Derivatives of oleanolic acid and their medicinal uses

A technology of oleanolic acid and derivatives is applied in the field of biomedicine to achieve the effects of strong AMPK agonistic activity, good oral bioavailability and good safety

Active Publication Date: 2022-01-28
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 and monkeys that the side effect of irreversible cardiac hypertrophy occurred in the animal heart (Science 2017, 357, 507)

Method used

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  • Derivatives of oleanolic acid and their medicinal uses
  • Derivatives of oleanolic acid and their medicinal uses
  • Derivatives of oleanolic acid and their medicinal uses

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] Dissolve compound A-1 (200mg, 0.4mmol) in pyridine (3mL), add 4-dimethylaminopyridine (5mg, 0.04mmol) and propionic anhydride (133uL, 1mmol) successively, stir at room temperature and react, 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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Abstract

The invention discloses a derivative of oleanolic acid, a novel pentacyclic triterpenoid AMPK agonist, and its medical application, specifically, a compound represented by formula I or formula II or a pharmaceutically acceptable salt or ester or solvent thereof Compounds, which can be used to prepare AMPK agonists with the activity of enhancing AMPK phosphorylation level and to prepare drugs for preventing or treating AMPK-mediated diseases. The novel pentacyclic triterpenoids of the present invention have significant AMPK agonistic activity, and its activity is significantly better than the recognized AMPK agonist AICAR, and has better oral bioavailability and other pharmacokinetic properties and very good safety sex.

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 energy metabolism and inflammatory responses in the body. 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)....

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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