Didanosine pro-medicament and preparation method thereof

A technology of didanosine and prodrugs, which is applied in the field of medicine, can solve the problems of high polarity, only oral bioavailability, poor membrane permeability of the small intestine, etc., and achieve the effect of simple preparation method

Inactive Publication Date: 2009-11-18
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, didanosine is easily decomposed under acidic conditions, has high polarity, and poor membrane permeability of the small intestine, resulting in only 20-40% of its oral bioavailability

Method used

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  • Didanosine pro-medicament and preparation method thereof
  • Didanosine pro-medicament and preparation method thereof
  • Didanosine pro-medicament and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] N-benzyloxycarbonyl-L-valine reacts with didanosine, adding dicyclohexylcarbodiimide and N,N-4-dimethylaminopyridine, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, cyclo Hexane or dimethylformamide, the reaction temperature is from 0°C to the boiling point of the solvent, preferably 20-60°C, and the reaction time is 8 hours; the reaction solution is cooled to room temperature, and the solvent is evaporated under reduced pressure. Extract with methyl chloride and wash with distilled water, saturated sodium bicarbonate and saturated brine successively, collect the organic layer, dry the column with sodium persulfate, after the filtrate is evaporated to dryness, recrystallize with ethyl acetate or dichloromethane, recrystallize the product, in acetic acid With ethyl acetate or dichloromethane as the solvent, add Pd / C as a catalyst, and perform catalytic hydrogenation under hydrogen conditions. The reaction time is 5 hours, suction filtration, and the filt...

Embodiment 2

[0032] N-benzyloxycarbonyl-L-isoleucine reacts with didanosine, adding dicyclohexylcarbodiimide and N,N-4-dimethylaminopyridine, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, Cyclohexane or dimethylformamide, the reaction temperature is 0°C to the boiling point of the solvent, preferably 20-60°C, and the reaction time is 8 hours; the reaction solution is cooled to room temperature, the solvent is evaporated under reduced pressure, and the residue is ethyl acetate or Extract with dichloromethane, and wash with distilled water, saturated sodium bicarbonate and saturated brine successively. Collect the organic layer, dry the column with sodium persulfate, and after the filtrate is evaporated to dryness, recrystallize with ethyl acetate or dichloromethane to recrystallize the product. With ethyl acetate or dichloromethane as the solvent, add Pd / C as a catalyst, and carry out catalytic hydrogenation under hydrogen conditions. The reaction time is 5 hours, suction ...

Embodiment 3

[0034] N-benzyloxycarbonyl-L-phenylalanine reacts with didanosine, adding dicyclohexylcarbodiimide and N,N-4-dimethylaminopyridine, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, Cyclohexane or dimethylformamide, the reaction temperature is 0°C to the boiling point of the solvent, preferably 20-60°C, and the reaction time is 8 hours; the reaction solution is cooled to room temperature, the solvent is evaporated under reduced pressure, and the residue is ethyl acetate or Extract with dichloromethane, and wash with distilled water, saturated sodium bicarbonate and saturated brine successively. Collect the organic layer, dry the column with sodium persulfate, and after the filtrate is evaporated to dryness, recrystallize with ethyl acetate or dichloromethane to recrystallize the product. With ethyl acetate or dichloromethane as the solvent, add Pd / C as the catalyst, and perform catalytic hydrogenation under hydrogen conditions. The reaction time is 5 hours, sucti...

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Abstract

The invention belongs to the technical field of medicaments, and discloses a substituted L-amino acid ester pro-medicament of an anti-AIDS medicament-didanosine and a preparation method thereof. The invention performs purposeful structural modification on the didanosine, ensures that the didanosine is combined with different amino acids, and designs and synthesizes a compound of a (I) structure, namely a didanosine pro-medicament. Compared with oral didanosine, the bioavailability of the compound is obviously improved and is equivalent to that of intravenously administrable didanosine. The pro-medicament and the preparation method are expected to develop a carrier pro-medicament with better therapeutic effect for treating AIDS. In the (I), R is L-type amino acid residue, and the L-type amino acid residue is preferably selected from L-valine, L-isoleucine, L-phenylalanine, L-proline and L-tryptophan.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to didanosine prodrugs and a preparation method thereof, and specifically relates to an anti-AIDS drug 2',3'-dideoxyinosine (ie "desoxyinosine") 5'substituted for L -Amino acid ester prodrugs and methods for their preparation. Background technique: [0002] Didanosine's chemical name is 2',3'-dideoxyinosine. Didanosine is a synthetic nucleoside drug. Compared with natural adenosine, the 3'-hydroxyl group of the latter is changed to hydrogen. Didanosine is phosphorylated by cellular kinases to form the active metabolite 5'-triphosphate dideoxyadenosine. 5'-dideoxyadenosine triphosphate inhibits HIV reverse transcriptase, and its mechanism includes competition with the natural substrate deoxyadenosine triphosphate and its incorporation into viral DNA to terminate the elongation of the DNA chain. Didanosine was launched in 1991. However, didanosine is easy to decompose under acidic conditio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/16C07H1/00A61K31/708A61P31/18
CPCC07H19/16A61P31/18
Inventor 何仲贵孙进许佑君闫中天施世良付强林琳常燕南
Owner SHENYANG PHARMA UNIVERSITY
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