20(S) camptotheca alkaloid derivatives, their preparing methods and uses

A derivative, camptothecin technology, applied in the field of medicinal chemistry and therapeutics, can solve the problems of poor water solubility and high toxicity

Inactive Publication Date: 2005-02-16
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

[0002] Camptothecin Camptothecin (compound I) is Wall M.E. etc. (Wall, M.E.et al., J.Am.Chem.Soc.1966, 88, 3888-3890) in 1966 from China's endemic ornamental plant Doveiaceae for the first time The pyrrolo[3,4-b]quinoline alkaloids isolated from the tree Camptotheca ac

Method used

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  • 20(S) camptotheca alkaloid derivatives, their preparing methods and uses
  • 20(S) camptotheca alkaloid derivatives, their preparing methods and uses
  • 20(S) camptotheca alkaloid derivatives, their preparing methods and uses

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Embodiment 1

[0029] Preparation of 7-Hydroxyethylcamptothecin

[0030] Dissolve 1g camptothecin in 30mL ethanol, stir, add 50mL 30% sulfuric acid solution dropwise under ice bath, then add 0.8g FeSO 4 ·7H 2 O, continue to slowly drop 9 mL of 30% H 2 o 2 , after the dropwise addition was completed, it was stirred overnight at room temperature. The reaction mixture was poured into distilled water, diluted to 800 mL, vacuum filtered, the filter cake was washed with distilled water, separated by silica gel column chromatography, and eluted with dichloromethane / methanol 50:1.2 to obtain 350 mg of a light yellow solid (produced rate 34%).

Embodiment 2

[0032] Preparation of 7-Hydroxyethylcamptothecin Succinate

[0033] Dissolve 1 g of 7-hydroxyethylcamptothecin in 50 mL of dry pyridine, add 2 g of succinic anhydride, stir and reflux for 24 hours, then add 2 g of succinic anhydride, and continue stirring and reflux for 24 hours. The reaction mixture was poured into a separatory funnel, 50 mL of distilled water was added, the aqueous solution was extracted with dichloromethane (200 mL×3), combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. It was separated by silica gel column chromatography and eluted with dichloromethane / methanol 50:1.5 to obtain 750 mg of light yellow solid (62% yield).

[0034] 1 H-NMR (400MHz, DMSO-d 6 , ppm): δ8.31 (1H, d, J = 8.4Hz), 8.22 (1H, d, J = 7.7Hz), 7.91 (1H, dd, J = 8.4, 7.0Hz), 7.78 (1H, dd, J=8.4, 7.0Hz), 7.35(1H, s), 5.40(2H, s), 5.33(2H, s), 4.40(2H, t), 3.53(2H, t), 3.38(2H, m), 3.36 (2H, m), 1.88 (2H, q, J=7.0 Hz), 0.89 (3H, t, J=7.0 Hz).

...

Embodiment 3

[0037] Preparation of 7-Hydroxyethylcamptothecin Succinate

[0038] Dissolve 1 g of 7-hydroxyethylcamptothecin in 40 mL of dry dimethyl sulfoxide, add 2 g of succinic anhydride, and then add 2 mL of dry pyridine, then stir and reflux for 12 hours. The reaction mixture was poured into a separatory funnel, 50 mL of distilled water was added, the aqueous solution was extracted with dichloromethane (200 mL×3), combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. It was separated by silica gel column chromatography and eluted with dichloromethane / methanol 50:1.5 to obtain 840 mg of a light yellow solid (66% yield).

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Abstract

The invention provides 20(S)-camptothecin ramification demonstrated by the figure (1) or its acceptable salt in the medicine. The m in the figure is one integer between 2 and 5; R is OH, OR1 (R1 is the alkyl of C1-5), NH2, NHR1 (R1 is the alkyl of C1-5) or NR1R2 ((R1 and R2 are the alkyl of C1-5 respectively). The invention also provides the preparation method of the ramification and its use in the antineoplastic medicines.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and therapeutics, in particular to novel camptothecin derivatives, their preparation methods and applications. Background technique [0002] Camptothecin Camptothecin (compound I) is Wall M.E. et al. (Wall, M.E.et al., J.Am.Chem.Soc.1966,88,3888-3890) in 1966 from China's endemic ornamental plant Davidiaceae for the first time The pyrrolo[3,4-b]quinoline alkaloids isolated from the tree Camptotheca acuminata Decne (Nyssaceae) have the effect on malignant tumors such as digestive tract tumors (such as gastric cancer, colon cancer, rectal cancer), liver cancer, bladder cancer and leukemia. It has good curative effect, but it is highly toxic and has poor water solubility. In 1985, HsiangY.H. et al. (Hsizng, Y.H.et al., J.Biol.Chem.1985, 260, 14873-14878) found that camptothecin had a mechanism of action on DNA topoisomerase I, which caused a new People's attention and interest have once again be...

Claims

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Application Information

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IPC IPC(8): A61K31/475C07D491/22
Inventor 张金生昌军楼丽广唐卫东
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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