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Polysubstituted phenanthrene ring statin lactone dehydrated compounds and application thereof

A technology of compounds and substituents, applied in the field of medicinal chemistry, can solve problems such as carcinogenic toxicity

Inactive Publication Date: 2015-01-28
SHANGHAI INST OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, statins also have adverse reactions, such as: liver disease, carcinogenic toxicity, muscle side effects, especially rhabdomyolysis, it is because of this serious side effect that cerivastatin (cerivastatin) has been withdrawn from the market

Method used

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  • Polysubstituted phenanthrene ring statin lactone dehydrated compounds and application thereof
  • Polysubstituted phenanthrene ring statin lactone dehydrated compounds and application thereof
  • Polysubstituted phenanthrene ring statin lactone dehydrated compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0203] Embodiment 1 Preparation of pravastatin lactone

[0204] Weigh 5.00g of pravastatin sodium salt, add it to a 250ml eggplant-shaped bottle, add 100ml of dichloromethane and about 10ml of 20-fold diluted hydrochloric acid, acidify, separate, and extract three times with 100ml of dichloromethane. The lower organic phases were combined and dried over anhydrous sodium sulfate. Concentrate and vacuumize with an oil pump to obtain 4.54 g of white powder, which is the crude product of pravastatin carboxylic acid

[0205] Weigh 4.5 g of the crude product of pravastatin carboxylic acid above, add it into a three-necked flask, add 0.05 g of p-dimethylaminopyridine, 50 ml of dichloromethane and a stirring bar. A solution obtained by dissolving 5.0 g of dicyclohexylcarbodiimide in 20 ml of dichloromethane was slowly injected under ice cooling. After the dropwise addition, the ice bath was removed and the reaction was carried out overnight at room temperature. After the completion...

Embodiment 2

[0206] Example 2 Preparation of Compound 001-004

[0207] Add a magnetic stirring bar of appropriate size into a 50ml two-necked reaction flask, add 0.50g of p-toluenesulfonic acid (PBSA) and 1.50g of mevastatin to replace the air and protect it with nitrogen, inject 30ml of tetrahydrofuran and heat the reaction vessel to reflux, After the reaction was completely monitored by thin-layer chromatography, add 5% NaHCO 3 Shake the aqueous solution, separate the lower organic phase, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (PE / EA gradient elution) to obtain the mevastatin derivative containing 2-hexenolactone fragment of the present invention (001) 0.76 g.

[0208] Compounds 002, 003 and 004 can be obtained by the same method.

Embodiment 3

[0209] Example 3 Preparation of Compound 005-008

[0210] 0.58 g of mevastatin was dissolved in 15 ml of methanol, 50 mg of 10% Pt / C hydrogenation catalyst was added, pressurized at 1.5 MPa, and reacted overnight at room temperature. After the reaction was complete, the catalyst was filtered off, concentrated and spin-dried to obtain 0.52 g of crude hydromevastatin. The crude product was as in Example 2, and 0.50 g of the crude product of hydromevastatin and 0.20 g of p-toluenesulfonic acid were added. Finally, column chromatography (PE / EA gradient elution) yielded 0.36 g of a hydromevastatin derivative (005) containing a 2-hexenolactone segment.

[0211] Compounds 006, 007 and 008 can be obtained by the same method.

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry and provides a kind of compounds. A structural formula of the compounds is described in the specification. Through tests, the compounds have the effect of inhibiting the HMG-coA reductase activity and can serve as a new generation of potential HMG-coA reductase inhibitors.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a statin drug, in particular to a multi-substituted phenanthrene ring statin lactone dehydration compound and its application. Background technique [0002] Hyperlipidemia is the cause of various cardiovascular and cerebrovascular diseases. The population epidemiological survey shows that for the Chinese male population, the concentration of low-density lipoprotein (most of the lipids in human blood combine with albumin to form lipoprotein) concentration per liter An increase of 1mmol / L can increase the incidence of coronary heart disease by 36%, and increase the risk of ischemic stroke by 31%. In today's world, the "three highs" (hyperlipidemia, hypertension, and hyperglycemia) are risk factors for various diseases or its immediate symptoms. Various medical and biological metabolism studies have proved that the content of blood lipid (lipoprotein) in human blood i...

Claims

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Application Information

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IPC IPC(8): C07D309/32C07C67/29C07C67/08C07C69/28C07C69/24C07C51/02C07C59/46C07C59/62C07C59/56C07D213/80C07D213/803C07D493/04A61K31/366A61K31/22A61K31/191A61K31/19A61K31/4406A61K31/34A61P3/06A61P9/10A61P3/10A61P9/12
CPCC07C59/46C07C59/62C07C69/28C07D213/80C07D213/803C07D309/32C07D493/04
Inventor 汪忠华吴范宏李兵俞晓东吴闯吕倩倩李丹丹巫辅龙
Owner SHANGHAI INST OF TECH
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