Pentacyclic triterpenoid cholesterol ester transfer protein (CETP) inhibitor, pharmaceutical composition thereof and medical application

A technology of pentacyclic triterpenes and transporters, which is applied in the direction of drug combinations, pharmaceutical formulas, steroids, etc., and can solve the problems of elevated aldosterone levels in the body, inability to be fully absorbed, and inaccessibility

Inactive Publication Date: 2015-06-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] However, the small molecule CETP inhibitors currently under development all have significant drawbacks
For example, these compounds are poorly soluble in water, are not well absorbed in the body, and do not achieve sufficient blood levels to produce medicinal effects even when administered orally in common formulations
In addition, these compounds have the potential ability to raise aldosterone levels in the body, thereby triggering the risk of high blood pressure

Method used

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  • Pentacyclic triterpenoid cholesterol ester transfer protein (CETP) inhibitor, pharmaceutical composition thereof and medical application
  • Pentacyclic triterpenoid cholesterol ester transfer protein (CETP) inhibitor, pharmaceutical composition thereof and medical application
  • Pentacyclic triterpenoid cholesterol ester transfer protein (CETP) inhibitor, pharmaceutical composition thereof and medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] 3β-Acetoxy-12-en-28-methyloleanane

[0055] 3β-Hydroxy-12-ene-28-methyloleanane (100 mg, 0.234 mmol) was dissolved in 3 mL of pyridine, acetic anhydride (96 mg, 0.937 mmol) and 4-dimethylaminopyridine (DMAP) (29 mg , 0.234mmol), stirred at room temperature for 24h. The disappearance of raw materials was detected by TLC, the solvent was evaporated to dryness under reduced pressure, 50 mL of water was added, extracted with ethyl acetate (3×10 mL), the organic layers were combined, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and a white solid (90 mg, 82%) was obtained by flash column chromatography (petroleum ether: ethyl acetate = 100:1). 1 H NMR (500MHz, CDCl 3 )δ5.18(t, J=3.6Hz, 1H), 4.55-4.46(m, 1H), 2.04(s, 3H), 2.03-0.79(m, 23H), 1.13(s, 3H), 0.97(s , 3H), 0.96(s, 3H), 0.88(m, 6H), 0.87(s, 3H), 0.86(s, 3H), 0.83(s, 3H); ESI MS m / z 491.39[M+Na] + .

Embodiment 2

[0057] 3β-Oleoyloxy-12-en-28-methyloleanane

[0058] 3β-Hydroxy-12-ene-28-methyloleanane (100 mg, 0.234 mmol) was dissolved in 3 mL of dichloromethane, and oleic acid (132 mg, 0.468 mmol), 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (90mg, 0.468mmol) and DMAP (57mg, 0.468mmol), heated to 50°C and stirred for 6h. TLC detected the disappearance of the starting material, added 50 mL of water, extracted with dichloromethane (3×10 mL), combined the organic layers, washed with 1N NaOH aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and a white solid (145 mg, 90%) was obtained by flash column chromatography (petroleum ether: ethyl acetate = 400:1). 1 H NMR (300MHz, CDCl 3 )δ5.34(s, 2H), 5.18(s, 1H), 4.56-4.45(m, 1H), 2.29(t, J=7.3Hz, 2H), 2.02-0.66(m, 52H), 1.13(s , 3H), 0.97(s, 6H), 0.87(s, 12H), 0.83(s, 3H); ESI MS m / z 691.16[M+Na] + .

Embodiment 3

[0060] 3β-Succinic acid monoacyloxy-12-en-28-methyloleanane

[0061] 3β-Hydroxy-12-ene-28-methyloleanane (100mg, 0.234mmol) was dissolved in 3mL of pyridine, succinic anhydride (94mg, 0.937mmol) and DMAP (29mg, 0.234mmol) were added, heated to 110°C, stirring for 12h. The disappearance of raw materials was detected by TLC, the solvent was evaporated to dryness under reduced pressure, 50 mL of water was added, extracted with ethyl acetate (3×10 mL), the organic layers were combined, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and a white solid (92 mg, 75%) was obtained by flash column chromatography (petroleum ether: ethyl acetate = 5:1). 1 H NMR (300MHz, DMSO-d 6 )δ5.18(s, 1H), 4.52(t, J=7.8Hz, 1H), 2.78-2.53(m, 4H), 2.00-0.70(m, 23H), 1.13(s, 3H), 0.96(s , 3H), 0.94(s, 3H), 0.92(s, 3H), 0.87(s, 6H), 0.82(s, 3H), 0.75(s, 3H); ESI MS m / z 549.78[M+Na] + .

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Abstract

The invention relates to the pharmaceutical field, in particular to application of a series of pentacyclic triterpenoid compounds as a cholesterol ester transfer protein (CETP) inhibitor, in particular to application in factors of preparing medicines for treating cardiovascular and cerebrovascular diseases, atherosclerosis diseases and hyperlipemia. The invention further discloses a series of novel pentacyclic triterpenoid compounds, application of the compounds as the CETP inhibitor and a pharmaceutical composition.

Description

technical field [0001] The invention relates to the pharmaceutical field, in particular to the use of a series of pentacyclic triterpenoids as cholesterol ester transfer protein (CETP) inhibitors, especially in the preparation of anti-cardiovascular and cerebrovascular disease drugs, anti-atherosclerotic disease drugs and anti-hyperlipidemia applications in disease medicine, etc. The invention also discloses a novel pentacyclic triterpene compound and its use as a CETP inhibitor and a pharmaceutical composition. [0002] This patent application claims the priority of the Chinese patent application (application number 201310719496.3, application date: December 24, 2013, invention and creation name: pentacyclic triterpene cholesterol transporter inhibitor, its pharmaceutical composition and medical use). Background technique [0003] Hyperlipidemia refers to a state in which serum lipid concentration is abnormally elevated. Serum lipids include cholesterol, phospholipids, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61K31/56A61P9/10A61P3/06A61P9/12A61P3/10A61P7/02A61P3/04A61P3/00A61P9/06A61P13/12A61P1/16A61P29/00A61P39/06A61P11/00A61P37/08A61P15/00A61P25/28A61P33/12A61P35/00
CPCC07J63/008Y02A50/30
Inventor 孙宏斌陈冬寅张丽颖温小安
Owner CHINA PHARM UNIV
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