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Prodrug with liver-targeted anti-HBV effect

An anti-hepatitis B, liver-targeting technology, applied in antiviral agents, medical preparations containing active ingredients, organic chemistry, etc. The effect of reducing dosage

Inactive Publication Date: 2008-11-19
江苏吴中苏药医药开发有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] Technical problem: the present invention proposes to provide some liver-targeting anti-hepatitis B virus prodrugs and their preparation methods for the ubiquitous disadvantages of nucleoside anti-hepatitis B drugs, such as unsatisfactory curative effect and large toxic and side effects. It can be used to treat hepatitis B, through its liver-targeting effect, it can improve curative effect, reduce dosage, and reduce toxic and side effects

Method used

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  • Prodrug with liver-targeted anti-HBV effect
  • Prodrug with liver-targeted anti-HBV effect
  • Prodrug with liver-targeted anti-HBV effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1: Preparation and identification of adefovir dipalmitoyloxymethyl ester

[0102]

[0103] A 250mL three-neck flask was equipped with a stirrer, a condenser, and a thermometer, and 52g of palmitic acid was added, and the temperature was raised to 80°C to dissolve the solid, then a few drops of DMF was added, and 50mL of thionyl chloride was slowly added dropwise under stirring, and hydrogen chloride gas was released. After the addition, stir for another 2 hours to obtain a yellow clear liquid. Add 6 g of paraformaldehyde and 0.6 g of anhydrous zinc chloride, stir for 3 hours, and the paraformaldehyde gradually dissolves. The reaction solution was poured into ice water, and sodium hydroxide solution was added under stirring to make it neutral. The oil was extracted with ethyl acetate, the ester layer was washed with water, and dried over anhydrous sodium sulfate. Evaporate to dryness under reduced pressure and solidify to obtain 58 g of chloromethyl palmitate...

Embodiment 2

[0105] Example 2: Preparation and Identification of Tenofovir Dipalmitoyloxymethyl Ester

[0106]

[0107] In the same manner as in Example 1 above, tenofovir was used instead of adefovir to obtain an off-white solid.

[0108] MS-ESI(+): 824[M+H] + .

Embodiment 3

[0109] Example 3: Preparation and identification of adefovir monopalmitoyloxymethyl ester

[0110]

[0111] Add 1.0 g of adefovir, 1.1 g of chloromethyl palmitate, 20 mL of N-methylpyrrolidone and 1 g of DCC into a 100 mL round bottom flask, and stir and react at 50° C. for 3 hours. Add 50mL of ethyl acetate, extract with 1M sodium hydroxide solution, neutralize the extract with hydrochloric acid and then extract with ethyl acetate, dry the ester phase with anhydrous sodium sulfate, make sand, and elute with ethyl acetate / absolute ethanol The reagent was separated by column chromatography to obtain 0.4 g of off-white solid. MS-ESI(-): 540[M-H]- .

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Abstract

The invention provides a prodrug of a hepatitis b virus resistant drug with a liver targeting action and a preparation method for the same. The prodrug is a prodrug of Adefovir or Tenofovir. Higher fatty acid, glyceride, cholic acid compounds or the base groups of derivatives thereof with the liver targeting action are connected with Adefovir or Tenofovir to prepare the prodrug. After being taken into a human body, the prodrug is concentrated in the liver and then is decomposed, thereby having the effects of reducing the dosage, improving the curative effect, reducing the drug concentration in a kidney and reducing the toxic and side effect. The invention also provides a method for synthesizing the prodrug.

Description

technical field [0001] The invention relates to some anti-hepatitis B virus drugs with liver-targeting effect and preparation methods thereof, in particular to prodrugs of adefovir dipivoxil and tenofovir and preparation methods thereof. Background technique [0002] Hepatitis B is a disease that seriously endangers human health. About 2 billion people in the world have been infected with hepatitis virus (HBV), of which 350 million are carriers of hepatitis B virus. my country is a country with a high incidence of hepatitis B. There are more than 120 million HBV carriers and more than 30 million hepatitis B patients. . The incidence of liver cirrhosis in patients with chronic hepatitis B is 2-20%, and the development of liver cancer accounts for 6-15%. In my country, 25-40% of patients with chronic hepatitis B died of liver cirrhosis or liver cancer. The risk of HBV carriers eventually dying from related liver diseases is 50% for men and 15% for women. The annual direct me...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P1/16A61P31/12
Inventor 秦引林张荣久曹庆先
Owner 江苏吴中苏药医药开发有限责任公司
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