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Indole andrographolide, ramification of indole andrographolide and preparing method and medical application of ramification

A technology of andrographolide and its derivatives, applied in chemical instruments and methods, drug combinations, antineoplastic drugs, etc., can solve the problems of disappearance, activity decline, unstable physical and chemical properties, etc.

Inactive Publication Date: 2014-08-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Due to the unstable physical and chemical properties of andrographolide, in the structural modification of its anti-tumor, the existing research work mainly focuses on the acylation of the hydroxyl groups at positions 3, 14, and 19, that is, ester modification, with little structural change ; There are also some research works that have made major changes to the structure of andrographolide, but often destroy the complete lactone ring structure, resulting in a decrease or disappearance of its activity

Method used

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  • Indole andrographolide, ramification of indole andrographolide and preparing method and medical application of ramification
  • Indole andrographolide, ramification of indole andrographolide and preparing method and medical application of ramification
  • Indole andrographolide, ramification of indole andrographolide and preparing method and medical application of ramification

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Preparation of 14,19-O-bis(tert-butyldimethylsilyl)-andrographolide (2):

[0083] 14-O-tert-butyldimethylsilyl-andrographolide (1.37g, 2.95mmol) was dissolved in 10ml DMF, TBSCl (0.89g, 5.90mmol) and imidazole (0.24g, 3.54mmol) were dissolved in 10ml DMF , under an ice bath, slowly add the reaction solution dropwise, react for 20min after the dropwise addition, add EA (60ml) to dilute after the reaction, wash with an aqueous solution containing sodium bicarbonate (3x60ml), wash with a large amount of water (3x60ml), and wash with saturated brine ( 3x60ml), the organic layer was dried over anhydrous sodium sulfate. The dried organic layer was concentrated and purified by column chromatography (PE:EA=6:1). Finally, dry white solid 14,19-O-di(tert-butyldimethylsilyl)-andrographolide (1.09g, 1.88mmol, yield 76%) was obtained, and 14-O-tert-butyldimethylsilyl was recovered Silyl-andrographolide (0.22 g, 0.47 mmol). MP: 110-112°C. 1 H-NMR (300MHz, CDCl 3, ppm) δ: 6.83(t,...

Embodiment 2

[0085] Preparation of 14,19-O-di(tert-butyldimethylsilyl)-3-oxo-andrographolide (3):

[0086] Dissolve 14,19-O-bis(tert-butyldimethylsilyl)-andrographolide (0.60g, 1.04mmol) in 14ml of dichloromethane, stir at room temperature, add PCC (0.45g, 2.07mmol) And sodium acetate (0.34g, 4.15mmol), finally add 0.45g of silica gel, and react at room temperature. Stop the reaction after 24h, add silica gel to filter, concentrate the filtrate, and purify by column chromatography (PE:EA=5:1) to obtain a transparent viscous liquid, which turns into a white solid 14,19-O-di(tert-butyldi Methylsilyl)-3-oxo-andrographolide (0.53 g, 0.92 mmol, 88% yield). Mp: 90-92°C.1H-NMR (300MHz, CDCl 3 , ppm) δ: 6.84(t, 1H, J=5.7Hz), 5.06-5.08(m, 1H), 4.94(s, 1H), 4.65(s, 1H), 4.43(dd, 1H, J=6.5Hz , 9.8Hz), 4.10(dd, 1H, J=3.1Hz, 9.8Hz), 3.87(d, 1H, J=9.9Hz), 3.54(d, 1H, J=9.9Hz), 2.61-3.64(m, 2H), 1.97-2.02(m, 3H), 1.70-1.80(m, 1H), 1.59-1.64(m, 3H), 1.12(s, 3H), 1.00(s, 3H), 0.93(s, 9H) , 0.85(s, 9H)...

Embodiment 3

[0088] 14,19-O-bis(tert-butyldimethylsilyl)-indolo[3,2-b]andrographolide (I 1 ), 14-O-tert-butyldimethylsilyl-indolo[3,2-b]andrographolide (I 2 ) and 14-O-tert-butyldimethylsilyl-19-O-acetyl-indolo[3,2-b]andrographolide (I 3 ) preparation:

[0089] Add phenylhydrazine hydrochloride (0.60g, 4.15mmol) into the reaction flask, dissolve in 5ml of acetic acid, and dissolve 14,19-O-di(tert-butyldimethylsilyl)-3-oxo-andrographolide in 22ml Add acetic acid to the dropping funnel, N 2 Protection, reflux oil bath at 90-100°C, slowly add F to the reaction solution dropwise, stop the reaction after 3.5h, add the reaction solution to ice water, extract with EA (3x50ml), wash with saturated sodium bicarbonate (3x60ml), and finally saturated with salt Wash with water (3x60ml), dry over anhydrous sodium sulfate, concentrate the dry organic layer, and purify by column chromatography (PE:EA=6:1) to give yellow solid 14,19-O-bis(tert-butyldimethylsilyl) -indolo[3,2-b]andrographolide (I 1 ) ...

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Abstract

The invention discloses indole andrographolide, ramification of the indole andrographolide and a preparing method and medical application of the ramification, and belongs to the field of medicinal chemistry. The structure general formulas of the ramification of the indole andrographolide are shown in (I) and (II) in the specification, R1 represents hydrogen, substituent or non-substituent C1-8 aliphatic series acyl, substituent or non-substituent aromatic acyl and silylation, R2 and R4 represent hydrogen, substituent or non-substituent C1-8 aliphatic series acyl, substituent or non-substituent aromatic acyl and silylation or double bond delta 14, 15 generated through the elimination reaction of 14 bit or 15 bit, and R3 represents hydrogen, substituent or non-substituent C1-8 aliphatic series acyl and substituent or non-substituent aromatic acyl. The invention further discloses the preparing method of the indole andrographolide and medical application of the ramification in preparing antineoplastic drugs.

Description

technical field [0001] The present invention relates to indoloandrographolide derivatives, their synthesis method and medical use, specifically referring to the parallel combination of indole ring at the 2,3-position of andrographolide and its derivatives to form indolo[3,2 -b] The synthesis method of andrographolide compound and its application in the preparation of antitumor drugs belong to the field of medicinal chemistry. Background technique [0002] Due to factors such as human living environment, the incidence of malignant tumors has been increasing year by year in recent years, becoming a common disease that seriously endangers human health. Although there are many types of anti-tumor drugs currently on the market, they still cannot meet the clinical needs. Therefore, it is particularly urgent to develop new anti-tumor drugs with definite curative effect and less side effects. [0003] Andrographolide is a diterpene lactone compound extracted from Andrographis panic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18C07D405/06A61P35/00
Inventor 薛晓文宋雅萍辛正远刘林义李嘉宾
Owner CHINA PHARM UNIV
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