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Delta-oleanolic acid saponin compound and medical application thereof

A compound and solvent compound technology, applied in the field of biomedicine, can solve problems such as unknown efficacy, and achieve the effects of improving oral bioavailability, good oral bioavailability, and high oral bioavailability

Active Publication Date: 2020-12-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the literature has only reported a δ-oleanolic acid saponin compound (Chem.Pharm.Bull.1997,45,1300), and there are very few literature reports on the biological activity of this type of compound (Biol.Pharm.Bull.2005 ,28,1995), especially the efficacy of this class of compounds on diseases related to AMPK signaling pathway is still unknown

Method used

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  • Delta-oleanolic acid saponin compound and medical application thereof
  • Delta-oleanolic acid saponin compound and medical application thereof
  • Delta-oleanolic acid saponin compound and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 3β-Hydroxy-oleanane-13(18)-ene-28-O-β-D-xylopyranoside (compound 1)

[0043]

[0044] Dissolve D-xylose (1g, 6.66mmol) in pyridine (20mL), slowly add benzoyl chloride (4.6mL, 39.97mmol) dropwise in an ice-water bath, react overnight at room temperature, and monitor the progress of the reaction by TLC , after the reaction is complete, add ethyl acetate (15mL) to dilute the reaction solution, followed by water (20mL), 1N hydrochloric acid aqueous solution (20mL), saturated NaHCO 3 The reaction solution was washed with aqueous solution (20 mL) and saturated NaCl aqueous solution (20 mL), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound 1-1 ( white solid).

[0045] Dissolve compound 1-1 in dichloromethane (20mL), add 33% hydrogen bromide acetic acid solution (2.5mL) under an ice-water bath, react overnight at room temperature, TLC monit...

Embodiment 2

[0050] 3β-Hydroxy-oleanane-13(18)-ene-28-O-β-D-galactopyranoside (compound 2)

[0051]

[0052] Referring to the method of Example 1, D-xylose was replaced by D-galactose to obtain compound 2 (white solid): 1 H NMR (300MHz, DMSO-d 6)δ5.31(d, J=7.3Hz, 1H), 4.89(d, J=5.3Hz, 1H), 4.78(d, J=4.9Hz, 1H), 4.61-4.54(m, 1H), 4.48( d,J=3.9Hz,1H),4.29(d,J=4.9Hz,1H),3.73-3.66(m,1H),3.59-3.51(m,1H),3.50-3.36(m,4H),3.07 -2.97(m,1H),2.77-2.66(m,1H),2.38(d,J=13.9Hz,1H),2.17-2.07(m,1H),1.13(s,3H),0.91(s,3H ),0.89(s,3H),0.84(s,3H),0.83(s,3H),0.72(s,3H),0.67(s,3H). 13 C NMR (75MHz, DMSO-d 6 )δ174.32,137.77,127.31,94.93,76.79,75.96,73.43,69.55,67.81,60.03,54.85,50.08,47.86,43.82,40.82,38.41,36.82,36.21,34.93,34.48,32.19,31.98,31.88,28.16,27.06 ,26.48,24.67,23.96,21.20,20.73,18.00,17.23,16.15,15.86.HRMS(ESI):m / z calcd for[M+Na] + C 36 h 58 o 8 Na: 641.4024; found: 641.4030.

Embodiment 3

[0054] 3β-Hydroxy-oleanane-13(18)-ene-28-O-α-L-arabinopyranoside (compound 3)

[0055]

[0056] Referring to the method of Example 1, D-xylose was replaced by L-arabinose to obtain compound 3 (white solid): 1 HNMR (300MHz, DMSO-d 6 )δ5.34(d, J=5.3Hz, 1H), 5.06(d, J=3.7Hz, 1H), 4.75(s, 1H), 4.63(d, J=3.7Hz, 1H), 4.29(d, J=4.9Hz, 1H), 3.80-3.67(m, 2H), 3.55-3.42(m, 3H), 3.04(dd, J=13.1, 7.6Hz, 1H), 2.73(d, J=12.8Hz, 1H ),2.39(d,J=14.0Hz,1H),2.20-2.12(m,1H),1.15(s,3H),0.92(s,3H),0.90(s,3H),0.86(s,3H) ,0.84(s,3H),0.73(s,3H),0.68(s,3H). 13 C NMR (75MHz, DMSO-d 6 )δ174.33,137.76,127.29,94.75,76.79,71.96,69.49,66.54,65.07,54.84,50.08,47.96,43.84,40.81,38.40,36.82,36.28,35.03,34.47,32.18,31.99,31.88,28.15,27.05,26.51 ,24.67,23.92,21.20,20.70,17.97,17.25,16.13,15.85.HRMS(ESI):m / z calcd for[M+Na] + C 35 h 56 o 7 Na: 611.3924; found: 611.39198.

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Abstract

The invention discloses a delta-oleanolic acid saponin compound and medical application thereof. The delta-oleanolic acid saponin compound is a compound with a structural formula shown as a formula (I), and pharmaceutically acceptable salt or ester or prodrug or solvate of the delta-oleanolic acid saponin compound. The compound of formula (I) of the invention has very strong agonistic activity toAMPK. The delta-oleanolic acid saponin compound can activate an AMPK signal path so that the delta-oleanolic acid saponin compound can be used for preparing medicines for preventing or treating AMPK mediated diseases, and meanwhile, the delta-oleanolic acid saponin compound has better pharmacokinetic properties such as oral bioavailability, strong metabolic stability and remarkable in-vitro and in-vivo anti-inflammatory curative effects.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a delta-oleanolic acid saponin compound with AMPK agonist activity, and also relates to the medical use of the compound as an AMPK agonist. 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). The anti-inflammatory effect of AMPK has attracted more and more attention, but its molecular mechanism is not fully understood (Nature 2013, 493, 346). In terms of the clinical application of AMPK agonists, although m...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/704A61P35/00A61P3/10A61P9/12A61P1/16A61P9/00A61P7/00A61P27/02A61P9/06A61P9/10A61P9/04A61P25/00A61P3/00A61P37/02A61P11/00A61P19/02A61P17/00A61P25/28A61P25/16A61P25/02A61P25/24A61P25/14
CPCC07J63/008A61P35/00A61P3/10A61P9/12A61P1/16A61P9/00A61P7/00A61P27/02A61P9/06A61P9/10A61P9/04A61P25/00A61P3/00A61P37/02A61P11/00A61P19/02A61P17/00A61P25/28A61P25/16A61P25/02A61P25/24A61P25/14
Inventor 孙宏斌李浩斌刘柳戴量胡凯文许庆龙柳军温小安
Owner CHINA PHARM UNIV
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