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3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection

A hepatitis C virus, cyclosporine technology, applied in the direction of peptides, etc., can solve problems such as nephrotoxicity

Active Publication Date: 2007-11-07
WATERSTONE PHARMA WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, a known problem with cyclosporines is their nephrotoxicity

Method used

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  • 3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection
  • 3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection
  • 3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0261] 5.1 Example 1: 3-methoxycyclosporine

[0262] 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 (compound A).

[0263] The NMR signal of this compound in deuterochloroform is at 5.83ppm (sarcosine H), 3.49ppm (methoxyl CH 3 ), 83.5ppm (sarcosine C) and 58.7ppm (methoxy CH 3 ).

Embodiment 2

[0264] 5.2 Example 2: 3-(2-Aminoethoxy)cyclosporine

[0265] To a solution of 3-(N-Fmoc-2-aminoethoxy)cyclosporin (0.52g, 0.35mmol) in dimethylformamide (16ml) was added piperidine (4ml). The mixture was stirred under nitrogen for 1.25 hours. The resulting mixture was diluted with ethyl acetate (25ml) and water (25ml). The organic phase was washed with water (20ml), brine (2?0ml), dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The resulting material was purified by repeated silica gel chromatography eluting with a gradient of methanol / ethyl acetate to 100% methanol to afford 3-(2-aminoethoxy)cyclosporin (compound B) as a white gum (130mg). The NMR signal of this compound in deuterochloroform is at 5.95 ppm (sarcosine H).

[0266] salt formation

[0267] Compound B (130 mg) was dissolved in dichloromethane, treated with a solution of methanesulfonic acid (1 ml of a 0.1 M solution in dichloromethane) and stirring was continued for 10 minutes. T...

Embodiment 3

[0268] 53 Example 3: 3-(2-Dimethylaminoethoxy)cyclosporine

[0269] A solution of 3-(2-aminoethoxy)cyclosporin (0.375 g, 0.3 mmol), formalin (0.8 mmol) and formic acid (1.33 mmol) in 1,4-dioxane was Heat at 80°C for 5 hours. The mixture was cooled to room temperature and diluted with saturated sodium bicarbonate. The resulting mixture was extracted with dichloromethane, and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by repeated column chromatography on silica gel eluting with a gradient of methanol / dichloromethane to 100% methanol to afford 3-(2-dimethylaminoethoxy)cyclosporine (compound C , 230mg).

[0270] The NMR signals of this compound in deuterochloroform are at 0.01 ppm (sarcosine H) and 82.6 ppm (sarcosine C).

[0271] salt formation

[0272] To a solution of compound C (194 mg) in tert-butyl methyl ether and methanol was added a solution of hydrochloric acid (2 ml of a 2.0 M solutio...

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Abstract

This invention relates to cyclosporin derivatives of general formula (I) wherein A, B, R<1>,R<2> and X are as defined in the specification, and pharmaceutical compositions prepared from the same, for use in treatment of hepatitis C virus.

Description

1. Field of invention [0001] The present invention provides cyclosporin derivatives and pharmaceutical compositions prepared therefrom for use in the treatment or prevention of hepatitis C virus infection in an individual in need thereof. In certain aspects, the invention provides methods for treating hepatitis C infection by administering to a subject in need thereof an amount of a 3-ether or 3-thioether cyclosporine of the invention effective to treat or prevent infection. 2. Background of the invention [0002] In 1989, a major pathogenic virus causing non-A and non-B post-transfusion hepatitis was discovered and named hepatitis C virus (HCV). Since then, several hepatitis virus types have been discovered in addition to hepatitis A, B, and C viruses, among which the hepatitis caused by HCV is called hepatitis C. Individuals infected with HCV are thought to affect several percent of the world's population, and HCV infection is characterized as a chronic disease. [0003]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64
Inventor 汉斯·吉奥格·弗莱里大卫·兰威克·霍克
Owner WATERSTONE PHARMA WUHAN
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