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tetracycline kinase inhibitors

An immunosuppressant, selected technology, applied in the field of medical technology, and can solve problems such as easy generation of drug resistance and the like

Active Publication Date: 2017-06-20
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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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0121] Step 1 Preparation of intermediate 1

[0122] Dissolve raw material 1 in a solvent (such as glacial acetic acid), add hydrobromic acid solution (such as 40% hydrobromic acid solution), cool in an ice-water bath, add an appropriate amount of bromine-dissolved solvent (such as glacial acetic acid) solution dropwise, Stir until the raw materials are completely consumed, cool (for example, add ice water), extract (with ethyl acetate), and separate and purify the combined organic phases (for example, by silica gel column chromatography) to obtain intermediate 1.

[0123] Step 2 Preparation of intermediate 3

[0124] Intermediate 1 and Intermediate 2 (for example, 1.2 equivalents) were dissolved in a solvent (such as tetrahydrofuran), heated to reflux until the reaction was complete, the solvent was removed by rotary evaporation, and intermediate 3 was obtained by separation and purification (for example, by silica gel column chromatography).

[0125] Step 3 Preparation of I...

experiment example 1

[0154] Experimental example 1 In vitro enzymatic activity test of the compound of the present invention

[0155] Test articles: compound 1 and compound 2 of the present invention, see the preparation examples of compound 1 and compound 2 for their chemical names and preparation methods.

[0156] Control drug: CH5424802, self-made (prepared with reference to the preparation method of patent CN102459172A)

[0157] The meanings represented by the abbreviations of the following experiments are as follows:

[0158] DMSO: dimethyl sulfoxide

[0159] DTT: Dithiothreitol

[0160] SEB: Enzyme Catalyst Buffer

[0161] ATP: adenosine triphosphate

[0162] ALK: Anaplastic Lymphoma Kinase

[0163] SA-XL665: Streptavidin-labeled donor

[0164] 2.5×, 5×, 10× “×” among them: times

[0165] experimental method:

[0166] ALK kinase buffer preparation:

[0167] Take 20 μL of MgCl2 with a mother solution concentration of 1000 mM, 40 μL of SEB with a mother solution concentration of 2500 ...

experiment example 2

[0187] Experimental example 2 In vitro cell activity test of the compound of the present invention

[0188] Test articles: compound 1 and compound 2 of the present invention, see the preparation examples of compound 1 and compound 2 for their chemical names and preparation methods.

[0189] The control drug CH5424802 is self-made (prepared with reference to the preparation method of patent CN102459172A), and its structural formula is as described in the background technology.

[0190] The meanings represented by the abbreviations of the following experiments are as follows:

[0191] rpm: revolutions per minute

[0192] DMSO: dimethyl sulfoxide

[0193] MTS: Thiazolium blue tetrazolium bromide

[0194] RPMI1640: 1640 medium (RPMI: Roswell Park Memorial Institute)

[0195] "×" in 500×, 1000×, 10×: times

[0196] experimental method:

[0197] (1) NCI-H3122, Karpas-299, SH-SY5Y cells:

[0198] (1) Medium preparation:

[0199] Take 10 mL of fetal bovine serum, 1 mL of a mi...

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Abstract

The present invention belongs to the field of medical technology, and specifically relates to tetracycline kinase inhibitors represented by general formula (I) or their stereoisomers, or pharmaceutically acceptable salts, esters or solvates thereof, wherein A 1 、A 2 、A 3 、A 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , M, X, Y, Q and n are as defined in the description. 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 ALK.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to tetracycline kinase inhibitors or their stereoisomers, or pharmaceutically acceptable salts, esters or solvates thereof, preparation methods of these compounds, pharmaceutical preparations and medicines containing these compounds The composition, and the application of the compound or its stereoisomer, or its pharmaceutically acceptable salt, ester or solvate in the preparation of medicines for treating and / or preventing cancer-related diseases mediated by ALK. 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 later found to be highly expressed in non-small cell lung cancer ...

Claims

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Application Information

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IPC IPC(8): C07D513/04C07D495/04C07D487/04A61K31/5377A61K31/496A61K35/00
CPCC07D513/04C07D487/04C07D495/04
Inventor 吴永谦
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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