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Sulfo-Adefovir and Tenofovir liver targeting ester prodrug

A prodrug, tenofovir technology, applied in the field of prodrugs, can solve problems such as inability to transport drugs, toxicity, lack of effective therapeutic drugs, etc., and achieve simple and easy production method, good oral absorption, and good market. Foreground effect

Active Publication Date: 2010-03-03
CUREGEN JIANGSU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, adefovir dipivoxil is mainly concentrated in the kidney, liver, and lung in the human body, and clinical studies have found that adefovir dipivoxil has greater nephrotoxicity
It is reported that the combination of pivalic acid and coenzyme A, the hydrolyzate of adefovir dipivoxil, cannot be metabolized through the oxidation pathway, and it is easy to accumulate in the cells to produce toxicity. To a certain extent, the therapeutic effect on the disease is limited
At the same time, long-term use of prodrugs containing pivalic acid will cause low levels of carnitine in plasma
The nephrotoxicity of tenofovir disoproxil is less than that of adefovir dipivoxil, but the oral dose needs to be 150mg~300mg, and the bioavailability is low. The bioavailability of tenofovir disoproxil administered orally to dogs can reach 30%, but human Oral bioavailability of tenofovir disoproxil is 25%, while its bioavailability is affected by food
[0007] Aiming at the defects of adefovir dipivoxil and tenofovir dipivoxil, the inventors have invented a phosphorothioate nucleotide compound, which improves the current low and low bioavailability of adefovir dipivoxil and tenofovir dipivoxil. The defect of adefovir dipivoxil nephrotoxicity provides a phosphorothioate nucleotide compound with broad-spectrum and high antiviral activity. The patent application number is: 200910116015.3, which is hereby used as a reference of the present invention
[0008] At present, the lack of effective therapeutic drugs for diseases such as hepatitis B and liver cancer is not only the pharmacological effect of the therapeutic drugs themselves is not ideal, but the main reason is that the drugs cannot be effectively transported to the lesion of the liver, that is, poor liver targeting

Method used

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  • Sulfo-Adefovir and Tenofovir liver targeting ester prodrug
  • Sulfo-Adefovir and Tenofovir liver targeting ester prodrug
  • Sulfo-Adefovir and Tenofovir liver targeting ester prodrug

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0030] Preparation Example 1: Preparation of sulfur instead of Nofovir

[0031] 1.1. Preparation of (R)-1,2-propanediol

[0032] The air in the hydrogenation kettle was replaced with N 2 Charge N after replacement 2 , add 5% Pd loaded on activated carbon (50% moisture content) catalyst 100g suspended in NaOH ethanol solution (composed of 7.85Kg ethanol and 16.7% NaOH solution 54g), stir and cool to 0 ° C (usually -5 ~ 0 ° C About), then add (S)-glycidol 1.0Kg (13.5mol), and then use H2 Replacement of N in the kettle 2 3 times, charge H 2 (pressure ≤ 13.79KPa or ≤ 20psi) reaction, the reaction temperature is controlled not to exceed 25°C. Charge H 2 The reaction ends when the hydrogen is no longer consumed. After the reaction was completed, the reaction solution was filtered through diatomaceous earth (150g) to remove solid insoluble matter, and the filtrate was evaporated in vacuo at 50°C to remove the solvent to obtain about 1.0Kg of oily R)-1,2-propanediol crude produc...

preparation example 2

[0042] Preparation Example 2: Preparation of Thioadefovir

[0043] Referring to the method of Examples 1.4-1.6, adefovir was prepared by substituting commercially available ethylene carbonate for (R)-1,2-propylene carbonate.

preparation example 3

[0044] Preparation Example 3: Preparation of (S)-(-)-1-(3-chlorophenyl)-1,3-propanediol

[0045] 3.1, Preparation of 3-(3-chlorophenyl)-3-oxo-propionic acid

[0046] Install a mechanical stirrer and an addition funnel in a dry and clean 5L three-neck round bottom flask. Nitrogen was blown to drive away the air, diisopropylamine (424ml) and THF (1.2L) were added thereto, the stirred contents were cooled to -30°C, and n-butyllithium (1.23L, 2.5 M in hexane), and maintain the temperature at -30 to -48°C. After the addition was complete (30 minutes), the addition funnel was rinsed with hexane (30 ml), then the stirred solution was cooled to -70° C., trimethylsilylethyl acetate (200 g) was added slowly under stirring, and the temperature Keeping at 4 , 100 g), filtered and concentrated under reduced pressure to give about 503 g of a yellow solid, the crude solid was slurried in hexane (3.5 L) and transferred to a round bottom flask equipped with a mechanical stirrer, the mixture ...

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PUM

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Abstract

The invention discloses a sulfo-Adefovir and Tenofovir liver targeting ester prodrug represented by the following general formula (I), or medicinal salt, hydrate or solvate thereof, which serves as the effective component of hepatitis B antivirus. The compound of the invention has liver targeting characteristic and better achieves the aim of small dose, high effect and low toxic or side effect.

Description

1. Technical field [0001] The present invention relates to a prodrug and its use, specifically a prodrug of adefovir thiovir, tenofovir liver targeting ester or its pharmaceutically acceptable salt, hydrate or solvate and its use. 2. Background technology [0002] Hepatitis B is an infectious disease that is caused by hepatitis B virus (hepatitis B virus, HBV) infection and seriously endangers human health. About 2 billion people in the world have been infected with HBV, and 350 million people carry HBV, and HBV infection persists It can lead to liver cirrhosis and primary liver cancer, and the mortality rate is very high. Although medical scientists at home and abroad adopt methods of systemic anti-virus and immune function regulation, the treatment effect is not satisfactory. The main reason may be that the drug is in the main replication site of HBV— — Less distribution in the liver. Although the drug can be administered through the hepatic artery or portal vein to impro...

Claims

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Application Information

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IPC IPC(8): C07F9/6574A61K31/665A61P31/20
Inventor 徐奎
Owner CUREGEN JIANGSU PHARMA
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