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Protopanoxadiol derivative, preparation method of derivative, composition containing derivative and application of composition

A technology of protopanaxadiol and derivatives, which can be used in drug combinations, steroids, pharmaceutical formulations, etc., can solve the problems of inability to achieve reversal concentration, changing pharmacokinetic parameters of antitumor drugs, and toxic and side effects.

Inactive Publication Date: 2014-02-12
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, clinically, these compounds cannot achieve effective reversal concentrations at doses tolerated by the human body, and once the dose is increased to make the blood drug concentration reach the concentration with reversal activity in vitro tests, severe toxic side effects will occur
In addition, when some reversal agents are used in combination with antineoplastic drugs, they will change the pharmacokinetic parameters of antineoplastic drugs, resulting in unforeseen toxic and side effects, which greatly limits their clinical use

Method used

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  • Protopanoxadiol derivative, preparation method of derivative, composition containing derivative and application of composition

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preparation example Construction

[0061] Preparation of compound 1-26:

[0062] The starting materials used in the preparation of the following compounds are protopanaxadiol (PPD), which is obtained by synergistic oxidation of total ginsenosides with oxygen and tert-butanol peroxide [CN200510100735]. As shown in Reaction Formula 1, at -78°C, the double bond of compound PPD is broken by ozone, and then amine and NaBH(OAc) are added at -3°C 3 , to obtain the target compound by reductive amination.

[0063]

[0064] Reaction 1

Embodiment 1

[0065] The preparation of embodiment 1 compound 1

[0066]

[0067] In a 50ml three-neck reaction flask, dissolve PPD (200mg, 0.435mmol) in 15ml CH 2 Cl 2 After stirring for 10 min at -78°C, O 3 Reaction 2min. Then warm up to -3°C, add methylamine (0.1ml), NaBH(OAc) 3 (368.8mg, 1.7mmol) and CH 3 OH (8ml), stir overnight, after the reaction is complete, add 15ml of water, 2 Cl 2 (30ml) extracted twice, dried over anhydrous sodium sulfate, concentrated CH under reduced pressure 2 Cl 2 , after silica gel column chromatography (dichloromethane / methanol / triethylamine, 40:1:0.5), the product 1 was obtained with a yield of 85%. 1 H NMR (300MHz, CDCl 3 )δ4.12(m,1H),3.52(td,J=13.0,6.2Hz,1H),3.21(dd,J=10.9,5.0Hz,1H),2.94(m,1H),2.62(m,1H ),2.47(s,3H),1.13(s,3H),0.99(s,3H),0.98(s,3H),0.88(s,6H),0.78(s,3H),0.73(d,J= 11.0Hz, 1H), other high-field H signals overlap at 1.24-2.10; ESI-MS 450.7[M+H] + .

Embodiment 2

[0068] The preparation of embodiment 2 compound 2

[0069]

[0070] Compound 2 was prepared in the same manner as in Example 1 except that ethylamine was used instead of methylamine; the yield was 86% by silica gel column chromatography (dichloromethane / methanol / triethylamine, 45:1:0.5). 1 H NMR (300MHz, CDCl 3 )δ3.55(td,J=12.9,6.3Hz,1H),3.19(dd,J=10.9,4.9Hz,1H),2.93(m,1H),2.72(m,1H),2.58(m,1H ),2.48(m,1H),2.09(m,1H),1.15(s,3H),1.11(t,J=7.2Hz,3H),0.99(s,3H),0.98(s,3H),0.89 (s,3H),0.88(s,3H),0.78(s,3H),0.73(d,J=10.7Hz,1H), other high-field H signals overlapped at 1.02-2.10; ESI-MS464.7[M +H] + .

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Abstract

The invention relates to a protopanoxadiol derivative shown as formula I in the specification, a preparation method of the derivative, a composition containing the derivative and an application of the derivative, and in particular relates to a derivative acquired by modifying protopanoxadiol which is used as a parent structure, a preparation method of the derivative, a composition containing the derivative and an application of the derivative in preparing a tumor cell multi-drug resistance reversal agent.

Description

technical field [0001] The present invention relates to a protopanaxadiol derivative and a preparation method thereof, a composition containing the derivative and its use, in particular to a derivative modified by taking protopanaxadiol as a parent structure, a preparation method thereof, and a composition containing the derivative Composition and its application in preparing tumor cell multidrug resistance reversal agent. Background technique [0002] Chemotherapy is one of the main treatments for malignant tumors. However, multidrug resistance (MDR) of tumor cells often leads to the failure of chemotherapy. According to statistics, more than 90% of chemotherapy failure cases are caused by multidrug resistance of tumor cells to chemotherapy drugs. The mechanism of MDR is very complicated, among which several mechanisms have been studied more: ① decrease in drug intake or increase in drug efflux (mainly mediated by P-gp protein, mdr and mrp protein); ② change in the target ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00C07J43/00A61K31/575A61K31/58A61P35/00A61P35/02
Inventor 胡立宏陈万涛刘军华王旭雷敏
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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