4JC-F=2.0Hz), 129.0,128.7,126.7,123.8(d,3JC-F=7.3Hz), 123.7,122.5 (d,3JC-F=6.8Hz), 119.6 (d,2JC-F =23.4Hz), 119.2,118.8 (d,2JC-F=18.1Hz), 117.3 (d,3JC-F=9.2Hz), 116.5 (d,2JC-F= 21.5Hz),116.4,115.3,110.8,110.6(d,3JC-F=7.4Hz), 48.6,46.4,34.6,8.4;IR νmax(KBr) cm-1:3431,2979,1720,1614,1498,1166,1029,891,810,547。
Embodiment 6
Synthesize compound F
In the present embodiment, is replaced and implemented with equimolar (Z) -1- (diethyllaminoethyl) -3- hydrazone -5--bromo indole quinoline -2- ketone (Z) -1- (diethyllaminoethyl) -3- hydrazone indole-2-ketone in example 4, other steps are same as Example 4, obtain red solid Body, that is, compound F 0.1518g, yield 78.6%, m.p.251.6-252.7 DEG C, structural characterization data are as follows: HRMS (C33H28Cl2FN7O2)m/z[M+H]+: 644.1731 (calculated values: 644.1744);1H NMR(600MHz,DMSO-d6)δ (ppm): 10.05 (s, 1H), 8.95 (s, 1H), 8.73 (s, 1H), 8.61 (s, 1H), 8.47 (m, 1H), 8.27 (d, J= 8.7Hz, 1H), 8.13 (d, J=4.5Hz, 1H), 7.84-7.80 (m, 2H), 7.59 (d, J=3.6Hz, 1H), 7.57 (dd, J= 8.5,1.8Hz, 1H), 7.46 (t, J=9.0Hz, 1H), 7.42 (d, J=3.6Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 4.10 (brs, 2H), 3.27 (brs, 4H), 1.21 (t, J=6.9Hz, 6H);13C NMR(151MHz,DMSO-d6)δ(ppm): 163.8,157.6,157.1,154.9,154.3,153.3,152.7,149.8(d,1JC-F=278.3Hz), 148.9,142.8, 136.1 132.5,129.0,128.9,128.6,127.1,126.6,124.2,124.0,122.8(d,3JC-F=6.7Hz), 119.4,118.8(d,2JC-F=18.1Hz), 117.9,116.5 (d,2JC-F=21.6Hz), 115.3,111.1,110.6, 47.8,46.4,34.7,8.8;IRνmax(KBr)cm-1:3525,2935,1722,1608,1496,1365,1031,804,630, 547。
Embodiment 7
Synthesize compound G
In the present embodiment, with equimolar 4- [the chloro- 4- of 3- (3- fluorine benzyloxy) phenylamino] -6- (5- formylfuran -2- Base) 4- (3- ethynylanilino) -6- (5- formylfuran -2- base) quinazoline in quinazoline alternative embodiment 1, other steps It is rapid same as Example 1, obtain red solid i.e. compound G 0.1389g, yield 64.7%, m.p.174.5-176.9 DEG C, structural characterization data are as follows: HRMS (C40H35ClFN7O3)m/z[M+H]+: 716.2556 (calculated values: 716.2552);1H NMR (600MHz,DMSO-d6)δ(ppm):10.23(s,1H),9.26(s,1H),9.06(s,1H),8.74(s,1H),8.65(s, 1H), 8.47 (d, J=7.2Hz, 1H), 8.36 (d, J=8.6Hz, 1H), 8.04 (s, 1H), 7.93 (d, J=8.7Hz, 1H), 7.83 (d, J=8.8Hz, 1H), 7.65 (d, J=2.8Hz, 1H), 7.54-7.45 (m, 3H), 7.31-7.35 (m, 3H), 7.28 (d, J=7.8Hz, 1H), 7.19 (t, J=7.0Hz, 2H), 5.29 (s, 2H), 4.16 (brs, 2H), 3.41 (d, J=4.3Hz, 2H), 3.26-3.27 (m, 4H), 1.22 (t, J=6.8Hz, 6H);13C NMR(151MHz,DMSO-d6)δ(ppm):163.8, 162.2(d,1JC-F=243,1Hz), 157.6,157.0,155.0,152.0,151.0,149.9,149.7,149.1,144.7, 139.6(d,3JC-F=7.6Hz), 133.4,133.1,130.5 (d,3JC-F=9.1Hz), 129.6,129.0,128.7,126.6, 124.4,123.9,123.3(d,4JC-F=1.5Hz), 123.1,122.7,122.1,121.1,119.1,116.5,115.4, 114.6(d,2JC-F=21.1Hz), 114.3,114.0 (d,2JC-F=22.6Hz), 110.5,109.8,109.5,69.4,48.4, 46.5,35.9,9.9;IR νmax(KBr)cm-1:3654,2968,1714,1604,1382,1267,1024,794,750,513。
