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Bcr-Abl amphiploid inhibitor, preparation method and application thereof

A technology of use and molar volume, applied in a class of Bcr-Abl diploid inhibitors and the fields of preparation and use, capable of solving drug resistance, decreased affinity, and decreased affinity between imatinib and Abl kinase and other problems, to achieve the effect of inhibiting tyrosine kinase activity and good therapeutic effect

Active Publication Date: 2015-11-11
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, preparation method and application thereof
  • Bcr-Abl amphiploid inhibitor, preparation method and application thereof
  • Bcr-Abl amphiploid inhibitor, preparation method and application thereof

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Embodiment 1

[0075] The preparation of embodiment 1 compound BDB of the present invention

[0076] The synthetic route is as follows:

[0077]

[0078]

[0079] Concrete synthetic steps are as follows:

[0080] Preparation of Compound 2:

[0081] Compound 1 (10g, 45.5mmol; manufacturer: Sigma-Aldrich) was dissolved in 500ml DCM, at room temperature, (Boc) 2 O (9.4g, 43.18mmol) was dissolved in 100ml of DCM, slowly added dropwise to the reaction bottle, and reacted overnight; 200ml of water was added to the reaction solution, and after adjusting the pH to 3-4, the organic phase impurities were extracted, and the aqueous phase Adjust the pH to 10, then add sodium chloride for saturation, extract the product, wash the organic phase with saturated sodium chloride aqueous solution (10ml×6) to remove unreacted raw materials, dry over sodium sulfate, and evaporate the solvent to obtain a colorless oil Compound 2 (4.7 g, yield 34.1%).

[0082] 1 HNMR (400MHz, CDCl3): δ5.11 (bs, 1H), 3.6...

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Abstract

The invention discloses a Bcr-Abl amphiploid inhibitor, a preparation method and an application thereof. A compound or pharmaceutically acceptable salts thereof provided in the invention can be used as the Bcr-Abl amphiploid inhibitor which can effectively inhibit the activity of tyrosine kinase. The Bcr-Abl amphiploid inhibitor can be effectively used in treatment of diseases related to abnormal activation of the tyrosine kinase and has excellent treatment effect on malignant tumors. The inhibitor is easy to prepare, is low in cost and is excellent in application prospect.

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): C07D519/00A61K31/496A61P35/00A61P35/02
CPCC07D519/00
Inventor 郑哲彬倪彩霞李宗河桑言奎刘碧崇金天
Owner SHENZHEN YONGZE PHARM CO LTD
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