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Fluorine-substituted e-ring camptothecin analogs and their use as medicines

A technology of fluorocamptothecin and camptothecin, applied in the field of deoxyfluorinated compounds at the 21-position of the E ring of camptothecin and its use as medicine

Inactive Publication Date: 2016-01-13
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The new structure compound we studied has not been reported at home and abroad, and it is a new structure compound invented

Method used

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  • Fluorine-substituted e-ring camptothecin analogs and their use as medicines
  • Fluorine-substituted e-ring camptothecin analogs and their use as medicines
  • Fluorine-substituted e-ring camptothecin analogs and their use as medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1、21

[0069] Embodiment 1, 21-hydroxycamptothecin

[0070] Suspend 1.00g of camptothecin in 50mL of methanol, stir at room temperature for 5 minutes, add 0.30g of potassium borohydride, and continue to react for 1h at room temperature. Make it dissolve, and then adjust the pH to be acidic with acetic acid in an ice-water bath. At this time, a large amount of solid precipitates, which is filtered, washed with water, and vacuum-dried to obtain 0.99 g of light yellow solid 21-hydroxycamptothecin (98.4%).

[0071] 1 HNMR (DMSO), δ:

[0072] 0.91(t, 3H), 1.72(q, 2H), 4.49-4.63(q, 2H), 4.94(s, 1H), 5.00(d, 1H), 5.25(s, 2H), 6.73(d, 1H) , 7.38(s, 1H), 7.69(t, 1H), 7.85(t, 1H), 8.11(d, 1H), 8.16(d, 1H), 8.66(s, 1H).

Embodiment 2、10

[0073] The synthesis of embodiment 2,10-methoxy-21-hydroxycamptothecin

[0074] Suspend 1.00 g of 10-methoxycamptothecin in 50 mL of methanol, stir at room temperature for 5 minutes, add 0.30 g of potassium borohydride, and continue to react for 1 h at room temperature. At this time, the reaction solution is clear, and the solvent is evaporated to obtain a light green solid , add 50mL of water to dissolve it, then adjust the pH to be acidic with acetic acid in an ice-water bath, at this time a large amount of solids precipitate out, filter and wash with water, and dry in vacuo to obtain 0.96g of light yellow solid 10-methoxy-21-hydroxycamptothecin (95.4%).

[0075] 1 HNMR (DMSO), δ:

[0076] 0.90(t, 3H), 1.70(q, 2H), 3.93(s, 3H), 4.46-4.64(q, 2H), 4.91(s, 1H), 4.97(d, 1H), 5.21(s, 2H) , 6.74(d, 1H), 7.30(s, 1H), 7.47(d, 1H), 7.50(s, 1H), 8.05(d, 1H), 8.51(s, 1H).

Embodiment 3

[0077] The synthesis of embodiment 3,9-nitro-21-hydroxycamptothecin

[0078] Suspend 1.00 g of 9-nitrocamptothecin in 50 mL of methanol, stir at room temperature for 5 minutes, add 0.30 g of potassium borohydride, and continue to react for 1 h at room temperature. At this time, the reaction solution is clear, and the solvent is evaporated to obtain a light green solid. Add 50mL of water to dissolve it, then adjust the pH to be acidic with acetic acid in an ice-water bath, at this time a large amount of solid precipitates, filter and wash with water, and dry in vacuo to obtain 0.95g of light yellow solid 21-hydroxycamptothecin (94.5%).

[0079] 1 HNMR (DMSO), δ:

[0080] 0.91(t, 3H), 1.72(q, 2H), 4.70-4.81(q, 2H), 4.94(s, 1H), 5.14(d, 1H), 5.27(s, 2H), 6.77(d, 1H) , 7.44(s, 1H), 8.03(t, 1H), 8.52(t, 1H), 8.57(d, 1H), 9.15(s, 1H).

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Abstract

The invention relates to the technical field of medicines and in particular relates to fluoro-substituted E cyclocamptothecin analogues and use thereof as a drug. The structure of the compounds is shown in a formula I; and the compounds exist in forms of raceme, diastereoisomer as well as any mixture of the forms or medical salts thereof. The compounds disclosed by the invention have the effect of restraining the activity of the topoisomerase I and can be used for preparing anti-tumor drugs and also can be used for preparing drugs for preventing virus and fungal infection.

Description

technical field [0001] The invention relates to the technical field of medicine, and relates to fluorine-substituted E-ring camptothecin analogs and their use as medicines, in particular to a class of camptothecin E-ring 21-position deoxyfluorinated compounds and their use as medicines. Background technique [0002] Camptothecin (Camptothecin) is an alkaloid extracted from Chinese Davidiaceae plant Camptotheca acuminata by American chemist Wall et al. Dendrine is a five-ring rigid structure composed of indolizine[1,2-b]quinoline fragments fused with six-membered-hydroxylactone. The 20th carbon with the -hydroxyl is asymmetrical, which endows the molecule with optical rotation. characteristic. Its structure is as follows: [0003] [0004] Camptothecin is the earliest discovered, most studied, and most widely used specific topoisomerase I inhibitor (TopoI), and it is also the most classic TopoI specific inhibitor. antitumor activity. After years of research on the stru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22A61K31/4745A61P35/00
Inventor 张万年缪震元祝令建盛春泉姚建忠董国强王胜正刘杨陈海
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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