Embodiment 8
Synthesize compound H
In the present embodiment, is replaced and implemented with equimolar (Z) -1- (diethyllaminoethyl) -3- hydrazone -5- fluoro indole quinoline -2- ketone (Z) -1- (diethyllaminoethyl) -3- hydrazone indole-2-ketone in example 7, other steps are same as Example 7, obtain red solid Body, that is, compound H 0.1405g, yield 63.8%, m.p.196.7-197.3 DEG C, structural characterization data are as follows: HRMS (C40H34ClF2N7O3)m/z[M+H]+: 734.2464 (calculated values: 734.2458);1H NMR(600MHz,DMSO-d6)δ (ppm): 10.00 (s, 1H), 8.98 (s, 1H), 8.72 (s, 1H), 8.60 (s, 1H), 8.25 (d, J=8.8Hz, 1H), 8.18 (d, J=6.4Hz, 1H), 8.03 (s, 1H), 7.83 (d, J=8.6Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.63 (d, J= 2.0Hz, 1H), 7.52-7.46 (m, 1H), 7.44 (d, J=2.6Hz, 1H), 7.37-7.32 (m, 3H), 7.28 (d, J= 9.0Hz,1H),7.22-7.17(m,2H),5.27(s,2H),3.95(brs,2H),2.99(brs,4H),1.06(brs,6H);13C NMR(151MHz,DMSO-d6)δ(ppm):163.7,162.2.(d,1JC-F=244.6Hz), 158.8 (d,1JC-F= 238.6Hz),157.6,157.2(d,3JC-F=6.0Hz), 155.1,153.0,150.9 (d,4JC-F=3.0Hz), 149.9, 149.8,149.0,145.8,141.0,139.6(d,3JC-F=7.5Hz), 132.9,130.5 (d,3JC-F=7.5Hz), 128.8, 128.7,126.5,124.4,124.1,123.5,123.3(d,4JC-F=3.0Hz), 122.6,122.3,121.0,119.5 (d,2JC-F=24.2Hz), 119.2,116.4 (d,2JC-F=25.7Hz), 115.3,114.7 (d,2JC-F=21.1Hz), 114.2, 114.0(d,2JC-F=21.1Hz), 110.6 (d,3JC-F=9.1Hz), 110.6,69.4,48.4,46.5,36.0,10.0;IR νmax(KBr)cm-1:3332,2636,1710,1617,1498,1417,1269,1028,810,518。
Embodiment 9
Synthesize compound I
In the present embodiment, is replaced and implemented with equimolar (Z) -1- (diethyllaminoethyl) -3- hydrazone -5--bromo indole quinoline -2- ketone (Z) -1- (diethyllaminoethyl) -3- hydrazone indole-2-ketone in example 7, other steps are same as Example 7, obtain red solid Body, that is, compound I 0.1379g, yield 61.3%, m.p.199.3-200.9 DEG C, structural characterization data are as follows: HRMS (C34H21Cl2FN6O3)m/z[M+H]+: 750.2166 (calculated values: 750.2162);1H NMR(600MHz,DMSO-d6)δ (ppm): 10.16 (s, 1H), 9.03 (s, 1H), 8.77 (d, J=4.6Hz, 1H), 8.62 (s, 1H), 8.52 (d, J=5.4Hz, 1H), 8.33 (t, J=7.7Hz, 1H), 7.97 (s, 1H), 7.85 (t, J=8.3Hz, 1H), 7.73 (d, J=8.3Hz, 1H), 7.68-7.56 (m, 2H), 7.52-7.42 (m, 2H), 7.33 (dd, J=27.2,8.6Hz, 4H), 7.20 (t, J=8.3Hz, 1H), 5.28 (s, 2H), 4.13 (brs, 2H), 3.40 (brs, 2H), 3.28 (brs, 4H), 1.22 (t, J=7.0Hz, 6H);13C NMR(151MHz,DMSO-d6)δ(ppm):163.8,162.2(d,1JC-F=244.6Hz), 157.9,157.1,154.8, 153.2,150.7,150.1,148.9,142.9,139.6(d,3JC-F=7.5Hz), 132.6,130.5 (d,3JC-F=7.5Hz), 129.0,127.9,127.1,126.7,125.9,124.6,124.3,123.3(d,4JC-F=3Hz), 122.8,122.6, 121.1,119.5,118.0,115.2,114.7(d,2JC-F=21.1Hz), 114.3,114.0 (d,2JC-F=21.1Hz), 111.5,111.2,110.7,69.4,47.8,46.4,34.6,8.3;IR νmax(KBr)cm-1:3422,2640,1714,1598, 1382,1261,1026,981,798,513。
