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Acyclic nucleoside phosphonate derivatives

A technology of nucleoside phosphonate and derivatives, which is applied in the field of anti-hepatitis B virus, and can solve the problem that there are only a handful of anti-hepatitis B virus drugs

Inactive Publication Date: 2005-09-21
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the number of people infected with hepatitis B is more than 10 times that of HIV infection, compared with anti-HIV drugs, there are only a handful of clinically effective anti-HBV drugs

Method used

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  • Acyclic nucleoside phosphonate derivatives
  • Acyclic nucleoside phosphonate derivatives
  • Acyclic nucleoside phosphonate derivatives

Examples

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reference example

[0024] Reference example 2-amino-6-(4-methoxyphenylthio)-9-[2-[bis(2,2,2-trifluoroethyl)phosphonomethoxy]propyl]-purine ( Synthesis of MCC-478)

[0025] Synthetic MCC-478 was used as a control substance for biological evaluation.

[0026] 1. 2-[bis(2,2,2-trifluoroethyl)-phosphonomethoxy]-ethyl chloride

[0027] In 46 grams of trifluoroethanol, 21 grams of phosphorus trichloride was added, and the mixture was stirred and reacted at 80-90° C. for 4 hours. Fractional distillation yielded 41 grams of tris-(2,2,2-trifluoroethyl)phosphite, 130-131°C / 74-78mmHg.

[0028] Suspend 26 grams of 2-chloroethanol and 10 grams of paraformaldehyde in 50 ml of dichloromethane, cool in an ice bath; under stirring, dry hydrogen chloride at 0°C for 10 hours, separate the water layer, and chlorinate the organic layer with anhydrous Calcium drying, filtration to remove solids and distillation to obtain 24 grams of chloroethyl chloromethyl ether, boiling point 78-82 ° C / 30 mmHg

[0029] 18 g of...

Embodiment 1

[0034]Example 1 2-amino-6-(3,4-dimethoxyphenylthio)-9-[2-[bis(2,2,2-trifluoroethyl)phosphonomethoxy]ethyl ]-purine (I 1 )

[0035] 1.1 3,4-Dimethoxybenzenethiol

[0036] Under mechanical stirring, 2.64 g of o-methoxyanisole was slowly added in batches to 5 g of chlorosulfonic acid within 20 minutes. After stirring for 20 minutes, the reaction mixture was poured into 40 ml of ice water. After the ice had completely melted, it was extracted twice with dichloromethane, 15 ml each time. The extracts were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was evaporated to dryness under reduced pressure to obtain a white solid, which was washed with a small amount of ether to obtain 3.3 g of 3,4-dimethoxybenzenesulfonyl chloride, melting point: 72-73°C.

[0037] Add 3.3 grams of 3,4-dimethoxybenzenesulfonyl chloride to 90 ml of ice water, add 5.5 ml of concentrated sulfuric acid, stir vigorously, add 5 grams of Zn powder in batche...

Embodiment 2

[0040] Example 2 2-amino-6-(2,4-dimethoxyphenylthio)-9-[2-[bis(2,2,2-trifluoroethyl)phosphonomethoxy]ethyl ]-purine (I 2 )

[0041] 2.1 2,4-Dimethoxybenzenethiol

[0042] Under full stirring, 29 grams of concentrated sulfuric acid was added dropwise to 27 grams of 1,3-dimethoxybenzene, and the addition was completed within 15 minutes. Stirring was continued for 1 hour, and slowly poured into 250 ml of saturated potassium carbonate aqueous solution. Filter the precipitate, dry it at 125°C, grind it finely, take 30 grams and add it to 35 grams of phosphorus oxychloride. The mixture was reacted in a steam bath for 2 hours. Cool to room temperature and pour into 300 ml of crushed ice. After the ice had completely melted, it was extracted twice with 150 ml of ether. The extracts were combined, washed with saturated brine, dried and evaporated to dryness under reduced pressure, and the obtained solid was washed with ether to obtain 18 g of 2,4-dimethoxybenzenesulfonyl chloride...

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Abstract

The invention provides acyclic nucleoside phosphonate derivatives and their pharmaceutically acceptable salts represented by the formula disclosed in the specification, wherein R1 and R2 represent C1-C3 alkoxy and halogen (un)substituted alkoxy, C1-C3 alkyl and halogen (un)substituted alkyl, halogen, R3 represents hydrogen, C1-C3 alkyl and halogen (un)substituted alkoxy, C1-C3 alkyl and halogen (un)substituted alkyl, halogen, R1, R2, R3 are identical or different, R4 represents H or C1-C3 alkyl, R5 represents H, CH2CF3, OCH2-OOR6, OCOOR6, R6=straight chain or branched chain C1-6 alkyl.

Description

field of invention [0001] The present invention relates to new acyclic nucleoside phosphonate derivatives, preparation method, pharmaceutical composition containing them, and application in anti-hepatitis B virus. Background technique [0002] Hepatitis B virus is a major disease that threatens people's life and health. The fundamental way to treat hepatitis B is antiviral therapy. Currently, the clinically effective anti-HBV drugs are mainly interferon and namivudine. However, the effective rate of interferon therapy is only 30-50%, and it has dose-limiting toxic and side effects; Namivudine has definite anti-hepatitis B virus effect, but long-term use is prone to drug resistance, and after 2 years of continuous medication , the incidence rate of drug resistance is as high as 40-50%, which can cause serious consequences such as acute attack of hepatitis (Fischer KP, Gutfreund KS, Tyrrell DL. Lamivudine resistance in hepatitis B: mechanisms and clinical implications. Drug ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/675A61P1/16A61P31/12C07F9/6561
Inventor 仲伯华陈兰福刘河王亚平靳雪源
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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