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Ethylene oxide compound, preparation method thereof and application of ethylene oxide compound in preparation of RET kinase inhibitor

A technology of ethylene oxide and compounds, applied in the field of medicine, can solve the problems of low selectivity and unseen RET

Inactive Publication Date: 2021-05-04
杨文普
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the response rate of these multi-targeted inhibitors is generally less than 50%, and the selectivity to RET is usually not high, often causing severe hypertension and other side effects due to simultaneous inhibition of VEGFR, which limits the use of patients
[0004] The present invention innovatively synthesizes an oxirane compound, which has a good inhibitory effect on RET kinase activity, and can inhibit the growth of RET abnormal tumor cells at the same time, and has significant anti-tumor activity, in order to obtain a RET kinase inhibitor that can be used to prepare The brand-new compound, the prior art has not seen the report of relevant structure

Method used

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  • Ethylene oxide compound, preparation method thereof and application of ethylene oxide compound in preparation of RET kinase inhibitor
  • Ethylene oxide compound, preparation method thereof and application of ethylene oxide compound in preparation of RET kinase inhibitor
  • Ethylene oxide compound, preparation method thereof and application of ethylene oxide compound in preparation of RET kinase inhibitor

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Embodiment 1

[0029] Embodiment 1, the preparation of formula I

[0030] (1) Synthesis of (E)-4-(1,2-dihydroacenaphthen-5-yl)-2-butenoic acid methyl ester (compound 3)

[0031]

[0032] (1,2-Dihydroacenaphthen-5-yl)boronic acid (compound 2) (100 mmol) was dissolved in 1,4-dioxane (12 mL), KF (120 mmol) was added thereto, and stirred for 30 minutes. Then, add Pd(OAc) 2 (10mmol) and a solution of (E)-4-bromo-2-butenoic acid methyl ester (compound 1) (100mmol) dissolved in 1,4-dioxane (100mL), the reaction mixture was stirred at room temperature 10 h, then filter it through silica gel with Et 2O (100 mL) wash. The solvent was removed by concentrating under reduced pressure to obtain a colorless oil, which was dissolved in ether (100ml) and crystallized with stirring to obtain a yellow solid (E)-4-(1,2-dihydroacenaphthen-5-yl)-2 - Methyl crotonate (compound 3), 21.60 g, yield 85.6%. LC-MS (ESI, pos, ion) m / z: 253.12 [M+H].

[0033] (2) Synthesis of (E)-4-(1,2-dihydroacenaphthen-5-yl)bu...

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Abstract

The invention belongs to the field of medicines, and relates to an ethylene oxide compound, a preparation method thereof and application of the ethylene oxide compound in preparation of an RET kinase inhibitor. A structural formula of the ethylene oxide compound is shown as a formula I. Pharmacological research shows that the compound prepared by the invention has a good inhibition effect on RET kinase activity, can inhibit growth of RET abnormal tumor cells, has remarkable anti-tumor activity and can be used for preparing an RET kinase inhibitor.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to an oxirane compound, its preparation method and its application in the preparation of RET kinase inhibitors Background technique [0002] As a proto-oncogene, RET (rearranged during transfection) has attracted much attention at home and abroad due to the successful development of specific small molecule inhibitors in the past two years. The RET gene is located on chromosome 10q 11.2 and encodes a tyrosine kinase receptor consisting of 1100 amino acids, namely the RET protein. The tyrosine kinase family is a family of signaling molecules involved in almost all cancer types, and it is also the basis for the development of cancer targeted therapy drugs. Genetic mutations in members of the tyrosine kinase family are major drivers of the development and progression of many different types of cancer. When the RET gene is mutated and activated, it may encode abnormal proteins, and the abnormal R...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D303/14C07D301/28A61P35/00A61P43/00
CPCA61P35/00A61P43/00C07D301/28C07D303/14
Inventor 杨文普李延升
Owner 杨文普