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Poly-substituted phenanthrene ring statin fluorine-containing derivative and uses thereof

A technology of substituents and substituent groups, applied in the field of medicinal chemistry, can solve the problems of side reactions, easy to cause liver disease, carcinogenic toxicity and so on

Active Publication Date: 2015-12-02
SHANGHAI ECUST BIOMEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aiming at the above-mentioned technical problems in the prior art, the present invention provides a multi-substituted indole statin fluorine-containing modification and its use. The multi-substituted indole statin fluorine-containing modification and its use should solve Statins in the prior art are likely to cause liver disease, carcinogenic toxicity, muscle side effects, and technical problems of rhabdomyolysis

Method used

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  • Poly-substituted phenanthrene ring statin fluorine-containing derivative and uses thereof
  • Poly-substituted phenanthrene ring statin fluorine-containing derivative and uses thereof
  • Poly-substituted phenanthrene ring statin fluorine-containing derivative and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0271] The preparation of embodiment 1 pravastatin lactone

[0272] 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

[0273] 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 comple...

Embodiment 2

[0274] Preparation of Example 2 Compound 001-004

[0275] Add a magnetic stirring bar of appropriate size into a 50ml reaction tube, replace the air and protect it with nitrogen, inject 30ml of dichloromethane, put the reaction vessel into a low-temperature stirring reaction bath (below -65°C), and inject 0.75ml of After stirring for about 15 minutes, 1.50 g of mevastatin dissolved in 5 ml of dichloromethane was added slowly. After stirring and reacting for about 30 minutes, about 0.3 ml of triethylamine was added by injection, and after 2 hours, the temperature was naturally raised to react overnight. After the completion of the reaction was monitored by thin-layer chromatography, it was suction-filtered, and the filtrate was dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography (PE / EA gradient elution) to obtain 0.76 g of mevastatin fluorinated product (001).

[0276] Compounds 002, 003 and 004 can be obtained by the same method.

Embodiment 3

[0277] Preparation of Example 3 Compound 005-008

[0278] 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, 0.40 ml of diethylaminosulfur trifluoride, and 0.2 ml of triethylamine were added. Finally, 0.36 g of hydromevastatin fluorinated product (005) was obtained by column chromatography (PE / EA gradient elution).

[0279] Compounds 006, 007 and 008 can be obtained by the same method.

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Abstract

The present invention belongs to the field of pharmaceutical chemistry, and provides 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, wherein a fragment containing 3-fluoro-caprolactone and a lactone thereof are subjected to ring opening to form a poly-substituted pyrimidine statin fluorine-containing modifier of 1-fluoro-3-hydroxy-pentanoic acid and a salt or ester thereof, ie., the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, and the structure formula is defined in the specification. According to the present invention, the test results show that the compounds have the HMG-CoA reductase activity inhibition effects, and can be used as the new generation of the 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 indole statin fluorine-containing modification 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 is close...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/30C07C69/28C07C69/732C07C69/675C07C59/56C07C59/62C07C59/115C07C59/135C07D213/80C07D493/04A61P3/06A61P9/10
CPCC07C59/115C07C59/135C07C59/56C07C59/62C07C69/28C07C69/675C07C69/732C07D213/80C07D309/30C07D493/04
Inventor 吴范宏汪忠华李兵俞晓东吕倩倩吴闯苏飞飞巫辅龙
Owner SHANGHAI ECUST BIOMEDICINE CO LTD
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