EGFR (epidermal growth factor receptor) TKI (tyrosine kinase inhibitor) BF3-AZD9291 with anti-tumor activity as well as preparation method and application thereof

A BF3-AZD9291, tyrosine kinase technology, applied in the field of biomedicine, can solve the problems of not significantly prolonging the survival period of patients, treatment failure, etc., achieving excellent anti-tumor activity and inhibiting proliferation.

Active Publication Date: 2018-05-15
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, reversible and irreversible EGFR TKIs have a significant curative effect on mutant EGFR non-small cell lung cancer in a short period of time, but they all eventually lead to treatment failure due to acquired drug resistance, and did not significantly prolong the survival of patients

Method used

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  • EGFR (epidermal growth factor receptor) TKI (tyrosine kinase inhibitor) BF3-AZD9291 with anti-tumor activity as well as preparation method and application thereof
  • EGFR (epidermal growth factor receptor) TKI (tyrosine kinase inhibitor) BF3-AZD9291 with anti-tumor activity as well as preparation method and application thereof
  • EGFR (epidermal growth factor receptor) TKI (tyrosine kinase inhibitor) BF3-AZD9291 with anti-tumor activity as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1E

[0036] Embodiment 1EGFR TKI-BF 3 - Preparation of AZD9291

[0037] The BF 3 -The molecular structural formula of AZD9291 is as shown in formula I:

[0038]

[0039] The preparation flow chart is asfigure 1 As shown, the specific preparation method is as follows:

[0040] (1) Under nitrogen protection, 50g (2-chloropyrimidin-4-yl)-1-methyl-3a, 7a-dihydro-1H-indole, 38.03g 4-fluoro-2-methoxy-5- Nitroaniline and 37.09g p-toluenesulfonic acid were mixed in 580ml 2-pentanol, stirred mechanically at 105°C for 2.5h, cooled to room temperature, filtered with suction, the filter cake was washed with 2-pentanol, and dried to obtain a light brown solid , separated and purified by column chromatography, and eluted with an eluent obtained by mixing methanol and dichloromethane according to a volume ratio of 1:100, and finally obtained a light yellow needle-shaped solid, namely compound 1, with a yield of 85%;

[0041] (2) Mix 65g of compound 1, 19.65g of N,N,N'-trimethylethylenediam...

Embodiment 2

[0047] Embodiment 2AZD9291 and BF 3 -AZD9291 inhibitory effect test on non-small cell lung cancer cell line H1975 with EGFR L858R mutation combined with T790M secondary mutation

[0048] 1. Test compounds: AZD9291 and BF 3 -AZD9291 (prepared by the method of Example 1)

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Abstract

The invention discloses an EGFR (epidermal growth factor receptor) TKI (tyrosine kinase inhibitor) BF3-AZD9291 with anti-tumor activity as well as a preparation method and application thereof, and belongs to the field of biomedicines. By optimizing and improving the chemical structure of AZD9291, a fully new EGFR TKI is obtained, and is named as BF3-AZD9291 (formula I). Proofed by study, the synthesized EGFR TKI BF3-AZD9291 has the advantages that the drug resistance of tumor cells can be effectively inhibited; compared with AZD9291, the stronger drug resistance inhibiting function is realizedfor the mutation EGFR tumor cell line H1975T790M, and the EGFR TKI BF3-AZD9291 can be used as an anti-tumor reagent in clinical application. The invention also discloses the method for preparing theEGFR TKI BF3-AZD9291 with the anti-tumor activity. The EGFR TKI BF3-AZD9291 provides an effective technical method for the treatment of tumors, especially non-small cell lung cancer. (The formula I isshown in the attached figure.).

Description

technical field [0001] The present invention relates to pyrimidine acrylamide compounds, in particular to EGFR TKI-BF with anti-tumor activity 3 -AZD9291 and its preparation method, the present invention also relates to the application of the drug as an antitumor agent, which belongs to the field of biomedicine. Background technique [0002] The currently discovered EGFR tyrosine kinase (EGFR TK) can catalyze the transfer of the high-energy phosphate bond of ATP to several tyrosine sites of EGFR to phosphorylate it, thereby activating downstream signaling pathways such as PI3K / Akt and Ras / MAPK , promote cell growth, proliferation, metabolism, and inhibit cell apoptosis. When EGFR is overexpressed and mutated in cells, it will hinder the programmed death of cells, make the growth regulation of cells out of control, and obtain unlimited proliferation and invasion ability, that is, develop into malignant tumor cells. EGFR TKI competes with ATP for the binding site of intracel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/506A61P35/00
CPCC07D403/04
Inventor 申宝忠孙夕林杨丽丽刘杨张重庆韩兆国肖亚迪白骁
Owner HARBIN MEDICAL UNIVERSITY
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