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Application of cyclophilin inhibitor

A cyclosporine and inhibitor technology, applied in the field of cyclophilin inhibitors, can solve the problems of insufficient inhibitory effect and weak anti-hepatitis B virus efficacy

Inactive Publication Date: 2017-06-30
WATERSTONE PHARMA WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the curative effect of ribavirin against hepatitis B virus is relatively weak, far inferior to the inhibitory effect of nucleoside drugs on hepatitis B virus, so ribavirin is gradually withdrawn from the hepatitis B virus treatment market

Method used

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  • Application of cyclophilin inhibitor
  • Application of cyclophilin inhibitor
  • Application of cyclophilin inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1 Preparation of 3-methoxycyclosporine

[0087] A solution of 3-(mercaptobenzothiazol-2-ylthio)cyclosporin (0.4 g, 0.28 mmol) and camphorsulfonic acid (0.7 g, 3 mmol) in dry tetrahydrofuran and dry methanol was heated at 50 °C for 2 h. The mixture was cooled to room temperature and saturated sodium bicarbonate, ether and water were added. The layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. Chromatography was repeated on silica gel, eluting with a mixture of dichloromethane and ethyl acetate, to obtain 120 mg of 3-methoxycyclosporin.

Embodiment 2

[0088] Example 2 Preparation of 3-(2-methoxyethylthio)-4-(γ-hydroxymethylleucine) cyclosporine

[0089] The liquid ammonia (30 mL) was concentrated under nitrogen. Sodium amide (1.0 g) was added followed by a solution of 4-(γ-hydroxymethylleucine)-cyclosporin (1.22 g, 1.0 mmol) in tert-butyl methyl ether (20 mL). The mixture was stirred at -35°C for 90 minutes. 2-Methoxyethyl disulfide (5.9 g) was added and stirring was continued for a further 2 hours at -35°C. Solid ammonium chloride (1.5 g) was added and the mixture was stirred at -33°C for 10 minutes. After returning to room temperature, the mixture was diluted with tert-butyl methyl ether, washed with water, brine, and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified using silica gel column chromatography, eluting first with ethyl acetate / heptane and then methanol / ethyl acetate to obtain 500 mg of 3-(2-methoxyethylthio)-4 -(γ-hydroxymethylleucine)cyclosporine.

Embodiment 3

[0090]Example 3 Preparation of 3-[(R)-2-(N,N-dimethylamino)ethylthio-Sar]-4-(γ-hydroxymethylleucine)cyclosporine

[0091] In an inert atmosphere, 4-(γ-hydroxymethylleucine) cyclosporine (1.22 g, 1.0 mmol) was added dropwise to a solution of lithium diisopropylamide (LDA) in dry tetrahydrofuran at low temperature. The tetrahydrofuran solution was dried. Stirring of the mixture was continued at -35°C for 90 minutes. 2-(N,N-Dimethylamino)ethyl disulfide (4.6 g) was added and stirring was continued for a further 2 hours at -35°C. Solid ammonium chloride (1.5 g) was added and the mixture was stirred at -33°C for 10 minutes. After returning to room temperature, the mixture was diluted with tert-butyl methyl ether, washed with water, brine, and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified using silica gel column chromatography, eluting first with ethyl acetate / heptane and then with methanol / ethyl acetate to obtain 260 mg of 3-[(R)-2-(...

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Abstract

The invention relates to application of a cyclophilin inhibitor, and particularly provides application of a cyclophilin inhibitor or pharmaceutically acceptable salt or solvate thereof in preparation of medicines. The medicines are used for treating and / or preventing diseases caused by hepatitis B virus infection.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular, the invention relates to the use of cyclophilin inhibitors. Background technique [0002] Hepatitis B (Hepatitis B) is an infectious disease caused by Hepatitis B virus infection. There are about 300 million people infected with Hepatitis B virus in the world, including 100 million people in China. Acute hepatitis B virus infection often transforms into chronic infection, and even into liver cirrhosis, liver dysfunction and liver cancer. Liver cancer caused by chronic hepatitis B accounts for 60%-80% of the total incidence of liver cancer in the world, and chronic hepatitis B has become a disease that seriously threatens human health. [0003] HBV belongs to the family Hepadnaviridae, and its genome is a 3.2kb incompletely closed double-stranded circular DNA. The complete virion consists of a nucleocapsid and an envelope. The nucleocapsid is mainly composed of the core antigen protein...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/13A61P31/20A61P1/16
CPCA61K38/13
Inventor 刘晓宇张发明白兰张思汉崔健喻耀胡名龙钱丽娜
Owner WATERSTONE PHARMA WUHAN
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