cdk kinase inhibitor

A technology of immunosuppressants and compounds, applied in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc.

Active Publication Date: 2017-04-19
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

[0078] The present invention also provides the preparation method of the compound of formula (I), but is not limited to the following methods:

[0079] The definitions represented by the following abbreviations are as follows:

[0080]

[0081] Routing:

[0082]

[0083] where R 1 , R 2 , R 3 , R 4 , R 5 , n as mentioned above, X represents halogen, selected from fluorine, chlorine, bromine, iodine; halogenating reagent

[0084] Selected from: I 2 , Br 2 .

[0085] method:

[0086] 1. Preparation of Intermediate 1

[0087] Raw material 1 and raw material 2 are dissolved in an appropriate organic solvent, an inorganic base is added, the reaction is heated under reflux overnight, cooled to room temperature and quenched with water, an organic solvent is added for extraction, the organic phase is dried, and concentrated to obtain Intermediate 1, wherein the organic solvent is preferably acetonitrile or acetonitrile. Ethyl acetate, the inorganic base is preferably ...

experiment example 1

[0109] Experimental Example 1 In vitro enzymatic activity test of the compounds of the present invention

[0110] Test substance: some compounds of the present invention, their chemical names and preparation methods are shown in the preparation examples of each compound.

[0111] Reference drug: LY2835219, see the background technology section for the structural formula, purchased from Wuhan Yongcan Biotechnology Co., Ltd.

[0112] The meanings of the abbreviations in the following experiments are as follows:

[0113]

[0114] Experimental method: Determination of inhibitory activity of CDK4 / 6 / 9 kinase by Caliper Mobility Shift method

[0115] 1.1x Kinase Buffer Preparation:

[0116] 1) Preparation of 1x CDK4 / 9 Kinase Buffer

[0117] Take HEPES of pH 7.5 with a mother liquor concentration of 1000 mM and Triton X-100 with a mother liquor concentration of 10%, respectively, add ultrapure water and mix well, so that the final concentration of HEPES is 20 mM, and the final c...

experiment example 2

[0162] Experimental Example 2 In vitro cytological inhibitory activity of the compounds of the present invention

[0163] Test substances Some compounds of the present invention, their chemical names and preparation methods are shown in the respective preparation examples.

[0164] Reference 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:

[0165]

[0166] Experimental method: BrdU method (Cell Signaling Technology company kit) was used for cell proliferation detection

[0167] 1. Reagent and Compound Preparation

[0168] 1.11 times lotion preparation:

[0169] Dilute the lotion with a concentration of 20 times of the mother liquor into a 1-fold lotion with ultrapure water.

[0170] 1. Preparation of 21 times detection antibody solution:

[0171] Dilute the BrdU detection antibody whose stock concentration ...

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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 compounds , its pharmaceutically acceptable salts, its esters, its solvates and their stereoisomers, in the preparation of medicines for the treatment and / or prevention of cancer-related diseases mediated by CDK kinases. Background technique [0002] Cyclin-Dependent-Kinases (CDKs), is a group of serine / threonine protein kinases, CDK drives the cell cycle through chemical action on serine / threonine proteins, and cooperates with cyclin, It is an important factor in cell cycle regulation. CDK can combine with cyclin to form a heterodimer, in which CDK is a catalytic subunit and cyclin is a regulatory subunit. Different cyclin-CDK complexes catalyze th...

Claims

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Application Information

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Patent Type & Authority Patents(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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