Embodiment 10
Indole-2-ketone derivative of the present invention and its application in preparation of anti-tumor drugs
Inventor using compound A~I of above-described embodiment synthesis as test-compound, tests it to tumour cell respectively Growth inhibiting effect, specific test situation is as follows:
1, cell strain
Application on human skin squamous cancer cell A431, human lung carcinoma cell NCI-H1975, human colon cancer cell SW480, people's non-small cell Lung cell A549 is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences.
2, reagent and material
MTT (MPBIO), 96 porocyte culture plates (CorningCostar), fetal calf serum (Gibco), DMEM (Dulbecco ' s Modified Eagle Medium powder, high glucose, Gibco BRL, Gibco), mould Element, streptomysin (the green skies), tryptic digestive juice (the green skies), microplate reader (PE Enspire).
3, experimental procedure
(1) cell culture
A431, NCI-H1975, SW480 and A549 cell complete medium (containing 10% (v/v) fetal calf serum, The DMEM culture medium of 100units/mL penicillin, 100 μ g/mL streptomysins and 2mmol/L L-Glutamine) in, it is placed in saturation Humidity, 37 DEG C, 5%CO2It is cultivated in incubator.It is primary every passage in 2~3 days.
(2) anti-tumor activity detects
Compound A~I is measured the growth inhibitory activity of tumour cell using mtt assay.Logarithmic growth phase respectively Human tumor cells, with 0.25% tryptic digestive juice digestion, centrifugation, be resuspended after count, prepare cell suspension, adjustment is thin Born of the same parents' suspension concentration is 2.0 × 104~5 × 104A/mL.Cell suspension inoculation (100 hole μ L/) in 96 well culture plates is taken, is set full With humidity, 37 DEG C and 5%CO2It is cultivated for 24 hours in incubator.Test-compound is diluted to required concentration with complete medium, is added (100 hole μ L/) has been inoculated in 96 well culture plates of human tumor cells, and DMSO final concentration of 0.5% is placed in incubator and cultivates 72h.MTT is added in 96 orifice plates (20 hole μ L/), reacts 4h in incubator.It inhales and abandons liquid in hole, DMSO (150 μ L/ are added Hole), 10min is shaken on shaking table, and Shi formazan is completely dissolved.Then the absorbance (OD value) at 570nm wavelength is measured with microplate reader, Absorbance at 630nm wavelength calculates inhibitory rate of cell growth using coordinative solvent as control as reference.
