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Application of indazole bi-aryl urea compound serving as protein kinase inhibitor

A technology for indazole biaryl urea and protein kinase, which is applied in the field of indazole biaryl urea compounds as protein kinase inhibitors, and can solve problems such as other uses that have not yet been reported.

Inactive Publication Date: 2012-01-18
JINAN HAILE MEDICAL TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent 102153551A discloses a series of antitumor drugs based on indazole or azaindazole bisaryl urea or thiourea structure, which are used to treat human lung cancer, human kidney cancer, human colon cancer, human liver cancer, human gastric cancer, Human breast cancer and other solid tumors, but other uses of this compound have not been reported

Method used

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  • Application of indazole bi-aryl urea compound serving as protein kinase inhibitor
  • Application of indazole bi-aryl urea compound serving as protein kinase inhibitor
  • Application of indazole bi-aryl urea compound serving as protein kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1, kinase test

[0041] experiment method:

[0042] The KINOMEscan screening platform is currently the most comprehensive, using a novel, proprietary active-site-directed competitive binding assay to quantify the interaction of test compounds with 450 human kinases and diseases associated with mutant variants. A system for high-throughput screening of compounds targeting human kinases. The test is carried out by combining with three compounds: DNA-labeled kinase, immobilized ligand, and test compound. The ability of the test compound to compete with the immobilized ligand was detected by quantitative PCR using DNA labeling.

[0043] Most of the experiments were performed on kinase-tagged T7 phage strains grown in E. coli host cells derived from the BL21 strain. E. coli was grown to logarithmic phase, infected with T7 phage, and incubated at 32° C. with shaking until the E. coli lysed. The lysate was centrifuged and filtered to remove cell debris. The rem...

Embodiment 2

[0059] Embodiment 2, pharmacokinetic experiment

[0060] 1. Experimental materials

[0061] 1. Reagents, medicines and consumables

[0062] Compound 1, compound 1 mesylate (1S), compound 2, compound 2 mesylate (2S), acetonitrile, ethyl acetate, methanol, column Hypersil ODS (4.6mm×200mm, 5mm), centrifugal tube, EP tube, pipette tip, rubber gloves, 1mL syringe, etc.

[0063] 2. Main instruments

[0064] Agilent 1200 high performance liquid chromatography (Agilent Technology Co., Ltd. of the United States); SHZ-88 water bath constant temperature oscillator (Jintan Cultural Instrument Factory Co., Ltd.); KQ3200DB ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.); UV-2102PCS Type UV Spectrophotometer (Shanghai Longnic Instrument Co., Ltd.); TGL-16 Desktop Centrifuge (Shanghai Anting Scientific Instrument Factory); XW-80A Vortex Mixer (Shanghai Jingke Industrial Co., Ltd.); Swiss Mettler- Toledo PL203 electronic balance (Switzerland).

[0065] 3. Experimental animal...

Embodiment 3

[0101] Embodiment 3, to S180 mouse sarcoma growth inhibition experiment

[0102] 1. Experimental materials

[0103] 1. Test drugs: Compounds 1 and 2;

[0104] 2. Experimental animals: Kunming mice weighing 19-22 g were purchased from the Experimental Center of Shandong University.

[0105] 3. Mouse S180 sarcoma: ascites was preserved for passage, purchased from Institute of Materia Medica, Shandong Academy of Medical Sciences.

[0106] 4. Other reagents and experimental equipment: physiological saline, ultra-clean workbench, laminar flow frame for large / mouse, surgical instruments, syringes, intragastric needles, autoclaves, etc.

[0107] 2. Experimental method

[0108] 1. Tumor cell inoculation method: Take the mice with S180 ascites for 5-7 days, extract the tumor cell fluid under aseptic conditions, count and dilute, and inoculate the right axillary subcutaneous of the mice, and the number of cells inoculated in each mouse is 2.5 ×10 6 / 0.2ml / piece. On the day after i...

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Abstract

The invention relates to application of a series of indazole bi-aryl urea compounds and pharmaceutically acceptable salts thereof serving as protein kinase inhibitors to preparation of medicaments for treating diseases relevant to protein kinase activity, including tumors, inflammations, diseases relevant to autoimmunity reaction and diseases relevant to stem cells. As proved by experimental study, the indazole bi-aryl urea compounds and the pharmaceutically acceptable salts thereof play important roles in medical treatment and adjusting the activities of kinases such as KIT, PDGF (Platelet Derivation Growth Factor)-alpha, PDGF-beta, CSF1R (Colony Stimulating Factor 1 Receptor), DDR1and FLT3 of an original and / or mutative receptor tyrosine kinase (RTK) family and / or CDK8 (Cyclin-Dependent Kinase 8), CDK11 and HIPK4 (Homeodomain Interacting Protein Kinase 4) and the like of a CDK family. Preferred protein kinases are Kit, PDGF-alpha, PDGF-beta and FLT3 of the RTK family as well as CDK8 and CDK11 of the CDK family.

Description

technical field [0001] The invention belongs to the field of medicaments, and relates to a series of new uses of compounds, in particular to a new use of an indazole bisaryl urea compound as a protein kinase inhibitor. Background technique [0002] Cancer is an important problem affecting global health. These cancer types include but are not limited to blood cancer, prostate cancer, bone cancer, skin cancer, lung cancer, colon cancer, breast cancer, ovarian cancer, brain cancer, kidney cancer, bladder cancer, pancreatic cancer, liver cancer, etc. Cancer rates will continue to climb as the population ages and new types of cancers emerge. There is an urgent need for a sustainable and effective treatment plan. [0003] Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine groups on proteins. PKs can be divided into two classes: tyrosine protein kinases (PTKs) and serine-threonine protein kinases (STKs). PTK-...

Claims

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Application Information

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IPC IPC(8): A61K31/416A61P35/00A61P29/00A61P37/02A61P35/02
Inventor 李文保
Owner JINAN HAILE MEDICAL TECH DEV
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