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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
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  • 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

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  • 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...

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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

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Application Information

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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
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