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Quinazoline derivative and application of quinazoline derivative to preparation of anti-tumor medicine

A technology of quinazoline and derivatives, which is applied in the field of preparation of antitumor drugs, and can solve problems such as serious side effects

Active Publication Date: 2017-09-26
SHAANXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the second-generation irreversible EGFR inhibitors, Afatinib (Dungo R T, Keating G M. Drug, 2013, 73(13): 1503-1515.), Dacomitinib, Neratinib (Hwei-ru T, et al. Journal of Medicinal Chemistry, 2005 ,48(4):1107-1131.), although they have good curative effect in the treatment of non-small cell lung cancer with T790M mutation, but their dose-related side effects are more serious, such as diarrhea, rash, etc. (Wenjun Z, Dalia E, Liang C, et al. Nature, 2009, 462(7276): 1070-1074.)

Method used

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  • Quinazoline derivative and application of quinazoline derivative to preparation of anti-tumor medicine
  • Quinazoline derivative and application of quinazoline derivative to preparation of anti-tumor medicine
  • Quinazoline derivative and application of quinazoline derivative to preparation of anti-tumor medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Embodiment 1: Synthesis of 6,7-difluoro-4-(3-chloro-4-fluoroanilino) quinazoline

[0079]

[0080] Add 6,7-difluoro-4-chloroquinazoline (740mg, 3.7mmol) and 3-chloro-4-fluoroaniline (537mg, 3.7mmol) into isopropanol (16mL), heat at reflux at 90°C for 4h, After the reaction solution was cooled, it was suction filtered, washed with isopropanol, and the filter cake was dried to obtain a light yellow solid 6,7-difluoro-4-(3-chloro-4-fluoroanilino)quinazoline (977mg, 3.16mmol ) with a yield of 85.3%. m.p.: 233.6-234.4°C, HRMS (C 14 h 7 CIF 3 N 3 )m / z[M+H] + :310.0361 (calculated value: 310.0353); 1 H NMR (600MHz, DMSO-d 6 )δ (ppm): 9.80 (s, 1H), 8.63 (s, 1H), 8.58 (dd, J = 11.6, 8.6Hz, 1H), 8.16 (dd, J = 6.8, 2.5Hz, 1H), 7.82- 7.77(m,2H),7.44(t,J=9.1Hz,1H); 13 C NMR (151MHz, DMSO-d 6 )δ (ppm): 156.92 (d, J = 3.7Hz), 154.85, 153.47 (d, J = 243.7Hz), 153.28 (dd, J = 254.9, 15.2Hz), 148.28 (dd, J = 248.2, 14.9Hz ), 147.87(d, J=11.4Hz), 136.05, 123.50, 122.30(d, J=...

Embodiment 2

[0081] Example 2: Synthesis of 6,7-difluoro-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline

[0082]

[0083] Add 6,7-difluoro-4-chloroquinazoline (800 mg, 4.0 mmol), 3-chloro-4-(3-fluorobenzyloxy)aniline (1.0 g, 4.0 mmol) into isopropanol (16 mL) , heated to reflux at 90°C for 4 hours, after cooling the reaction solution, suction filtered, washed with isopropanol, and dried the filter cake to obtain a yellow solid 6,7-difluoro-4-[3-chloro-4-(3-fluorobenzyl Oxy)anilino]quinazoline (1.5 g, 3.6 mmol), 90.2% yield. m.p.: 207.2-208.9°C, HRMS (C 21 h 13 CIF 3 N 3 O)m / z[M+H] + :416.0768 (calculated value: 416.0772); 1 H NMR (600MHz, DMSO-d 6 )δ (ppm): 9.72 (s, 1H), 8.61-8.57 (m, 2H), 8.01 (s, 1H), 7.79 (dd, J = 11.0, 8.1Hz, 1H), 7.70 (dd, J = 8.8 ,1.9Hz,1H),7.48(dd,J=14.2,7.5Hz,1H),7.34-7.31(m,2H),7.27(d,J=8.9Hz,1H),7.20-7.17(m,1H) ,5.26(s,2H); 13 C NMR (151MHz, DMSO-d 6 )δ (ppm): 162.99, 161.37, 157.05 (d, J = 3.8Hz), 155.08, 153.20 (dd, J = 254.3, 15.2Hz), 149.8...

