Pyrimidine Derivatives Anaplastic Lymphoma Kinase Inhibitors

A technology for immunosuppressants and drugs, applied to salts, esters or solvates of receptors, which can solve problems such as easy generation of drug resistance

Active Publication Date: 2018-07-03
SHANDONG XUANZHU PHARMA TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Small-molecule inhibitors of ALK can affect the growth of tumor cells and play an anti-tumor role. However, a large number of clinically proven first-generation ALK inhibitors, Crizotinib, are prone to drug resistance. Therefore, patients who are resistant to Crizotinib should be designed and screened It is also a second-generation ALK inhibitor with good curative effect and has significant clinical significance

Method used

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  • Pyrimidine Derivatives Anaplastic Lymphoma Kinase Inhibitors
  • Pyrimidine Derivatives Anaplastic Lymphoma Kinase Inhibitors
  • Pyrimidine Derivatives Anaplastic Lymphoma Kinase Inhibitors

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0074] For the preparation method of intermediate 8, refer to patent 201410072908.3.

[0075] The preparation of step 1 intermediate 1

[0076] Intermediate 1 was purchased or prepared separately.

[0077] Step 2 Preparation of intermediate 2

[0078] Intermediate 1 is dissolved in an appropriate solvent (such as N,N-dimethylformamide), and an appropriate amount (such as 2 equivalents) of N-bromosuccinimide is added, heated (such as 55°C) and stirred overnight, cooled to room temperature, and added with water The reaction is quenched, extracted with an organic solvent (such as ethyl acetate), concentrated, and purified by an appropriate method (such as silica gel column chromatography) to obtain intermediate 2.

[0079] Step 3 Preparation of intermediate 3

[0080] Dissolve intermediate 2 in a suitable solvent (e.g. ethanol), add acetic acid, add reduced iron powder in batches (e.g. at 70°C), heat (e.g. 80°C) and stir (e.g. 3 hours), filter off the solid, and add water to q...

experiment example 1

[0111] Experimental Example 1 The in vitro enzymatic activity test of the compound of the present invention

[0112] Test product: trifluoroacetate of compound 1 of the present invention, its chemical name and preparation method are shown in the preparation example of compound 1 trifluoroacetate.

[0113] Control drug: LDK378, self-made (prepared with reference to the preparation method of patent WO2008 / 073687A2).

[0114] The meanings represented by the abbreviations of the following experiments are as follows:

[0115] DMSO: dimethyl sulfoxide

[0116] DTT: Dithiothreitol

[0117] SEB: Enzyme Catalyst Buffer

[0118] ATP: adenosine triphosphate

[0119] ALK: Anaplastic Lymphoma Kinase

[0120] SA-XL665: Streptavidin-labeled donor

[0121] 2.5×, 5×, 10× “×” among them: times

[0122] experimental method:

[0123] ALK kinase buffer preparation:

[0124] Take 20 μL of MgCl2 with a mother solution concentration of 1000 mM, 40 μL of SEB with a mother solution concentrat...

experiment example 2

[0143] Experimental Example 2 The in vitro cell activity test of the compound of the present invention

[0144] Test product: trifluoroacetate salt of compound 1 of the present invention, see the preparation example of trifluoroacetate salt of compound 1 for its chemical name and preparation method.

[0145] The control drug 1LDK-378 is self-made (refer to the preparation method of patent WO2008 / 073687A2), and its structural formula is as described in the background technology.

[0146] The reference drug 2CH5424802 is self-made (prepared with reference to the preparation method of patent CN102459172A), and its structural formula is as described in the background technology.

[0147] The meanings represented by the abbreviations of the following experiments are as follows:

[0148] rpm: revolutions per minute

[0149] DMSO: dimethyl sulfoxide

[0150] MTS: Thiazolium blue tetrazolium bromide

[0151] RPMI1640: 1640 medium (RPMI: Roswell Park Memorial Institute)

[0152]...

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Abstract

The present invention belongs to the technical field of medicine, and specifically relates to pyrimidine derivatives anaplastic lymphoma kinase inhibitors represented by general formula (I) or their stereoisomers, or pharmaceutically acceptable salts, esters or solvates thereof, wherein R1, R2, R3, R4, R5 and ring A are as defined in the specification. The present invention also relates to the preparation methods of these compounds, the pharmaceutical preparations and pharmaceutical compositions containing these compounds, and the compounds or their stereoisomers, or their pharmaceutically acceptable salts, esters or solvates in the preparation of therapeutic and / or Use in drugs for the prevention of cancer-related diseases mediated by anaplastic lymphoma kinase. .

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to anaplastic lymphoma kinase inhibitors of pyrimidine derivatives or their stereoisomers, or pharmaceutically acceptable salts, esters or solvates thereof, and methods for preparing these compounds, which contain these compounds The pharmaceutical preparation and pharmaceutical composition, and the compound or its stereoisomer, or its pharmaceutically acceptable salt, ester or solvate in the preparation of treatment and / or prevention of cancer-related diseases mediated by anaplastic lymphoma kinase application in medicines. Background technique [0002] Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase family, which can recruit downstream proteins through autophosphorylation, and then express specific genes to regulate cell metabolism and growth. Anaplastic lymphoma kinase was first discovered in anaplastic large cell lymphoma (ALCL), and la...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14C07D491/056A61K31/506A61P35/00
CPCC07D405/14C07D491/056
Inventor 吴永谦
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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