Adenine derivative and inclusion compound thereof

A technique of inclusion compound of adenine and cyclodextrin, which is applied in the direction of drug combination, non-active ingredients of polymer compounds, compounds of Group 5/15 elements of the periodic table, etc., which can solve the problem that the bioavailability is affected by food, etc. Achieve excellent bioavailability, good safety, and excellent antiviral activity

Active Publication Date: 2013-03-20
STAR LAKE BIOSCI CO INC ZHAOQING GUANGDONG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although compared with PMPA, the bioavailability of Bis-(POC)-PMPA is significantly improved, and the oral bioavailability of people is about 25%, but this index is far lower than that of similar drugs adefovir dipivoxil (bioavailability about

Method used

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  • Adenine derivative and inclusion compound thereof
  • Adenine derivative and inclusion compound thereof
  • Adenine derivative and inclusion compound thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1, Preparation of (R)-9-[2-(pivaloyloxymethyl)-(isopropoxycarbonyloxymethyl)phosphonomethoxypropyl]adenine (I)

[0020] 1.1. Synthesis of diethyl p-toluenesulfonyloxymethyl phosphate:

[0021] In a 1000ml three-necked flask, add 200ml toluene, 400ml diethyl phosphite, 120g paraformaldehyde and 50ml triethylamine, stir and heat to 70°C, keep the temperature for 2 hours, then heat up to reflux and continue the reaction until the TLC ( The developing agent uses n-hexane:ethyl acetate=1:4) and the reaction ends when diethyl phosphite cannot be detected. The solution was cooled to below 10°C, 560g of p-toluenesulfonyl chloride was added, and then 560ml of triethylamine was slowly added at about 5°C, maintaining the temperature not exceeding 10°C. After the dropwise addition, it was raised to room temperature and reacted for 8 hours until p-toluenesulfonyl chloride could not be detected by TLC. The solid was removed by suction filtration, and the filter cake was was...

Embodiment 2

[0033] Example 2, β-cyclodextrin inclusion of (R)-9-[2-(pivaloyloxymethyl)-(isopropoxycarbonyloxymethyl)phosphonomethoxypropyl]adenine compound preparation

[0034] Weigh 20g of (R)-9-[2-(pivaloyloxymethyl)-(isopropoxycarbonyloxymethyl)phosphonomethoxypropyl]adenine, add 40ml of absolute ethanol to dissolve. Mix 45g of β-cyclodextrin with 567ml of water to make a 60°C saturated aqueous solution. Drop the ethanol solution of (R)-9-[2-(pivaloyloxymethyl)-(isopropoxycarbonyloxymethyl)phosphonomethoxypropyl]adenine into β-cyclodextrin In a saturated aqueous solution, keep stirring for 30 minutes, stop heating and continue stirring for 4 hours. Put it in the refrigerator to freeze for 24 hours, filter it with suction, wash the filter cake with absolute ethanol, dry it under reduced pressure, and grind it finely to get (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy Carbonyloxymethyl)phosphonomethoxypropyl]adenine β-cyclodextrin inclusion complex 62.5g.

Embodiment 3

[0035] Example 3, Preparation of (R)-9-[2-(pivaloyloxymethyl)-(isopropoxycarbonyloxymethyl)phosphonomethoxypropyl]adenine fumarate

[0036] Take 5.3g of (R)-9-[2-(pivaloyloxymethyl)-(isopropoxycarbonyloxymethyl)phosphonomethoxypropyl]adenine dissolved in 30ml of ethanol, stir, slowly Add 10ml of ethanol solution containing 1.16g of fumaric acid dropwise, and finish the dropwise addition in about 30 minutes, continue stirring for 1 hour, and filter with suction, stir the filtrate to cool down to 0-4°C, continue stirring for 5 hours, and filter with suction to obtain 4.8 grams of white solid.

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Abstract

The invention discloses the technical field of medicines and particularly discloses a new prodrug, namely (R)-9-(2-(phosphonyl methoxyl)propenyl) adenine, a cyclodextrin inclusion compound of the prodrug and a non-toxic and pharmaceutically acceptable salt of the prodrug. The prodrug disclosed by the invention can be metabolized into PMPA in vivo, and has the bioavailability of about 39%, and the bioavailability of the prodrug is better than that of tenofovir disoproxil fumarate (Bis-(POC)-PMPA); and the prodrug has more excellent antiviral activity and better safety compared with the tenofovir disoproxil fumarate.

Description

technical field [0001] The present invention relates to novel prodrugs of (R)-9-[2-(phosphonomethoxy)propyl]adenine, cyclodextrin inclusion complexes of the prodrugs, non-toxicity of the prodrugs Pharmaceutically acceptable salts. Background technique [0002] Phosphonomethoxy nucleotide analogs are a class of known broad-spectrum antiviral compounds with activity against viruses such as HIV, HBV, CMV, HSV-1, HSV-2 and human herpes virus. 9-[2-(phosphorylmethoxy)ethyl]adenosine (PMEA for short) and 9-[(R)-2-(phosphorylmethoxy)propyl]adenosine (PMPA for short) are the Two examples of compounds that have been used in clinical antiviral therapy. Since the phosphonate groups contained in phosphonomethoxy nucleotide analogs affect the body's absorption, it is generally necessary to convert phosphonomethoxy nucleotide analogs into lipophilic prodrugs to improve their bioavailability Spend. For example, adefovir dipivoxil, which is approved by the FDA for the treatment of hepat...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61K47/40A61P31/18A61P1/16A61P31/20
Inventor 龚美义许赵辉周莹潘小锋崔锦栋朱文佳杨艳庆朱耀匡
Owner STAR LAKE BIOSCI CO INC ZHAOQING GUANGDONG
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