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Aniline quinazoline compounds containing nitroimidazole groups and their preparation methods and applications

A compound, dimethylformamide technology, applied in the field of aniline quinazoline compounds and their preparation, can solve the problems of lack of similar compounds and ineffective curative effect

Active Publication Date: 2019-07-09
INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The present invention aims at the technical defects of the prior art, and provides a kind of aniline quinazoline compound containing nitroimidazole group and its preparation method and application, so as to solve the technical problem of lacking a similar compound in the prior art
[0007] Another technical problem to be solved by the present invention is that the curative effect of drugs used to inhibit the EGFR signaling pathway in the prior art is not obvious

Method used

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  • Aniline quinazoline compounds containing nitroimidazole groups and their preparation methods and applications
  • Aniline quinazoline compounds containing nitroimidazole groups and their preparation methods and applications
  • Aniline quinazoline compounds containing nitroimidazole groups and their preparation methods and applications

Examples

Experimental program
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Embodiment 14

[0060] Example 1 Preparation of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate

[0061] Synthesized with reference to literature J.Med.Chem., 2002, 45, 1300. White solid; melting point 74.3-76.1°C; yield 93.8%. MS M / z: 214.77[M-1]; 1 H NMR (400MHz, DMSO-d 6 )δ0.95(ddd, J 1 =24.8Hz,J 2 =12.8Hz,J 3 =4.4Hz, 2H), 1.37(s, 9H), 1.49(m, 1H), 1.59(d, J=13.2Hz, 2H), 2.65(s, 2H), 3.23(t, J=6.0Hz, 2H ), 3.93 (d, J=12.4Hz, 2H), 4.42 (t, J=5.2Hz, 1H).

Embodiment 24

[0062] Example 2 Preparation of 4-methylbenzenesulfonic acid-(1-tert-butoxycarbonylpiperidin-4-yl)methyl ester

[0063] Synthesized with reference to literature J.Med.Chem., 2002, 45, 1300. White solid; melting point 72.4-73.6°C; yield 85.2%. MS M / z: 370.18[M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ0.96(ddd, J 1 =24.4Hz,J 2 =12.4Hz,J 3 =4.4Hz, 2H), 1.36(s, 9H), 1.53(d, J=11.2Hz, 2H), 1.76(m, 1H), 2.41(s, 3H), 2.63(s, 2H), 3.87(d , 4H), 7.47(d, J=8.0Hz, 2H), 7.77(d, J=8.0Hz, 2H).

Embodiment 34

[0064] Example 3 Preparation of 4-p-toluenesulfonyloxymethylpiperidine methanesulfonate

[0065] Synthesized with reference to the literature J.Org.Chem.2010, 75, 8117. White solid; melting point 113.0-114.5°C; yield 84.3%. MS M / z: 270.38[M+1]; 1 H NMR (400MHz, DMSO-d 6)δ1.31(m, 2H), 1.72(d, J=12.8Hz, 2H), 1.93(m, 1H), 2, 32(s, 3H), 2.42(s, 3H), 2.83(m, 2H ), 3.23(d, J=12.8Hz, 2H), 3.92(d, J=6.0Hz, 2H), 7.48(d, J=8.4Hz, 2H), 7.78(d, J=8.4Hz, 2H), 8.12 (br s, 1H), 8.50 (br s, 1H).

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Abstract

The invention provides a brand new anilinoquinazoline compound of the structure in the formula (I). The anilinoquinazoline compound has a tyrosine kinase inhibiting effect. Real-time fluorogenic quantitative PCR measurement results indicate that the VEGF expression quantity is reduced by 1000 times or more through the target compound, the inhibiting effect on VEGF expression is quite obvious, and the inhibiting activity is far higher than that of vandetanib. Further experiments indicate that the target compound has the better antineoplastic activity compared with vandetanib under the anoxia condition and is expected to be the medicine for treating tumors.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to aniline quinazoline compounds containing nitroimidazole groups, a preparation method and application thereof. Background technique [0002] The following background introduction related to the present invention is used to help the understanding of the present invention, but should not be considered as the prior art of the present invention. All cited publications are incorporated by reference in full. [0003] Tumor cells grow with blood vessels as the center. Cells that are more than 180 μm away from blood vessels are prone to form necrotic areas due to the drop in oxygen concentration and lack of nutrients. The low oxygen concentration area at the front of the necrotic area is hypoxic tissue, and hypoxic cells account for about 10-50% of tumor cells. %, most of them are in the G0 phase of cell dynamics, showing no proliferation or slow proliferation, relying on the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61K31/517A61P35/00
CPCC07D401/14
Inventor 李祎亮魏会强李德冠唐卫生段玉清尚海花樊赛军
Owner INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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