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Cyclic nucleoside phosphate compound and preparation method and application thereof

A nucleoside cyclic phosphate ester and compound technology, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., to achieve good antiviral effects, small doses, and less toxic and side effects

Active Publication Date: 2014-06-11
ANHUI BIOCHEM UNITED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Metabolic by-product aryl vinyl ketone can quickly undergo 1,4-addition to glutathione, which is abundant in liver cells and has anti-oxidation and anti-free radical effects, and is eliminated. No side effects have been found for this addition product to report

Method used

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  • Cyclic nucleoside phosphate compound and preparation method and application thereof
  • Cyclic nucleoside phosphate compound and preparation method and application thereof
  • Cyclic nucleoside phosphate compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1 Preparation of Formula VIII Compounds

[0072]

[0073] The preparation method of the compound of the present embodiment formula VIII comprises the following steps:

[0074] 1) Suspend 20g of the compound of formula II in 300ml of anhydrous tetrahydrofuran under anhydrous, anaerobic, -5°C and stirring conditions to prepare a suspension of the compound of formula II, and then add dropwise 1M tert-butylmagnesium chloride ( t BuMgCl) tetrahydrofuran solution 160ml, at -5°C, after stirring for 0.5h, the temperature was raised to 20°C, continued stirring for 0.5h, the reaction mixture was cooled to 5°C, and a solution of 34g of the compound of formula VII dissolved in 200ml of tetrahydrofuran was added dropwise , at 5°C, after stirring for 20 h, the reaction mixture was cooled to -5°C, 80 ml of 2N hydrochloric acid aqueous solution was added dropwise, and the temperature was raised to room temperature under stirring to obtain a reaction solution;

[0075] 2) ...

Embodiment 2

[0080] Example 2 The preparation of formula IX compound

[0081]

[0082] The preparation method of formula IX compound, comprises the steps:

[0083] 1) Suspend 20g of the compound of formula III in 300ml of anhydrous tetrahydrofuran under anhydrous, anaerobic, -5°C and stirring conditions to prepare a suspension of the compound of formula II, and then add dropwise 1M tert-butylmagnesium chloride ( t BuMgCl) tetrahydrofuran solution 150ml, stirred at -5°C for 0.5h, then warmed up to 20°C, stirred for 0.5h, cooled the reaction mixture to 5°C, added dropwise a solution of 34g of the compound of formula VII dissolved in 200ml of tetrahydrofuran, stirred at 5°C for 20h Afterwards, the reaction mixture was cooled to -5°C, 80 ml of 2N hydrochloric acid aqueous solution was added dropwise, and the temperature was raised to room temperature under stirring to obtain a reaction solution;

[0084] 2) Remove the tetrahydrofuran in the reaction solution by rotary evaporation under r...

Embodiment 3

[0089] Example 3 Liver targeting evaluation of test compounds in mice

[0090] Referring to the method disclosed in Document 3 (Clin. Chem. 1992, 38, 480-485.), the liver targeting properties of the compounds to be tested (Sofosbuvir, Formula VIII, F-Sofosbuvir, Formula IX) in mice were comparatively studied.

[0091] After dissolving the compounds to be tested (Sofosbuvir, Formula VIII, F-Sofosbuvir and Formula IX) in dimethyl sulfoxide, they were diluted to the required concentration with phosphate buffer to prepare solutions of the compounds to be tested at the required concentrations.

[0092] Forty-eight BACLB / c mice weighing 20-25 g were randomly divided into four groups with 12 mice in each group. After 12 hours of fasting, 30 mg / Kg dose of the compound to be tested (that is, compound Sofosbuvir, formula VIII, F-Sofosbuvir and formula IX) solution was given by intragastric administration; after 60 minutes (min) and 120 minutes of administration, 6 The small intestine...

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Abstract

The invention relates to a cyclic nucleoside phosphate compound in a structure shown as a formula I described in the specification and a preparation method and an application thereof. The cyclic nucleoside phosphate compound in the structure shown as the formula I is a precursor drug with an antivirus effect, wherein X is selected from any one of hydrogen, fluorine, chlorine, bromine and iodine, Y is selected from any one of oxygen and sulfur, and Z is arycyclo or arycyclo with 1-3 substituents; the arycyclo is selected from any one of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl and 3-thienyl, the substituent on the arycyclo is selected from any one of fluorine, chlorine, bromine, iodine, trifluoromethyl, C1-3 alkyl and -OR, and R is selected from any one of trifluoromethyl and C1-3 alkyl.

Description

technical field [0001] The invention belongs to the technical field of compound preparation, and in particular relates to a nucleoside cyclic phosphate compound, a preparation method and an application thereof. Background technique [0002] Hepatitis C virus (HCV) infection can directly lead to liver cirrhosis and liver cancer, seriously threatening human health. The World Health Organization (WTO) survey results show that more than 200 million people in the world are infected with hepatitis C virus, of which about 20% of the infected people rely on their own immune system to clear the HCV virus, while the rest of the HCV virus infected people are HCV The virus remains dormant for the rest of its life and kills about 10-20% of infected people who develop cirrhosis or liver cancer. [0003] Currently, the combination of pegylated interferon (alfa-2a or alfa-2b) and ribavirin (Ribavirin), Boceprevir (Boceprevir) or Telaprevir (Telaprevir) has become an effective treatment for...

Claims

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Application Information

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IPC IPC(8): C07H19/11C07H1/00A61P31/14A61P31/20A61P31/18
Inventor 岳祥军钟晓锋邹春伟陈小峰王志邦
Owner ANHUI BIOCHEM UNITED PHARMA CO LTD
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