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Substitutional pyrazol kinase inhibitor

An alkyl and heterocyclic group technology, applied in the field of substituted pyrazole kinase inhibitors, can solve problems such as poor selectivity and insufficient activity

Active Publication Date: 2013-06-19
BEIJING AOHE DRUG RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These compounds have problems such as poor selectivity or insufficient activity, so it is necessary to carry out

Method used

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  • Substitutional pyrazol kinase inhibitor
  • Substitutional pyrazol kinase inhibitor
  • Substitutional pyrazol kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0101] (1) Preparation of TM1

[0102] In the three-necked flask, add 5-bromo-2,3-dihydro-1H-inden-1-one O-methyloxime SM1 (prepared with reference to US2007 / 99954A1 (2007)), freshly distill tetrahydrofuran, and store in a dry ice bath at -75°C Under the same conditions, n-butyllithium (1.4 equivalents) was added with a syringe, and the reaction was stirred for 0.5 hours. Add isopropyl borate (1.4 eq) and continue to stir the reaction, then remove the dry ice bath, the mixture is slowly raised to room temperature, and stir the reaction. Then 2M hydrochloric acid was added and the reaction was stirred. After the reaction, saturated sodium chloride water was added, the liquid was separated, the organic phase was dried, concentrated under reduced pressure, separated and purified by silica gel column chromatography to obtain the intermediate TM1.

[0103] (2) Preparation of TM2

[0104] Weigh isonicotinic acid methyl ester SM3 and add it into an appropriate amount of tetrahydro...

experiment example 1

[0127] Experimental Example 1 The in vitro enzymatic activity test of the compound of the present invention

[0128] Need testing product: the compound 2 that embodiment 2 prepares

[0129] Reference substance: SB-590885, commercially available

[0130] experimental method:

[0131] The meanings of the English and English abbreviations in the following tests are as follows:

[0132] HEPES: Hydroxyethylpiperazineethanesulfonic acid;

[0133] Brij-35: lauryl polyethylene glycol ether;

[0134] EDTA: ethylenediaminetetraacetic acid;

[0135] Fluorescein-MAP2K1: Fluorescein-labeled MAP2K1;

[0136] ATP: adenosine triphosphate;

[0137] DMSO: dimethyl sulfoxide;

[0138] MgCl 2 : Magnesium chloride.

[0139] 1. Preparation of test reagents

[0140] ① 1X Kinase Buffer (50mM HEPES, PH7.5, 10mM MgCl 2 , 1mM EGTA, 0.01%Brij-35);

[0141] ② 2-fold kinase solution (add corresponding kinase to 1-fold kinase buffer to prepare 2-fold kinase solution, the final concentration is ...

experiment example 2

[0157] Experimental Example 2 Pharmacokinetics of the compounds of the present invention in male SD rats

[0158] Need testing product: the compound 2 that embodiment 2 prepares

[0159] Control drug: SB-590885, commercially available

[0160] (SB-590885)

[0161] Experimental Animals Male SD rats, 3 / administration route / compound, body weight 220-250g.

[0162] Dissolution scheme

[0163] Compound 2 of the present invention: 1%DMSO+15%HP-β-CD solution+84% normal saline.

[0164] Control drug SB-590885: 1%DMSO+10%HP-β-CD solution+89% normal saline;

[0165] experimental method

[0166]Administration The test product is administered by intravenous injection (IV), the dosage is 1mg / kg, and the volume of administration is 1mL / kg; Volume 2mL / kg.

[0167] 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours after administration of blood collection; 0.17 hours, 0.5 hours, 1 hour, 2 hours, At 4 hours, 6 hours, 8 hours, and 24 hours, about ...

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Abstract

The invention belongs to the field of medical technology, in particular to a substitutional pyrazol kinase inhibitor which is shown by general formulas (I), (II), (III) or (IV), salt or a stereoisomer which are acceptable in pharmacy, wherein R<1>, R<2>, L1and L2 are defined as same as the definitions in an instruction book. The invention further relates to preparation methods of the compounds, application of the compounds, the salt or the stereoisomer which is acceptable in pharmacy in the drugs of preparing, treating and/or preventing diseases which are related to or not related to cancers caused by mutation of b-RAF.

Description

technical field [0001] The invention belongs to the field of medical technology, and in particular relates to substituted pyrazole kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations and pharmaceutical compositions containing these compounds, and the Application of the compound, its pharmaceutically acceptable salt or its stereoisomer in the preparation of medicines for treating and / or preventing cancer-related diseases or non-cancer-related diseases caused by b-RAF mutation. Background technique [0002] Receptor tyrosine kinases (RTKs) are involved in cell growth, differentiation, development, proliferation, division, and adhesion, and are also related to cell transcription regulation, angiogenesis, and endothelial cell proliferation. has a wide range of effects. The regulation of these kinases can control cell proliferation and differentiation, regulate cell cycle, especially f...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4439A61P35/00A61P17/00A61P13/08
Inventor 周岩
Owner BEIJING AOHE DRUG RES INST
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