Multi-substituted quinoline statin fluorine-containing derivatives and uses thereof

A drug and compound technology, applied in the field of multi-substituted quinoline statin fluorine-containing modifiers and statins, can solve problems such as rhabdomyolysis, carcinogenic toxicity, and easy liver disease

Active Publication Date: 2018-05-22
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 quinoline statin fluorine-containing modification and its use. The multi-substituted quinoline 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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  • Multi-substituted quinoline statin fluorine-containing derivatives and uses thereof
  • Multi-substituted quinoline statin fluorine-containing derivatives and uses thereof
  • Multi-substituted quinoline statin fluorine-containing derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1 Preparation of pitavastatin lactone

[0135] Weigh 5.00g of pitavastatin calcium 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 2.87g of white powder, namely the crude product of pitavastatin carboxylic acid

[0136] Weigh 2.50 g of the above-mentioned pitavastatin carboxylic acid crude product, 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 3.0 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 com...

Embodiment 2

[0138] Example 2 Preparation of Compound 001,002

[0139] 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 pitavastatin 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, suction filtration, the filtrate was dried over anhydrous sodium sulfate, spin-dried, and separated by silver nitrate complexed silica gel column chromatography (gradient elution of isopropanol / petroleum ether) to obtain the fluorinated product of pitavastatin (001) 0.76 g.

[0140] 0.58 g of pi...

Embodiment 3

[0141] Example 3 Preparation of Compounds 003,004,005,006

[0142] Take 1.00 g of pitavastatin fluoride (001), dissolve it in 6 ml of tetrahydrofuran, and put it in an ice bath, add 1.5 ml of 1 mol / L LiOH solution and stir for 2 hours, acidify it with 10% hydrochloric acid until the pH is 2-3, and depressurize Evaporate the solvent at 45°C, add about 10ml of acetone to dissolve, then slowly add 10% Na 2 CO 3 Aqueous solution, flocs and turbidity can be seen, add dropwise until flocs no longer appear. Heat until the turbidity dissolves, let it stand, and cool down slowly overnight. The next day, 0.68 g of needle-like crystals was obtained, namely pitavastatin fluoride sodium salt (003). Similarly, compound 004 can be obtained by using target compound 002 in Example 3 as a substrate.

[0143] Take 1.00 g of pitavastatin fluoride (001), dissolve it in 6 ml of tetrahydrofuran, and put it in an ice bath, add 1.5 ml of 1 mol / L LiOH solution and stir for 2 hours, then acidify it ...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and provides a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor is a polysubstituted miazine statin fluorine-containing modifier of 1-fluoro-3-hydroxypentanoic acid and its salt or ester formed after ring opening of 3-fluoro-caprolactone fragment and its lactone. The structural formula of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor is shown in the specification. A result of test of like compounds shows that the compounds have an HMG-CoA reductase activity inhibition effect, and can be used as a new-generation latent HMG-CoA reductase inhibitor.

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 quinoline 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 re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06A61K31/4709A61P3/06A61P9/10C07D215/14A61K31/47C07D401/12C07D493/04
CPCC07D215/14C07D401/12C07D405/06C07D493/04
Inventor 汪忠华吴范宏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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