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Dihydroartemisinin dithiocarbamate as well as preparation method and application of dihydroartemisinin dithiocarbamate

A technology of dihydroartemisinin carbamate and amino, which is applied in the field of dihydroartemisinin carbamate and its preparation and application, and can solve the problems of poor oral availability, short half-life, and water-soluble and poor fat solubility

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

Long-term clinical findings that artemisinin has poor water-solubility and fat-solubility, repeated attacks after treatment, short half-life and poor oral availability limit its application, so a large number of semi-synthetic derivatives have been developed, such as: dihydro Artemisinin, artemether, artether, artesunate, etc.

Method used

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  • Dihydroartemisinin dithiocarbamate as well as preparation method and application of dihydroartemisinin dithiocarbamate
  • Dihydroartemisinin dithiocarbamate as well as preparation method and application of dihydroartemisinin dithiocarbamate
  • Dihydroartemisinin dithiocarbamate as well as preparation method and application of dihydroartemisinin dithiocarbamate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-( N , N -diethylaminodithiocarboxy)methylene-6,9-dimethyl-3,12-oxo-12H-pyrano[4,3-j]-1,2-benzodithia Preparation of Ping-10(3H)alcohol (1)

[0019] The structure of compound (1) is shown below:

[0020]

[0021] 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 25mL DMF, stirring, adding 2.05g (0.012mol) of N , N -Sodium diethylaminodithioformate, reacted for 12 hours, and evaporated the solvent under reduced pressure. Add 20mL ethyl acetate and 20mL water 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 the target compound (1), with a yield of 76% .

Embodiment 2

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

[0024] The structure of compound (2) is shown below:

[0025]

[0026] 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 25mL isopropanol, stirred, added 1.55g (0.012mol) N -Sodium methylcarbamate and 0.82 g (0.0005mol) KI were reacted for 12 hours, and the solvent was distilled off under reduced pressure. Add 20mL ethyl acetate and 20mL water 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 the target compound (2), with a yield of 67% .

Embodiment 3

[0028] (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-[ N –(α-Methoxycarbonyl)methylaminodithiocarboxy]methylene-6,9-dimethyl-3,12-oxo-12H-pyrano[4,3-j]-1, Preparation of 2-benzodithiapine-10(3H)alcohol (3)

[0029] The structure of compound (3) is shown below:

[0030]

[0031] With 2.24g (0.012mol) N -Sodium (α-methoxycarbonyl)methylcarbamate instead N , N -Sodium diethylaminodithioformate, other operations are the same as in Example 1, to obtain compound (3), yield 79%.

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PUM

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Abstract

The invention discloses dihydroartemisinin dithiocarbamate (general formula I) or a pharmaceutically-acceptable hydrate and salt of the dihydroartemisinin dithiocarbamate, wherein R1 and R2 are respectively independent H and alkyls; and the alkyls can be randomly substituted by substituent groups of halogens, amino groups, substituted amino groups, hydroxyls, carboxyls, ester groups, cyano groups, nitryls, aryls and substituted aryls. The dihydroartemisinin dithiocarbamate disclosed by the invention has a remarkable effect on inhibiting rat sarcoma S180 cells so as to be applied to preparation of anti-tumor drugs. The invention discloses a preparation method of the dihydroartemisinin dithiocarbamate.

Description

technical field [0001] The invention relates to dihydroartemisinin carbadithiocarbamate, a preparation method thereof and application as an anticancer drug. Background technique [0002] Artemisinin is a sesquiterpene lactone compound with a peroxide bridge structure extracted and isolated from the leaves of Artemisia annua by Chinese scientists for the first time in 1971, and it was applied to the treatment of falciparum malaria. Long-term clinical findings that artemisinin has poor water-solubility and fat-solubility, repeated attacks after treatment, short half-life and poor oral availability limit its application, so a large number of semi-synthetic derivatives have been developed, such as: dihydro Artemisinin, artemether, artether, artesunate, etc. In addition to having antimalarial activity, artemisinin compounds have a good inhibitory effect on human acute promyelocytic leukemia cell HL-60, mouse leukemia cell P388, human breast cancer cell MCF7 and other tumor cells...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/20A61K31/357A61P35/00
CPCC07D498/20
Inventor 张宝华刘斯婕史兰香郭瑞霞
Owner SHIJIAZHUANG UNIVERSITY
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