4'-amino-4'-dehydroxyl-oleandrin and 4'-amino-4'-dehydroxyl-odoroside A and use thereof

A pharmacy and compound technology, applied in the field of medicinal chemistry, can solve the problems of unpredictable anti-tumor activity, no clear correlation between anti-tumor activity and cardiotonic activity, etc., and achieves the effects of abundant synthetic raw materials, easy preparation and simple synthesis

Inactive Publication Date: 2015-11-11
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

It can be seen that the mechanism of the cardiotonic activity and the antitumor activity of oleandrin compounds are not exactly the same, and there is no clear correlation between the antitumor activity and the cardiotonic activity of this type of compound. antitumor activity

Method used

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  • 4'-amino-4'-dehydroxyl-oleandrin and 4'-amino-4'-dehydroxyl-odoroside A and use thereof
  • 4'-amino-4'-dehydroxyl-oleandrin and 4'-amino-4'-dehydroxyl-odoroside A and use thereof
  • 4'-amino-4'-dehydroxyl-oleandrin and 4'-amino-4'-dehydroxyl-odoroside A and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the extraction and separation process of compound OL and compound OR

[0048]

[0049] Take about 50kg of oleander leaves, add 40% ethanol for cold soaking, the soaking liquid is absorbed by D101 macroporous resin, and then eluted with 40%-70% ethanol / water gradient, collect the eluate containing OL and OR, elute After the solution was concentrated, the crude products of compound OL and compound OR were obtained by silica gel column chromatography, respectively. The crude product was recrystallized to obtain the pure products of compound OL and compound OR, which were used in the following reactions.

Embodiment 2

[0050] Embodiment 2: the synthesis of compound A01 and A02

[0051]

[0052] Compound OL (2.88 g, 5 mmol) was dissolved in dichloromethane (100 mL), and pyridinium chlorochromate (4.31 g, 20 mmol) was slowly added in portions. After the reaction solution was stirred and reacted at room temperature for 24 h, pyridinium chlorochromate (2.16 g, 10 mmol) was added, and the reaction was continued for 24 h. After the reaction, the reaction solution was diluted with dichloromethane (50mL), filtered through diatomaceous earth, the filtrate was concentrated, and intermediate B (2.70g, 94% ).

[0053] Intermediate B (2.70g, 4.7mmol) was dissolved in methanol (50mL), sodium acetate (771mg, 9.4mmol) and hydroxylamine hydrochloride (654mg, 9.4mmol) were added, and the reaction was stirred at room temperature for 2h. After the reaction, the reaction solution was concentrated under reduced pressure to remove methanol, dichloromethane (100 mL) was added to dilute, the reaction solution w...

Embodiment 3

[0057] Embodiment 3: the synthesis of compound A03 and A04

[0058]

[0059] Compound OR (518mg, 1mmol) was dissolved in pyridine (3mL), and p-toluenesulfonyl chloride (381mg, 2mmol) was slowly added dropwise under ice-bath stirring. After the dropwise addition, the temperature was raised to 60°C and stirred overnight. After the disappearance of the starting material was detected by TLC, sodium azide (130 mg, 2 mmol) was added to the reaction solution, and the stirring reaction was continued for 3 h. After the reaction, the reaction solution was diluted with dichloromethane (20mL), washed twice with water, washed with saturated brine, and the dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (4:1, petroleum ether / acetone) to obtain intermediate D1 (326mg, 60%).

[0060] Intermediate D1 (326mg, 0.6mmol) was dissolved in tetrahydrofuran / water (8mL, 8:1), triphenylphosphine (1.69g, 6mmol) ...

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Abstract

The invention relates to 4'-amino-4'-dehydroxyl-oleandrin and 4'-amino-4'-dehydroxyl-odoroside A and use thereof. The invention provides a compound represented by the following general formula I shown in the description or pharmaceutically acceptable salts thereof, a preparation method therefor, a pharmaceutical composition containing the compound represented by the following general formula I shown in the description or pharmaceutically acceptable salts thereof and use thereof. The compound has inhibitory activity to the propagation of humanized tumor cell lines and can serve as a drug for treating malignant tumors.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, specifically, the present invention relates to 4'-amino-4'-dehydroxy-oleandrin and 4'-amino-4'-dehydroxy-oleandrin A, their preparation methods, A pharmaceutical composition comprising the derivative, and uses thereof. The 4'-amino-4'-dehydroxy-oleandrin and 4'-amino-4'-dehydroxy-oleandrin A have inhibitory activity on the proliferation of human tumor cell lines, and can be used as a treatment for malignant Drugs for tumors. Background technique [0002] Cardiac glycosides selectively inhibit Na + / K + ATPase is clinically used to treat heart diseases such as congestive heart failure and arrhythmia. In 1967, Shiratori et al found for the first time through in vitro and in vivo experiments that ouabain had the effect of inhibiting the proliferation of malignant tumor cells in vitro (Shirator, O.Growthinhibitoryeffectofcardiacglycosidesandaglyconesonneoplasticcellsinvitroandinvivostud...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J19/00A61K31/7048A61P35/00A61P35/02
CPCC07J19/005
Inventor 胡立宏刘璇雷敏果德安刘军华
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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