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Oleanolic acid derivative and medical application thereof
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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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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)
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[0050] Dissolve compound I-1 (5 g, 10 mmol) in anhydrousdichloromethane (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...
[0056] Compound A-2 (3.5g, 6.6mmol) was dissolved in 50mL of methanol, potassiumhydroxide (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 anhydroussodiumsulfate, concentrate under reduced pressure, and perform silica gelcolumn chromatography (petroleumEther: 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] + .
[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 sodiumsulfate, concentrated under reduced pressure, and subjected to silica gelcolumn chromatography (petroleumether: acetic acidEthyl 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 pentacyclic triterpenoid novel AMPKagonistoleanolic 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 AMPKagonist 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 proteinkinase) 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...
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