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Novel acyclic nucleoside phosphonate and its medical use

A pharmaceutical and drug technology, applied in the field of acyclic nucleoside phosphonate derivatives, can solve the problems of kidney and toxicity, and achieve strong anti-hepatitis B virus activity and good liver protection effect

Inactive Publication Date: 2005-12-07
FUKANGREN BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical application of adefovir dipivoxil can produce nephrotoxicity

Method used

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  • Novel acyclic nucleoside phosphonate and its medical use
  • Novel acyclic nucleoside phosphonate and its medical use
  • Novel acyclic nucleoside phosphonate and its medical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 2-amino-6-(2,3-dihydrobenzofuran-5-sulfanyl)-9-[2-[bis(2,2,2-trifluoroethyl)phosphonomethoxy ] Ethyl] - purine (I 1 ) preparation

[0040] 1.1 2,3-Dihydrobenzofuran-5-thiol

[0041] 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.

[0042] 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...

Embodiment 2

[0051] Example 2 2-Amino-6-(1,3-benzodioxol-5-thio)-9-[2-[bis(2,2,2-trifluoroethyl)phosphonomethyl Oxygen] ethyl] - purine (I 2 ) preparation

[0052] 2.1 1,3-benzodioxene-5-thiol

[0053] 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-dimethoxybenzen...

Embodiment 3

[0057] Example 3 2-Amino-6-(1,4-benzodioxin-5-thio)-9-[2-[bis(2,2,2-trifluoroethyl)phosphonomethyl Oxygen] ethyl] - purine (I 3 ) preparation

[0058] 3.1 1,4-Benzodioxene-5-thiol

[0059] 5 g of 2-fluoroanisole was dissolved in 6.6 ml of dichloromethane, and 6.34 g of bromine was added dropwise with stirring at room temperature. After the dropwise addition was complete, the mixture was stirred for another 1 hour. The reaction was terminated by adding 5 mL of saturated sodium bisulfite solution. The aqueous layer was separated, and the organic layer was washed with 10 ml of water and dried over anhydrous sodium sulfate. It was filtered and evaporated to dryness to obtain 7.32 g of 2-fluoro-4-bromoanisole.

[0060] Suspend 0.87 g of magnesium chips in 30 ml of anhydrous tetrahydrofuran, and add dropwise a solution of 7.32 g of 2-fluoro-4-bromoanisole dissolved in 10 ml of tetrahydrofuran under nitrogen within 1 hour. After the dropwise addition was completed, the reaction...

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Abstract

The invention provides a novel acyclic nucleoside phosphonate having a formula (I) and its medical use, wherein these compounds can be used as antivirus medicaments, especially medicaments for anti-hepatitis B, wherein R1 is H or C1-C3 alkyl, R2 is H, CH2CF3, OCH2-OOR3, OCOOR3, R3 is iPr, tBu, X is O, CH2, n=1-3.

Description

Technical field: [0001] The present invention relates to a new acyclic nucleoside phosphonate derivative with high-efficiency anti-hepatitis B virus activity and low cytotoxicity and its application as medicine. Background technique: [0002] There are as many as 400 million hepatitis B virus carriers worldwide, and about 40 million people die of liver cirrhosis or liver cancer due to hepatitis B infection every year. Currently clinically effective anti-HBV drugs mainly include interferon, lamivudine and adefovir dipivoxil. However, the effective rate of interferon treatment is only 30-50%, and it is often accompanied by toxic side effects such as flu-like symptoms and leukopenia; lamivudine treatment is prone to drug resistance, and the incidence rate is as high as 40-50% after 2 years of continuous treatment . Nucleotide analogues such as adefovir dipivoxil do not require phosphorylation in cells, are not prone to drug resistance, and can overcome lamivudine drug resista...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 王进京
Owner FUKANGREN BIO PHARMA
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