Fluorine-containing AZD9291 derivative as well as preparation method and application thereof

A technology of AZD9291 and derivatives, applied in the field of fluorine-containing AZD9291 derivatives and their preparation, can solve problems such as poor metabolism, and achieve the effects of good inhibitory effect, strong in vitro anti-tumor activity, and enhanced in vitro anti-tumor activity

Inactive Publication Date: 2020-01-14
SHANGHAI INST OF TECH
View PDF7 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the current dosage of AZD9291 is relatively high, resulting in adverse metabolism, such as a high incidence of diarrhea, rash and nausea. Therefore, it is necessary to optimize the structure of the compound. On the premise of achieving the required inhibitory effect, Improve the physical properties of the compound itself, enhance the anti-tumor activity, reduce the dosage of the drug, and reduce the toxicity of the drug

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Fluorine-containing AZD9291 derivative as well as preparation method and application thereof
  • Fluorine-containing AZD9291 derivative as well as preparation method and application thereof
  • Fluorine-containing AZD9291 derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] N-(2-((difluoromethyl)(2-(dimethylamino)ethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indole- The preparation of 3-yl) pyrimidin-2-yl) amino-yl) phenyl) acrylamide, that is, the AZD9291 derivative with structure a, is prepared by the following method, and the preparation route is as follows: figure 1 Shown:

[0038] Weigh compound N1-(2-(dimethylamino)ethyl)-5-methoxy-N 4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl )-2-nitrobenzene-1,4-diamine (461mg, 1mmol) was placed in a 100ml eggplant-shaped bottle, acetonitrile and water 20:1 were added, then sodium hydroxide (440mg, 11mmol) was added, and finally 564mg ( 2mmol) 2,2-difluoro-2-iodo-1-phenylethan-1-one, react at room temperature for 15 minutes. After the reaction is completed, spin dry, add water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and undergo reduction and amidation. The reduction uses a Pb / C structure with a palladium ratio of 10% as a catalyst. Unde...

Embodiment 2

[0040] N-(2-((difluoromethyl)(2-((difluoromethyl)(methyl)amino)ethyl)amino)-4-methoxy-5-((4-(1-methyl The preparation of base-1H-indol-3-yl)pyrimidinepyridin-2-yl)amino)phenyl)acrylamide, that is, the AZD9291 derivative with structure b, is prepared by the following method, and the preparation route is as follows figure 2 Shown:

[0041]Weigh the compound 2-methoxy-N4-methyl-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N4-(2-(methylamino ) ethyl)-5-nitrobenzene-1,4-diamine (461mg, 1mmol) was placed in a 100ml eggplant-shaped bottle, added acetonitrile and water 20:1, then added sodium hydroxide (440mg, 11mmol), and finally Add 564 mg (2 mmol) of 2,2-difluoro-2-iodo-1-phenylethan-1-one and react at room temperature for 15 minutes. After the reaction is completed, spin dry, add water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, undergo reduction and amidation, quench with saturated sodium bicarbonate solution, extra...

Embodiment 3

[0043] N-(2-((difluoromethyl)(2-((difluoromethyl)(methyl)amino)ethyl)amino)-4-methoxy-5-((4-(1-methyl The preparation of base-1H-indol-3-yl)pyrimidinepyridin-2-yl)amino)phenyl)acrylamide, that is, the AZD9291 derivative with structure c, is prepared by the following method, and the preparation route is as follows image 3 Shown:

[0044] Weigh compound 2-methoxy-N 1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N4-(2-(methylamino)ethyl) -5-nitrobenzene-1,4-diamine (447mg, 1mmol) was placed in a 100ml eggplant-shaped bottle, acetonitrile and water 20:1 were added, then sodium hydroxide (440mg, 11mmol) was added, and finally 564mg (2mmol ) 2,2-difluoro-2-iodo-1-phenylethan-1-one, react at room temperature for 15 minutes. After the reaction is completed, spin dry, add water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, undergo reduction and amidation, quench with saturated sodium bicarbonate solution, extract with ethyl ac...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention relates to a fluorine-containing AZD9291 derivative as well as a preparation method and application thereof. The derivative has a structure of a formula (I) shown in the description, inthe formula, R1 is -CF2H or -CH3; R2 is -CF2H or -CH3; and at least one of R1 and R2 is -CF2H. Compared with the prior art, the derivative is capable of improving the in-vitro anti-tumor activity, hasa good inhibition function on multiple tumor cells, is capable of inhibiting activation or resistance mutation of EGFRs (epidermal growth factor receptors), is applied to treatment on EGFR sensitivemutation cancer, and is an ideal treatment medicine for diseases caused by EGFR mutation.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a fluorine-containing AZD9291 derivative and its preparation method and application. Background technique [0002] AZD9291 (Osimertinib; AstraZeneca) is a novel third-generation irreversible small molecule inhibitor developed to target sensitizing and resistant mutant forms of EGFR while retaining the wild-type receptor. This mono-anilino-pyrimidine compound is structurally and pharmacologically distinct from all other TKIs. AZD9291 treats non-small cell lung cancer (NSCLC) by irreversibly binding EGFR kinase via covalent bond formation targeting the cysteine-797 residue in the ATP binding site. [0003] However, the current dosage of AZD9291 is relatively high, resulting in adverse metabolism, such as a high incidence of diarrhea, rash and nausea. Therefore, it is necessary to optimize the structure of the compound. On the premise of achieving the required inhibitory eff...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61P35/00
CPCA61P35/00C07D403/04
Inventor 汪忠华陈秀萍胡银杰吴范宏韩杰冉剑雄王祥聪李云芳
Owner SHANGHAI INST OF TECH
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap