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2-indolinone derivatives, preparation and applications thereof

A technology of indolinone and its derivatives, which is applied in the field of 2-indolinone derivatives and their pharmacological activity and pharmaceutical use, can solve the problem of no 2-indolinone derivative pharmaceutical composition, etc., and achieve good anti-tumor and Effect of anti-angiogenic activity

Inactive Publication Date: 2016-04-13
INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, there is no report on the 2-indolinone derivatives provided by the present invention and the pharmaceutical composition thereof as an active ingredient, and there is no such derivative or its pharmaceutical composition applied in the preparation or treatment of tumors caused by various factors. or anti-angiogenesis and other disease drugs reported

Method used

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  • 2-indolinone derivatives, preparation and applications thereof
  • 2-indolinone derivatives, preparation and applications thereof
  • 2-indolinone derivatives, preparation and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of 3-(3-bromo-4,5-dimethoxyphenylmethylene)-N-(4-bromophenyl)-2-indolinone-5-sulfonamide (compound 1):

[0038](1) Carefully add 10 ml of chlorosulfonic acid into a 50 ml three-neck flask, add 10 mmoles of 2-indolinone under ice bath, stir at room temperature, react at 65 degrees Celsius for 1 hour, cool to room temperature, add to In ice water, filter and dry to obtain a pink intermediate;

[0039] (2) Dissolve 1.15 grams of the intermediate in 50 milliliters of tetrahydrofuran, then add 1.8 grams of 4-bromoaniline, heat to 80 degrees Celsius for 3 hours, evaporate THF under reduced pressure, and add 25 milliliters of PH=3 to the residual solid Dilute hydrochloric acid, stir, and filter with suction to obtain a pink solid;

[0040] (3), then dissolve it in 50 ml of absolute ethanol, add 5 mmoles of 3-bromo-4,5-dimethoxybenzaldehyde, add dropwise 100 microliters of piperidine as a catalyst, and reflux for 3 hours , cooled, filtered, washed with water and d...

Embodiment 2

[0042] 3-(2,3-dibromo-4,5-dimethoxyphenylmethylene)-N-(4-bromophenyl)-2-indolone-5-sulfonamide (compound 2) preparation:

[0043] The preparation method of compound 2 is similar to the preparation method of compound 1, and its difference from Example 1 is that the raw material 3-bromo-4,5-dimethoxybenzaldehyde is replaced by 2,3-dibromo-4,5 -Dimethoxybenzaldehyde, compound 2 was prepared, yellow solid, yield 83%, 1HNMR (DMSO-d6, 500MHz, ppm): δ11.16 (s, 1H), 10.24 (s, 1H), 7.66 ( s,1H),7.60(d,1H,J=8.5Hz),7.57(s,1H),7.52(s,1H),7.31(d,2H,J=8.5Hz),6.99(d,1H,J =8.5Hz),6.90(d,2H,J=8.5Hz),3.86(s,3H),3.82(s,3H); 13CNMR(DMSO-d6,125MHz,ppm):δ168.5,152.8,148.6,147.2, 137.5, 136.8, 132.4(2C), 132.2, 131.7, 130.0, 128.0, 122.2(2C), 122.1, 121.7, 121.2, 117.0, 116.6, 113.9, 110.9, 60.9, 60.7; ESIMS: m / z668[M-SIMH]-HRE :calcforC23H16Br3N2O5S[M-H]-668.8334,found668.8335.

Embodiment 3

[0045] Determination of the inhibitory activity of 2-indolinone derivatives on various tumor cells:

[0046] The cytotoxicity of synthetic derivatives to human tumor cells cultured in vitro was detected by the commonly used tetrazolium salt (MTT) method. Cell lines selected for anti-tumor experiments in vitro: human lung cancer cell A549, human liver cancer cell Bel7402, human liver cancer cell HepG2, human cervical cancer cell Hela, human colon cancer cell HCT116, etc. Determination method: take the cells in the logarithmic growth phase, inoculate the cell suspension into a 96-well plate, so that the number of cells per well is 3×103, at 37°C, 100% relative humidity, containing 5% CO2 by volume, 95 % air incubator pre-cultivation for 24h, and then add drugs. In addition, each concentration of compound 1 and 2 with a concentration of 1.25, 2.5, 5.0, 10.0, and 20.0 μg / ml was set as a negative control (equal concentration of DMSO) and a blank background (without adding cells), ...

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Abstract

The present invention relates to a class of 2-indolinone derivatives, a combination of the class of the compounds, and applications of the 2-indolinone derivatives in anti-tumor and / or anti-cancer and / or anti-angiogenesis drugs. The present invention further relates to a preparation method of the compounds, wherein the chemical structure general formula of the compounds is defined in the specification, and R1, R2, R3 and R4 are individually H, br and OCH3 and / or the combination of R1, R2, R3 and R4 is H, br and OCH3. The present invention further relates to a composition containing at least one compound, or a salt formed from the compound and a physiologically acceptable inorganic or organic acid, or if appropriate, a pharmaceutically acceptable excipient and / or diluent or excipient. The present invention further relates to the compound administration dosage form containing at least one compound having the structure formula or the salt thereof, wherein the dosage form is tablet, capsule, solution for infusion, suppository, patch, powder, suspension and the like.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a class of 2-indolinone derivatives and their pharmacological activity and pharmaceutical application. The compound and its derivatives can be used to prevent and / or treat tumors or cancers and / or angiogenesis and other diseases caused by various factors. Background technique [0002] Malignant tumors seriously affect people's health and have become the second leading cause of human death, second only to cardiovascular and cerebrovascular diseases. According to the statistics of the World Health Organization, more than 10 million cancer patients are newly diagnosed every year in the world, and the total number of cancer deaths worldwide reaches 7 million people every year. With the aggravation of environmental pollution, the incidence of cancer is increasing year by year, showing a trend of multiple occurrences. The WHO 2014 report predicts that global cancer cases will show a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34A61K31/404A61P35/00
Inventor 史大永王立军王帅玉江波吴宁
Owner INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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