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Sarsasapogenin-structure-modified derivatives, pharmaceutical compositions thereof and applications of the compositions

A technology of timogenin and derivatives, applied in the field of timogenin structurally modified derivatives, which can solve the problems of scarcity of derivatives and immature research on timogenin structurally modified derivatives

Active Publication Date: 2017-06-30
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] From the above research on timosaponin, it is shown that timosaponin is a good lead compound for treating nervous system diseases, but the research on derivatives of timosaponin structure modification is still immature. The timogenin structurally modified derivatives that can be used to prepare drugs for the treatment of nervous system diseases such as Alzheimer's drugs are still too rare

Method used

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  • Sarsasapogenin-structure-modified derivatives, pharmaceutical compositions thereof and applications of the compositions
  • Sarsasapogenin-structure-modified derivatives, pharmaceutical compositions thereof and applications of the compositions
  • Sarsasapogenin-structure-modified derivatives, pharmaceutical compositions thereof and applications of the compositions

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] The preparation method of timogenin AA is as follows:

[0081] The anemarrhena rhizome medicine is refluxed and extracted three times according to the weight ratio of 50%-90% ethanol at 1:2-1:4, filtered, and the ethanol is evaporated to dryness. The ethanol crude extract was dispersed in 5% H 2 SO 4 , heated and hydrolyzed for 4-10 hours, the acid hydrolyzed product was extracted with DCM several times, and the DCM was removed to obtain the crude product of timogenin. The crude product was eluted with petroleum ether-acetone (20:1) to obtain timogenin AA.

[0082] Timogenin AA

[0083] 1 H NMR (400MHz, CDCl 3 )δ4.42(m,1H,H-20),4.12(s,1H,H-3),3.97(d,J=11.0Hz,1H,H-26),3.31(d,J=11.0Hz, 1H,H-26),2.07–0.98(m,37H),0.77(s,3H). 13 C NMR (100MHz, CDCl 3 )δ109.75, 81.02, 67.08, 65.14, 62.08, 56.47, 42.11, 40.67, 40.31, 39.85, 36.52, 35.27 (2C), 33.53, 31.74, 29.95, 27.81, 27.08, 26.56, 26.54, 25.97 20.90,16.50,16.05,14.34.MS(ESI):m / z 416.45[M+H] + ;HRMS(ESI):m / z[M+H] ...

Embodiment 2

[0085] Preparation method of timogenin derivative ZM1:

[0086] At room temperature, mix timogenin AA with acetic anhydride and ammonium chloride, then heat the reaction to 50-150°C for 4-24 hours, then add 2%-10% methanol-sodium hydroxide solution, and react at room temperature After 4-24 hours, the mother sapogenin derivative ZM1 was obtained by extraction and column chromatography.

[0087] Timogenin Derivative ZM1

[0088] 1H NMR (400MHz, CDCl 3 )δ4.73(ddd, J=16.2, 7.1Hz, 1H), 4.11(s, 1H), 3.47(d, J=21.0Hz, 2H), 2.47(d, J=10.0Hz, 1H), 1.28- 1.93(m,30H),0.98(s,3H),0.92(d,3H),0.67(s,3H).13C-NMR(101MHz,CDCl 3 )δ151.59,103.80,84.40,68.05,67.07,64.39,54.97,43.72,39.98,39.82,36.51,35.35,35.26,35.07,34.05,33.53,30.38,29.96,27.84,26.69,26.54,23.90,23.15,21.04,16.43 ,14.20,11.66,ESI-MS m / z 417.4[M+H] + .

Embodiment 3

[0090] Preparation method of timogenin derivative ZM13:

[0091] Under the protection of argon, react the timogenin derivative ZM1 with p-toluenesulfonyl chloride for 1-10 hours, then add sodium azide, and raise the temperature to 40-100°C, react for 1-10 hours, then add triphenyl After 1-10 hours of reaction at room temperature, the mother sapogenin derivative ZM13 was obtained by extraction and column chromatography. Wherein, the molar ratio of ZM1 to toluenesulfonyl chloride, sodium azide and triphenylphosphine is 1:1:1:1 to 1:10:10:10.

[0092] Timogenin Derivative ZM13

[0093] 1H NMR (400MHz, CDCl 3 )δ4.71(m, 1H), 4.32(d, J=5.6Hz, 1H), 4.11(s, 1H), 3.03(dd, J=13.6, 6.8Hz, 2H), 2.46(d, J=10.0 Hz, 1H), 1.32-1.83(m, 30H), 0.98(s, 3H), 0.91(d, J=6.6Hz, 3H), 0.65(s, 3H), ESI-MS: m / z 416.3[M +H] + .

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Abstract

The invention relates to sarsasapogenin-structure-modified derivatives. The derivatives are characterized in that the structure formulas of the derivatives are shown as (I) and (II); pharmaceutical compositions of the derivatives and applications thereof are also provided; and many of the newly synthesized compounds show activity superior to activity of lead compounds through activity testing aiming at AD related targets. The compositions have high practical value for treating senile dementia. Defects of sarsasapogenin-structure-modified derivatives in the prior art are made up. The derivatives and the compositions are of great significance.

Description

[0001] This application is a divisional application of the invention patent application with the filing date of January 27, 2015, the application number of 201510042229.6, and the title of the invention being "Derivatives with modified timogenin structure, pharmaceutical compositions and applications thereof". technical field [0002] The invention relates to the field of medical technology, in particular to the field of chemical synthesis of medicines, in particular to timogenin structurally modified derivatives, pharmaceutical compositions and applications thereof. Background technique [0003] Alzheimer's disease (AD) is the most common senile dementia, a degenerative disease of the central nervous system that is highly age-related and characterized by progressive cognitive impairment and memory impairment. Early symptoms are often mistaken for age-related problems or clinical signs of stress. In the early stage of symptoms, the most common is the decline of memory and re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61K31/58A61P25/28
CPCC07J71/0005C07J71/0031
Inventor 马磊王蕊周南南徐婷赵建宏张骥张忠国徐刘昕杨雅琴熊加伟尹欢欢潘辉
Owner EAST CHINA UNIV OF SCI & TECH