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tetracycline kinase inhibitors

A technology for selecting compounds, applied in the field of medical technology, and can solve problems such as malignant transformation

Active Publication Date: 2017-02-15
SHANDONG XUANZHU PHARMA TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The analysis of these fusion genes shows that they all contain the gene sequence encoding the intracellular kinase region at the 3' end of the ALK gene, and the gene fragments fused with ALK all contain promoter elements and sequences that encode and mediate self-dimerization, resulting in cell The fusion protein with ALK kinase activity is highly expressed and overactivated, causing malignant transformation of cells

Method used

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Examples

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preparation example Construction

[0144] The present invention also provides the preparation method of above-mentioned compound, but not limited to following method, and reaction equation is as follows:

[0145]

[0146] Reaction steps:

[0147] Step 1 Preparation of intermediate 1

[0148] Dissolve raw material 1 in glacial acetic acid, add 40% hydrobromic acid solution, cool in an ice-water bath, add an appropriate amount of bromine-dissolved glacial acetic acid solution dropwise, stir until the raw material is consumed, add ice water, and extract with ethyl acetate. The combined organic phases were separated and purified by silica gel column chromatography to obtain Intermediate 1.

[0149] Step 2 Preparation of Intermediate 3

[0150] Intermediate 1 and 1.2 equivalents of intermediate 2 were dissolved in 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 by silica gel column ch...

experiment example

[0174] Experimental example The in vitro enzymatic activity experiment of the compound of the present invention

[0175] Test product: compound 1 of the present invention, its chemical name and preparation method are shown in the preparation examples of compound 1.

[0176] Control drug: CH5424802, self-made (prepared with reference to the preparation method of patent CN102459172A), the structural formula is as follows:

[0177] (CH5424802)

[0178] The meanings represented by the abbreviations of the following experiments are as follows:

[0179] DMSO: dimethyl sulfoxide

[0180] DTT: Dithiothreitol

[0181] SEB: Enzyme Catalyst Buffer

[0182] ATP: adenosine triphosphate

[0183] ALK: Anaplastic Lymphoma Kinase

[0184] SA-XL665: Streptavidin-labeled donor

[0185] Experimental method: HTRF KinEASE-TK method was used to measure the inhibitory activity of ALK kinase.

[0186] 1. ALK kinase buffer preparation:

[0187] Take 20 μL of MgCl with a stock solution conc...

Embodiment 1

[0206] Example 1: 4,4-dimethyl-2-(4-morpholinopiperidin-1-yl)-9-oxo-5,9-dihydro-4H-thiazolo[5,4- f] Preparation of thieno[3,2-b]indole-7-carbonitrile (compound 1)

[0207]

[0208] (1) Preparation of 2,2-dimethyl-1,3-cyclohexanedione

[0209]

[0210] Dissolve 2-methyl-1,3-cyclohexanedione (10.1 g, 80 mmol), methyl iodide (12.5 mL, 200 mmol), and potassium carbonate (22.1 g, 160 mmol) in acetone (60 mL), Heat to reflux for 8 hours, cool, remove the solvent by rotary evaporation, then add water (200 mL), extract with dichloromethane (500 mL), take the organic layer and dry it with anhydrous sodium sulfate, remove the solvent by rotary evaporation, and cool to 0 °C. The product (7.7 g, yield 69%) was obtained.

[0211] (2) Preparation of 4-bromo-2,2-dimethyl-1,3-cyclohexanedione

[0212]

[0213] Dissolve 2,2-dimethyl-1,3-cyclohexanedione (6.4 g, 45.7 mmol) in glacial acetic acid (100 mL), add 40% hydrogen bromide solution (0.4 mL), and cool in an ice-water bath ...

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Abstract

The invention belongs to the technical field of medicines and relates to a tetra-cyclo-kinase inhibitor shown in the general formula (I) and its pharmaceutically acceptable salt, stereisomer, ester or solvate. In the general formula (I), R1, R2, R3, R4, M, W, X, Y and Z are defined in the specification. The invention also relates to a preparation method of the compounds, a drug containing the compounds, and a use of the compounds and its pharmaceutically acceptable salt, stereisomer, ester or solvate in preparation of a drug for treating and / or preventing ALK-mediated cancer-related diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to tetracycline kinase inhibitors, pharmaceutically acceptable salts thereof, stereoisomers, esters thereof or solvates thereof, preparation methods of these compounds, pharmaceutical preparations containing these compounds and The pharmaceutical composition, and the application of the compound, its pharmaceutically acceptable salt, its stereoisomer, its ester or its 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. [0003] Anaplastic lymphoma kinase was first discovered in anaplastic large cell lymphoma (ALCL), and later found to be highly expressed in non-sm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/14A61K31/5377A61P35/00
CPCC07D513/14
Inventor 吴永谦
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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