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Phosphoramidate prodrug of nucleoside analogues, a pharmaceutical composition and applications of the phosphoramidate prodrug

A technology of nucleoside analogs and phosphoramidite esters, which can be used in drug combinations, compounds of Group 5/15 elements of the periodic table, medical preparations containing active ingredients, etc., and can solve problems such as lack of effective means

Pending Publication Date: 2019-03-29
HANGZHOU HERTZ PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For this clinical problem, there has been a lack of effective means

Method used

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  • Phosphoramidate prodrug of nucleoside analogues, a pharmaceutical composition and applications of the phosphoramidate prodrug
  • Phosphoramidate prodrug of nucleoside analogues, a pharmaceutical composition and applications of the phosphoramidate prodrug
  • Phosphoramidate prodrug of nucleoside analogues, a pharmaceutical composition and applications of the phosphoramidate prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] Embodiment 1. The preparation of intermediate 1a~1e

[0147]

[0148] Operation steps: Step 1: Dissolve p-bromophenol or substituted p-bromophenol (11.56mmol), p-toluenesulfonic acid (0.116mmol) in 15mL of dichloromethane solution, then add dropwise 3.2mL of 2,3-dihydropyridine Furan (34.68mmol), stirred and reacted at room temperature for 1 hour, washed with 5% sodium hydroxide solution and saturated brine respectively, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a white solid, which was directly used in the next reaction.

[0149] The second step: in DMF, add the product of previous step (6.87mmol), 5-picoline (4.58mmol), anhydrous potassium carbonate (5.50mmol) and CuI (0.55mmol), the mixture is heated to 140 ℃ of reaction 5 hours, cooled to room temperature, filtered and collected the filtrate, evaporated to remove DMF, then dissolved in ethyl acetate, washed with water and saturated brine respectively, added anhydrous...

Embodiment 2

[0156] Embodiment 2. Preparation of intermediate 1f

[0157]

[0158] Operation steps: Step 1: Add 4-bromo-2-chloro-phenol (11.56mmol), potassium carbonate (17.34mmol), benzyl chloride (13.87mmol) into 15mL DMF, react at room temperature for 24 hours, filter, add 200mL of filtrate Ethyl acetate was then washed with 5% sodium hydroxide solution, water, and saturated brine, and the organic phase was dried by adding anhydrous sodium sulfate and concentrated to obtain a yellow concentrate, which was directly used in the next reaction.

[0159] Second step: in DMF, add the product (6.87mmol) of last step, 5-picoline (4.58mmol), cesium carbonate (5.50mmol) and CuI (0.55mmol), the mixture is heated to 140 ℃ of reaction 10 hours, Cool to room temperature, collect the filtrate after filtration, remove DMF by subtractive evaporation, then dissolve in ethyl acetate, wash with water and saturated brine respectively, add anhydrous sodium sulfate to the organic phase, dry and concentrate...

Embodiment 3

[0161] Embodiment 3. Preparation of Intermediates 2a~2c

[0162]

[0163] Operation steps: Step 1: Dissolve p-bromophenol (11.56mmol) and p-toluenesulfonic acid (0.116mmol) in 15mL of dichloromethane solution, then add 3.2mL of 2,3-dihydropyran (34.68mmol) dropwise, After stirring and reacting at room temperature for 1 hour, the mixture was washed with 5% sodium hydroxide solution and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a white solid, which was directly used in the next reaction.

[0164] The second step: add the product of the previous step (6.87mmol), pyridone or substituted pyridone (4.58mmol), anhydrous potassium carbonate (5.50mmol) and CuI (0.55mmol) in DMF, and the mixture is heated to 140 ° C for reaction After 5 hours, cool to room temperature, collect the filtrate after filtration, remove DMF by subtractive evaporation, then dissolve in ethyl acetate, wash with water and saturated brine respecti...

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Abstract

The invention relates to phosphoramidate prodrug of nucleoside analogues, or stereoisomers of the phosphoramidate prodrug, or a mixture of the stereoisomers of the phosphoramidate prodrug, or pharmaceutically acceptable salts or solvates of the phosphoramidate prodrug, and applications in the preparation of medicine for preventing or treating hepatitis B virus (HBV) and / or human immunodeficiency virus (HIV) infection alone or in combination with other medicine. The anti-HBV activity of the compound of the invention is equivalent to that of tenofovir alafenamide fumarate (TAF), and the compoundof the invention has the anti-liver fibrosis effect, can help improve the therapeutic effect of patients, and has good safety important clinical significance.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry antiviral, and relates to a nucleoside analog phosphoramidate prodrug, a pharmaceutical composition and its application in medicines for preventing or treating hepatitis B virus and / or human immunodeficiency virus infection. Background technique [0002] Hepatitis B is an infectious disease caused by hepatitis B virus (hepatitis B virus, hereinafter referred to as HBV), which takes the liver as the target organ and can cause damage to various organs, and is mainly transmitted through blood. Hepatitis B virus infection is one of the most threatening infectious diseases in the world. 2 billion people in the world have been infected with HBV, and about 400 million people are chronically infected with HBV. China is a high prevalence area of ​​HBV infection. According to statistics, there are about 1.2 billion hepatitis B virus surface antigen (HBsAg) carriers in China, and the total infection rate o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20A61P1/16
CPCC07F9/65616
Inventor 周星露刘兴国胡苗董晓武黄文海
Owner HANGZHOU HERTZ PHARMA
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