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Quinazoline derivative and application thereof

A technology of quinazoline and its derivatives, which is applied in the field of chemical synthesis of drugs, can solve problems such as C797S drug-resistant mutations, and achieve significant curative effect and high in vitro inhibitory activity

Active Publication Date: 2020-01-03
烟台药物研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients who have used osimertinib have developed a C797S drug-resistant mutation, and there is currently no therapeutic drug available

Method used

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  • Quinazoline derivative and application thereof
  • Quinazoline derivative and application thereof
  • Quinazoline derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Adopt synthetic route one to prepare 6-methoxy-4-(2-isopropylsulfonylanilide) base-7-(2-thiomethylethylamine) ketoquinazoline, the specific process is as follows:

[0046] 1) Intermediate 1, namely 6-methoxy-4-chloro-7-(2-thiomethyl ether ethylamine) ketone quinazoline (0.3g, 1mmol), was dissolved in DMF, and iodomethane ( 0.17g, 1.2mmol), anhydrous sodium carbonate (0.011g, 0.1mmol), react at room temperature for 12h. After the reaction was completed, a large amount of water was added to the reaction solution, and a large amount of solid precipitated out of the solution, which was suction filtered, and the filter cake was washed with a small amount of water and dried to obtain 0.3 g of a yellow product.

[0047] 2) Dissolve the product obtained in step 1) in DMF, add sodium hydride (0.08g, 1.8mmol) in batches under ice-cooling, react for 30min, add 2-isopropylsulfonanilide (0.23g, 1.2mmol) at 0°C ), return to room temperature and react for 2 hours, add a large amount ...

Embodiment 2

[0050] Adopt synthetic route one to prepare 6-methoxy-4-(2-isopropylsulfonylanilide) base-7-(2-thioformylethylamine) ketoquinazoline, the specific process is as follows:

[0051]1) Intermediate 1, namely 6-methoxyl-4-chloro-7-(2-thiomethyl ether ethylamine) ketone quinazoline (0.3g, 1mmol), was dissolved in DMF, and acetyl chloride ( 0.17g, 1.2mmol), anhydrous sodium carbonate (0.11g, 1mmol), react at room temperature for 12h. After the reaction was completed, a large amount of water was added to the reaction solution, and a large amount of solid precipitated out of the solution, which was filtered with suction, and the filter cake was washed with a small amount of water and dried to obtain 0.33 g of a yellow product.

[0052] 2) Dissolve the product obtained in step 1) in DMF, add sodium hydride (0.08g, 1.8mmol) in batches under ice-cooling, react for 30min, add 2-isopropylsulfonanilide (0.23g, 1.2mmol) at 0°C ), return to room temperature and react for 2 hours, add a large ...

Embodiment 3

[0055] Adopt synthetic route two to prepare 6-methoxyethoxy-4-(2-isopropylsulfonanilide) base-7-(2-thiomethyl ether ethylamine) ketone quinazoline, the specific process is as follows:

[0056] 1) Dissolve intermediate 4, namely 4,6-dichloro-7-(2-thiomethyletherethylamine)methanone quinazoline (0.6g, 2mmol) in DMF, add iodomethane (0.34g, 2.4mmol), anhydrous sodium carbonate (0.46g, 2mmol), react at room temperature for 12h. After the reaction was completed, a large amount of water was added to the reaction solution, and a large amount of solid precipitated out of the solution, which was suction filtered, and the filter cake was washed with a small amount of water and dried to obtain 0.6 g of a yellow product.

[0057] 2) Dissolve the product obtained in step 1) into DMF, add potassium carbonate (0.35g, 3mmol) and ethylene glycol methyl ether (0.5g, 3mmol), and react at 80°C for 8h. After the reaction is complete, add With a large amount of water, a yellow solid precipitated o...

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Abstract

The invention relates to a quinazoline derivative shown in a formula (1) and a pharmaceutically acceptable salt thereof. In the formula (1), R<1> is selected from one or more halogens, trifluoromethyl, trifluoromethoxy, nitro, cyano, hydroxyl or sulfonyl isopropyl; R<2> is selected from methoxy, ethoxy, 3-methyl ether ethoxy, 4-methylpiperazine ethoxy, 4-(N,N-dimethyl)amino-2-butene acylamino or 2-morpholine ethoxy; and R<3> is selected from methyl, ethyl or acetyl. The quinazoline derivative provided by the invention, pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs ofthe quinazoline derivative all have remarkable EGFR inhibitory activity, have high in-vitro inhibitory activity on EGFR, T790M and C797S drug resistance mutation, and have remarkable curative effectsin treatment of EGFR-related diseases.

Description

technical field [0001] The invention relates to a quinazoline derivative, which can be used as an inhibitor of epidermal growth factor receptor (EGFR) sensitive mutation and resistant mutation, and belongs to the technical field of chemical synthesis medicine. Background technique [0002] Malignant tumors pose a great threat to human health and are increasing year by year. Among them, lung cancer is one of the cancers with the highest incidence rate in the world. In China, the incidence rate of lung cancer ranks first. [0003] About 30% of lung cancer patients in my country are caused by EGFR mutations. Therefore, the development of EGFR inhibitors has important practical significance. The first generation of reversible EGFR inhibitors on the market, such as erlotinib and gefitinib, have achieved remarkable efficacy, which can significantly shrink the tumors of about 60% of the patients and improve the quality of life of the patients. However, the vast majority of patie...

Claims

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Application Information

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IPC IPC(8): C07D239/94A61K31/517A61K31/5377A61P35/00A61P3/10A61P37/02A61P25/00A61P9/00
CPCC07D239/94A61P35/00A61P3/10A61P37/02A61P25/00A61P9/00
Inventor 谢洪磊李亚平邢晓东李艺侯玉乾高帅王琛
Owner 烟台药物研究所
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