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Derivatives of oleanolic acid and delta-oleanolic acid and medical application thereof

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

Active Publication Date: 2020-12-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, very few literatures have reported the biological activity of δ-oleanolic acid

Method used

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  • Derivatives of oleanolic acid and delta-oleanolic acid and medical application thereof
  • Derivatives of oleanolic acid and delta-oleanolic acid and medical application thereof
  • Derivatives of oleanolic acid and delta-oleanolic acid and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] (2-(Trimethylammonio)ethyl)-3β-(2-carboxybenzoyl)oxy-oleanane-13(18)-ene-28-amide bromide (Compound A-1)

[0094]

[0095] Put compound I-1 (1.27g, 5.0mmol) into a Shrek tube, add trimethylamine in tetrahydrofuran (20mL, 40mmol), and heat at 55°C for 24 hours under argon atmosphere. After the reaction was completed, the mixture in the reaction tube was moved to an eggplant-shaped flask with dichloromethane, concentrated under reduced pressure, the residue was filtered with suction, and the filter cake was washed with dichloromethane (5mL×3) to obtain compound I-2 (white solid , 1.166 g, yield 75%).

[0096] Take compound I-2 (1.166g, 3.723mmol) and suspend it in a mixed solution of chloroform and ethanol (20mL, v:v=7:3), add hydrazine hydrate (340μL) after cooling to 0°C, and argon atmosphere Under reflux at 50°C for 12 hours. After the reaction was completed, the reaction solution was filtered with suction, the filter cake was washed with a mixed solvent of chloro...

Embodiment 2

[0102] N-(2-(Dimethylamino)ethyl)-3β-(2-carboxybenzoyl)oxy-oleanane-13(18)-ene-28-amide (Compound A-3)

[0103]

[0104] Dissolve δ-oleanolic acid (5 g, 0.011 mol) in anhydrous pyridine (35 mL), slowly add acetic anhydride (4 mL) dropwise under stirring, and heat to reflux for 1 hour after the dropwise addition. After TLC detected that the reaction was complete, the reaction solution was cooled to room temperature, and it was dropped into ice water (20mL×2). ), dried in vacuo, and recrystallized from ethanol to obtain compound II-1 (white solid, 4.52 g, yield 83%).

[0105] Dissolve compound II-1 (150 mg, 0.30 mmol) in anhydrous dichloromethane (5 mL), slowly add oxalyl chloride (130 μL, 1.50 mmol) and N,N-dimethylformamide (1 drop) dropwise under stirring , react at room temperature for 3 hours. After the reaction was detected by TLC, the solvent was evaporated under reduced pressure to obtain compound II-2 (yellow solid, 155 mg, yield 100%).

[0106] Dissolve N,N-dimet...

Embodiment 3

[0110] N-(2-(1-piperidinyl)ethyl)-3β-(2-carboxybenzoyl)oxy-oleanane-13(18)-ene-28-amide (Compound A-4)

[0111]

[0112] Referring to the method of Example 2, replace N,N-dimethylethylenediamine with 1-(2-aminoethyl)piperidine to obtain compound A-4: 1 H NMR (300MHz, CDCl 3 )δ7.74(d,J=7.1Hz,1H),7.52(d,J=6.9Hz,1H),7.47–7.29(m,2H),6.77–6.64(m,1H),4.78–4.59(m ,1H),3.75–3.46(m,2H),3.08–2.67(m,7H),2.43(d,J=13.6Hz,1H),2.31(d,J=10.1Hz,1H),1.16(s, 3H),0.98(s,3H),0.88(s,3H),0.86(s,6H),0.79(s,3H),0.72(s,3H).ESI-MS: m / z 715.5[M+H ] + .

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PUM

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Abstract

The invention discloses derivatives of oleanolic acid and delta-oleanolic acid as pentacyclic triterpenoid novel AMPK agonists and medical application of the derivatives, and particularly relates to compounds shown as a formula I or a formula II and pharmaceutically acceptable salts or esters or solvates of the compounds. The compounds can be used for preparing AMPK agonists with activity of enhancing the phosphorylation level of AMPK and preparing drugs for preventing or treating AMPK-mediated diseases. The novel pentacyclic triterpenoid compounds disclosed by the invention have remarkable AMPK agonist activity, the activity of the novel pentacyclic triterpenoid compounds are remarkably superior to that of an acknowledged AMPK agonist AICAR, and meanwhile, the novel pentacyclic triterpenoid compounds have pharmacokinetic properties such as better 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 derivatives of oleanolic acid and δ-oleanolic acid and their medical applications. The present invention also relates to the use of such compounds in Use in the preparation of medicines for preventing or treating AMPK-mediated diseases and pharmaceutical compositions 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,...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/56A61K31/58A61P3/00A61P9/00A61P29/00A61P37/02A61P25/28A61P35/00A61P3/10A61P5/50A61P3/04A61P3/06A61P9/10A61P9/06A61P9/12A61P9/04A61P1/16A61P19/06A61P11/00A61P11/06A61P11/02A61P37/08A61P1/00A61P17/00A61P1/18A61P13/12A61P25/00A61P21/00A61P25/16A61P25/24
CPCC07J63/008A61P3/00A61P9/00A61P29/00A61P37/02A61P25/28A61P35/00A61P3/10A61P5/50A61P3/04A61P3/06A61P9/10A61P9/06A61P9/12A61P9/04A61P1/16A61P19/06A61P11/00A61P11/06A61P11/02A61P37/08A61P1/00A61P17/00A61P1/18A61P13/12A61P25/00A61P21/00A61P25/16A61P25/24A61K31/56A61K31/58C07J63/00
Inventor 孙宏斌胡凯文刘柳程亚龙秦鹿柘李浩斌戴量柳军
Owner CHINA PHARM UNIV
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