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Statins antilipemic drugs furazan nitroxides derivates and preparation method thereof

A technology of fluvastatin and pravastatin, which is applied in the field of furazanoxide derivatives of statin blood lipid-lowering drugs and its preparation, and can solve the problem of creatine kinase increase

Active Publication Date: 2009-11-18
四川抗菌素工业研究所有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, because the lipid-lowering treatment itself can affect many aspects of the AS process, it is difficult to separate these effects from its lipid-lowering effect.
[0005] However, statins also have adverse reactions, such as: hepatotoxicity, nephrotoxicity, potential carcinogenicity, and myotoxicity, etc., the most important one is myotoxicity, and the clinical manifestations are myalgia, muscle tenderness, muscle weakness, and often accompanied by There is an increase in creatine kinase (CK), and the most serious is rhabdomyolysis. Cerivastatin was withdrawn from the market in 2001 because of the severe rhabdomyolysis it caused

Method used

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  • Statins antilipemic drugs furazan nitroxides derivates and preparation method thereof
  • Statins antilipemic drugs furazan nitroxides derivates and preparation method thereof
  • Statins antilipemic drugs furazan nitroxides derivates and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6R,8S,8αR)-2,6-dimethyl-8-(2,2-dimethylbutyryloxy )-1,2,6,7,8,8α-hexahydro-1-naphthyl]heptanoic acid-(4-phenyl-1,2,5-oxadiazole-2-oxide-3-)methanol Synthesis of Esters (Simvastatin (4-Phenyl-1,2,5-oxadiazole-2-oxide-3-) Methyl Ester)

[0103]

[0104] a) (3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6R, 8S, 8αR)-2,6-dimethyl-8-(2,2-dimethylbutyryl Oxy)-1,2,6,7,8,8α-Hexahydro-1-naphthyl]heptanoate sodium (simvastatin sodium)

[0105] Add 1N sodium hydroxide solution (12ml) in the absolute ethanol (12ml) solution of simvastatin (5.0g, 12mmol), the reaction mixture was stirred and reacted at room temperature for 4 hours, and the reaction solution was decolorized by adding an appropriate amount of active carbon, and filtered The filtrate was concentrated under reduced pressure to obtain 4.7 g of a yellow-white solid.

[0106] b) (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6R,8S,8αR)-2,6-dimethyl-8-(2,2-dimethylbutyryl Oxy)-1,2,6,7,8,8α-hexahydro-1-naphthyl]h...

Embodiment 2

[0111] (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6R,8S,8αR)-2,6-dimethyl-8-(2,2-dimethylbutyryloxy )-1,2,6,7,8,8α-hexahydro-1-naphthyl]heptanoic acid-4-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4 Synthesis of -)oxybutyl ester (simvastatin-4-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4-)oxybutyl ester)

[0112]

[0113] a) (3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6R, 8S, 8αR)-2,6-dimethyl-8-(2,2-dimethylbutyryl Oxy)-1,2,6,7,8,8α-Hexahydro-1-naphthyl]heptanoic acid sodium

[0114] The preparation method is the same as in Example 1a).

[0115] b) (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6R,8S,8αR)-2,6-dimethyl-8-(2,2-dimethylbutyryl Oxy)-1,2,6,7,8,8α-hexahydro-1-naphthyl]heptanoic acid-4-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide -4-)Oxybutyl ester

[0116] N, N'-dimethylformamide ( 5.0ml) solution was added dropwise to a solution of simvastatin sodium (0.33g, 0.8mmol) in N,N'-dimethylformamide (5.0ml), and the reaction mixture was stirred at room temperature for 24h. The reaction solution ...

Embodiment 3

[0120] (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-5-isopropyl-4-(phenylcarbamoyl)pyrrole-1-]-3,5-dihydroxy Heptanoic acid-(4-phenyl-1,2,5-oxadiazole-2-oxide-3-)methyl ester (atorvastatin-(4-phenyl-1,2,5-oxadiazole -Synthesis of 2-oxide-3-)methyl ester)

[0121]

[0122] A solution of 2-oxo-3-chloromethyl-4-phenyl-1,2,5-oxadiazole (0.38g, 1.8mmol) in N,N'-dimethylformamide (5.0ml) was gradually Add atorvastatin calcium (0.50 g, 1.2 mmol) in N, N'-dimethylformamide (5.0 ml) dropwise, and stir the reaction mixture at room temperature for 16 h. The reaction solution was treated with water and diethyl ether. The diethyl ether layer was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column (eluent: n-hexane / ethyl acetate 2 / 1) to obtain 0.68 g of the title compound as a yellow oil.

[0123] MS: 733.6(M+1) +

[0124] 1 H-NMR (CDCl 3 , 400MHz): 7.67-7.69(m, 2H), 7.52-7.58(m, 3H), 6.86-7.26(m, 14H), 5.14-5.22(m, 2H), 4.06-4.17(m,...

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Abstract

The invention relates to a statins antilipemic drugs furazan nitroxides derivates and a preparation method thereof, and solves the problems of nonlipid-lowering and low activity in statins antilipemic drugs and adverse effect. The invention is shown as formula (1).

Description

Technical field: [0001] The present invention relates to a novel statin blood lipid-lowering drug furazan-nitroxyl derivative and a preparation method thereof. The derivative is prepared by coupling a furazan-nitrogen compound as a nitric oxide donor with a statin compound. As obtained, they can be used for lowering blood lipids, can obviously improve the non-lipid-lowering activity of statins, and can also reduce adverse reactions of statins. Background technique: [0002] Statins refer to a group of compounds, the main compounds include Mevastatin, Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin Atorvastatin, Cerivastatin, Rosuvastatin, and Pitavastatin. Among them, mevastatin, lovastatin and pravastatin are compounds derived from microorganisms, simvastatin is a semi-synthetic compound, and the other compounds are fully synthetic compounds. [0003] Statins are lipid-lowering drugs that are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (H...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08C07D413/12A61K31/4245A61K31/4709A61K31/506A61K31/405A61P7/02A61P3/06
Inventor 陈宇瑛任文杰
Owner 四川抗菌素工业研究所有限公司
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