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Cholic acid derivative and application thereof in lowering cholesterol

A derivative, cholic acid technology, applied in the field of medicine and its preparation and application, achieves good application prospects, reduces the increase of HMGCR protein, and reduces the effect of endogenous cholesterol levels

Active Publication Date: 2021-10-29
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The research work was published in the international authoritative journal "Nature Communications" (Nature Communications, 2018, 9, 5138) in December 2018. Through follow-up research, we found that although the first-generation compounds involved in the article can significantly promote the ubiquity of HMGCR protein It can reduce the accumulation of HMGCR protein induced by statins, effectively inhibit the synthesis of cholesterol in mice, and reduce the generation of atherosclerotic plaques, but this first-generation compound can also lead to the accumulation of cholesterol in cells (such as figure 1 shown)

Method used

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  • Cholic acid derivative and application thereof in lowering cholesterol
  • Cholic acid derivative and application thereof in lowering cholesterol
  • Cholic acid derivative and application thereof in lowering cholesterol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0445] The preparation of embodiment 1 compound Q2-Q4

[0446] Compound Q1 (10g, 0.03mol) was placed in a 250mL single-necked flask, 150mL of anhydrous DMF was added and stirred until it dissolved, and imidazole (16.34g, 0.24mol), TBSCl (18.09g, 0.12mol), N 2 Replaced three times, stirred evenly and raised to room temperature, stirred for 5 hours, after TLC detected that the raw materials had reacted completely, added 50mL saturated ammonium chloride solution to quench the reaction, added ethyl acetate (100mL) for extraction and separation, and then used ethyl acetate for the aqueous phase (30mL×3) for extraction, and the organic phases were combined. The organic phase was washed with saturated ammonium chloride solution (50mL×2), water (50mL×3), saturated sodium chloride solution (50mL×2), and anhydrous Na 2 SO 4 It was dried and concentrated under reduced pressure to obtain compound Q2 (white solid 13.45 g, yield 99%), which was directly used in the next step.

[0447] Pu...

Embodiment 2

[0449] The preparation of embodiment 2 compound Q5

[0450] Compound Q4 (6.88g, 0.019mol), PDC (10.84g, 0.029mol), and silica gel (10.84g, 0.029mol) were placed in a 250mL single-necked flask, 100mL of anhydrous dichloromethane was added, stirred at room temperature for 8 hours, and detected by TLC The reaction of the raw materials is complete, remove the silica gel by suction filtration, wash the filter cake with dichloromethane (20mL×3), add saturated sodium sulfite to the system to quench for ten minutes until the system turns light green, extract and separate the liquid, and use dichloromethane (20mL×3) for the aqueous phase 3) extraction, combined organic phase. The organic phase was washed with water (30mL×3), saturated sodium chloride solution (30mL×2), and anhydrous Na 2 SO 4 After drying and concentration under reduced pressure, silica gel column chromatography (PE:EA=15:1) gave compound Q5 (6.83 g of white solid, yield 99%). 13 C NMR(101MHz,CDCl3)δ216.74,205.03,14...

Embodiment 3

[0451] The preparation of embodiment 3 compound Q6

[0452] Add NaH (3.42g, 0.142mol) in 250mL three-necked flask under ice-cooling, N 2 Replace three times, add 50 mL of anhydrous THF, stir to dissolve, slowly drop triethyl phosphoacetate (18.85 mL, 0.095 mol), drop it in about 10 minutes, and it can be seen that the system generates bubbles. The system was raised to room temperature and stirred for 10 minutes. Compound Q5 (6.83g, 0.019mol) was dissolved in anhydrous THF (50mL), dropped into the aforementioned system, stirred at room temperature for 1 hour, TLC detected that the reaction of the raw materials was complete, adding 50mL of saturated ammonium chloride solution to quench for ten minutes, and adding 60mL of acetic acid Ethyl extraction and liquid separation were performed, and the aqueous phase was extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated ammonium chloride (30mL×2), water (30mL×3), s...

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Abstract

The invention discloses a cholic acid derivative as shown in a formula (I) and a preparation method thereof, and the target product cholic acid derivative is prepared through reactions such as TBS protection, 4, 4-dimethylation, deprotection, oxidation, Witting reaction, reduction, hydrolysis, acylation and deprotection. The invention further provides an application of the cholic acid derivative in preparation of drugs for preventing and / or treating hypercholesteremia and hypertriglyceridemia, resisting atherosclerosis and resisting non-alcoholic steatohepatitis, the cholic acid derivative can effectively promote degradation of hydroxymethyl glutaryl-coenzyme A reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, HMGCR), and reduce HMGCR protein increase caused by statins, so that the endogenous cholesterol level is reduced, a beneficial reference is provided for research and development of new cholesterol-reducing medicines, and the application prospect is good.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a cholic acid derivative, its preparation method and its application in anti-atherosclerosis and anti-nonalcoholic steatohepatitis. Background technique [0002] Cardiovascular disease is a class of diseases with a very high incidence rate. High levels of cholesterol in the blood, especially low-density lipoprotein, are one of the most important pathogenic factors. The current mainstream drugs for lowering high cholesterol are mainly statins, including: Atorvastatin, Simvastatin, Lovastatin, Pravastatin, Fluvastatin ( Fluvastatin) and Rosuvastatin (Rosuvastatin), etc. The mechanism of action of statins is mainly that its structure mimics HMG-CoA, so it can competitively bind HMG-CoA reductase (HMGCR), thereby inhibiting the conversion of HMG-CoA into mevalonate, which also limits cholesterol. Biosynthesis in vivo. [0003] The ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00C07J71/00A61P3/06A61P9/10A61P1/16
CPCC07J9/005C07J71/0047C07J71/0094C07J71/0063A61P3/06A61P9/10A61P1/16Y02A50/30
Inventor 仇文卫宋保亮江倩茹江世友史熊杰李晨晨
Owner EAST CHINA NORMAL UNIV
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