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Caffeoyl-substituted pentacyclic triterpene derivatives and uses thereof

A pentacyclic triterpenoid and caffeoyl technology, applied in the field of medicine, can solve the problems of not showing expected effects, weak clinical efficacy results of neuroprotective agents, and clinical application of large toxic and side effects.

Inactive Publication Date: 2016-09-14
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the one hand, quite a lot of neuroprotective agents work in vitro or are effective in animal experiments, but they do not show the expected effect or the effect is very poor when they enter clinical trials; on the other hand, the clinical efficacy results of some neuroprotective agents are not strong , and have relatively large toxic and side effects, which limits clinical application

Method used

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  • Caffeoyl-substituted pentacyclic triterpene derivatives and uses thereof
  • Caffeoyl-substituted pentacyclic triterpene derivatives and uses thereof
  • Caffeoyl-substituted pentacyclic triterpene derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0172] Example 1: Preparation of Compounds 001-005

[0173] The root bark (20Kg) of C.orbiculatus (C.orbiculatus, collected from Huaihua, Hunan Province, in April 2009) dried in the shade and crushed was extracted by percolation with 95% ethanol at room temperature (30L×3), and the extract was concentrated under reduced pressure to obtain ethanol extract . The ethanol extract was suspended and dissolved in 10% methanol (1.5L), and extracted three times with ethyl acetate (1.5L×3) to obtain the extract of ethyl acetate (400g). Ethyl acetate extract was subjected to normal phase separation and gradient elution with petroleum ether-ethyl acetate (10:1,6:1,4:1,2:1,1:1) to obtain 4 components (Fr.1 -4). Among them, Fr.2 was subjected to reverse phase, normal phase, LH-20, HW-40 repeated column chromatography to obtain compound 002 and compound 004; Fr.3 was subjected to reversed phase, normal phase, LH-20, HW-40 repeated column chromatography Compounds 001, 003 and 005 were obta...

Embodiment 2

[0179] Example 2: Synthesis of 3β-hydroxyl-28-caffeoyloxy-20(29)-ene-lupine (006)

[0180]

[0181] Under ice bath conditions, to betulin (200mg, 452.5mmol) in DCM (CH 2 Cl 2 ) solution (20 mL), add freshly prepared caffeoyl chloride (179.2 mg, 905.0 mmol), and stir at room temperature. After the completion of the reaction as detected by TLC, add saturated NaHCO 3 The solution (50 mL) was quenched. Extracted with DCM (50mL x3), washed with saturated brine, anhydrous Na 2 SO 4 dry. The residue after evaporating DCM to dryness was purified by a normal-phase silica gel column, eluting with petroleum ether:ethyl acetate (5:1), to obtain a white powdery solid, compound 006, 164 mg, yield 60%. 1 H NMR (500MHz, deuterated chloroform): δ0.77(s,3H),0.82(s,3H),0.97(s,3H),0.98(s,3H),1.04(s,3H),1.69(s ,3H),0.68-2.00(m,25H),2.46(dt,J=10.8,5.7Hz,1H),2.68(m,1H),3.21(dd,J=11.3,4.6Hz,1H),3.97( d,J=11.0Hz,1H),4.37(d,J=11.0Hz,1H),4.60(s,1H),4.70(s,1H),6.28(d,J=16.0Hz,1H),6.45( br s,1...

Embodiment 3

[0182] Example 3: Synthesis of 3β-caffeoyloxy-20(29)-en-28-ol-lupinane (007).

[0183]

[0184] Step 1: To a freshly prepared solution of 3,4-diacetoxycaffeoyl chloride in dry DCM (5ml) with stirring in an ice bath, was added 3β-hydroxy-20(29)-ene-28-acetoxy- Lupinane (218mg, 0.45mmol), pyridine (113mg, 1.35g), stirred at room temperature for 4h. After the reaction solution was concentrated, it was directly separated by normal phase column chromatography, eluting with petroleum ether: ethyl acetate (10:1), to obtain compound 3β-(3,4-diacetoxy-caffeoyloxy)-20(29 )-ene-28-acetoxy-lupin (230 mg, 0.32, 71% yield).

[0185] Step 2: To the methanol (3mL ) solution was added a catalytic amount of sodium metal, stirred at room temperature for 30min, TLC detected no raw material point, added hydrochloric acid solution (1M, 10mL), stirred at room temperature for 30min, extracted with ethyl acetate (10mLx3), and the extract was decompressed to remove the solvent Afterwards, it was ...

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Abstract

Provided are a caffeoyl substituted pentacyclic triterpene derivative as represented by formula (I) and pharmaceutical composition containing the same. Also provided are uses of the derivative in the preparation of drugs or health-care products for preventing and treating brain injury induced by cerebral ischemia, glucose deprivation, and cerebral anoxia, and / or nervous dysfunction, and / or cognitive dysfunction.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a class of caffeoyl-substituted pentacyclic triterpene derivatives and their use in the preparation and prevention and treatment of brain damage and / or neurological dysfunction induced by cerebral ischemia, glucose deficiency and hypoxia. And / or use in medicine or health products for cognitive dysfunction. Background technique [0002] Advances in Drugs for Cerebral Ischemia Injury [0003] Acute ischemic stroke belongs to a class of sudden cerebral blood circulation disorders, which extensively affects the transduction of cell signals in the brain, and then induces a large number of neurons in the brain to die, and finally causes severe neurological damage. Based on the pathological characteristics of the disease, it is of great significance to find drugs with neuroprotective effects. Such drugs protect neurons by inhibiting the cascade of pathological reactions in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/56A61P9/10A61P25/28A61P25/00A61P39/00A23L33/10
CPCA61K31/165A61K31/216A61P9/10A61P25/00A61P25/28A61P39/00C07J63/008
Inventor 赵维民章海燕王红敏唐希灿吴剑阮志李金龙傅燕
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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