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Lovastatin, simvastatin and simvastatin-6-oxide nitro-oxo-derivative and preparation method thereof

A technology of simvastatin and lovastatin, applied in the field of statin hypolipidemic drugs, can solve the problems of difficult separation and increased creatine kinase.

Active Publication Date: 2009-12-30
四川抗菌素工业研究所有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because lipid-lowering therapy 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 Cerivastatin was withdrawn from the market in 2001 because of the severe rhabdomyolysis it caused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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  • Lovastatin, simvastatin and simvastatin-6-oxide nitro-oxo-derivative and preparation method thereof
  • Lovastatin, simvastatin and simvastatin-6-oxide nitro-oxo-derivative and preparation method thereof
  • Lovastatin, simvastatin and simvastatin-6-oxide nitro-oxo-derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121](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-(nitrooxy)butyl ester (simvastatin-4-(nitrooxy)butyl ester )Synthesis

[0122]

[0123] 1a) (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-bromobutyl ester

[0124] A solution of 1,4-dibromobutane (0.75ml, 6.3mmol) in N,N'-dimethylformamide (6ml) was added dropwise to a solution of simvastatin sodium (1.60g, 3.5mmol) in N,N' -Dimethylformamide (9ml) solution, the reaction mixture was stirred at room temperature for 24 hours. Water (15ml) was added to the reaction solution, followed by extraction with ether (15ml×3), the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column, and eluted with n-hexane / ethyl acetate 1 / 1. 0...

Embodiment 2

[0129] (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-2-[2-(nitrooxy)ethoxy]ethyl ester (simvastatin-2-[ Synthesis of 2-(nitrooxy)ethoxy]ethyl ester)

[0130]

[0131] 2a) (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-2-(2-bromoethoxy)ethyl ester to simvastatin sodium salt (0.55g, 1.2 mmol) in N,N'-dimethylformamide (10ml) was added dropwise to 2,2'-dibromodiethyl ether (0.3ml, 2.4mmol) in N,N'-dimethylformamide (10ml ) solution, and the reaction mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure and then treated with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1.3 g of oil, which was directly used for the next reaction without separation. ...

Embodiment 3

[0136] (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-(nitrooxymethyl)benzyl ester (simvastatin-4-(nitrooxymethyl) base) benzyl ester) synthesis

[0137]

[0138] 3a) (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-(bromomethyl)benzyl ester

[0139] To a solution of simvastatin sodium salt (0.55g, 1.2mmol) in N,N'-dimethylformamide (10ml) was added dropwise a solution of p-dichlorobenzyl (0.42g, 2.4mmol) in N,N'-di Methylformamide (10ml) solution was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction solution was treated with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2.0 g of oil, which was directly used for the next reaction without separation.

[0140] 3b) (3R...

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Abstract

The invention describes lovastatin, simvastatin and simvastatin-6-oxide (L-669262) nitro-oxo-derivative of which the general formula is shown in formula (I) and the drugs can increase the non-lipid activity of statins such as anti-inflammatory and the like. The invention also relates to a preparation method of the drugs.

Description

Technical field: [0001] The invention relates to a novel nitrooxy derivative of a statin blood lipid-lowering drug and a preparation method thereof. The derivative can be used for lowering blood fat and can improve non-lipid-regulating activities of statin drugs such as anti-inflammatory. 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. L-669262 is a derivative of simvastatin-6-oxo (iso-simvastatin-6-one), isolated from the sodium salt of simvastatin through microbial transformation, L-669262 inhibits the in vitro activity of HMG-CoA reductase 6-7 times that of simvastatin (IC 50 0.66 ng / ml and 0.10 ng / m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C203/04C07C201/02C07D213/30A61K31/22A61K31/44A61P3/06A61P29/00
Inventor 陈宇瑛任文杰李坤
Owner 四川抗菌素工业研究所有限公司
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