Oleanolic acid derivative and medical application thereof

A kind of technology of oleanolic acid and derivatives, applied in the field of biomedicine

Active Publication Date: 2020-05-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, although the broad-spectrum AMPK-β subunit agonist MK-8722 can lower blood sugar, it was found in rats ...

Method used

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  • Oleanolic acid derivative and medical application thereof
  • Oleanolic acid derivative and medical application thereof
  • Oleanolic acid derivative and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 12-ene-3β-acetoxy-28-(oxazolin-2-yl)-oleanane (Compound A-2)

[0048]

[0049] Dissolve oleanolic acid (OA, 10g, 21.9mmol) in pyridine (150mL), add 4-dimethylaminopyridine (0.26g, 2.19mmol), slowly add acetic anhydride (8.3mL, 87.6mmol), and stir at room temperature overnight. After the reaction is complete, add 1N hydrochloric acid (300mL), extract with ethyl acetate (300mL×3), wash with saturated brine (300mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, make a slurry (petroleum ether: dichloromethane =50:1) Suction filtration to obtain compound I-1 (white solid, 8.2 g, yield 75%).

[0050] Dissolve compound I-1 (5 g, 10 mmol) in anhydrous dichloromethane (80 mL), slowly add oxalyl chloride (1.7 mL, 20 mmol) and N,N-dimethylformamide (5 drops) dropwise under stirring, React at room temperature for 5 hours. After the reaction was detected by TLC, the solvent was evaporated under reduced pressure to obtain compound I-2 (yellow solid, 5...

Embodiment 2

[0054] Oleanane-12-ene-28-(oxazolin-2-yl)-3β-ol

[0055]

[0056] Compound A-2 (3.5g, 6.6mmol) was dissolved in 50mL of methanol, potassium hydroxide (3.7g, 66mmol) was added, heated to 50°C and stirred to react, TLC detected that the reaction was complete. After the reaction was completed, cool to room temperature, add 50 mL of water, extract with ethyl acetate (50 mL×3), wash with saturated brine (50 mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (petroleum Ether: ethyl acetate = 10: 1) purification to obtain compound A-1 (white solid, 3.0 g, yield 95%): 1 H NMR(300MHz,DMSO)δ5.36-5.18(m,1H),4.26-4.03(m,2H),3.88-3.63(m,2H),3.27-3.15(m,1H),2.93-2.77(m ,1H),1.13(s,3H),0.99(s,3H),0.94(s,3H),0.90(s,6H),0.78(s,3H),0.76(s,3H).ESI-MS: m / z 482.4[M+H] + .

Embodiment 3

[0058] 12-en-3β-propionyloxy-28-(oxazolin-2-yl)-oleanane (Compound A-3)

[0059]

[0060] Take compound A-1 (200mg, 0.4mmol) and dissolve it in pyridine (3mL), add 4-dimethylaminopyridine (5mg, 0.04mmol) and propionic anhydride (133uL, 1mmol) successively, stir the reaction at room temperature, and TLC detects that the reaction is complete After that, 1N hydrochloric acid (5 mL) was added, extracted with ethyl acetate (5 mL×3), washed with saturated brine (5 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether: acetic acid Ethyl ester=10:1), to obtain compound A-3 (white solid, 178mg, yield 80%): 1 H NMR (300MHz, CDCl 3 )δ5.32-5.20(m,1H),4.58-4.42(m,1H),4.22-4.03(m,2H),3.91-3.71(m,2H),2.94-2.79(m,1H),2.32( q,J=7.6Hz,2H),0.93(s,6H),0.90(s,3H),0.86(s,9H),0.76(s,3H).ESI-MS:m / z 538.5[M+H ] + .

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PUM

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Abstract

The invention discloses a pentacyclic triterpenoid novel AMPK agonist oleanolic acid derivative and medical application thereof, and specifically, a compound shown in the formula I or the formula II or a pharmaceutically acceptable salt or an ester or a solvate of the compound can be used for preparing an AMPK agonist with activity of enhancing the phosphorylation level of AMPK and preparing a medicine for preventing or treating AMPK-mediated diseases. The novel pentacyclic triterpenoid compound has remarkable AMPK agonist activity, the activity of the novel pentacyclic triterpenoid compound is remarkably superior to that of an acknowledged AMPK agonist AICAR, and meanwhile the novel pentacyclic triterpenoid compound has better pharmacokinetic properties such as oral bioavailability and the like and very good safety.

Description

technical field [0001] The present invention relates to the field of biomedicine, and relates to novel pentacyclic triterpenoid compounds with AMPK agonistic activity, in particular to oleanolic acid derivatives and their medical applications. Use in medicine for diseases and pharmaceutical composition thereof. Background technique [0002] AMPK (adenylate-activated protein kinase) is a key kinase that regulates the body's energy metabolism and inflammatory response. Its phosphorylation activation can overcome insulin resistance, lower blood sugar, lower blood lipids (by inhibiting the synthesis of fatty acids and cholesterol), anti-inflammation, and anti-apoptosis. Death, anti-fibrosis, promotion of mitochondrial synthesis, enhancement of mitochondrial oxidative metabolism, anti-aging and anti-tumor, etc. (Physiol. Rev. 2009, 89, 1025). In recent years, the anti-inflammatory and anti-fibrotic effects of AMPK have attracted more and more attention (Nature 2013, 493, 346). T...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/58A61P3/00A61P3/10A61P3/06A61P3/04A61P9/10A61P9/06A61P9/00A61P9/12A61P9/04A61P1/16A61P29/00A61P11/00A61P11/06A61P11/08A61P11/02A61P37/08A61P1/00A61P13/12A61P19/02A61P17/06A61P17/00A61P13/10A61P25/16A61P25/28A61P25/24A61P21/00A61P25/04A61P25/14A61P21/04A61P35/00A61P35/02
CPCC07J63/008A61P3/00A61P3/10A61P3/06A61P3/04A61P9/10A61P9/06A61P9/00A61P9/12A61P9/04A61P1/16A61P29/00A61P11/00A61P11/06A61P11/08A61P11/02A61P37/08A61P1/00A61P13/12A61P19/02A61P17/06A61P17/00A61P13/10A61P25/16A61P25/28A61P25/24A61P21/00A61P25/04A61P25/14A61P21/04A61P35/00A61P35/02
Inventor 孙宏斌程亚龙温小安
Owner CHINA PHARM UNIV
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