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HGF/c-Met signalling channel restrainer, preparation method and application thereof

A general formula and solvate technology, applied in the field of prevention and treatment of tumor diseases, can solve the problems of high toxicity and side effects, poor bioavailability, poor selectivity, etc., and achieve the effect of inhibiting invasion and growth

Inactive Publication Date: 2008-12-03
INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although existing c-Met inhibitors such as members of the antibiotic geldanamycin family can reduce the expression of c-Met receptors, they have relatively large toxic and side effects and poor selectivity; the HGF antagonist NK4 also has Large, poor bioavailability and other reasons, it is very difficult to develop into drugs; a series of small molecule compounds developed by SUGEN can inhibit the kinase activity of Met at the nanomolar level, but so far there is no report on the activity data of these compounds in vivo. Therefore, it is necessary to find more safe and effective inhibitors

Method used

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  • HGF/c-Met signalling channel restrainer, preparation method and application thereof
  • HGF/c-Met signalling channel restrainer, preparation method and application thereof
  • HGF/c-Met signalling channel restrainer, preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0294] The preparation of M24 adopts the classic Knorr reaction, and the corresponding oxime is obtained by reacting tert-butyl acetoacetate with an equivalent amount of sodium nitrite in acetic acid at 10°C for 2 hours. Stand at room temperature to obtain granular M23 solid. Then heat the acetic acid solution of ethyl acetoacetate to 60°C, start the mechanical stirring, and add the acetic acid solution of zinc powder and oxime in turn from the left and right ports of the three-necked bottle respectively, and do not let the temperature exceed 75°C during the addition (otherwise, the temperature will rapidly Rising, if not controlled in time, bumping will occur rapidly and rush out of the reaction bottle, which is very dangerous), after the addition is completed, react at 75-80°C for 1 hour, and after cooling to room temperature, pour the reaction solution into 10 times the volume of ice-water mixture , Stirring while adding, the waxy solid was precipitated rapidly. After filt...

Embodiment 1

[0322] Example 1 3-(2'hydroxyphenylmethylene)-5-(α-phenethylaminosulfo)-2-indolone;

[0323] In a 10ml eggplant-shaped bottle, add 80mg (0.65mmol) of salicylaldehyde and 5-(α-phenethylaminosulfo)-2-indolinone; 161mg (0.50mmol), add 6ml of absolute ethanol, piperidine 2 drops, then the temperature was raised to reflux, and the reaction was stopped after stirring and reacting for 20 minutes under reflux. After standing at room temperature for 2 hours, flash chromatography gave 101 mg of the target product (eluent petroleum ether: ethyl acetate = 1:1), with a yield of 51%. 1 H-NMR (DMSO-d 6 )δ(ppm): 10.95(s, 1H), (s, 1H), 8.09(m, 1H), 7.78(m, 2H), 6.88-7.52(m, 11H), 4.27(q, 1H, J= 6.4 Hz), 1.18 (d, 3H, J = 6.4 Hz). FAB-Ms: 421.0 (M + +1).

Embodiment 2

[0324] Example 2 3-(5'-methoxy-indole-3'-methylene)-5-(α-phenethylaminosulfo)-2-indolone;

[0325] In a 10ml eggplant-shaped bottle, add 80 mg (0.50 mmol) of 5-methoxy-3-indole aldehyde and 5-(α-phenethylaminosulfo)-2-indolinone; 161 mg (0.50 mmol), add 6ml of absolute ethanol, 2 drops of piperidine, and then the temperature was raised to reflux, and the reaction was stirred and reacted under reflux for 20 minutes, and then the reaction was stopped. After standing at room temperature for 5 hours, 121 mg of the target product was precipitated, with a yield of 54%. FAB-Ms: 473.0 (M + +1).

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Abstract

The invention relates to 2-indolone derivative series (formula I), medicinal salts thereof, isomers thereof, hydrates thereof or solvates thereof and the preparation method thereof; and the invention also relates to a pharmaceutical composition containing the same with an effective dosage and the application thereof in prevention and treatment of tumor diseases by blocking the HGF / c-Met signal channels.

Description

technical field [0001] The present invention relates to a class of 2-indolone derivatives (general formula I), its pharmaceutically acceptable salts, its isomers and hydrates or solvates and preparation methods thereof, and also relates to said compounds containing effective doses A pharmaceutical composition, and its application in preventing and treating tumor diseases by blocking HGF / c-Met signaling channel. Background technique [0002] With the change / deterioration of human consumption structure, lifestyle and living environment, the incidence of malignant tumors has risen rapidly, and it has become the most terrible killer that threatens human life and health. Despite advances in its treatment over the past century, anticancer research remains one of the most challenging and significant areas of life science. [0003] Conquering cancer continues to pose major challenges to medicine. Cancer is quite complex, arising from multiple mutations in normal cells, affecting a...

Claims

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Application Information

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IPC IPC(8): C07D209/34C07D403/06A61K31/404A61P35/00
Inventor 杨晓明王林王海勇詹轶群李长燕武维斌
Owner INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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