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Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof

A technology of decitabine and ester prodrugs, which is applied in the field of medicine, can solve the problems of poor permeability of the small intestinal membrane, and achieve the effect of improving membrane permeability and oral bioavailability

Active Publication Date: 2013-02-13
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, decitabine has high polarity and poor intestinal membrane permeability, resulting in its oral bioavailability of only 3.9%~14%.

Method used

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  • Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof
  • Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof
  • Decitabine 5'-O-amino-acid ester prodrug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] N-benzyloxycarbonyl-L-valine reacts with dicyclohexylcarbodiimide, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane or N,N-4-dimethylformamide, and the reaction temperature is from 0°C to 80°C, preferably 0°C-50°C, the reaction time is 1 hour; the reaction solution is slowly added dropwise to the mixture of decitabine and N,N-4-dimethylaminopyridine. After the addition is complete, continue to react for 12 hours at a temperature of 0°C-40°C, preferably 10-30°C; Wash with distilled water, saturated sodium bicarbonate and saturated saline, collect the organic layer, dry the column with sodium persulfate, evaporate the filtrate to dryness, add Pd / C as a catalyst under the solvent of ethyl acetate, dichloromethane or isopropanol, and Catalytic hydrogenation was carried out under hydrogen conditions, the reaction time was 6 hours, suction filtration, and the filtrate was evaporated under reduced pressure to obtain the compound ( ).

Embodiment 2

[0035] N-benzyloxycarbonyl-D-valine reacts with dicyclohexylcarbodiimide, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane or N,N-4-dimethylformamide, and the reaction temperature is from 0°C to 80°C, preferably 0°C-50°C, the reaction time is 1 hour; the reaction solution is slowly added dropwise to the mixture of decitabine and N,N-4-dimethylaminopyridine. After the addition is complete, continue to react for 12 hours at a temperature of 0°C-40°C, preferably 10-30°C; Wash with distilled water, saturated sodium bicarbonate and saturated saline, collect the organic layer, dry the column with sodium persulfate, evaporate the filtrate to dryness, add Pd / C as a catalyst under the solvent of ethyl acetate, dichloromethane or isopropanol, and Catalytic hydrogenation was carried out under hydrogen conditions, the reaction time was 6 hours, suction filtration, and the filtrate was evaporated under reduced pressure to obtain the compound ( ).

Embodiment 3

[0037] Reaction of N-benzyloxycarbonyl-L-isoleucine with dicyclohexylcarbodiimide, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane or N,N-4-dimethylformamide, the reaction temperature is 0℃ to 80°C, preferably 0°C-50°C, and the reaction time is 1 hour; slowly add the reaction liquid dropwise into the mixed liquid of decitabine and N,N-4-dimethylaminopyridine. After the addition is complete, continue to react for 12 hours at a temperature of 0°C-40°C, preferably 10-30°C; Wash with distilled water, saturated sodium bicarbonate and saturated saline, collect the organic layer, dry the column with sodium persulfate, evaporate the filtrate to dryness, add Pd / C as a catalyst under the solvent of ethyl acetate, dichloromethane or isopropanol, and Catalytic hydrogenation was carried out under hydrogen conditions, the reaction time was 6 hours, suction filtration, and the filtrate was evaporated under reduced pressure to obtain the compound ( ).

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Abstract

The invention belongs to the technical field of medicine, and discloses a decitabine 5'-O-amino-acid ester prodrug for treating myelodysplastic syndrome and a preparation method thereof. The decitabine is subjected to purposeful structure modification, so that the decitabine is combined with different amino acids, thereby designing and synthesizing the compound decitabine 5'-O-amino-acid ester prodrug disclosed as (I). In (I), R is an amino acid, preferably L-valine, D-valine, L-isoleucine, L-phenylalanine or L-tryptophane. Compared with oral decitabine, the invention obviously enhances the bioavailability of the prodrug, and is hopeful to develop a carrier prodrug with more definite curative effect for treating myelodysplastic syndrome.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a prodrug of decitabine (5-aza-2-deoxycytidine) and a preparation method thereof, in particular to a 5-aza-2 for treating myelodysplastic syndrome - 5'-O-amino acid ester prodrugs of deoxycytidine and processes for their preparation. Background technique [0002] The chemical name of decitabine is 5-aza-2-deoxycytidine. As a specific inhibitor of DNA methyltransferase, decitabine is phosphorylated by deoxycytidine kinase and mixed with DNA in the form of phosphate, which can reverse the methylation process of DNA and induce tumor cells to differentiate into normal cells Or induce tumor cell apoptosis. Decitabine was approved for marketing in the United States in 2006, and its trade name is Dacogen. However, decitabine has high polarity and poor intestinal membrane permeability, resulting in its oral bioavailability of only 3.9%-14%. Therefore, it is necessary to find a way to ...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/00A61P35/00
CPCY02P20/55
Inventor 孙进何仲贵张又夕王永军孙英华刘晓红
Owner SHENYANG PHARMA UNIVERSITY
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