Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Phosphate derivative of acyclovir and medical application thereof

A derivative, nucleoside phosphate technology, applied in the field of phosphate derivatives of acyclovir, can solve the problems of carcinogenicity, easy to produce drug resistance, easy to rebound, etc.

Inactive Publication Date: 2014-05-21
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
View PDF1 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lamivudine has definite anti-hepatitis B virus effect, but long-term use is prone to drug resistance; adefovir dipivoxil has renal toxicity, and entecavir has carcinogenicity in animal experiments; tenofovir dipivoxil is prone to rebound after drug withdrawal

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Phosphate derivative of acyclovir and medical application thereof
  • Phosphate derivative of acyclovir and medical application thereof
  • Phosphate derivative of acyclovir and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The preparation of embodiment 1 acyclovir phosphate (II)

[0022] In a sealed reactor, add 227 g (1.0 mol) anhydrous acyclovir (water content less than 0.1%), 5000 ml triethyl phosphite, pass nitrogen, and stir and cool the reaction mixture to -15°C to -20°C °C. Under nitrogen, 137 g (1.2 mol) phosphorus oxychloride was mixed with 400 ml of anhydrous dichloromethane, the mixture was cooled to -15°C to -0°C, pumped into the reactor, flow rate 50 ml / min, cooled to maintain the temperature of the reaction mixture from -15°C to -20°C. Continue stirring until the unreacted acyclovir is below 3%.

[0023] The reaction mixture was poured into a mixture of 2000 ml of deionized water and 2000 grams of ice and cooled to maintain a temperature of 15°C. After the addition was complete, the mixture was warmed to 20°C to 25°C and stirred for 45-60 minutes. Add 5000 ml of dichloromethane, stir vigorously for 30 minutes, stand for 30 minutes, separate the layers, and discard the di...

Embodiment 2

[0024] Example 2 2-[(guanin-9-yl)-methoxy]-ethyl-bis(propionyloxymethyl)-phosphate (I 1 ) preparation

[0025]

[0026] In 50mL of anhydrous DMF, add 3.1g (10mmoL) II and 2g (20mmoL) triethylamine, stir at room temperature for 10 minutes under nitrogen protection, add 4.6g (40mmoL) chloromethyl propionate, stir at room temperature under nitrogen protection React for 24 hours. Transfer to a separatory funnel, add 600 mL of water, extract with ethyl acetate (3×200 mL), combine the organic layers, and wash with saturated brine (3×200 mL). The oil layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was separated by silica gel column chromatography, eluted with dichloromethane containing 5% methanol, the desired fractions were collected and evaporated to dryness under reduced pressure. get I 1 1.6g. 1 H-NMR (DMSO-d6, 400MHz) δ: 10.60 (s, 1H), 7.79 (s, 1H), 6.40 (bs, 2H), 5.6...

Embodiment 32-

[0027] Example 32-[(guanin-9-yl)-methoxy]-ethyl-bis(isobutyryloxymethyl)-phosphate (I 2 ) preparation

[0028]

[0029] With reference to the method of Example 2, chloromethyl isobutyrate is used instead of chloromethyl propionate to react with II, and the reaction product is separated by silica gel column chromatography to obtain I 2 , the yield is 27%. 1 H-NMR (DMSO-d6, 400MHz) δ: 10.65 (s, 1H), 7.81 (s, 1H), 6.5 (bs, 2H), 5.65-5.70 (m, 4H), 5.35 (s, 2H), 4.1 -4.0 (t, 2H), 3.7-3.6 (t, 2H), 2.53 (m, 2H), 1.13 (d, 12H).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention aims to provide a ring-free nucleoside phosphate derivative having an anti-hepatitis B virus activity and represented by formula I shown in the specification and a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 represents H or methyl; absolute configuration of carbon atoms connected with R1 is an R or S isomer or an RS racemate; R2 represents -R3 or -OR3; R3 represents C1-C8 alkyl or cycloalkyl, and is selected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl and the like.

Description

technical field [0001] The present invention relates to a phosphate derivative of acyclovir with potent anti-hepatitis B virus activity and low cytotoxicity, a preparation method thereof and its use for preparing a medicine for treating hepatitis B virus infection. Background technique [0002] Hepatitis B is a major disease that threatens people's lives and health. The fundamental way to treat hepatitis B is antiviral therapy. At present, the clinically effective anti-HBV drugs are mainly lamivudine, adefovir dipivoxil, entecavir, tenofovir dipivoxil, etc. Lamivudine has definite anti-HBV effects, but long-term use is prone to drug resistance; adefovir dipivoxil is nephrotoxic, and entecavir is carcinogenic in animal tests; tenofovir dipivoxil is prone to rebound after stopping the drug. Therefore, high-efficiency, safe and durable anti-HBV drugs are urgently needed in clinical practice. SUMMARY OF THE INVENTION [0003] The object of the present invention is to provide...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07F9/6561A61K31/675A61P31/20
Inventor 仲伯华樊士勇周磊史卫国姚宜山何新华贾红新
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com