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

A pyrimidine and drug technology, applied in the field of medicinal chemistry, 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 pyrimidine statin fluorine-containing modification and its use. The multi-substituted pyrimidine statin fluorine-containing modification and its use solve the existing Statins in technology are likely to cause liver disease, carcinogenic toxicity, muscle side effects, and technical problems of rhabdomyolysis

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] Embodiment 1 Preparation of rosuvastatin lactone

[0136] Weigh 5.00g of rosuvastatin 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 4.87g of white powder, that is, the crude product of rosuvastatin carboxylic acid. Weigh 4.50 of the above crude product of pravastatin carboxylic acid, add it to a three-necked flask, add 0.05g of p-dimethylaminopyridine, 50ml of dimethicone Chloromethane and a stir 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 of t...

Embodiment 2

[0137] Example 2 Preparation of reduced rosuvastatin lactone

[0138] Weigh 500 mg of the above-mentioned rosuvastatin lactone, add it to a 25 ml reaction tube, add a stirring bar, about 5 ml of methanol, about 1 ml of tetrahydrofuran and 20 mg of 10% Pt / C catalytic hydrogenation catalyst, replace the air, and catalyze at room temperature and pressure hydrogenation. After 12 hours, the reaction was complete as monitored by TLC. Pt / C was removed by filtration, the filtrate was dried over anhydrous sodium sulfate, spin-dried in vacuo, and separated by column chromatography (PE / EA gradient elution) to obtain 360 mg of rosuvastatin lactone reduction product, HRMS (ESI): C 24 h 28 FNO 3 ,466.18565(M+H) + , theoretical value 466.18119; H-NMR: 7.63 (dd, 2H, J = 8.6, 5.5Hz), 7.45 (dd, 1H, J = 8.5, 5.4Hz), 7.13 (t, 1H, J = 8.6Hz), 7.07 (t, 2H, J=8.6Hz), 6.34(d, 1H, J=16.0Hz), 5.46(dt, 1H, J=15.8, 6.9Hz), 3.90(s, 1H), 3.55(s, 3H) ,3.51(s,2H),3.35(dt,1H,J=13.3,6.6Hz),2.60(t,1H,J=7....

Embodiment 3

[0139] Example 3 Preparation of Compounds 001 and 002

[0140] 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, and after stirring for about 15 minutes, a solution of 1.50 g of rosuvastatin 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, separated by silver nitrate complexed silica gel column chromatography (gradient elution of isopropanol / petroleum ether) to obtain rosuvastatin fluorinated ...

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PUM

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Abstract

The present invention belongs to the field of pharmaceutical chemistry, and provides a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, which is a poly-substituted pyrimidine statin fluorine-containing modifier of 1-fluoro-3-hydroxy pentanoic acid and a salt or an ester thereof formed by carrying out ring opening on 3-fluoro-caprolactone-containing fragment and a lactone thereof, wherein the structure formula is represented in the specification. According to the present invention, the test results show that the compounds have the HMG-CoA reductase activity inhibition effect, 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 pyrimidine 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 r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06C07D239/42C07D401/12C07D493/04A61K31/506A61K31/505A61P3/06A61P9/10A61P3/10
CPCC07D239/42C07D401/12C07D405/06C07D493/04
Inventor 吴范宏李兵汪忠华俞晓东吕倩倩吴闯苏飞飞巫辅龙
Owner SHANGHAI ECUST BIOMEDICINE CO LTD
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