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Semicarbazide dihydroartemisinin derivative as well as preparation method and application of semicarbazide dihydroartemisinin derivative

A technology of semicarbazide dihydroartemisinin and derivatives, which is applied in the field of semicarbazide dihydroartemisinin derivatives and their preparation and application, and can solve the problems of less research on the modification of dihydroartemisinin

Inactive Publication Date: 2015-09-09
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the prior art, many active dihydroartemisinin derivatives are mostly obtained by modifying the carbon 9, carbon 10 and carbon 11 positions of the dihydroartemisinin structure. There are few studies on the modification of the 3-C position of artemisinin

Method used

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  • Semicarbazide dihydroartemisinin derivative as well as preparation method and application of semicarbazide dihydroartemisinin derivative
  • Semicarbazide dihydroartemisinin derivative as well as preparation method and application of semicarbazide dihydroartemisinin derivative
  • Semicarbazide dihydroartemisinin derivative as well as preparation method and application of semicarbazide dihydroartemisinin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-(aminothiocarbazido)methylene-6,9-dimethyl-3,12-oxo-12H - Preparation of pyrano[4,3-j]-1,2-benzodithiapine-10(3H)alcohol (1)

[0024] The structure of compound (1) is shown below:

[0025]

[0026] Add 3.62 g (0.01 mol) of (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-bromomethylene-6,9-dimethyl-3,12 to the dry reactor -Oxo-12H-pyrano[4,3-j]-1,2-benzodithiapine-10(3H)alcohol and 20mLTHF, stirred, added 1.58g (0.02mol) of pyridine and 1.09g (0.012 mol) thiosemicarbazide, reacted for 12 hours, and evaporated the solvent under reduced pressure. Add 20mL of ethyl acetate and 20mL of saturated sodium bicarbonate solution to the residue, stir, separate layers, extract 15mLX2 of the aqueous layer with ethyl acetate, combine the organic phases, dry, filter, concentrate, and purify by column chromatography to obtain the target compound (1), The yield is 55%.

Embodiment 2

[0028] (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-(carbahydrazino)methylene-6,9-dimethyl-3,12-oxo-12H-pyridine Fro[4,3-j]-1,2-benzodithiapine-10(3H)alcohol (2); the structure of compound (2) is shown below:

[0029]

[0030] Add 3.62 g (0.01 mol) of (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-bromomethylene-6,9-dimethyl-3,12 to the dry reactor -Oxo-12H-pyrano[4,3-j]-1,2-benzodithiapine-10(3H)alcohol and 22mLTHF, stirred, added 1.58g (0.02mol) of pyridine and 1.09g (0.012 mol) semicarbazide, reacted for 12 hours, and evaporated the solvent under reduced pressure. Add 20mL ethyl acetate and 20mL saturated sodium bicarbonate solution to the residue, stir, separate layers, extract 15mLX2 of the aqueous layer with ethyl acetate, combine the organic phases, dry, filter, concentrate, and purify by column chromatography to obtain 3-ureaaminodihydro Artemisinin, yield 52%.

Embodiment 3

[0032] (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-(methylcarbahydrazino)methylene-6,9-dimethyl-3,12-oxo-12H- Pyrano[4,3-j]-1,2-benzodithiapine-10(3H)ol (3);

[0033] The structure of compound (3) is shown below:

[0034]

[0035] Add 3.18 g (0.01 mol) of (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-chloromethylene-6,9-dimethyl-3,12 to the dry reactor -Oxo-12H-pyrano[4,3-j]-1,2-benzodithiapine-10(3H)alcohol and 20mL acetonitrile, stirred, added 1.58g (0.02mol) pyridine, 0.82 g (0.0005 mol) KI and 1.07g (0.012mol) methylcarbamohydrazide were reacted for 24 hours, and the solvent was distilled off under reduced pressure. Add 20mL ethyl acetate and 20mL saturated sodium bicarbonate solution to the residue, stir, separate layers, extract the aqueous layer with ethyl acetate 15mLX2, ​​combine the organic phases, dry, filter, concentrate, and purify by column chromatography to obtain compound (3). The rate is 66%.

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Abstract

The invention relates to a semicarbazide dihydroartemisinin derivative (general formula I) or a pharmaceutically-acceptable hydrate and salt of the semicarbazide dihydroartemisinin derivative, wherein R is H and various kinds of alkyls; the alkyls can be randomly substituted by substituent groups of halogens, amino groups, substituted amino groups, carboxyls, hydroxyls, ester groups, cyano groups, nitryls, aryls and substituted aryls; and Z is O, S and NH. The semicarbazide dihydroartemisinin derivative disclosed by the invention has a remarkable effect on inhibiting Hela and A549 cells so as to have a relatively-good anti-tumor effect. The invention discloses a preparation method of the semicarbazide dihydroartemisinin derivative.

Description

technical field [0001] The invention relates to a semicarbazide dihydroartemisinin derivative, a preparation method thereof and an application as an anticancer drug. Background technique [0002] Malignant tumor is one of the most serious diseases that endanger people's life and health. At present, the chemical drugs for clinical treatment of cancer are unsatisfactory due to their high toxicity and high drug resistance. There is an urgent need to develop anti-cancer active ingredients with low toxicity and high curative effect. Since Professor Lai Henry discovered a drug that is highly toxic to cancer cells and has little effect on normal cells - artemisinin, and said that it may become a non-toxic and highly effective anticancer drug (US55578637), there has been a great deal of interest in artemisinin The preparation and activity research of artemisinin and its derivatives has become a hot spot. Scholars at home and abroad have carried out a large number of structural mod...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/357A61P35/00
CPCC07D493/20
Inventor 张宝华史兰香刘斯婕郭瑞霞
Owner SHIJIAZHUANG UNIVERSITY
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