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Indolizine heterocyclic nitrogen naphthoquinone derivatives as well as preparation method and anticancer use thereof

A technology of naphthoquinones and derivatives, which is applied in the field of preparation of cancer drugs, can solve the problem of unsatisfactory anti-tumor activity of camptothecin, and achieve the effect of low toxicity and strong inhibitory activity of normal cells

Inactive Publication Date: 2008-05-21
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the anti-tumor activity of camptothecin is still unsatisfactory. If its structure can be modified to enhance its anti-tumor activity, the application prospect will be very broad.

Method used

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  • Indolizine heterocyclic nitrogen naphthoquinone derivatives as well as preparation method and anticancer use thereof
  • Indolizine heterocyclic nitrogen naphthoquinone derivatives as well as preparation method and anticancer use thereof
  • Indolizine heterocyclic nitrogen naphthoquinone derivatives as well as preparation method and anticancer use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1. Synthesis of Indenaza naphthoquinone derivatives NP1-A and NP1-B

[0020] Add 0.01mol of 6,7-dichloro-5,8-quinolinedione and 0.04mol of ethyl acetoacetate into 20-80ml of absolute ethanol, add 0.01-0.08mol of 3-fluoropyridine under stirring, reflux The reaction is carried out for 5 to 20 hours. Terminated, cooled, and solids were precipitated. Filtration, the obtained solid was separated by silica gel column chromatography, and a pair of indolizine aza naphthoquinone derivative isomers NP1-A and NP1-B were obtained at the same time.

[0021] NP1-A: 12% yield; m.p.=197-200°C; ESI: 339.0 (100%), 340.1 (20%) [M+1] + ; 1 H NMR (300MHz, CDCl 3 , TMS): δ9.64 (d, 1H, J=6.8Hz), 9.06 (dd, 1H, J=4.8, 1.6Hz), 8.54 (dd, 1H, J=8.0, 1.6Hz), 7.67 (dd, 1H, J=8.0, 4.8Hz), 7.16-7.06 (m, 2H), 4.54 (q, 2H, J=7.2Hz), 1.47 (t, 3H, J=7.2Hz).

[0022] NP1-B: 18% yield. m.p.=200-202°C; ESI: 339.0 (100%), 340.1 (20%) [M+1] + ; 1 H NMR (300MHz, CDCl 3 , TMS): δ9.49 (dd, 1H, J=...

Embodiment 2

[0025] Example 2. Synthesis of Indenaza naphthoquinone derivatives NP2-A and NP2-B

[0026] The method is the same as in Example 1, except that ethyl acetoacetate is replaced by nitroethane, and 3-fluoropyridine is replaced by pyridine, and a pair of indolizazine naphthoquinone derivative isomers NP2-A and NP2-A are obtained simultaneously. NP2-B.

[0027] NP2-A: 19% yield; m.p.=233°C; ESI: 263.3 (100%) [M+1] + ; 1 HNMR (300MHz, CDCl 3 , TMS): δ9.77 (d, 1H, J=6.6Hz), 8.99 (d, 1H, J=3.0Hz), 8.49 (d, 1H, J=7.5Hz), 7.67 (d, 1H, J= 9.0Hz), 7.57 (dd, 1H, J=7.4, 4.8Hz), 7.27 (t, 1H, J=7.4Hz), 7.11 (t, 1H, J=6.6Hz), 2.70 (s, 3H).

[0028] NP2-B: 15% yield; m.p.=238°C; ESI: 263.3 (100%) [M+1] + ; 1 HNMR (300MHz, CDCl 3 , TMS): δ9.64 (d, 1H, J=6.6Hz), 8.94 (d, 1H, J=2.6Hz), 8.58 (d, 1H, J=7.5Hz), 7.69 (d, 1H, J= 9.0Hz), 7.63 (dd, 1H, J=7.4, 4.8Hz), 7.26 (t, 1H, J=7.4Hz), 7.10 (t, 1H, J=6.6Hz), 2.74 (s, 3H).

[0029] The structural formulas of NP2-A and NP2-B are as follows:

...

Embodiment 3

[0031] Example 3. Synthesis of Indenaza naphthoquinone derivatives NP3-A and NP3-B

[0032] The method is the same as in Example 1, except that pyridine is used instead of 3-fluoropyridine to obtain a pair of indolizine aza naphthoquinone derivative isomers NP3-A and NP3-B.

[0033] NP3-A: 31% yield; m.p.=226-227°C; ESI: 321.2 (100%) [M+1] + ; 1 H NMR (300MHz, CDCl 3 , TMS): δ9.92 (d, 1H, J=7.2Hz), 9.01 (d, 1H, J=3.9Hz), 8.54 (d, 1H, J=7.5Hz), 8.34 (d, 1H, J= 9.0Hz), 7.64 (dd, 1H, J=7.5, 4.5Hz), 7.49 (t, 1H, J=8.0Hz), 7.24 (t, 1H, J=6.9Hz), 4.52 (q, 2H, J= 7.1Hz), 1.51(t, 3H, J=7.1Hz).

[0034] NP3-B: 12% yield; m.p.=200-201°C; ESI: 321.2 (100%) [M+1] + ; 1 H NMR (300MHz, CDCl 3 , TMS): δ9.78 (d, 1H, J=6.9Hz), 8.99 (d, 1H, J=3.6Hz), 8.55 (d, 1H, J=7.8Hz), 8.38 (d, 1H, J= 9.0Hz), 7.65 (dd, 1H, J=7.8, 4.5Hz), 7.47 (ddd, 1H, J=8.7, 6.9, 0.9Hz), 7.20 (td, 1H, J=6.9, 1.2Hz), 4.50 ( q, 2H, J=7.2Hz), 1.52(t, 3H, J=7.2Hz).

[0035] The structural formulas of NP3-A and NP3-B ...

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Abstract

The present invention discloses an indolizine and nitrogen heterocyclic naphthoquinone derivative, a preparation method and an anticancer application thereof. The structure of the indolizine and nitrogen heterocyclic naphthoquinone derivative is shown as a formula (I). The preparation method is that 6, 7-dichloro nitrogen heterocyclic naphthoquinone and active methylene reagent are put in to anhydrous alcohol, and pyridine derivative is added under stirring for the reflux reaction for 5 to 20 hours; the reaction finished for cooling, solid is separated out to be filtered and processed for the chromatographic separation by silicon gel column to obtain the target compound. The indolizine and nitrogen heterocyclic naphthoquinone derivative has obvious inhibitory effect towards various kinds of tumour cells, has comparatively small virulence towards the normal cell and has the prospect of preparing for the anticancer medicine.

Description

technical field [0001] The present invention relates to a class of indolizine aza naphthoquinone derivatives and their use in preparing medicines for treating cancer. Background technique [0002] Tumor is a major disease that threatens human health and life safety. The research and development of new antitumor drugs has always been an important research area for chemists and pharmacologists. [0003] Camptothecin is a class of natural alkaloids with good antitumor activity. Studies have found that camptothecin mainly exerts its anticancer effect by inhibiting topoisomerase 1 (TOP1) in tumor cells. However, the anti-tumor activity of camptothecin is still unsatisfactory. If its structure can be modified to enhance its anti-tumor activity, the application prospect will be very broad. SUMMARY OF THE INVENTION [0004] The object of the present invention is to provide a new class of indolazine naphthoquinone derivatives. [0005] Another object of the present invention is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14C07D471/04C07D487/14A61K31/437A61K31/4375A61K31/5025A61P35/00
Inventor 安林坤古练权程瑜沈德清王晓冬黄志纾
Owner SUN YAT SEN UNIV