Bcr-Abl amphiploid inhibitor, preparation method and application thereof

A solvent and compound technology, applied in the field of Bcr-Abl diploid inhibitors, can solve the problems of decreased affinity between imatinib and Abl kinase, decreased affinity, and drug resistance

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

Examples

Experimental program
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Effect test

Embodiment 1

[0069] Example 1 Preparation of the compound BP of the present invention

[0070] The synthetic route is as follows:

[0071] a. Preparation of compound 12:

[0072]

[0073] b. Preparation of compound BP:

[0074]

[0075] Preparation of compound 4

[0076] 2-Methyl-5-nitrotrifluorotoluene (compound 1) (30g, 0.15mol) was added to carbon tetrachloride (200ml), under nitrogen protection, N-bromosuccinimide (28.8 g, 0.16 mol), AIBN (2.5 g, 0.01 mol), stir electromagnetically, heat up to reflux for 24 h, stop the reaction, cool to room temperature, filter the reaction solution, wash the solid with ethyl acetate, combine the ethyl acetate phases, and use Wash with saturated aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution (10 ml×2), dry over anhydrous sodium sulfate, evaporate the solvent to dryness to obtain a yellow oil, which is compound 2, which is directly used in the next step without purification.

[0077] Preparation of co...

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PUM

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Abstract

The invention discloses a Bcr-Abl amphiploid inhibitor, a preparation method and an application thereof. A compound represented as the formula (I) or pharmaceutically acceptable salts thereof are provided in the invention. The compound represented as the formula (I) or the pharmaceutically acceptable salts thereof 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 present invention relates to a Bcr-Abl diploid inhibitor and its preparation method and use. Background technique [0002] Chronic myeloid leukemia is a chromosomal gene mutation [t(9:22)(q34; q11)] mutual translocation, the ABL gene on chromosome 9 and the BCR gene on chromosome 22 are fused to produce BCR-ABL, the fusion gene Encodes a 210kDa tyrosine kinase Bcr-Abl, which is the main cause of chronic myeloid leukemia. c-Abl is a haploid tyrosine kinase existing in the cytoplasm in normal cells. After fusion with Bcr, its shape changes from haploid to tetramer, so the kinase is always activated. lead to the occurrence of tumors. The presence of amino acid sequences in the Bcr protein sequence that can cause multimerization results in Bcr-Abl tetramerization. Since c-Abl plays an important role in normal cells such as myocardium, the development of inhibitors that selectively inhibit oncogenic Bcr-Abl rather than Abl is expected to greatly redu...

Claims

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Application Information

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