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1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof

A technology of arylsulfonyl and benzimidazole, applied in the field of chemical medicine, can solve the problems of high treatment cost, serious side effects, and decreased replication ability of clemizole hydrochloride-resistant virus strains

Inactive Publication Date: 2012-07-11
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The traditional standard regimen approved by the FDA for the treatment of chronic hepatitis C is the combined application of PEG-interferon-α and ribavirin, which has the following problems: ①. Low effective rate; ②. Long treatment cycle and high treatment cost ; ③. Toxic and side effects are more serious
By inducing drug-resistant mutations, the replication ability of clemizole hydrochloride-resistant virus strains is greatly reduced, which means that the drug resistance of this type of NS4B inhibitor may be slower than that of protease inhibitors such as Boceprevir.

Method used

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  • 1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof
  • 1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof
  • 1-arylsulfonyl-1H-benzimidazole derivative and preparation method and application thereof

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Experimental program
Comparison scheme
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preparation example Construction

[0038] The preparation method of compound 1 is:

[0039] 1. R 1 Independently H, C1~C8 alkyl, C1~C8 cycloalkyl, halogen substituted C1~C8 alkyl, hydroxyl substituted C1~C8 alkyl, CF 3 , , , Or the ring skeleton with a substituent is an epoxy group with 1 to 8 Cs; when the substituent is independently H or a C1 to C8 alkyl group, the synthetic route is as follows:

[0040]

[0041] Compound 3 was prepared by dehydration ring closure with compound 4.

[0042] During the reaction, compounds 3 and 4 are added to hydrochloric acid solution for reflux reaction, then the reaction solution is poured into water, and the pH is adjusted to about 8 with concentrated ammonia water.

[0043] 2. When R 1 Hydroxyl substituted C1~C8 alkyl, , , the synthetic route can be:

[0044]

[0045] K is halogen.

[0046] Compound 5 can be prepared by nucleophilic reaction with a nucleophile. The nucleophile is compound 6, compound 7 or sodium alkylate.

[0047] The reaction solven...

Embodiment 1

[0049] The synthesis of embodiment 1 2-chloromethyl benzimidazole

[0050] The synthetic route is as follows:

[0051]

[0052] Add o-phenylenediamine (20.01 g, 184.95 mmol) and chloroacetic acid (22.72 g, 240.43 mmol) into a 250 mL three-necked flask, then add 150 mL of 4 mol / L hydrochloric acid, stir at room temperature for 3 h under nitrogen protection, and then heat up to Reflux at 110°C for 6 hours, stop the reaction, pour the reaction solution into 300 mL of cold water while it is hot, neutralize it with dilute ammonia water (5 mol / L) to pH 8 under vigorous stirring, filter with suction, wash twice with cold water, and dry The filter cake was recrystallized with ethanol as a solvent to obtain 25.12 g of the product with a yield of 81.08%. Purity (HPLC) ≥ 95%.

[0053] 1 H-NMR (400MHz, DMSO-D6) δ:4.93(s, 2H, -CH 2 -), 7.22(m, 2H), 7.59(m, 2H), 12.21(s, 1H).

Embodiment 2

[0054] The synthesis of embodiment 2 2-methylbenzimidazole

[0055] The synthetic route is as follows:

[0056]

[0057] According to the preparation method of the intermediate 2-chloromethylbenzimidazole, the raw materials were replaced with o-phenylenediamine and glacial acetic acid, and 2-methylbenzimidazole was directly obtained after filtration, with a yield of 85.50%. Purity (HPLC) ≥ 95%.

[0058] 1 H-NMR (400MHz, DMSO-D6) δ: 2.51(s, 3H, -CH 3 ), 7.12(m, 2H), 7.47(m, 2H), 12.18(s, 1H).

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Abstract

The invention relates to a 1-arylsulfonyl-1H-benzimidazole derivative and a preparation method and application thereof, belonging to the field of chemical medicine. The 1-arylsulfonyl-1H-benzimidazole derivative has a structure shown by formula I in the specification. According to the invention, the 1-arylsulfonyl-1H-benzimidazole derivative is obtained based on massive screening, and has anti-HCV activity; and a new option is provided for the development and application of a medicine for resisting chronic hepatitis C.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and particularly relates to 1-arylsulfonyl-1H-benzimidazole derivatives and their preparation methods and applications. Background technique [0002] Chronic hepatitis C, a chronic liver disease caused by the hepatitis C virus (HCV), is the leading cause of cirrhosis and liver cancer, and is currently the leading cause of liver transplantation. According to the World Health Organization (WHO) survey in 1999, about 3% of the world's people (170 million people) were infected with HCV ( J. Viral. Hepat. 1999, 6: 35-47), the infection rate in China is about 3.2% (40 million people) ( Lancet Infect. Dis. 2005. 5: 558–67), and the number of infected people tends to increase year by year. After the incubation period of 10-20 years, about 80% of these HCV-infected people will develop into chronic hepatitis C, 20% will further develop into liver cirrhosis, and 1%-4% will eventually develop into ...

Claims

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Application Information

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IPC IPC(8): C07D235/10C07D235/12C07D235/08C07D405/04C07D235/14A61K31/4184A61K31/5377A61P31/14
Inventor 余洛汀魏于全
Owner SICHUAN UNIV
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