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CDK kinase inhibitor

A solvate, selected technology, used in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc.

Active Publication Date: 2016-07-06
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] So far, there is no CDK inhibitor drug on the market. Some pharmaceutical companies, including Pfizer, Eli Lilly and Novartis, have successively reported a series of CDK4 / 6 inhibitors with better selectivity, which are in clinical trials

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0056] The present invention also provides a preparation method for the compound of formula (I), which includes but is not limited to the following process route (wherein, the definitions represented by each abbreviation are as follows: DCM: dichloromethane; DIPEA: N,N-diisopropyl Ethylamine; DMSO: dimethyl sulfoxide; EA: ethyl acetate; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Esters; MeOH: methanol; NBS: N-bromosuccinimide; PE: petroleum ether; THF: tetrahydrofuran; Xant-phos: 4,5-bisdiphenylphosphine-9,9-dimethyloxa anthracene; x-phos: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl):

[0057] Routing:

[0058]

[0059] R 1 , R 2 , R 3 , R 4 , n, A 1 、A 2 、A 3 As mentioned above, X represents a halogen selected from fluorine, chlorine, bromine and iodine.

[0060] The specific exemplary steps are as follows:

[0061] 1. Preparation of Intermediate 1

[0062] Dissolve raw material 1 and organic base in an organic solven...

experiment example 1

[0090] Experimental Example 1 The in vitro enzymatic activity test of the compound of the present invention

[0091] Test substance: some compounds 1 and 3 of the present invention, see the preparation examples of each compound for their chemical names and preparation methods.

[0092] Control drug: LY2835219, see the background technology section for the structural formula, purchased from Wuhan Yongcan Biotechnology Co., Ltd. The meanings represented by the abbreviations in the following experiments are as follows:

[0093]

[0094] Experimental method: Determination of inhibitory activity of CDK kinases by CaliperMobilityShift method

[0095] 1.1x kinase buffer preparation:

[0096] 1) Preparation of 1x CDK4 / 9 kinase buffer

[0097] Take HEPES with a mother liquor concentration of 1000mM at pH 7.5 and TritonX-100 with a mother liquor concentration of 10%, add ultrapure water and mix well so that the final concentration of HEPES is 20mM and the final concentration of Tr...

experiment example 2

[0126] In vitro cytological inhibitory activity of experimental example 2 compounds of the present invention

[0127] Test substance: some compounds 1 and 3 of the present invention, see the preparation examples of each compound for their chemical names and preparation methods.

[0128] Control drug: LY2835219, see the background technology section for the structural formula, purchased from Wuhan Yongcan Biotechnology Co., Ltd.

[0129] The meanings represented by the abbreviations of the following experiments are as follows:

[0130]

[0131] Experimental method: adopt BrdU method (BrdU cell proliferation test kit, CellSignalingTechnology company) to carry out cell proliferation detection

[0132] 1. Reagent and Compound Preparation

[0133] 1) 1 times lotion preparation:

[0134] Dilute the washing solution whose mother liquor concentration is 20 times to 1 times washing solution with ultrapure water.

[0135] 2) Preparation of 1-fold detection antibody solution:

...

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a CDK kinase inhibitor represented as the general formula (I), pharmaceutically-accepatable salt, ester and solvate thereof, and stereisomers thereof. The R1, R2, R3, R4, A1, A2, A3 and n are defined as the specification. The invention also relates to a preparation method of the compounds, a medicine preparation and a medicine composition comprising the compounds, and an application of the compounds, the pharmaceutically accepatable salt, ester and solvate thereof, and the stereisomers thereof in preparation of a medicine for treating and / or preventing cancer-related diseases induced by the CDK kinase.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to CDK kinase inhibitors, their pharmaceutically acceptable salts, their esters, their solvates and their stereoisomers, pharmaceutical preparations and pharmaceutical compositions containing these compounds, and the compound , its pharmaceutically acceptable salts, its esters, its solvates and their stereoisomers, in the preparation of medicines for treating and / or preventing cancer-related diseases mediated by CDK kinases. Background technique [0002] Tumor occurrence is related to the imbalance of various oncogenes and tumor suppressor genes. The functional effects of almost all oncogenes and tumor suppressor genes will eventually converge on the cell cycle. Therefore, it can be said that tumors are a type of cell cycle disease (Cell Cycle Disease, CCD), and regulating or blocking the cell cycle is one of the ways to treat tumors. At present, many molecules...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/506A61K31/496A61P35/00
CPCC07D471/04
Inventor 吴永谦王统建
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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