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Pyrimidine derivative type anaplastic lymphoma kinase inhibitor

A compound and solvate technology, applied in the field of pyrimidine derivatives anaplastic lymphoma kinase inhibitors, can solve the problems of drug resistance and other problems

Active Publication Date: 2015-09-02
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 derivative type anaplastic lymphoma kinase inhibitor
  • Pyrimidine derivative type anaplastic lymphoma kinase inhibitor
  • Pyrimidine derivative type anaplastic lymphoma kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0075] Step 1 Preparation of Intermediate 1

[0076] Dissolve raw material 1 in a solvent (such as N,N-dimethylformamide), add potassium hydroxide and iodine, stir (for example, 30 minutes), then add potassium hydroxide and p-toluenesulfonyl chloride, and stir at room temperature (such as 2 hours), quenched by adding water, and obtained intermediate 1 by suction filtration.

[0077] Step 2 Preparation of Intermediate 2

[0078] Intermediate 1 is dissolved in a solvent (such as dioxane), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane and a suitable palladium catalyst (such as tetrathree Phenylphosphine palladium) is added with a base (such as triethylamine), heated (such as 80° C.) overnight under nitrogen protection, cooled (such as room temperature), quenched with water, extracted with an organic solvent (such as ethyl acetate), concentrated, and purified ( Such as silica gel column chromatography) to obtain intermediate 2.

[0079] Step 3 Preparation of intermediate 3

[00...

experiment example 1

[0141] Experimental example 1 In vitro enzymatic activity test of the compound of the present invention

[0142] Test product: trifluoroacetate salt of compound 1, compound 2 and compound 4 of the present invention. For their chemical names and preparation methods, see the preparation examples of trifluoroacetate salt of compound 1, compound 2 and compound 4.

[0143] The control drug ceritinib is self-made (refer to the preparation method of patent WO2008 / 073687A2).

[0144] The meanings represented by the abbreviations of the following experiments are as follows:

[0145] DMSO: dimethyl sulfoxide

[0146] DTT: Dithiothreitol

[0147] SEB: Enzyme Catalyst Buffer

[0148] ATP: adenosine triphosphate

[0149] ALK: Anaplastic Lymphoma Kinase

[0150] SA-XL665: Streptavidin-labeled donor

[0151] 2.5×, 5×, 10× “×” among them: times

[0152] experimental method:

[0153] ALK kinase buffer preparation:

[0154] Take an appropriate amount of MgCl2, 2500nM SEB, 100mM DTT, ...

experiment example 2

[0178] Experimental example 2 In vitro cell activity test of the compound of the present invention

[0179] Test product: trifluoroacetate salt of compound 1 and compound 2 of the present invention. For their chemical names and preparation methods, see the preparation examples of trifluoroacetate salt of compound 1 and compound 2.

[0180] The control drug 1 Ceritinib is self-made (prepared with reference to the preparation method of patent WO2008 / 073687A2), and its structural formula is as described in the background technology.

[0181] The control drug 2 Alectinib is self-made (prepared with reference to the preparation method of patent CN102459172A), and its structural formula is as described in the background technology.

[0182] The meanings represented by the abbreviations of the following experiments are as follows:

[0183] rpm: revolutions per minute

[0184] DMSO: dimethyl sulfoxide

[0185] MTS: Thiazolium blue tetrazolium bromide

[0186] RPMI1640: 1640 medi...

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Abstract

The invention belongs to the field of a medical technology and specifically relates to a pyrimidine derivative type anaplastic lymphoma kinase inhibitor as shown in the general formula (I) or its stereisomer, or its pharmaceutically acceptable salt, ester or solvate, wherein R1, R2, R3, R4, R5 and A ring are as defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutic preparation and a pharmaceutical composition containing the compounds and an application of the compound or its stereisomer, or its pharmaceutically acceptable salt, ester or solvate in the preparation of medicines for treating and / or preventing diseases related to anaplastic lymphoma kinase-mediated cancer.

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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IPC IPC(8): C07D403/14C07D401/14A61K31/506A61P35/00
CPCA61K31/506A61K45/06C07D401/14C07D403/14
Inventor 吴永谦
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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