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5'-position dibenzyl phosphoric acid ester of 5-azacytidine or 2'-deoxy body thereof

An azacytidine and benzyl technology, which is applied in the field of novel 5'-dibenzyl phosphate compounds, can solve the problems that the evaluation of the stability of the chemical structure cytidine deaminase and the biological activity has not been reported.

Inactive Publication Date: 2018-07-17
OHARA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its specific chemical structure, stability against cytidine deaminase, and evaluation of its biological activity have not been reported yet.

Method used

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  • 5'-position dibenzyl phosphoric acid ester of 5-azacytidine or 2'-deoxy body thereof
  • 5'-position dibenzyl phosphoric acid ester of 5-azacytidine or 2'-deoxy body thereof
  • 5'-position dibenzyl phosphoric acid ester of 5-azacytidine or 2'-deoxy body thereof

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preparation example Construction

[0068] The preparation method of compound (1) of the present invention

[0069] For example, compound (1) of the present invention can be produced according to the following method or other similar methods.

[0070] Method A

[0071] Can according to routine method or other similar methods (refer to Bulletin of the Chemical Society, 1969,42 (12), 3505-8, Nucleic Acids Research, 1984, 12, 5025-36, Chemical & Pharmaceutical Bulletin, 1995, 43 (2), 210 -215, and WO-2011113173) to prepare compound (1) or a salt thereof. For example, commercially available 5-azacytidine or 2'-deoxy-5-azacytidine is activated by phosphorus oxychloride in a suitable solvent, and then reacted with benzyl alcohol which may have a substituent in the presence of a base . 5'-dibenzyl phosphate of 5-azacytidine as the target compound can be obtained (see chemical formula (1)).

[0072] Method B

[0073] It can be prepared, for example, by reacting commercially available 5-azacytidine or 2'-deoxy...

Embodiment 1

[0101] Activation of 5-azacytidine with phosphorus oxychloride and subsequent condensation with benzyl alcohol

[0102] Suspend 122 mg of 5-azacytidine in about 1.0 mL of triethyl phosphate solution. When cooled to 0° C., 93 μL of phosphorus oxychloride (about 2.0 times that of 5-azacytidine as a starting material in terms of mol) was added, and stirred for about 1 hour. Then, about 0.5 mL (about 5 times in mol) of the corresponding benzyl alcohol and about 0.4 mL (about 9 times in mol) of pyridine were added to the solution, and stirred at 0° C. for another 1 hour. The reaction solution was poured into an ethyl acetate / water mixture, and neutralized with dilute sodium bicarbonate solution before extraction with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. After removing insoluble matter by suction, the extract was concentrated to dryness under reduced pressure. The obtained oily residue was separated and purified w...

Embodiment 2

[0104] Condensation of 5-azacytidine with dibenzyl phosphorochloride derivatives

[0105] Suspend 122 mg of 5-azacytidine in 1.0 mL of anhydrous pyridine. When cooled to 0 °C, about 0.25 mL (about 1.2 times in mol) of the corresponding dibenzyl chlorophosphate derivative was added and stirred for about 1 hour. The reaction solution was poured into an ethyl acetate / water mixture, and neutralized with dilute sodium bicarbonate solution before extraction with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. After removing insoluble matter by suction, the extract was concentrated to dryness under reduced pressure. The obtained oily residue was separated and purified with a silica gel column (Yamazen Smart Flash MS system) to obtain a 5'-dibenzyl phosphate derivative of 5-azacytidine as the target compound. This is referred to as Synthesis Method B hereinafter.

[0106] The 5'-dibenzyl (or diphenylethyl, diphenyl) phosphate...

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Abstract

The abovementioned problem is solved by a novel compound represented by formula (1): (in the formula, R is a hydroxyl group or a hydrogen atom, and R1 and R2 are benzyl groups that may have a substituent group).To provide a drug that substitutes for injections (5-azacytidine or 2'-deoxy-5-azacytidine) that are clinically used as bone marrow tumor therapeutic drugs, said drug having high stabilitywith respect to metabolic enzyme cytidine deaminase, being absorbed in the body even by means of oral administration, and having an effect of being integrated into an RNA and DNA biosynthesis pathwayand inhibiting protein synthesis.

Description

technical field [0001] The present invention relates to novel 5'-dibenzyl phosphate compounds of 5-azacytidine or 2'-deoxy-5-azacytidine which exhibit remarkable stability against the metabolic hydrolase cytidine deaminase, It is easily incorporated into the nucleic acid biosynthetic pathway in vivo, and can be used as a prodrug of the anti-myeloma agents 5-azacytidine and 2'-deoxy-5-azacytidine. Background technique [0002] 5-azacytidine (also known as azacytidine or product name) and 2'-deoxy-5-azacytidine (also known as decitabine or product names) have the following chemical structures (i) and (ii), respectively. [0003] [0004] It has been found that azacytidine and its 2'-deoxy form (hereinafter in this specification, sometimes also collectively referred to as "azacytidine or 5-azacytidine"), through nucleic acid biosynthesis in frequently dividing cells It is incorporated into RNA or DNA to inhibit protein synthesis and some enzymes, and shows cytotoxicity ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12A61K31/706A61P31/04A61P35/00A61P43/00
CPCC07F9/65586A61P19/08A61P31/04A61P35/00A61P43/00A61K31/665A61K31/706
Inventor 酒向孙市罗雄
Owner OHARA PHARMA
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