Embodiment 3

[0084] Example 3: Synthesis of 6,7-difluoro-4-(3-ethynylanilino)quinazoline

[0085]

[0086] Add 6,7-difluoro-4-chloroquinazoline (500mg, 2.5mmol) and 3-ethynylaniline (293mg, 2.5mmol) into isopropanol (10mL), heat and reflux at 90°C for 4h, and cool the reaction solution After that, it was suction filtered, washed with isopropanol, and the filter cake was dried to obtain 7-difluoro-4-(3-ethynylanilino)quinazoline (572 mg, 2.0 mmol) as a yellow solid with a yield of 81.3%. m.p.: 233.7-234.8°C, HRMS (C 16 h 9 f 2 N 3 )m / z[M+H]+ :282.0834 (calculated value: 282.0837); 1 H NMR (600MHz, DMSO-d 6 )δ (ppm): 9.85 (s, 1H), 8.70-8.67 (m, 1H), 8.65 (s, 1H), 8.05 (s, 1H), 7.89 (d, J = 8.1Hz, 1H), 7.83- 7.79(m, 1H), 7.43(t, J=7.9Hz, 1H), 7.27(d, J=7.6Hz, 1H), 4.22(s); 13 CNMR (151MHz, DMSO-d 6 )δ (ppm): 158.97 (d, J = 2.9Hz), 154.32 (dd, J = 260.1, 15.8Hz), 151.61, 149.08 (dd, J = 251.0, 14.0Hz), 137.67 (d, J = 9.5Hz ),136.85,129.61,129.11,127.02,125.02,122.00,113.69(d,J=21.1...

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Abstract

The invention discloses a quinazoline derivative and application of the quinazoline derivative to preparation of anti-tumor medicine. The chemical structure of the derivative is shown as the formula in the specification; in the formula, the R1 and the R2 respectively and independently represent hydrogen, halogen, ethynyl, propylene-1-yl or halogenated benzyloxy; R3 represents fluorine, piperazinyl, 1-methyl piperazine, morpholinyl, 1-(2-methoxy ethyl) piperazinyl, 1-(2-diethylaminoethyl) piperazinyl or 1-acryloyl piperazinyl. The compound provided by the invention has the obvious proliferation inhibition effects on human colon cancer cells, human non-small cell lung cancer cells, human skin squamous carcinoma cells and EGFR T790M / L858R double mutation containing human lung cancer cells, and can be used for preparing anti-tumor medicine.

Description

technical field [0001] The present invention relates to a class of novel quinazoline derivatives and their salts and solvates; a preparation method of the compounds and their application in the preparation of antitumor drugs. Background technique [0002] The commonly used antineoplastic drugs in clinical practice are mainly cytotoxic drugs, which have unavoidable toxic and side effects. The recently emerging targeted tumor therapy has brought good news to cancer patients. Targeted tumor therapy drugs enter the body and can specifically combine with cancer-causing targets to play a role, causing tumor cells to specifically die without affecting the surrounding normal cells. Epidermal growth factor receptor is a receptor tyrosine kinase, and studies have shown that epidermal growth factor receptor (EGFR) is an important target for cancer treatment. With the understanding of the EGFR signal transduction pathway, some drugs targeting EGFR have been developed at this stage, in...

Claims

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Application Information

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IPC IPC(8): C07D239/94A61K31/517A61K31/5377A61P35/00
CPCC07D239/94
Inventor 李宝林侯巧丽张娅玲李夏冰王伟
Owner SHAANXI NORMAL UNIV
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