Benzothiophene derivative, preparation method and application thereof

A thiophene and benzo technology, applied in the field of hepatitis C virus replication inhibitors, can solve problems such as adverse reactions, hematological toxicity, and successful cure rate of less than 10%

Inactive Publication Date: 2013-12-04
GINKGO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, from the perspective of sustained viral response rate (SVR), the current standard treatment is not very effective, and the clinical cure rate is about 50%.
And at present, the treatment time of this therapy is relatively long. For example, patients with hepatitis C type HCVI need continuous medication for 48 weeks. At the same time, serious adverse reactions often occur, such as mental problems, influenza-like symptoms and blood production. Therefore, it is particularly important to develop a new mechanism of HCV inhibitors that are more efficient and less toxic

Method used

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  • Benzothiophene derivative, preparation method and application thereof
  • Benzothiophene derivative, preparation method and application thereof
  • Benzothiophene derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1 Compound Ia: 3-(nitrogen-isopropyl-4-methylcyclohexylcarboxamido)-7-phenylbenzo[b]thiophene-2-carboxylic acid

[0087]

[0088] First, intermediate IIIa: methyl 3-amino-7-bromobenzo[b]thiophene-2-carboxylate should be synthesized, and the target compound should be synthesized from intermediate IIIa.

[0089]

[0090] According to the synthetic route (1), under the protection of nitrogen, 3-bromo-2-fluorobenzocyanide (5.0g, 25.1mmol) was dissolved in 20.0ml of DMF, and sodium carbonate (5.3g, 50.0mmol) was added to cool to 0°C. Methyl thioglycolate (2.9 g, 27.5 mmol) was added dropwise with stirring, and the reaction solution was raised to room temperature and stirred overnight. After adding water, a white solid was precipitated, filtered, washed with water and petroleum ether, and dried to obtain a white powder (6.4 g), with a yield of 89.5%.

[0091]1 H NMR (CDCl 3 , 300MHz) δ7.64-7.60(m, 2H), 7.29-7.24(m, 1H), 5.86(br, 2H), 3.90(s, 3H); ESI-MS m / z 28...

Embodiment 2

[0106] Example 2 Compound Ib: 3-(nitrogen-isopropyl-4-methylcyclohexylcarboxamido)-6-phenylbenzo[b]thiophene-2-carboxylic acid

[0107]

[0108] Synthesis of Intermediate IIIb

[0109] 3-Amino-6-bromobenzo[b]thiophene-2-carboxylic acid methyl ester

[0110]

[0111] According to the synthetic route (1), under nitrogen protection, 4-bromo-2-fluorobenzocyanide (5.0g, 25.1mmol) was dissolved in 20.0ml DMF, and sodium carbonate (5.3g, 50.0mmol) was added to cool to 0°C, and stirred Methyl thioglycolate (2.9 g, 27.5 mmol) was added dropwise under the conditions of , the reaction solution was raised to room temperature, and stirred overnight. After adding water, a white solid was precipitated, filtered, washed with water and petroleum ether, and dried to obtain a white powder (6.0 g), with a yield of 83.9%.

[0112] 1 H NMR (CDCl 3 , 300MHz) δ7.88(s, 1H), 7.48(s, 2H), 5.88(s, 2H), 3.89(s, 3H); ESI-MS m / z 284(M + -H + ).

[0113] The following steps follow the method for...

Embodiment 3

[0115] Example 3 Compound Ic: 3-(nitrogen-ethyl-4-methylcyclohexylcarboxamido)-6-phenylbenzo[b]thiophene-2-carboxylic acid

[0116]

[0117] Compound Ic can be prepared according to the method for preparing compound Ib in Example 2.

[0118] 1 H NMR (DMSO-d6, 300MHz) δ8.40(s, 1H), 7.86-7.74(m, 4H), 7.53-7.41(m, 3H), 3.82-3.58(m, 2H), 2.10-2.02(m , 1H), 1.84-1.80(m, 3H), 1.66-1.63(m, 3H), 1.43-1.24(m, 6H), 0.83(d, J=6.6Hz, 3H); ESI-MS m / z 422 (M+H) + .

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PUM

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Abstract

The invention discloses a compound with general formula (I) structure or salt which can be received in pharmacy. The compound or the salt which can be received in pharmacy can restrain hepatitis C virus NS5B polymerase in vitro with high efficiency, can have anti-hepatitis C virus activity in vivo, and has higher inhibitory activity when being compared with NS5B polymerase inhibitors with the similar structure.

Description

technical field [0001] The invention relates to a benzothiophene carboxylic acid compound as an antiviral agent, its preparation method and use, especially as an inhibitor of hepatitis C virus (HCV) replication. Background technique [0002] Hepatitis C virus (HCV) infection is the main cause of liver disease in the world. According to the World Health Organization (WHO) estimates, there are currently 170 million to 200 million people with chronic hepatitis C infection in the world, accounting for about 3% of the global population, and new ones are added every year. There are 3 to 4 million hepatitis C patients. According to the statistics of the Centers for Disease Control and Prevention (CDC), there are nearly 3 million chronic hepatitis C patients in the United States alone, and 300,000 new hepatitis C patients are added every year in the United States. In China, survey data show that the positive rate of hepatitis C antibody is 3.2%, and there are about 40 million patie...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/70C07D409/04A61K31/381A61K31/404A61K31/4436A61P31/14
Inventor 陈力谢欣
Owner GINKGO PHARMA
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