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Multi-substituted indole statin fluorine-containing modification and use thereof

A technology of indole and drugs, applied in the field of medicinal chemistry, can solve problems such as rhabdomyolysis, side effects, and easy liver disease

Active Publication Date: 2018-01-26
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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  • Multi-substituted indole statin fluorine-containing modification and use thereof
  • Multi-substituted indole statin fluorine-containing modification and use thereof
  • Multi-substituted indole statin fluorine-containing modification and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Example 1 Preparation of fluvastatin lactone and reduction of fluvastatin lactone

[0129]Weigh 5.00g of fluvastatin sodium salt, add it to a 250ml eggplant-shaped bottle, add 100ml of dichloromethane and about 10ml of dilute hydrochloric acid diluted with 20 times concentrated hydrochloric acid, shake vigorously, and let stand to separate layers. Take the upper aqueous phase, and when the pH test paper detects and controls it at 2-3, it can be considered to be completely free. Liquid separation, 100ml dichloromethane equal volume extraction three times, combined lower organic phase, 20ml water backwash once, organic phase dried with anhydrous sodium sulfate. Vacuum spin dry at 45°C, evacuate with an oil pump until white bubbles appear, cool, and crush to obtain 4.23 g of white powder, the crude fluvastatin carboxylic acid is used in the next step without refining.

[0130] Weigh 4.00g of the above-mentioned fluvastatin carboxylic acid crude product, add it to a 250ml ...

Embodiment 2

[0132] Example 2 Preparation of Compounds 001 and 002

[0133] 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 Diethylaminosulfur trifluoride, after stirring for about 15 minutes, a solution of 1.50 g of fluvastatin dissolved in 10 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 fluvastatin fluorinate...

Embodiment 3

[0134] Example 3 Preparation of Compounds 003, 004, 005, 006

[0135] Take 1.00 g of fluvastatin fluoride (001), dissolve it in 6 ml of tetrahydrofuran, and put it in 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 then 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 crystals were obtained, namely fluvastatin fluoride sodium salt (003). The same method can be used to obtain the reduced fluoride sodium salt 004.

[0136] Get 1.00 g of fluvastatin 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 with 10% hydrochloric aci...

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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 indole 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 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 relat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06C07D209/24C07D405/12C07D493/04A61K31/405A61K31/4439A61P9/10A61P3/06
CPCC07D209/24C07D405/06C07D405/12C07D493/04
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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