New acyclic nucleoside phosphonate compound as well as composition, preparation method and application thereof

A non-cyclic nucleoside phosphonate and cyclic nucleoside phosphonate technology, which is applied in the fields of pharmacy, drug synthesis and pharmacology, can solve the problem of unstable chemical properties, inability to effectively increase drug concentration at the site of action, and highly sensitive hydrolysis reactions And other issues

Inactive Publication Date: 2009-11-25
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Moreover, acyclic nucleoside phosphonate drugs generally have the following disadvantages: (1) The chemical properties are unstable, and they are highly sensitive to the hydrolysis reaction mediated by serum enzymes, and cannot effectively increase the drug concentration at the site of action [Pharmaceutical Research.1997, 14 (4): 492-496.]; (2) converting one molecule of nucleic acid requires the release of two equivalents of potentially toxic formaldehyde and pivalic acid [Drugs of the Future 2004, 29(2); 163-177]

Method used

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  • New acyclic nucleoside phosphonate compound as well as composition, preparation method and application thereof
  • New acyclic nucleoside phosphonate compound as well as composition, preparation method and application thereof
  • New acyclic nucleoside phosphonate compound as well as composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] The preparation of embodiment 1 L-valine methyl ester hydrochloride

[0096]

[0097] At -10°C, valine (10g, 85.5mmol) was dissolved in methanol (120ml), and thionyl chloride (22.4ml, 307mmol) was slowly added dropwise. Hour. After cooling down to room temperature, the methanol was distilled off under reduced pressure, and the residue was recrystallized from a methanol-ether mixture to obtain the title product (10 g, 70%). 1 H NMR (CDCl 3 ): 8.8(br, 3H), 4.0(t, 1H), 3.8(s, 3H), 2.5(m, 1H), 1.1(d, 6H).

[0098] The compounds listed in the following table can be prepared from various natural amino acids and unnatural amino acids according to the same steps as in Example 1.

Embodiment 2-10

[0100]

[0101] Reality

[0102] H)

Embodiment 11

[0103] The preparation of embodiment 11 N-benzyl-L-valine methyl ester

[0104]

[0105] At 0°C, L-valine methyl ester hydrochloride (7g, 41.8mmol) was dissolved in methanol (150ml), then sodium cyanoborohydride (2.63g, 41.8mmol) was added, and then benzene was added dropwise Formaldehyde (4.43g, 41.8mmol) was raised to room temperature and reacted overnight. Cool to 0°C, acidify the reaction solution with concentrated hydrochloric acid until pH = 1, stir at the same temperature for 3.5 h, distill under reduced pressure, add water, adjust pH = 9 with saturated sodium carbonate solution, extract twice with ethyl acetate, wash with water, After washing with saturated sodium chloride, it was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title product (6 g, 64.9%). 1 H NMR (CDCl 3 ): 7.2-7.4(m, 5H), 3.82, 3.6(dd, 2H), 3...

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Abstract

The invention provides a new acyclic nucleoside phosphonate compound as well as a composition, a preparation method and application thereof, in particular an acyclic nucleoside phosphonate compound presented in a general formula (1), an inorganic salt or an organic salt pharmaceutically accepted and a composition containing the compound of the general formula (1). The invention also provides the preparation method of the compound and the application of the compound of the general formula (1) to the treatment of virus infective diseases, in particular virus infective diseases caused by an HBV virus or an HIV virus.

Description

technical field [0001] The invention belongs to the field of pharmacy, relates to the fields of drug synthesis and pharmacology, more specifically, relates to acyclic nucleoside phosphonate compounds containing amino acid groups, their compositions, preparation methods and their use in the preparation of antiviral drugs use. Background technique [0002] According to the estimation of the World Health Organization, there are currently about 350 million HBV (hepatitis B virus, HBV) carriers in the world, and there are 120 million HBV carriers in China alone. Chronic HBV infection can cause related diseases such as chronic hepatitis B (CHB), liver cirrhosis, and primary hepatocellular carcinoma (HCC). At present, the main drugs for the treatment of hepatitis B are interferon and nucleoside compounds. Alpha-interferon combined with ribavirin not only has limited curative effect but also has many adverse reactions, so nucleoside compounds are the main field of hepatitis B anti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6584A61K31/675A61P31/12A61P31/18
CPCY02P20/55
Inventor 杨玉社卢朋李战嵇汝运
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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