Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

A multi-targeted kinase inhibitor

A protein kinase inhibition, multi-target technology, applied in the field of medicine, can solve the problems of cytotoxicity, toxic side effects, unfavorable treatment of liver cancer, etc.

Active Publication Date: 2020-10-27
SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Chinese patent application CN103214489A discloses a kind of N-(6-substituted-3,4,6,7-tetrahydro-2H-pyrimido[1,6-c]quinazolin-2-enyl) substituted anilines Anti-tumor compound, the compound has a broad spectrum of inhibitory activity on a variety of tumor-associated kinases, but some of the compounds have obvious cytotoxicity
p38α is reported to be a liver cancer suppressor protein, therefore, inhibiting its activity is obviously not conducive to the treatment of liver cancer, and it is likely to bring unexpected toxic side effects

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A multi-targeted kinase inhibitor
  • A multi-targeted kinase inhibitor
  • A multi-targeted kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1 [synthesis of compound]

[0058] (1) Synthesis of compound td32-4

[0059] N-(3-fluoro-4-((2-(1-(2-hydroxy)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yl)oxy Substitute) phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (compound td32-4) synthetic route is as follows:

[0060]

[0061] In a 100mL single-necked flask, add compound 5 (2.00g, 5.18mmol, 1.00eq), 1A-4 (1.73 g, 6.22mmol, 1.20eq), Pd(dppf)Cl 2 (379.03mg, 518.00μmol, 0.10eq), Cs 2 CO 3 (5.06g, 15.54mmol, 3.00eq), the above mixture was washed with 60mL THF / H 2 O(5:1, v:v) was dissolved, and the resulting solution was stirred and reacted at 50° C. for 5 hours under nitrogen protection. The reaction was monitored by LC-MS until the complete disappearance of compound 5 and the formation of the target product 1-4. After the reaction was completed, 50 mL of purified water was added, extracted with ethyl acetate three times (50 mL each time), and the obtained organic layer was rotary e...

Embodiment 2

[0189] Example 2【Screening of Compounds for Inhibitory Activity of Protein Kinase】

[0190] Using the methods of Mobility Shift Assay and Lanthascreen Assay, the inhibitory activities of representative compounds (shown in Table 1) on the following kinases were tested: VEGFR2, c-Met, c-kit, B-Raf, EGFR, RET.

[0191] Table 1 Purchase information of the kinases used

[0192] Kinase name source product number batch number BRAF Invitrogen PR 6995A 1258788L CKIT Millipore 14-559k 2060980 EGFR Carna 08-115 13CBS-0005L VEGFR2 Carna 08-191 07CBS-0540 CMET Carna 08-151 10CBS-1118K RET Carna 08-159 06CBS-3284

[0193] The experimental method is as follows:

[0194] 1) Prepare 1x kinase buffer and stop solution

[0195] 1x kinase buffer: 50mM HEPES, pH 7.5, 0.0015% Brij-35, 2mM DTT;

[0196] Stop solution: 100 mM HEPES, pH 7.5, 0.015% Brij-35.

[0197] 2) Compound preparation

[0198] Prepare 50-fold compo...

Embodiment 3

[0214] Example 3 [Test of Compound Inhibiting Tumor Cell Proliferation Activity in Vitro]

[0215] According to the results of protein kinase inhibitory activity in Example 2, the compounds whose effect is better than or similar to that of the reference products Sorafenib and Cabozantinib were selected, that is, compounds td32-4, td32-5, td32-6, t-3, 51, and 29 were selected for Inhibitory cell proliferation activity test.

[0216] Instruments and materials:

[0217] Cell Titer-Glo luminescent cell viability assay (Promega, Cat. No. G7573, Lot. No. 0000181739).

[0218] TT (ATCC, Cat.No.CRL-1803, Lot.No.58785858)

[0219] SNU-5 (ATCC, Cat.No.CRL-5973, Lot.No.58033358)

[0220] Hs746T (ATCC, Cat.No.HTB-135, Lot.No.5006453)

[0221] U87MG (ATCC, Cat.No.HTB-14, Lot.No.5018014)

[0222] HepG2 (ATCC, Cat. No. HB-8065, Lot. No. 7579337)

[0223] A673 (ATCC, Cat.No.CRL-1598, Lot.No.58075870)

[0224] F-12K medium (Invitrogen, Cat.No.21127-022, Lot.No.1759876)

[0225] MEM med...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention provides a multi-target protein kinase inhibitor, a pharmaceutical composition thereof, and a use of the multi-target kinase inhibitor in the preparation of a medicament for treating diseases caused by abnormal protein kinase activity. The multi-target kinase inhibitor of the present invention has the general structural formula represented by formula (I). The multi-target kinase inhibitor has an ideal inhibitory effect and specific selectivity, and has a great prospect in the treatment of complex heterogeneous diseases and overcoming of drug resistance.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a novel multi-target protein kinase inhibitor. Background technique [0002] Protein kinase is a class of enzymes that catalyze protein phosphorylation reactions, and most important life activities in cells are related to protein phosphorylation. By mediating cell signal transduction, protein phosphorylation regulates cell fate, such as Cell proliferation, differentiation and apoptosis. Some human fatal diseases, such as tumors, are significantly related to the abnormal activity of protein kinases. Therefore, protein kinases have become popular drug targets, and kinase inhibitor drugs have become the most important component of tumor targeted therapy. [0003] Most tumors have significant heterogeneity, which may be due to the fact that most tumors are not caused by a single molecular abnormality, but from the synergistic effect of multiple abnormal molecules. On the other hand, as drugs, ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04C07D513/04C07D401/04C07D239/47C07D519/00A61K31/4365A61K31/506A61K31/438A61K31/4545A61K31/5377A61P35/00
CPCC07D239/47C07D401/04C07D495/04C07D513/04C07D519/00A61K31/4365A61K31/438A61K31/4545A61K31/506A61K31/5377A61P35/00
Inventor 金锋冯贻东王彦青佘琴靳如意石涛唐田冯汉林于琳
Owner SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com