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Imidazole [2, 1-b] thiazole derivative as well as preparation method and application thereof

A derivative, thiazole technology, applied in the field of chemical medicine, can solve the problems of long treatment cycle, high treatment cost and low efficiency

Active Publication Date: 2016-10-05
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 more serious side effects
However, these drugs still have problems such as rapid drug resistance mutations, long treatment cycles, and high treatment costs. Therefore, it is necessary to develop new chronic hepatitis C drugs.

Method used

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  • Imidazole [2, 1-b] thiazole derivative as well as preparation method and application thereof
  • Imidazole [2, 1-b] thiazole derivative as well as preparation method and application thereof
  • Imidazole [2, 1-b] thiazole derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Example 1 Preparation of 4-(5-chloroimidazo[2,1-b]thiazole-6-carbonyl)-1-cyclopentylpiperazin-2-one (compound 1)

[0107]

[0108](1) Synthesis of 2-(4-nitrobenzenesulfonamido)acetic acid:

[0109] Glycine (10 g, 133 mmol) was dissolved in 1N sodium hydroxide solution (140 mL, 140 mmol) under ice-cooling, and p-nitrobenzenesulfonyl chloride (29.5 g, 133 mmol) was slowly added thereto. Half an hour later, the reaction solution was slowly raised to room temperature, and 1N sodium hydroxide solution was added to pH>9. React for 2 hours, add 150mL sodium hydroxide solution (1N) to the reaction solution, and extract with ethyl acetate (100mL×3), filter to remove the insoluble matter in the water phase, and adjust the pH of the filtrate to 1 with 6N hydrochloric acid, wait for the mixture The suspension continued to stir for half an hour, filtered, and the filter cake was washed with a small amount of ice water and dried in vacuo to obtain 19.73 g of a white product with ...

Embodiment 2

[0124] Example 2 Synthesis of 4-(5-chloro-2-methylimidazo[2,1-b]thiazole-6-carbonyl)-1-cyclopentylpiperazin-2-one (compound 2)

[0125]

[0126] (1) Synthesis of ethyl 2-methylimidazo[2,1-b]thiazole-6-carboxylate:

[0127] 5-Methyl-2-aminothiazole (1.0eq) and ethyl bromopyruvate (1.0eq) were dissolved in methyl ethyl ketone and heated to 80°C for reflux reaction for 12h, and ethyl bromopyruvate (1.0 eq) and continue the reflux reaction for 12 h, after cooling the reaction solution, the solvent was evaporated under reduced pressure, the residue was extracted with ethyl acetate and water, the aqueous layer was back-extracted twice with ethyl acetate, the ethyl acetate layers were combined and washed with saturated brine, Dry over anhydrous magnesium sulfate, mix the sample with silica gel and purify by column chromatography to obtain the corresponding product with a yield of 16.86%.

[0128] (2) Synthesis of ethyl 5-chloro-2-methylimidazo[2,1-b]thiazole-6-carboxylate:

[01...

Embodiment 3

[0134] Example 3 Synthesis of 4-(5-chloro-2-isopropylimidazo[2,1-b]thiazole-6-carbonyl)-1-cyclopentylpiperazin-2-one (compound 3)

[0135]

[0136] (1) Synthesis of 5-isopropylthiazol-2-amine:

[0137]To isovaleraldehyde (1.721g, 20mmol) in dichloromethane / dioxane (V / V=4 / 1) solution was slowly added dropwise liquid bromine (1.0mL, 20mmol) in dichloromethane / dioxane at 0°C Hexane (V / V=4 / 1, 12 mL) solution. The reaction solution was continued to react at 10° C. for 2 h to obtain an intermediate of 2-bromoisovaleraldehyde.

[0138] The dichloromethane / dioxane solution of 2-bromoisovaleraldehyde intermediate was slowly added dropwise to the dichloromethane / dioxane solution (30mL) of thiourea (1.523g, 20mmol), and ethanol (6mL ) and triethylamine (2.424g, 24mmol). After reacting for 20 hours at room temperature, add 100 mL of distilled water to the reaction solution, and adjust the pH to 12 with 12N sodium hydroxide solution. After stirring for 1 hour at room temperature, the...

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PUM

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Abstract

The invention belongs to the field of chemical pharmaceuticals, and particularly relates to an imidazole [2, 1-b] thiazole derivative as well as a preparation method and an application thereof. The structure of the imidazole [2, 1-b] thiazole derivative is shown by a formula I. The invention also provides a preparation method and an application of the imidazole [2, 1-b] thiazole derivative. The compound provided by the invention has the advantages of having good activity, having no cross tolerance with an NS3 / 4A inhibitor, an NS5A inhibitor, and nucleoside and non-nucleoside type NS5B inhibitors, and being capable of cooperatively resisting viruses when applied in combination with the NS3 / 4A inhibitor, the NS5A inhibitor, the nucleoside and non-nucleoside type NS5B inhibitors, and can be used for treating HCV (hepatitis C virus) infected patients independently or in a manner of forming a pharmaceutical composition together with one or more of ribavirin, PEG-interferon-[alpha], the NS3 / 4A inhibitor, the NS5A inhibitor, and the nucleoside and non-nucleoside type NS5B inhibitors.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and specifically relates to imidazo[2,1-b]thiazole 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 survey of the World Health Organization (WHO) in 1999, about 3% of people (170 million people) in the world are infected with HCV (J.Viral.Hepat.1999,6:35-47), and 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 has a tendency 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 live...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61K31/496A61P31/14
Inventor 余洛汀魏于全王宁宇
Owner SICHUAN UNIV
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