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Multi-target kinase inhibitor

A protein kinase inhibition, multi-target technology, applied in the field of medicine, can solve the problems of unfavorable liver cancer treatment, toxic side effects, cytotoxicity, etc., and achieve the effect of avoiding the occurrence of toxic side effects and excellent selection specificity

Active Publication Date: 2018-09-14
SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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  • 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

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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.

[...

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...

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Abstract

The invention provides a multi-target kinase inhibitor, a medicinal composition thereof, and application of the multi-target kinase inhibitor to preparation of medicines for treating diseases caused by abnormal protein kinase activity. The multi-target kinase inhibitor adopts a structural general formula shown as a formula (I). The multi-target kinase inhibitor has an ideal inhibitory effect and specific selectivity, has a great prospect in treating complex heterogeneous diseases and overcoming the medicine 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

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Application Information

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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
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