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Arctigenin carboxamide derivative, preparation method thereof, composition comprising arctigenin carboxamide derivative and uses thereof

The technology of aglycone carboxamide and arctium seed is applied in arctigen aglycone carboxamide derivative and preparation thereof, a composition comprising the derivative, and the field of use thereof, which can solve the problem of unseen arctigen aglycone, system structure Modified issues such as unreported

Inactive Publication Date: 2013-12-25
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

In 2001, Jang Y.P. reported that arctiin and aglycon had strong neuroprotective effects on primary cultured rat cortical cells damaged by glutamate [Jang P.J., et al. Neuroprotective dibenzylbutyrolactone lignans of Torreya nucifera, Planta Medica, 2001,67:470-472.]; but so far there is no report on the molecular mechanism of arctigenin reducing Aβ production, and no report on the structural modification of its system

Method used

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  • Arctigenin carboxamide derivative, preparation method thereof, composition comprising arctigenin carboxamide derivative and uses thereof
  • Arctigenin carboxamide derivative, preparation method thereof, composition comprising arctigenin carboxamide derivative and uses thereof
  • Arctigenin carboxamide derivative, preparation method thereof, composition comprising arctigenin carboxamide derivative and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Preparation of compound A-01

[0062]

[0063] Under argon protection, dissolve arctigenin 1 (1mmol) in 10mL of anhydrous tetrahydrofuran, then add diisopropylethylenediamine (DIPEA, 1.5mmol), heat the mixture to 70°C, and add ethyl acetate. Isocyanate (2mmol), incubated for 24h. After the reaction, cool to room temperature, add 20 mL of dichloromethane, wash the organic phase with water (20 mL×2) twice, then with saturated brine (20 mL), dry with anhydrous magnesium sulfate, and filter. The solvent was removed from the filtrate under reduced pressure, and column chromatography (petroleum ether / acetone=3:1) was used to obtain compound A-01 as a white powder with a yield of 74%. 1 HNMR(300MHz, CDCl 3 )δ: 7.00 (d, J=8.0Hz, 1H), 6.80-6.71 (m, 2H), 6.65 (d, J=8.8Hz, 1H), 6.59-6.45 (m, 2H), 5.03 (s, 1H) ), 4.19-4.08 (m, 1H), 3.89-3.92 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 3.35 to 3.25 (m, 2H), 2.97(d,J=5.7Hz,2H),2.69-2.45(m,4H),1.21(t,J=7.2Hz,3H); ESI-...

Embodiment 2

[0064] Example 2: Preparation of Compound A-02

[0065]

[0066] Under argon protection, dissolve arctigenin (1mmol) in 10mL anhydrous tetrahydrofuran, then add diisopropylethylenediamine (DIPEA, 1.5mmol) and p-nitrophenyl chloroformate (1.5mmol) The mixture was heated to 70°C for 6 hours. Then, n-propylamine (2mmol) was added to the reaction solution, and the reaction was continued at 70°C for 10 hours. After the reaction, cool to room temperature, add 20 mL of dichloromethane, wash the organic phase with water (20 mL×2) twice, then with saturated brine (20 mL), dry with anhydrous magnesium sulfate, and filter. The solvent was removed from the filtrate under reduced pressure, and column chromatography (petroleum ether / acetone=3:1) was used to obtain compound A-02 as a white powder with a yield of 80%. 1 H NMR (300MHz, CDCl 3 )δ: 7.00(d,J=8.0Hz,1H),6.80-6.71(m,2H),6.65(d,J=8.0Hz,1H),6.58-6.48(m,2H),5.07(t,J =6.2Hz,1H), 4.16(dd,J=9.1,6.8Hz,1H), 3.90(d,J=8.0Hz,1H), 3.85(s,3H), 3....

Embodiment 3

[0067] Example 3: Preparation of Compound A-03

[0068]

[0069] Except that butyl isocyanate was used instead of ethyl isocyanate, compound A-03 was prepared in the same manner as in Example 1; silica gel column chromatography eluent: petroleum ether\acetone=3:1 column chromatography to obtain white powder The yield of compound A-03 was 72%. 1 H NMR (300MHz, CDCl3) δ: 6.99 (d, J=8.0Hz, 1H), 6.80-6.71 (m, 2H), 6.64 (d, J=8.0Hz, 1H), 6.57-6.47 (m, 2H) ,5.04(s,1H),4.14(dd,J=15.8,8.0Hz,1H),3.93-3.85(m,2H),3.86-3.73(m,9H),3.25(q,J=6.7Hz,2H ), 2.96(d,J=5.7Hz,2H),2.70-2.46(m,4H),1.45-1.33(m,2H),0.94(t,J=7.2Hz,3H); ESI-MS(m / z):472.3[M+H] + .

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Abstract

The invention relates to an arctigenin carboxamide derivative, a preparation method thereof, a composition comprising the arctigenin carboxamide derivative and medical uses thereof, and particularly relates to the arctigenin carboxamide derivative shown in a general formula(I) or a pharmaceutically acceptable salt thereof, the preparation method thereof, the pharmaceutical composition comprising the arctigenin carboxamide derivative and the medical uses thereof. The arctigenin carboxamide derivative shown in the general formula(I) or the pharmaceutically acceptable salt thereof can be used for inhibiting formation of amyloid beta, so that the arctigenin carboxamide derivative shown in the general formula(I) or the pharmaceutically acceptable salt thereof can be used for preparation of drugs for treatment or prevention of alzheimer's disease (AD) or for improvement of memory.

Description

Technical field [0001] The present invention relates to arctigenin carboxamide derivatives, preparation methods thereof, compositions containing them, and medical uses thereof, and more specifically, to a general formula for inhibiting the formation of β-amyloid peptide (Amyloid beta, Aβ) (I) The arctigenin carboxamide derivative or its pharmaceutically acceptable salt, its preparation method, and the pharmaceutical composition containing it and its medical use. Background technique [0002] Alzheimer's disease (Alzheimer's disease, AD, Alzheimer's disease) is a degenerative disease of the central nervous system that is highly correlated with age and is dominated by progressive cognitive impairment and memory impairment. The main clinical manifestations of AD are the continuous deterioration of cognitive and memory functions, progressive decline in the ability of daily living, and various neuropsychiatric symptoms and behavioral disorders. The early stage mainly manifests as rec...

Claims

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Application Information

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IPC IPC(8): C07D307/33C07D405/12A61K31/365A61K31/404A61K31/4525A61K31/5377A61P25/28
Inventor 胡立宏沈旭朱志远雷敏陈静颜建明
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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