Test-compound is as follows to the calculation of growth of tumour cell inhibiting rate:
Growth of tumour cell inhibiting rate %=[1- (ODs-ODNC)/(ODPC-ODNC)] × 100%
Wherein:
ODSIndicate the absorbance value (cell+untested compound+MTT) of sample well;
ODPCIndicate the absorbance value (cell+DMSO+MTT) of control wells;
ODNCIndicate the absorbance value (complete medium+DMSO+MTT) of zeroing hole;
ODs=OD570s-OD630s;ODPC=OD570PC-OD630PC;ODNC=OD570NC-OD630NC。
Fitting and IC of the test-compound to growth of tumour cell suppression curve50Calculating:
Using Graphpad Prism5 fitting test-compound to the suppression curve of growth of tumour cell, and obtain IC50 Value.3 multiple holes of every group of setting, are at least repeated 3 times.
4, experimental result
Using the anti-tumor drug Lapatinib of clinical use as positive control, experimental result is as shown in table 1.
The IC of 1 test-compound of table inhibition tumor cell proliferation50(μmol/L)
Available by the data in table 1, test-compound A, B, E, G are to application on human skin squamous cancer cell A431, human lung cancer Cell NCI-H1975, human colon cancer cell SW480, Non-small cell lung carcinoma cell A549 proliferation all have apparent inhibition Effect, effect are substantially better than Lapatinib;Test-compound C, D are to human colon cancer cell SW480, human lung carcinoma cell NCI- The proliferation of H1975 and Non-small cell lung carcinoma cell A549 all have apparent inhibiting effect, and effect is better than Lapatinib;By Examination compound F has apparent inhibiting effect to human colon cancer cell SW480;Test-compound H and I is to application on human skin squamous cancer cell The proliferation of A431 significantly inhibits.Pharmacological activity statistics indicate that, test-compound A, B, C, D, E, G show compared with The effect of strong inhibition tumor cell proliferation.

Claims (3)

1. the Isatine derivatives that one kind N- replaces the synthesis of isatin heterozygosis quinazoline compounds, it is characterised in that under the derivative is Any one in column compound A~I:
A:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (3- 3-ethynylphenylamino) quinazoline -6- base) furans -2- Base) methylene) hydrazono-) indole-2-ketone
B:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (3- 3-ethynylphenylamino) quinazoline -6- base) furans -2- Base) methylene) hydrazono-) -5- fluoro indole quinoline -2- ketone
C:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (3- 3-ethynylphenylamino) quinazoline -6- base) furans -2- Base) methylene) hydrazono-) -5--bromo indole quinoline -2- ketone
D:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- fluoroanilino of 3-) quinazoline -6- base) furan Mutter -2- base) methylene) hydrazono-) indole-2-ketone
E:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- fluoroanilino of 3-) quinazoline -6- base) furan Mutter -2- base) methylene) hydrazono-) -5- fluoro indole quinoline -2- ketone
F:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- fluoroanilino of 3-) quinazoline -6- base) furan Mutter -2- base) methylene) hydrazono-) -5--bromo indole quinoline -2- ketone
G:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenylamino) quinoline azoles Quinoline -6- base) furans -2- base) methylene) hydrazono-) indole-2-ketone
H:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenylamino) quinoline azoles Quinoline -6- base) furans -2- base) methylene) hydrazono-) -5- fluoro indole quinoline -2- ketone
I:(E) -1- (2- (diethyllaminoethyl) -3- (((E)-(5- (4- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenylamino) quinoline azoles Quinoline -6- base) furans -2- base) methylene) hydrazono-) -5--bromo indole quinoline -2- ketone
2. N- described in claim 1 replace the Isatine derivatives of isatin heterozygosis quinazoline compounds synthesis prepare it is antitumor Purposes in drug.
3. N- according to claim 2 replaces the purposes of Isatine derivatives in the preparation of antitumor drugs, it is characterised in that: The tumour is people's cutaneous squamous cancer cell A431, human colon cancer cell SW480, Non-small cell lung carcinoma cell A549, people Any one in lung carcinoma cell NCI-H1975.
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