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EGFR-TK (epidermal growth factor receptor tyrosine kinase) inhibitor BF3-AZD9291 with antitumor activity as well as preparation method and application of EGFR-TK inhibitor BF3-AZD9291

A technology of BF3-AZD9291 and tyrosine kinase, which is applied in the field of biomedicine, can solve the problems of treatment failure and no obvious prolongation of patient survival, and achieve the effect of inhibiting proliferation and excellent anti-tumor activity

Inactive Publication Date: 2017-12-22
HARBIN MEDICAL UNIVERSITY
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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-TK (epidermal growth factor receptor tyrosine kinase) inhibitor BF3-AZD9291 with antitumor activity as well as preparation method and application of EGFR-TK inhibitor BF3-AZD9291
  • EGFR-TK (epidermal growth factor receptor tyrosine kinase) inhibitor BF3-AZD9291 with antitumor activity as well as preparation method and application of EGFR-TK inhibitor BF3-AZD9291
  • EGFR-TK (epidermal growth factor receptor tyrosine kinase) inhibitor BF3-AZD9291 with antitumor activity as well as preparation method and application of EGFR-TK inhibitor BF3-AZD9291

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 实施例1 EGFR TKI—BF 3 -AZD9291的制备

[0035] 所述的BF 3 -AZD9291的分子结构式如式I所示:

[0036]

[0037] 制备流程图如 figure 1 As shown, the specific preparation method is as follows:

[0038](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%;

[0039] (2) Mix 65g of compound 1, 19.65g of N,N,N'-trimethylethylenediamine and 26.93N,N-diisopropylethylamine in 600ml of DMF solvent and stir, react at 120°C for 4h, ...

Embodiment 2

[0045] Example 2 Inhibitory effect test of BF3-AZD9291 on mutant EGFR non-small cell lung cancer cell line H1975

[0046] 1. The test compound: BF3-AZD9291, prepared by the method of Example 1

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Abstract

The invention discloses an EGFR-TK (epidermal growth factor receptor tyrosine kinase) inhibitor BF3-AZD9291 with antitumor activity as well as a preparation method and an application of the EGFR-TK inhibitor BF3-AZD9291, and belongs to the field of biomedicine. Brand-new EGFRTKI is obtained by optimizing and improving chemical structure of AZD9291 and named BF3-AZD9291 shown as formula I in the description. Research proves that the synthesized EGFR TKI BF3-AZD9291 can effectively inhibit drug resistance of tumor cells, has stronger drug resistance habitation effect on a mutant EGFR lung cancer cell line H1975T790M than AZD9291 and can be clinically applied as an antitumor agent accordingly. Besides, the invention discloses the preparation method of the EGFR-TK inhibitor BF3-AZD9291 with antitumor activity. With provision of the invention, an effective technological means for tumor treatment, especially treatment of non-small-cell lung cancer.

Description

technical field [0001] 本发明涉及嘧啶丙烯酰胺类化合物,尤其涉及具有抗肿瘤活性的EGFRTKI—BF 3 -AZD9291及其制备方法,本发明还涉及该药作为抗肿瘤剂的应用,属于生物医药领域。 Background technique [0002] 目前发现的EGFR酪氨酸激酶(EGFR TK)可以催化ATP的高能磷酸键转移到EGFR的数个酪氨酸位点,使其磷酸化,从而激活下游的PI3K / Akt、Ras / MAPK等信号通路,促进细胞进生长增殖、代谢,抑制细胞凋亡。细胞中EGFR过度表达和突变时,会阻碍细胞程序死亡,使细胞的生长调节失控,而获得无限增殖和侵袭能力,即发展成为恶性肿瘤细胞。EGFR TKI通过与ATP竞争胞内酪氨酸激酶的结合位点,阻止受体内酪氨酸的自身磷酸化,抑制EGFR酪氨酸激酶激活,从而抑制肿瘤细胞生长、加速肿瘤细胞凋亡,抑制血管生成和肿瘤细胞浸润、转移。小分子EGFR TKI的基本结构为喹唑啉胺。EGFR TKI可分为:1)可逆性TKI主要有:吉非替尼(gefitinib),厄洛替尼(erlotinib),拉帕替尼(Lapatinib),2)不可逆性TKI主要有:阿法替尼(Afatinib),达可替尼(Dacomitinib)。目前,可逆性和不可逆性EGFR TKI对突变EGFR非小细胞肺癌短时间内具有显著的疗效,但最终均因产生获得性耐药而导致治疗失败,并没有明显延长患者的生存期。因此,开发和研制具有更强、更持久抗肿瘤活性的新型EGFR TKI将可能为突变EGFR非小细胞肺癌患者带来生机。 Contents of the invention [0003] 本发明的目的之一是提供全新的表皮生长因子受体酪氨酸激酶抑制剂(EGFRTKI)—BF 3 -AZD9291及其制备方法。 [0004] 本发明的目的之二是提供BF 3 -AZD9291在促进肿瘤细胞凋亡中的用途,其机制是通过抑制表皮生长因子受体酪氨酸激酶磷酸化从而促进肿瘤细胞凋亡、抑制肿瘤血管生成、侵袭和转移。 [0005] Above-mentioned purpose of the present invention is achieved through the following technical solutions: ...

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
Owner HARBIN MEDICAL UNIVERSITY
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