The sugar moiety silyl ether derivatives of 5-azacytidine

A silyl group and azacytidine technology, applied in sugar derivatives, drug combinations, extracellular fluid diseases, etc., can solve the problems of undisclosed and disclosed stability and reactivity

Active Publication Date: 2021-11-05
OHARA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the stability and reactivity of these derivatives have not been disclosed, and there are no examples of detailed disclosures on their use as chemotherapeutic agents (Patent Documents 3, 4)

Method used

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  • The sugar moiety silyl ether derivatives of 5-azacytidine
  • The sugar moiety silyl ether derivatives of 5-azacytidine
  • The sugar moiety silyl ether derivatives of 5-azacytidine

Examples

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preparation example Construction

[0075] The preparation method of compound (1) of the present invention

[0076] For example, the compound (1) of the present invention can be prepared according to the following method or other similar methods (for example, the silyletherification method disclosed in Corey, E.J.et al., J.Am.Chem.Soc., 94, 6190 , 1972; Morita, T.etal., Tetrahedron Lett., 21, 835, 1980; Y.Kita, et al., Tetrahedron Lett., 4311, 1979etc.; As a review, refer to Lalonde, M., Chan, T.H., Synthesis, 817-845, 1985 etc.).

[0077] Compound (1) or a salt thereof can be produced according to a conventional method or a method analogous thereto. For example, commercially available 5-azacytidine or 2'-deoxy-5-azacytidine is reacted with a silyl halide compound in a suitable solvent in the presence of a base. A sugar moiety silyl ether derivative of 5-azacytidine can be obtained as the target compound.

[0078] Silyl halide compound

[0079] The kind of the silyl halide compound is not particularly lim...

Embodiment 1

[0110] Synthesis of 5'-(trisubstituted)silyloxy-5-azacytidines (5'-(trisubstituted)silyloxy-5-azacytidines, 1a)

[0111]

[0112]Add imidazole (1.5 mM) to a suspension of 5-azacytidine (I) (1 mM) in dry N,N-dimethylformamide (3 mL), and then add the corresponding silyl group dropwise under ice-bath Chlorine (1.2mM) for about 10 minutes. It is then stirred for about 1 to 17 hours until gradually warming to room temperature and starting material disappears. The reaction solution was poured into 50 mL of a mixture of ethyl acetate / saturated brine (2:1) and extracted with ethyl acetate. The extract was washed twice with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The extract after removing the insoluble matter was concentrated to dryness under reduced pressure. The obtained oily residue was separated and purified with a silica gel column (YamazenSmart Flash MS system), thereby obtaining a 5'-silyl ether derivative of the target compound 5-azacytidine (c...

Embodiment 2

[0114] Synthesis of 3',5'-di(trisubstituted)silyloxy-5-azacytidines (3',5'-di(trisubstituted)silyloxy-5-azacytidines, 1b)

[0115]

[0116] To a suspension of 5-azacytidine (I) (1 mM) in anhydrous N,N-dimethylformamide (3 mL) was added imidazole (2 mM), followed by the corresponding silyl chloride dropwise in an ice bath (1.5mM) for about 10 minutes. The mixture was stirred for several hours until gradually warming to room temperature and starting material disappeared. The reaction solution was poured into 50 mL of a mixture of ethyl acetate / saturated brine (2:1) and extracted with ethyl acetate. The extract was washed twice with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The extract after removing the insoluble matter was concentrated to dryness under reduced pressure. The obtained oily residue was separated and purified with a silica gel column (YamazenSmart Flash MS system), thereby obtaining the 3',5'-disilyl ether derivative of the target comp...

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Abstract

The present invention provides a prodrug of 5-azacytidine or 2'-deoxy-5-azacytidine with high stability to the metabolic enzyme cytidine deaminase, to replace clinically used drugs in patients with myelodysplastic syndromes including myelodysplastic syndromes. Injection (5-azacytidine or 2'-deoxy-5-azacytidine) used for the treatment of various bone marrow tumors in China. Above-mentioned technical problem is solved by the compound or its salt represented by chemical formula (1) (in said chemical formula, R is OR 3 group or hydrogen atom, R 1 , R 2 and R 3 Each is a hydrogen atom or a silyl group represented by the chemical formula (2) (in the chemical formula, R 4 , R 5 and R 6 Each is an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted arylalkyl group). And, R 1 , R 2 and R 3 are not hydrogen atoms at the same time).

Description

technical field [0001] The present invention relates to cytidine deaminase, a metabolic hydrolase, which has remarkable stability and can be used as a prodrug of the anti-myeloma agent 5-azacytidine or 2'-deoxy-5-azacytidine compound. 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 respectively. These are sometimes collectively referred to as "azacytidine or 5-azacytidine" in this specification. These azacytidines are known to inhibit protein synthesis and some enzymes by being incorporated into RNA or DNA during nucleic acid biosynthesis in frequently dividing cells, and show cytotoxicity (Patent Documents 1, 2 and Non-Patent Document 1) . [0003] [0004] When incorporated into the DNA of the cell, azacytidine binds irreversibly to DNA methyltransferase to cause enzyme inhibition, and a large amount of cytosine rin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/12A61K31/706A61P7/06A61P35/00A61P43/00
CPCC07H19/12C07H23/00A61P35/00A61P43/00A61P7/06
Inventor 酒向孙市杉山晋平
Owner OHARA PHARMA
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