Pentacyclic triterpene compound and application of pentacyclic triterpene compound in preparation of medicine for treating Alzheimer's disease

A technology of pentacyclic triterpenoids and compounds, applied in the field of medicinal chemistry

Active Publication Date: 2015-09-16
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

[0006] Although great progress has been made in the research and development of drugs targeting Aβ in recent years, no related drugs have been approved for marketing

Method used

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  • Pentacyclic triterpene compound and application of pentacyclic triterpene compound in preparation of medicine for treating Alzheimer's disease
  • Pentacyclic triterpene compound and application of pentacyclic triterpene compound in preparation of medicine for treating Alzheimer's disease
  • Pentacyclic triterpene compound and application of pentacyclic triterpene compound in preparation of medicine for treating Alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0040] Preparation Example 1: Synthesis of Compound C33

[0041]

[0042] (1) Benzyl betulinate

[0043] Dissolve the raw material betulinic acid (4g, 8.76mmol) (purchased from Xi'an Haoxuan Biotechnology Co., Ltd.) in DMF (50mL) at room temperature, add anhydrous potassium carbonate (2.4g, 17.37mmol), and slowly drop it under stirring After adding benzyl chloride (1.2 mL, 10.52 mmol) dropwise, the reaction solution was moved to 50° C. and stirred overnight. The next day, the mixture was cooled to room temperature, diluted with 100 mL of deionized water, extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with deionized water and saturated brine, dried over sodium sulfate and reduced Pressure distillation gave the desired white solid compound benzyl betulinate (4.62 g), molar yield: 97%. 1 H NMR (300MHz, CDCl 3 )δ7.34(m,5H),5.09(d,1H,J=11.7Hz),5.17(d,1H,J=11.7Hz),4.75(s,1H),4.62(s,1H),3.21- 3.15(m,1H),2.92-2.80(m,1H),2.10-1.90(m,2H),1.87...

preparation Embodiment 2

[0050] Preparation Example 2: Synthesis of Compound C35

[0051]

[0052] Betulinic acid (48mg, 0.11mmol) was dissolved in methanol / dichloromethane (5mL / 5mL), and ozone was passed through at -78°C. TLC showed that the reaction was complete. After the supply of ozone was stopped, the residual ozone was exhausted with oxygen, and the reaction was quenched by adding dimethyl sulfide (25 μL), and the temperature was slowly raised to room temperature, and reacted overnight. The next day, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol=50 / 1, V / V) to obtain compound C35 (21 mg, yield 43.6%). 1 H NMR (300MHz, CDCl 3 ),1.00(s,3H),0.96(s,3H),0.91(s,3H),0.82(s,3H),0.75(s,3H); ESI-MS(m / z):481.3(M+ Na) + (C 29 h 46 o 4 Theoretical value: 458.34).

preparation Embodiment 3

[0053] Preparation Example 3: Synthesis of Compound C41

[0054]

[0055] Compound C42 (12mg, 0.02mmol) was dissolved in ethanol / water (4mL / 1mL) mixed solvent, 2N sodium hydroxide (1mL) was added, and stirred overnight at room temperature. The next day, TLC detected that the reaction was complete. After concentrating the solvent under reduced pressure to remove ethanol, adjust the pH to 3 with 1N hydrochloric acid solution, then extract with ethyl acetate, combine the organic phases and wash with saturated sodium chloride solution, dry the organic phase, and concentrate , the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol=10 / 1, V / V) to obtain compound C41 (6 mg, yield: 50%) as a white solid. 1 H NMR (300MHz, CDCl 3 )δ4.78 (s, 1H), 2.28-2.18 (m, 4H), 1.98-1.15 (m, other alicyclic hydrocarbon protons), 1.01 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H),0.85(s,3H),0.83(s,3H),0.76(s,3H),0.74(s,3H); ESI-MS(m / z):553.3(M+Na) + (C 32 h 50 o ...

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Abstract

Disclosed are a pentacyclic triterpene compound represented by general formula (I) and pharmaceutical compositions containing the compound. Also disclosed is use of the compound in preparation of a PS1 / BACE1 interaction inhibitor, and uses thereof in preparation of drugs for treating Alzheimer's disease. Disclosed for the first time is that a pentacyclic triterpene compound represented by general formula (I) can be used as a PS1 / BACE1 inhibitor, having activity of inhibiting PS1 / BACE1 interaction, and can reduce generation of Aβ and be used in preparation of drugs for treating Alzheimer's disease.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of pentacyclic triterpenoids, a pharmaceutical composition containing the compound, and the preparation of PS1 (PS1, Presenilin1, presenilin 1) / BACE1 (βsite Amyloid Protein Precursor Cleaving Enzyme 1, the use of amyloid protein precursor Cleaving Enzyme 1, also known as β-secretase) interaction inhibitors, and its use in the preparation of drugs for treating Alzheimer's disease. Background technique [0002] Alzheimer's disease (Alzheimer's Disease, AD) is an incurable, progressive brain disease and the leading cause of Alzheimer's disease. AD can lead to the death of a large number of nerve cells, destroy the normal cognitive and behavioral abilities of patients, and eventually cause the patients to lose basic self-care ability and physiological functions until death (Prince et al., World Alzheimer Report 2009.London: Alzheimer's Disease International, 200...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61K31/56A61K31/58A61P25/28
CPCC07J63/008A61K31/56A61K31/58A61P25/28
Inventor 南发俊谢欣裴钢王宵音崔进赵简张仰明张晨露
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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