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Benzothiadiazole compound and preparation method and use thereof

A technology of benzothiadiazoles and compounds, which is applied in the field of benzothiadiazoles, their preparation and application, and can solve problems such as the unclear mechanism of tumor action

Active Publication Date: 2018-07-31
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] More and more studies have shown that the activating mutation and overexpression of SHP2 may be closely related to the occurrence and metastasis of tumors, but its mechanism of action in the occurrence, development, evolution and metastasis of tumors has not yet been clarified

Method used

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  • Benzothiadiazole compound and preparation method and use thereof
  • Benzothiadiazole compound and preparation method and use thereof
  • Benzothiadiazole compound and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Embodiment 1 (taking compound 6 synthesis as example):

[0113]

[0114] Reagents and conditions: a) p-toluenesulfonyl chloride, pyridine; b) fuming nitric acid, acetic acid; c) concentrated sulfuric acid; d) thionyl chloride, toluene; e) tert-butylacetylene, bistriphenylphosphine dichloride Palladium, cuprous iodide, triethylamine; f) iron powder, ammonium chloride, ethanol, water.

[0115] Add the pyridine solution (20mL) of p-toluenesulfonyl chloride (10.19g, 53.4mmol) to the pyridine solution (20mL) of 4-bromo-o-phenylenediamine (5g, 26.7mmol). Reflux and stir in the pot, react for 18h, after the thin layer chromatography monitors that the reaction is complete, place the reaction system at room temperature to cool, and slowly pour it into a mixed solution (250mL) of ice water:hydrochloric acid (4:1), there is The solid was precipitated, filtered with suction, and the filter cake was washed with distilled water to obtain a brown solid product, which was dried for...

Embodiment 2

[0125]

[0126] Reagents and conditions: a) trimethylethynyl silicon, bistriphenylphosphine palladium dichloride, cuprous iodide, triethylamine; b) tetrabutylammonium fluoride, tetrahydrofuran; c) iron powder, chloride Ammonium, ethanol, water; d) palladium carbon, hydrogen.

[0127] Will contain compound 4 (400mg, 1.54mmol), PdCl 2 (PPh 3 ) 2 (54mg, 0.07mmol), CuI (14.6mg, 0.07mmol) and Et 3 The mixture of N (4mL) was placed in an oil bath at 50°C, trimethylethynyl silicon (300mg, 3.08mmol) was added dropwise, and reacted for about 2h. After monitoring the completion of the reaction, diluted with ethyl acetate and water, extracted, and combined phase, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (30:1 petroleum ether / ethyl acetate) to obtain compound 7 (300 mg, 70.8%).

[0128] Under ice bath condition, tetrabutylammonium fluoride (1.6mL, 5.84mmol) was added dropwise to a THF (3mL) solution of compound 7 (250mg, 0.903mmol). ...

Embodiment 3

[0132]

[0133] Reagents and conditions: a) benzyl azide, cuprous iodide, glycerin; b) iron powder, ammonium chloride, ethanol, water.

[0134] A mixture of compound 8 (20mg, 0.098mmol), benzyl azide (14mg, 0.098mmol), CuI (0.92mg, 0.0048mmol) and glycerol (0.5mL) was placed in a 40°C oil bath for overnight reaction. After the reaction was monitored by thin-layer chromatography, it was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (6:1 petroleum ether / ethyl acetate) to obtain compound 11 (20mg, yield 62.5%). 1 H NMR (400MHz, CDCl 3 )δ:8.57(s,1H),8.46(s,1H),7.70(s,1H),7.45-7.32(m,5H),5.63(s,2H).

[0135] Will contain compound 11 (20mg, 0.059mmol) and NH 4 The solution of Cl (12.5mg, 0.237mmol) in ethanol and water (2:1, 1mL) was placed in an oil bath at 90°C for reflux reaction for 30min, then iron powder (13.27mg, 0.237mmol) was added, and the reaction was continued for 1h under ...

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Abstract

The present invention relates to a benzothiadiazole compound represented by the following formula I, and a preparation method and use thereof, the benzothiadiazole compound has the biological activityof inhibiting protein-tyrosine-phosphatase SHP2, can be used as a tool compound to study the biological functional relevance of the protein-tyrosine-phosphatase SHP2 in a cell signal transduction process, and provides a new means for prevention and treatment of cancer and metabolic and immune diseases.

Description

technical field [0001] The present invention belongs to the field of medical technology, and specifically relates to a benzothiadiazole compound represented by the following general formula I and its preparation method and application. The compound has the biological activity of inhibiting protein tyrosine phosphatase SHP2, and can be used as a tool compound for research The biological function correlation of protein tyrosine phosphatase SHP2 in the process of cell signal transduction provides new means for the prevention and treatment of cancer, metabolic and immune diseases. [0002] Background technique [0003] Cancer seriously threatens human health. Among many anticancer drugs, inhibitors of protein tyrosine kinases (such as imatinib and other tinib drugs) have the characteristics of high selectivity and small side effects, and have become the first-line drugs for the treatment of tumors. However, the problem of drug resistance caused by long-term medication has fo...

Claims

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Application Information

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IPC IPC(8): C07D285/14C07D417/12C07D417/04C07F7/10A61K31/433A61K31/454A61K31/496A61K31/4439A61K31/695A61P35/00A61P37/02A61P25/00A61P9/00A61P3/00
CPCC07D285/14C07D417/04C07D417/12C07F7/0812C07F7/083
Inventor 李佳王文龙陈晓禹周宇波李静雅高雅
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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