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Quinazoline compound, preparation method and application thereof

A compound, selected technology, applied in the fields of organic chemistry, drug combination, anti-tumor drugs, etc., can solve the problems of prolonging the overall survival of patients, difficult to take effect, and no observed therapeutic effect.

Inactive Publication Date: 2015-09-16
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the second-generation inhibitors have shown good inhibitory effect on T-790M mutant drug-resistant tumors in preclinical, no outstanding therapeutic effect has been observed clinically
Although the third-generation irreversible inhibitors such as CO-1686 and AZD-9291 have shown better effects on T-790M mutant tumors, initial clinical trials have shown a certain therapeutic effect on mutation-activated tumors, but considering the growth of T-790M mutant tumors , Invasion still requires EGFR signal transduction, so it is difficult for such inhibitors to really work and prolong the overall survival of patients

Method used

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  • Quinazoline compound, preparation method and application thereof
  • Quinazoline compound, preparation method and application thereof
  • Quinazoline compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1: (S, E)-N-(4-(3-chloro-4-fluoroanilino)-7-(tetrahydrofuran-3-yloxy) Synthesis of quinazolin-6-yl)-4-(cyclopropylamino)-2-butenamide (compound 1)

[0103]

[0104] a. Synthesis of N-(3-chloro-4-fluorophenyl)-6-nitro-7-fluoroquinazolin-4-amine

[0105]

[0106]Take 4-hydroxy-7-fluoro-6-nitroquinazoline (20g) into a 1000ml single-necked bottle, add 390ml of chloroform (W / V=1:19.5), and start to cool down to below 5°C under stirring . The reaction temperature was controlled below 5°C, and 24.5g (2eq) of oxalyl chloride was added dropwise with stirring. After dropping, control the internal temperature below 5°C, and drop DMF in chloroform solution (2.4ml dissolved in 100ml chloroform) under stirring. After dropping, the temperature of the reaction began to rise, and the reaction was stirred in an oil bath at 70° C. (reflux), followed by TLC until the reaction was completed, and the temperature was lowered to 20° C. A mixture of anhydrous magnesium su...

Embodiment 2

[0118] Example 2: (R, E)-N-(4-(3-chloro-4-fluoroanilino)-7-(tetrahydrofuran-3-yloxy) Synthesis of quinazolin-6-yl)-4-(cyclopropylamino)-2-butenamide (compound 2)

[0119]

[0120] In a similar manner to the preparation of compound 1, compound 2 (19% yield) could be obtained as a khaki granular solid using (R)-3-hydroxytetrahydrofuran as a starting material.

[0121] ESI-MS (m / z): [M+H] + 498.2.

Embodiment 3

[0122] Example 3: (E)-N-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl)-4-(3, Synthesis of 3-difluorocyclobutylamino)-2-butenamide (Compound 3)

[0123]

[0124] Similar to the preparation of compound 1, using methanol and 3,3-difluorocyclobutylamine as starting materials, compound 3 (13% yield) could be obtained as a yellow solid.

[0125] 1 H-NMR (600MHz, DMSO-d 6 ,δ ppm ): 9.81(s, 1H), 9.65(s, 1H), 8.92(s, 1H), 8.34(s, 1H), 8.13(dd, 1H, J 1 =7.2Hz,J 2 =3.0Hz), 7.80(m, 1H), 7.43(t, 1H), 7.29(s, 1H), 6.85(m, 1H), 6.56(d, 1H, J=15.0Hz), 4.04(s, 3H ), 3.30(d, 2H), 3.15(m, 1H), 2.75(m, 2H), 2.34(m, 2H).

[0126] ESI-MS (m / z): [M+H] + 492.4.

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Abstract

The invention belongs to the medicine chemical field, and more specifically relates to a novel quinazoline compound having antineoplastic activity in a formula I and a preparation method. The compound 1 has effective protein tyrosine kinases irreversible inhibition effect and / or has good internal pharmacokinetics behavior, and is an effective protein tyrosine kinases irreversible inhibitor.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a new class of quinazoline derivatives with anti-tumor activity and a preparation method thereof. The quinazoline derivatives have effective protein tyrosine kinase inhibitory effect and have Use in medicine for treating or adjuvantly treating tumors mediated by receptor tyrosine kinases or proliferation and migration of tumor cells driven by receptor tyrosine kinases in mammals (including humans). Background technique [0002] According to the global cancer report (2014) released by WHO, the number of people who died of cancer in the world in 2012 reached 8.2 million. Due to the change of living environment and living habits, under the influence of adverse environment and some unfavorable factors, the morbidity and mortality of tumors are on the rise. According to the WHO report, the number of new cancer cases in the world will increase from 14 million i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D239/94A61K31/517A61P35/00A61P35/02
CPCC07D405/12C07D239/94
Inventor 张龙范传文杨莹莹郑庆梅周豪杰赵树雍李玉浩邢昭彬李成龙
Owner QILU PHARMA CO LTD
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