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CDK kinase inhibitor

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

Active Publication Date: 2015-09-16
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no public reports of CDK4 / 6 / 9 compounds, so the development of CDK4 / 6 / 9 inhibitors has a good prospect, which is of great significance for us to explore new anti-tumor drugs in this field

Method used

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Examples

Experimental program
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Effect test

preparation example Construction

[0077] The present invention also provides the preparation method of formula (I) compound, but not limited to following method:

[0078] The definitions represented by the following abbreviations are as follows:

[0079]

[0080] Routing:

[0081]

[0082] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , n As mentioned above, X represents halogen, selected from fluorine, chlorine, bromine, iodine; halogenation reagent

[0083] Selected from: I 2 、Br 2 .

[0084] method:

[0085] 1. Preparation of Intermediate 1

[0086] Dissolve raw material 1 and raw material 2 in an appropriate organic solvent, add an inorganic base, heat and reflux overnight, cool to room temperature and add water to quench, add an organic solvent for extraction, dry the organic phase, and concentrate to obtain intermediate 1, wherein the organic solvent is preferably acetonitrile or Ethyl acetate, inorganic base preferably potassium carbonate, sodium carbonate or sodium bicarbonate.

[0087] 2. ...

experiment example 1

[0108] Experimental Example 1 The in vitro enzymatic activity test of the compound of the present invention

[0109] Test substance: some compounds of the present invention, see the preparation examples of each compound for their chemical names and preparation methods.

[0110] Control drug: LY2835219, see the background technology section for the structural formula, purchased from Wuhan Yongcan Biotechnology Co., Ltd.

[0111] The meanings represented by the abbreviations of the following experiments are as follows:

[0112]

[0113] Experimental method: Determination of CDK4 / 6 / 9 kinase inhibitory activity by Caliper Mobility Shift method

[0114] 1.1x kinase buffer preparation:

[0115] 1) Preparation of 1x CDK4 / 9 kinase buffer

[0116] Take HEPES with a mother liquor concentration of 1000mM at pH 7.5 and Triton X-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 ...

experiment example 2

[0161] In vitro cytological inhibitory activity of experimental example 2 compounds of the present invention

[0162] Test substance Some compounds of the present invention, their chemical names and preparation methods are shown in each preparation example.

[0163] Control drug: LY2835219, see the background technology section for the structural formula, purchased from Wuhan Yongcan Biotechnology Co., Ltd. The meanings of all abbreviations in the following experiments are as follows:

[0164]

[0165] Experimental method: BrdU method (Cell Signaling Technology company kit) was used for cell proliferation detection

[0166] 1. Reagent and Compound Preparation

[0167] 1.11 times lotion preparation:

[0168] Dilute the washing solution whose mother liquor concentration is 20 times to 1 times washing solution with ultrapure water.

[0169] 1. Preparation of 21 times detection antibody solution:

[0170] Dilute the BrdU detection antibody whose stock concentration is 100 ti...

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Abstract

The present invention belongs to the technical field of medicine, and particularly relates to a CDK kinase inhibitor represented by a general formula (I), a pharmaceutically acceptable salt of the CDK kinase inhibitor, an ester of the CDK kinase inhibitor, a solvate of the CDK kinase inhibitor and stereoisomers of the CDK kinase inhibitor, the pharmaceutically acceptable salt, the ester and the solvate, wherein R1, R2, R3, R4, R5 and n are defined in the specification. The present invention further relates to preparation methods of the compounds, pharmaceutical formulations containing the compounds, pharmaceutical compositions containing the compounds, and applications of the compound, the pharmaceutically acceptable salt, the ester, the solvate and the stereoisomers in preparation of treatment and / or preparation of CDK kinase-mediated cancer associated diseases. The formula (I) is defined in the specification.

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] Cell cycle-dependent protein kinases (Cyclin-Dependent-Kinases, CDKs) are a group of serine / threonine protein kinases. CDKs drive the cell cycle through the chemical action on serine / threonine proteins, and cooperate with the cyclin cyclin, It is an important factor in cell cycle regulation. CDK can combine with cyclin to form a heterodimer, in which CDK is the catalytic subunit, and cyclin is the regulatory sub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D471/10C07D471/08C07D487/10C07D487/08C07D498/04A61K31/496A61K31/444A61K31/5365A61K31/5377A61K31/4995A61P35/00
CPCC07D401/14C07D471/08C07D471/10C07D487/08C07D487/10C07D498/04C07D498/08
Inventor 吴永谦
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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