Anticancer compound osimertinib and synthesis method thereof

A technology for omegatinib and its synthesis method, which is applied in the field of anticancer compound omegatinib and its synthesis, can solve the problems of low selectivity, poor kinase inhibitory effect, etc., and achieve good product quality, simple and easy synthesis method, growth inhibitory effect

Inactive Publication Date: 2016-06-08
南京迪缘医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the prior art, compounds that inhibit aurora kinases to achieve anti-tumor effects have been studied, but there are also some defects, such as poor inhibitory effect on kinases, low selectivity, etc.

Method used

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  • Anticancer compound osimertinib and synthesis method thereof
  • Anticancer compound osimertinib and synthesis method thereof
  • Anticancer compound osimertinib and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of compound (2)

[0033] Under the protection of nitrogen, 1.5kg (5mol) of compound (1) was added into 15L of anhydrous tetrahydrofuran into a 50L reactor at -20°C, and 352g (5.5mol) of sec-butyl lithium was slowly added dropwise. After stirring for half an hour, 264 g (6 mol) of dry ice was slowly added. After the reaction was monitored by TLC, the reaction solution was neutralized to pH 6.8 with 5% dilute hydrochloric acid, filtered, and the filter cake was washed with 5 L of tetrahydrofuran. The combined filtrate and washings were concentrated to obtain the compound (3) The crude product was recrystallized from ethyl acetate to obtain 1.65 kg (4.8 mol) of the refined product of compound (3), with a yield of 96%. Purity by HPLC: 99.2%.

[0034] 1 HNMR (400MHz, DMSO-d 6 )δ12.62(b,1H),9.88(s,1H),8.79(dd,J=14.9,3.0Hz,1H),8.20(dd,J=14.9,3.0Hz,1H),8.07(d,J =3.0Hz,1H),7.72(dt,J=14.7,7.4Hz,2H),7.48(dd,J=14.9,3.0Hz,1H),1.49(s,9H).

[0035] ESI+[M+H] + =344. ...

Embodiment 2

[0051] Example 2: Inhibitory effect of compounds of the present invention on aurora kinase

[0052] Aurora Kinase HTRF Assay

[0053] The Aurora-A-TPX2-HTRF assay for Aurora-A was started in the presence of ATP-phosphorylated biotinylated polypeptide PLK. The test was carried out for about 120 minutes, and after 120 minutes, the detection reagent was added to extract it. These detection reagents stop the reaction by diluting the kinase and chelating heavy metal ions with EDTA. Leave it overnight after adding the detection reagent, so that the detection reagent reaches equilibrium.

[0054] The Aurora-A-HTRF assay used 1uL of omeretinib in 100% DMSO solution, 20uL of ATP and biotinylated PLK, and 20uL of Aurora-A-TPX2-KGDGST kinase. The buffer conditions are: 60mM HEPES (4-hydroxyethylpiperazineethanesulfonic acid) pH7.5, 25mM aqueous sodium chloride, 10mM MgCl aqueous solution, 2mM DTT (dithiothreitol), 0.05% BSA (Bovine Serum Albumin).

[0055] The experiment was extract...

Embodiment 3

[0058] Example 3: High Selectivity of Compounds of the Invention to Aurora Kinases

[0059] The line containing Aurora kinase, p38α, Tyk2, JNK2, Met or Tie2 is selected for cultivation, and then the compound obtained by the present invention is added for detection.

[0060] Assay results show that the compounds of the present invention are 28 times, 35 times, 24 times, 38 times and 35 times more selective for Aurora kinase than for p38α, Tyk2, JNK2, Met and Tie2.

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Abstract

The invention provides an anticancer compound osimertinib and a synthesis method thereof. The chemical name of osimertinib is (4-(4-chlorothiophene-2-yl)-N-(6-(2-(ethylamino) pyridine-4-yl) diphenyl (b,d) thiophene-2-yl)-phthalazinyl-1-amine) with the structural formula shown in formula I. The synthesis process is shown in the specification. The compound is an effective and high-selectivity pan-Aurora kinase inhibitor and acts on Aurora kinase, so that growth of tumor cells is effectively inhibited, and the anticancer effect is realized. Besides, the synthesis method of the compound is simple and easy to implement, the cost is low, the yield is high, the product quality is good, and the synthesis method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to an anticancer compound omeretinib and a synthesis method thereof, belonging to the technical field of drug development and synthesis. Background technique [0002] The Aurora family is a serine / threonine protein kinase, and there are three types in mammals: Aurora-A, Aurora-B, and Aurora-C. Aurora kinase inhibitors are a new field of molecularly targeted therapy for tumors. The function of the three members of the Aurora family is to participate in the regulation of centrosome and microtubule functions, to ensure the precise separation of chromosomes and effective cytoplasmic separation. They usually reach their peak in the G / M phase and regulate the G2 / M transition in the cell cycle. It is a key factor regulating the progression of M phase. Among them, Aurora-A and Aurora-B are closely related to tumors. First, Aurora-A is located at 20q13, and Aurora-B is located at 17p13, both of which are translocated, deleted or amplifi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14
CPCC07D409/14
Inventor 黄燕鸽
Owner 南京迪缘医药科技有限公司
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