Bcr-Abl amphiploid inhibitor and preparation method and application thereof

A technology of usage and molar volume, applied in the field of Bcr-Abl diploid inhibitors, can solve the problems of decreased affinity, drug resistance, decreased affinity between imatinib and Abl kinase, etc., and achieves a preparation method. Simple, low cost, good application prospects

Active Publication Date: 2015-10-28
SHENZHEN YONGZE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Subsequent studies have shown that the occurrence of IM drug resistance may be related to gene mutations in the active region of Abl kinases such as G250E, Q252H, Y253F, Y253H, E255K, E355G, E255V, T315A, T315I, F317L, F317V, M351T, F359V, H396P, and M244V , a genetic mutation leading to a decrease in the affinity of imatinib to Abl kinase
Most gene mutations reduce the affinity of imatinib by 5-30 times, which is the main reason for drug resistance

Method used

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  • Bcr-Abl amphiploid inhibitor and preparation method and application thereof
  • Bcr-Abl amphiploid inhibitor and preparation method and application thereof
  • Bcr-Abl amphiploid inhibitor and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0052] Embodiment 1 The preparation of compound BGC of the present invention

[0053] The synthetic route is as follows:

[0054]

[0055] (2) Preparation of compound BGC:

[0056]

[0057] Concrete synthetic steps are as follows:

[0058] a) preparation of compound 2

[0059] Compound 1 (5.0g, 18.0mmol; manufacturer: Shanghai Xugang Biotechnology Co., Ltd.), triethylamine (3.6g, 35.6mmol) were dissolved in dichloromethane (400ml), and 4-(chloromethyl) Benzoyl chloride (4.0g, 21.3mmol) was dissolved in dichloromethane (100ml), and was added dropwise to the reaction solution at 0°C. After the addition, it was naturally raised to room temperature and stirred for 18h. A solid precipitated in the reaction bottle. The reaction mixture was filtered, and the collected solid was washed with dichloromethane and water to obtain compound 2 as a yellow solid (5.3 g; yield 68%).

[0060] 1 H NMR (400MHz, DMSO-d6): δ10.23(s, 1H), 9.28(s, 1H), 8.97(s, 1H), 8.69(d, J=4.4Hz, 1H), 8....

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Abstract

The invention discloses a Bcr-Abl amphiploid inhibitor and a preparation method and application thereof. The structural formula of compound or pharmaceutically acceptable salt of the compound is shown in the specification as I. The compound or pharmaceutically acceptable salt of the compound in the formula I serves as the Bcr-Abl amphiploid inhibitor, can effectively restrain activity of tyrosine kinase, can effectively used for treating diseases related to kinase abnormal excitation and has a good treatment effect on the malignant tumor. The preparation method of the Bcr-Abl amphiploid inhibitor is simple, convenient to implement and low in cost and has good application prospects.

Description

technical field [0001] The invention relates to a Bcr-Abl diploid inhibitor, a preparation method and application thereof. Background technique [0002] Chronic myelogenous leukemia is a chromosomal gene mutation [t(9:22)(q34;q11)] reciprocal translocation, the ABL gene at chromosome 9 and the BCR gene at chromosome 22 are fused to produce BCR-ABL, the fused gene Encodes a 210kDa tyrosine kinase Bcr-Abl, which is the main cause of chronic myelogenous leukemia. c-Abl is a haploid tyrosine kinase that exists in the cytoplasm in normal cells. After fusion with Bcr, its morphology changes from haploid to tetramer, so the kinase is always activated. lead to the occurrence of tumors. The presence of amino acid sequences that can cause multimerization in the Bcr protein sequence leads to Bcr-Abl tetramerization. Since c-Abl plays an important role in normal cells such as cardiac muscle, if inhibitors that selectively inhibit oncogenic Bcr-Abl but not Abl are developed, it is exp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00A61P35/02
CPCC07D401/14C07D519/00
Inventor 郑哲彬
Owner SHENZHEN YONGZE PHARM CO LTD
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