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One class with urine-pyrine-pyrazole structure derivatives, their preparation methods and anti-HCV drugs

A technology for benzothiazole and derivatives is applied in the field of preparing anti-hepatitis C drugs, and achieves the effects of reasonable route design, good inhibitory activity and high yield

Active Publication Date: 2021-05-04
杭州市西溪医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no vaccine for HCV prevention, and timely antiviral treatment is the key to improving the prognosis. Direct-acting antiviral agents (DAAs) can clear the virus by directly acting on the target of HCV. Therefore, the development of new, highly effective DAAs treatment drugs with less toxic and side effects are imminent

Method used

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  • One class with urine-pyrine-pyrazole structure derivatives, their preparation methods and anti-HCV drugs
  • One class with urine-pyrine-pyrazole structure derivatives, their preparation methods and anti-HCV drugs
  • One class with urine-pyrine-pyrazole structure derivatives, their preparation methods and anti-HCV drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Synthesis of 2-bromo-6-nitro-benzo[d]thiazole (compound 2)

[0043]

[0044] 2-Amino-6-nitrobenzothiazole (10.0 g, 51.0 mmol) and CuBr (0.88 g, 6.1 mmol) were suspended in 48% aqueous HBr (100 mL) and water (90 mL), and NaNO was added slowly 2 (30.5g, 442mmol), continue to react at room temperature for 1 hour, extract with DCM and EtOAC respectively after the reaction to obtain the crude product, then recrystallize with isopropanol, filter and dry. Yield 88.4%; 1 H-NMR (400MHz, CDCl 3): δ = 8.78 (d, J = 2.0Hz, 1H), 8.38 (dd, J = 1.6Hz, 7.2Hz, 1H), 8.11 (d, J = 7.2Hz, 1H).

Embodiment 2

[0045] Example 2 Synthesis of 2-bromo-6-amino-benzo[d]thiazole (compound 3)

[0046]

[0047] Compound 2 (45mmol, 11.6g), Fe (225mmol, 12.6g), NH 4 Cl (135mmol, 7.22g) was placed in a 500mL round-bottomed flask, added to absolute ethanol (150mL) and water (50mL), under nitrogen protection, heated to reflux at 100°C for 2-3h, and filtered with diatomaceous earth after the reaction was completed , filtrate with K 2 CO 3 After adjusting the base, extract with DCM (50 mL×2), evaporate the solvent under reduced pressure, and recrystallize from isopropanol to obtain compound 3. Yield 78.2%; 1 H-NMR (400MHz, d 6 -DMSO): δ=7.61(d, J=7.6Hz, 1H, Ar), 7.05(d, J=2.0Hz, 1H, Ar), 6.76(dd, J=1.6Hz, 6.8Hz, 1H, Ar) ,5.53(s,2H,NH).

Embodiment 3

[0048] Example 3 Synthesis of (E)-N-((2-bromobenzo[d]thiazol-6-yl)carbamoyl)-3-ethoxyacrylamide (compound 6)

[0049]

[0050] Silver isocyanate (12.0g, 80mmol) at 100°C with P 2 o 5 Vacuum-dry, add anhydrous toluene 80mL, nitrogen protection, avoid light, heat to reflux for 0.5h; 3-ethoxyacryloyl chloride (4.82g, 40mmol) is dissolved in anhydrous toluene 15mL, and slowly dropwise added to the above reaction solution , after continuing to heat and reflux for 0.5h, react at room temperature for 3h;

[0051] Compound 3 (1.64g, 7.14mmol) was dissolved in anhydrous DMF solution (60mL), and the supernatant of the above reaction solution was slowly added to the reaction solution, and reacted overnight at room temperature. Chromatographic separation (EtOAC: PE5: 3) gave compound 6 with a yield of 71.9%; 1 H-NMR (400MHz, CDCl 3 ):δ=11.1(s,1H,Ar),10.6(s,1H,Ar), 8.43(d,J=2.0Hz,1H,CH),7.93(d,J=7.2Hz,1H,CH), 7.71(dd, J=2.0Hz, 7.2Hz, 1H, Ar), 7.55(q, J=2.0Hz, 7.2Hz, 1H, NH), 5.61(d...

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PUM

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Abstract

The present invention designs and synthesizes a new class of uracil-benzothiazole-based NS5B RdRp inhibitors with a general formula (1): the uracil-benzothiazole-based NS5B RdRp inhibitors provided by the present invention have better Anti-1b genotype hepatitis C virus replicon (HCV-1b) activity in vitro, the raw materials required for the synthesis of the compound of the present invention are easy to get, the route design is reasonable, the reaction conditions are mild, the yield of each step is high, the operation is simple and convenient, and it is suitable for industrial production; and as The novel NS5B RdRp inhibitor is expected to provide a new drug option for the clinical treatment of HCV.

Description

technical field [0001] The present invention relates to the field of medicine, in particular, the present invention relates to a novel derivative with uracil-benzothiazole structure, its preparation method and application, and the application of the compound in the preparation of anti-hepatitis C medicine. Background technique [0002] Hepatitis C (Hepatitis C) is a contagious liver disease caused by Hepatitis C Virus (Hepatitis C Virus, HCV), which seriously threatens human health. The virus mainly replicates in liver cells, damages liver cells, and causes The inflammation, degeneration and necrosis of liver cancer are the main causes of liver cirrhosis and liver cancer, which are extremely harmful to the health and life of patients. HCV is prevalent in the world. According to the statistics of the World Health Organization (WHO), the global HCV infection rate is 2.8%, about 185 million people are infected with HCV, and nearly 400,000 patients die each year due to HCV infec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D417/14A61P31/14A61K31/506A61K31/5377
CPCA61P31/14C07D417/04C07D417/14
Inventor 席建军庄让笑张建康何若愚赵艳梅邵益丹潘旭旺刘寿荣蔡兆斌
Owner 杭州市西溪医院
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