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Tyrosine kinase inhibitor and application thereof

A tyrosine kinase and inhibitor technology, applied in the field of tyrosine kinase inhibitors, can solve problems such as prolonging the life of patients

Inactive Publication Date: 2018-08-03
GUANGZHOU LIUSHUN BIO TEC CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In 2004, the U.S. FDA approved bevacizumab (Avastin), an antibody targeting VEGF. The drug can significantly prolong the life of patients when it is combined with chemotherapy drugs in the clinical treatment of colon cancer. Side effects such as high blood pressure, bleeding, thrombosis, etc.

Method used

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  • Tyrosine kinase inhibitor and application thereof
  • Tyrosine kinase inhibitor and application thereof
  • Tyrosine kinase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] This embodiment provides a preparation method of the tyrosine kinase inhibitor of the present invention, comprising the following steps:

[0038] (1) Preparation of 2-fluoro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline [compound (Ⅳ)]:

[0039] Add 4-amino3-fluorophenol [compound (Ⅲ)] (4.0g, 31.4mmol) in 250ml there-necked flask, NaH (content 60%, 1.26g, 31.4mmol) and dimethyl sulfoxide 50ml are mixed and stirred, will 50ml of dimethyl sulfoxide is mixed with 4-chloro-6,7-dimethoxyquinoline [compound (II)] (5g, 22.4mmol), added to the above reaction solution to control the temperature below 25°C, dropwise After the addition, the temperature was raised to 100°C, reacted for 2 hours, the reaction stopped, cooled to 15-20°C, poured the reaction mixture into 100ml of ice water, controlled the temperature at 15-30°C, added 20ml of ethyl acetate, separated the solids, stirred and filtered, The solid was washed once with 10 ml of ethyl acetate, and dried under vacuum at 40°C for...

Embodiment 2

[0046] This example studies the inhibitory activity of the tyrosine kinase inhibitor [compound (I)] of the present invention on VEGFR1, VEGFR2 and VEGFR3.

[0047] (1) Experimental steps:

[0048] 1. Accurately weigh the compound to be tested, add DMSO solvent to form a mother solution, and then use buffer to prepare the solution of the compound to be tested to the required concentration;

[0049] 2. Add VEGFR1 or VEGFR2 or VEGFR3 kinase solution to the 384 reaction vessel, Z'-LYTE each corresponds to the substrate solution, buffer or test compound, ATP. React at room temperature for 1 hour;

[0050] 3. Add fluorescence enhancer to each well and incubate at room temperature for 1 hour;

[0051] 4. Use the fluorescence analyzer to read the data separately.

[0052] (2) Data processing

[0053] 1. Calculate the ratio of the fluorescence intensity at 445nm and 520nm of each well according to the formula (Ratio445 / 520);

[0054] 2. Calculate the relative inhibition rate of ea...

Embodiment 3

[0062] This example studies the in vivo antitumor activity (gastric cancer) of the tyrosine kinase inhibitor [compound (I)] provided by the present invention.

[0063] (1) Experimental method

[0064] 1. Establishment of tumor model: BGC-823 gastric cancer cells were routinely cultured in high-glucose DMEM containing 10% fetal bovine serum in a 37°C, 5% CO2 incubator. After three passages in vitro, the cells grew to a fusion rate of over 80%. And when the required amount is reached, digest and collect the cells, and suspend them with Matrigel 1:1. Will be about 2 x 10 6 One BGC-823 gastric cancer cell was injected into the left axilla of each nude mouse.

[0065] 2. Grouping and administration of experimental animals: when the tumor grows to 100-200mm 3 Afterwards, the animals were randomly divided into groups to start dosing. From 35 BALB / c nude mice pre-inoculated with BGC-823 gastric cancer cells, 28 nude mice with consistent tumor growth were selected and randomly divi...

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Abstract

The invention discloses a tyrosine kinase inhibitor. A chemical name of the tyrosine kinase inhibitor is 1-(2-chloro-4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-3-(4-fluorophenyl)carbamide and a structure is shown as a formula (I). Meanwhile, the invention further discloses application of the tyrosine kinase inhibitor. The tyrosine kinase inhibitor provided by the invention can be used for effectively inhibiting enzymatic activity of VEGFR2 (Vascular Endothelial Growth Factor Receptor 2) and VEGFR3 (Vascular Endothelial Growth Factor Receptor 3) and can be used for effectively treating diseases which are regulated and controlled through tyrosine kinase and are related with anomaly of a tyrosine kinase signal transduction pathway, and the diseases comprise cancers of breasts, respiratory tracts, brains, reproductive organs, digestive tracts, urinary tracts, eyes, livers, skin, heads and / or necks and distant metastasis of the cancers, lymphoma, sarcoma, leukemia and the like.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a tyrosine kinase inhibitor and its application. Background technique [0002] Receptor tyrosine kinases (RTK.s) are a large class of important receptor families on the cell surface, which are mainly involved in the regulation of cell growth and differentiation. It has been confirmed that the interactions between the three receptor tyrosine kinase families and their ligands are Tumor angiogenesis plays a key regulatory role, including vascular endothelial growth factor (vascular endothelial growth factor, VEGF) / vascular endothelial growth factor receptor (vascular endothelial growth factor receptor, VEGFR), Angiopoietin / Tie and Ephrin / Eph system ( Roskoski R Jr, Crit Rev Oncol Hematol., 2007, 62(3), 179-213.). Wherein VEGF is the most powerful and specific factor to stimulate vascular endothelial cell hyperplasia found so far, and all links of angiogenesis all ...

Claims

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Application Information

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IPC IPC(8): C07D215/22A61K31/47A61P35/00A61P35/02
CPCC07D215/22A61P35/00A61P35/02
Inventor 刘兵钱学启王嫣邓联武谢爽马超廖美华李大萍
Owner GUANGZHOU LIUSHUN BIO TEC CO LTD
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