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Benzothiadiazine derivatives as well as preparation method and application thereof

A technology of benzothiadiazines and derivatives, applied in the field of medicine

Active Publication Date: 2017-12-01
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Through directional chemical synthesis and further screening of anti-HBV activity at the cell level in vitro, benzothiadiazine derivatives with high efficiency, low toxicity and anti-drug resistance have been found. Such compounds have not been reported in the prior art

Method used

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  • Benzothiadiazine derivatives as well as preparation method and application thereof
  • Benzothiadiazine derivatives as well as preparation method and application thereof
  • Benzothiadiazine derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1. Preparation of compound 1-2

[0062] Take a 250mL double-necked flask, dissolve chlorosulfonyl isocyanate (3.36mL, 38.66mmol) in nitromethane (60mL) under ice-salt bath, slowly add dropwise the nitromethane (60mL) containing aniline (2.94mL, 32.21mmol) Methane solution (10mL), after dropping, add anhydrous aluminum trichloride (5.58g, 41.88mmol) in batches, raise the temperature to 101°C and reflux for 0.5h; after the reaction is complete, pour the reaction solution into ice water, filter and wash with water Filter cake, dissolve the filter cake in saturated sodium bicarbonate solution, heat until most of the precipitate is dissolved, decolorize the suspension with activated carbon, filter, adjust the pH of the filtrate to 1 with dilute hydrochloric acid, filter, wash the filter cake with water, and vacuum dry to obtain a pink color Solid 5.72g, yield 89.6%.

[0063]

[0064] Compound I-2 spectral data: 1 H NMR (400MHz, DMSO-d6) δppm: 12.71(s, 1H), 11...

Embodiment 2

[0065] Embodiment 2. Preparation of compound 1-3

[0066] Take a 25mL round-bottomed flask, dissolve intermediate I-2 (200mg, 1.01mmol) in 5mL DMF, add sodium carbonate (107mg, 1.01mmol) and benzyl bromide (173mg, 1.01mmol) sequentially under stirring, and react at room temperature; After the reaction is complete, add an appropriate amount of water (30mL), extract three times with ethyl acetate (15mL x3), combine the organic phases, wash once with saturated brine (30mL), and dry over anhydrous sodium sulfate; concentrate, dry sample, and quickly prepare chromatographic silica gel Column separation and recrystallization yielded 186 mg of white solid with a yield of 64%.

[0067]

[0068] Spectral data of compound I-3: 1 H NMR (400MHz, DMSO-d6) δppm: 11.49 (s, 1H), 7.88 (d, J = 7.8Hz, 1H), 7.73 (t, J = 7.6Hz, 1H), 7.49–7.12 (m, 7H) ,4.99(s,2H); 13 C NMR (100MHz, DMSO-d6) δppm: 150.14, 136.95, 135.40, 134.93, 128.88, 128.19, 128.02, 123.98, 122.57, 122.52, 117.69, 43.96; ES...

Embodiment 3

[0069] Embodiment 3. Preparation of compound 1-4

[0070] Take a 50mL round bottom flask, dissolve intermediate I-3 (200mg, 0.69mmol) in 10mL DMF, slowly add sodium hydride (30.5mg, 0.76mmol) under ice bath, and then slowly add [(2-chloroethoxy ) methyl]diethyl phosphonate (240mg, 1.04mmol) and potassium iodide (230mg, 1.39mmol), reacted at 80°C; after the reaction was complete, an appropriate amount of water (30mL) was added, extracted three times with ethyl acetate (15mL x3), and combined The organic phase was washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate; concentrated, dry-loaded, separated on a silica gel column by flash preparative chromatography, and recrystallized to obtain 163 mg of an oily liquid with a yield of 60%.

[0071]

[0072] Compound I-4 spectral analysis data: 1 H NMR (400MHz, DMSO-d6) δppm: 7.95 (d, J = 7.7Hz, 1H), 7.78 (dd, J = 16.3, 8.0Hz, 2H), 7.44 (t, J = 7.4Hz, 1H), 7.38 –7.21(m,5H),5.00(s,2H),4.30(s,2H),3.98–3.88(...

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Abstract

The invention discloses benzothiadiazine derivatives as well as preparation methods and application thereof. The compounds have the structures of formula I or II. The invention also relates to preparation methods of the compounds containing the structures of formula I or II, pharmaceutical compositions and the application of the compounds in the preparation of anti-HBV drugs. The formula I or II are shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to benzothiadiazine derivatives, their preparation method and their pharmaceutical application. Background technique [0002] Viral hepatitis type B (viral hepatitis type B), referred to as hepatitis B (Hepatitis B), is a major infectious disease caused by hepatitis B virus (HBV), long-term development can lead to acute and chronic viral hepatitis, severe hepatitis, liver cirrhosis and primary hepatocellular carcinoma (hepatocellular carcinoma, HCC). According to the report of the World Health Organization (WHO), nearly 2 billion people in the world have been infected with HBV, of which about 257 million people are chronic HBV infected people, and an average of about 887,000 people die each year from acute and chronic hepatitis and related complications caused by HBV infection. disease. At present, the hepatitis B drugs approved by the US FDA are all nucleoside (acid)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/24C07F9/6547A61K31/549A61K31/675A61P31/20
CPCC07D285/24C07F9/6547
Inventor 刘新泳贾海永展鹏刘娜俞霁
Owner SHANDONG UNIV
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