5'-position dibenzyl monophosphate derivative of nucleoside-based anticancer agent or antivirus agent

A technology of antiviral drugs and nucleosides, applied in the field of compounds, can solve the problems of low stability, high cytotoxicity of compounds, and inability to show clinical effects, etc.

Inactive Publication Date: 2020-01-10
OHARA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, in many attempts, due to the extremely low stability to various hydrolytic enzymes present in the blood or the liver, or the high cytotoxicity of the compounds generated during the deprotection process, the desired clinical effect could not be shown

Method used

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  • 5'-position dibenzyl monophosphate derivative of nucleoside-based anticancer agent or antivirus agent
  • 5'-position dibenzyl monophosphate derivative of nucleoside-based anticancer agent or antivirus agent
  • 5'-position dibenzyl monophosphate derivative of nucleoside-based anticancer agent or antivirus agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Activation of nucleosides with phosphorus oxychloride and subsequent condensation with benzyl alcohol

[0098] Suspend nucleosides (0.5 mM) in about 1 mL of triethyl phosphate at room temperature, add 93 μL of phosphorus oxychloride (about 2 times the raw material in terms of moles) to it under cooling to 0 ° C, and stir about 2 hours. Next, the corresponding benzyl alcohol (about 10 times by mole) and about 0.4 mL (about 10 times by mole) of pyridine were added to the solution, and stirred for another hour while cooling to 0°C. The reaction solution was poured into an ethyl acetate-water mixture, neutralized with dilute sodium bicarbonate solution, and then extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The extract after removing the insoluble matter was dried under reduced pressure, and the obtained oily residue was separated and purified with a silica gel column (Yamazen Smart Flash MS system),...

Embodiment 2

[0100] Condensation of nucleosides and dibenzyl phosphorochloride derivatives

[0101] Suspend nucleosides (0.5mM) in 1.0mL of anhydrous pyridine at room temperature, and add about 0.25mL (about 1.2 times by mole) of the corresponding dibenzyl chlorophosphoric acid under cooling to 0°C ester derivative and stirred for about 1 hour. This reaction solution was poured into an ethyl acetate-water mixture, neutralized with dilute sodium bicarbonate solution, and then extracted with ethyl acetate. The extract was washed with saturated brine, then dried over anhydrous magnesium sulfate, the extract from which insoluble matter was removed was dried under reduced pressure, and the obtained oily residue was separated and purified with a silica gel column (Yamazen Smart Flash MS system) , thereby obtaining a 5'-position dibenzyl monophosphate derivative of a nucleoside as the target compound. This method is referred to as Synthetic Method B hereinafter.

[0102] The following shows th...

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Abstract

The invention provides, in place of injected agents (nucleoside-based anticancer agents or antivirus agents) clinically used as therapeutic drugs for cancer or virus infections, a medicine that has high stability with respect to various hydrolytic metabolic enzymes, is absorbed into the body even by oral administration, and exhibits a cytocidal effect by being incorporated into a DNA and RNA biosynthetic route and inhibiting the modification and extension of DNA and RNA or inhibiting reverse transcriptases or inhibiting protein synthesis. The aforementioned problem is solved by a novel compound represented by formula (I). (In the formula, D is the 5'-position moiety of a nucleoside-based anticancer agent or an antivirus agent, and R1 and R2 are each a benzyl group that may have the same substituent or different substituents.)

Description

technical field [0001] The present invention relates to a compound which has high stability against various hydrolytic metabolic enzymes and can be used as a prodrug of the 5'-position monophosphate of nucleoside anticancer drugs or antiviral drugs. Background technique [0002] At present, as anticancer nucleosides used clinically, cytarabine (Cytosine arabinoside) (Cytosine arabinoside), arabinocytosine (Ara-C), "Cytosar-U (registered trademark) )", "Depocyt (registered trademark)"), Floxuridine (Floxuridine) ("FUDR (registered trademark)"), Pentostatin (Deoxycoformycin (Deoxycoformycin), "Nipent (registered trademark) ”), Fludarabine (“Fludara(registered trademark)”), Cladribine (“Leustatin(registered trademark)”), Gemcitabine (“Gemzar(registered trademark)”), 5-Azacytidine (Azacitidine, "Vidaza (registered trademark)"), 2'-deoxy-5-azacytidine (Decitabine, " Dacogen (registered trademark)"), Clofarabine (Clolar (registered trademark)", "Evoltra (registered trademark)"),...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/09A61K31/7068A61P31/12A61P35/00C07H19/04C07H19/10C07H19/20
CPCA61K31/7068A61P31/12A61P35/00C07F9/09C07H19/04C07H19/10C07H19/20
Inventor 酒向孫市
Owner OHARA PHARMA
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