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

A drug and oxo-generation technology, which is applied in the field of statin derivatives and multi-substituted pyrrole statins containing fluorine modification, can solve the problems of side effects, liver disease, carcinogenic toxicity, etc.

Active Publication Date: 2017-12-26
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 pyrrole statin fluorine-containing modification and its application. Statins in technology are likely to cause liver disease, carcinogenic toxicity, muscle side effects, technical problems of rhabdomyolysis

Method used

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  • Multi-substituted pyrrole statin fluorine-containing derivatives and uses thereof
  • Multi-substituted pyrrole statin fluorine-containing derivatives and uses thereof
  • Multi-substituted pyrrole statin fluorine-containing derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Example 1 Preparation of Atorvastatin Lactone

[0116] Weigh 5.00g of atorvastatin 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 evacuate with an oil pump to obtain 4.54 g of white powder, namely the crude product of atorvastatin carboxylic acid.

[0117] Weigh 4.00 of the crude product of atorvastatin 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

[0118] Example 2 Preparation of Compound 001

[0119] 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, slowly added 1.50 g of atorvastatin lactone dissolved in 5 ml of dichloromethane. 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 atorvastatin fluorinated product (001).

Embodiment 3

[0120] Example 3 Preparation of Compounds 002 and 003

[0121]Take 1.00 g of atorvastatin 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 acid until the pH is 2-3, then reduce Evaporate the solvent at 45°C, add about 10ml of acetone to dissolve, and 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. On the next day, 0.57 g of flocculent crystals, ie atorvastatin fluoride sodium salt (002), was obtained.

[0122] Take 1.00 g of atorvastatin 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 acid until the pH is 7-8, then reduce Evaporate the solvent at 45°C, add about 10ml...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, provides a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor and particularly provides a polysubstituted pyrimidine statin fluorinated modifier containing a 3-fluoro-caprolactone fragment and 1-fluoro-3-hydroxy pentanoic acid formed after the ring opening of lactone and salts or esters thereof, wherein the polysubstituted pyrimidine statin fluorinated modifier has a structural formula described by a formula shown in the description or a formula shown in the description or a formula shown in the description. Proven by tests, the compound has the effect of inhibiting the activity of the HMG-coA reductase and can serve as a new-generation potential HMG-CoA reductase inhibitor.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a statin derivative, in particular to a multi-substituted pyrrole 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 i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06C07D207/34C07D401/12C07D493/04A61K31/40A61K31/4439A61K31/4025A61P3/06A61P9/10
CPCC07D207/34C07D401/12C07D405/06C07D493/04
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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