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Abietane compound with C-ring combined lactone ring novel skeleton as well as preparation method and application of abietane compound

A technology of abietane and lactone rings, which is applied in the field of abietane compounds and their preparation, can solve the problems that are not commonly used, and the C ring is difficult to transform, and achieve good protective effect, good tumor suppression effect, and reduce the scope of cerebral infarction. Effect

Active Publication Date: 2020-09-01
杭州禾橼医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But in modern times, this strategy of improving water solubility at the expense of drug efficacy is no longer commonly used
In addition, these structural modification methods are also limited by two conditions: (1) the A ring must be an alicyclic ring; (2) the D-furan ring must exist
[0006] After research, the applicant found that this type of compound can significantly improve its antibacterial and antitumor activities (Zeng, L.W.; Zhou, C.X.; et al.Design, synthesis, and antimicrobial activities of new tanshinone) IIA esters.Natural Product Research,2016,30,2662-2668. Hou Afang, Zeng Linwei, Gan Lishe et al. Design, synthesis and antitumor activity of Danshenxinone C-cyclic phenolic ester derivatives. Chinese Modern Applied Pharmacy, 2016,33, 1396 -1402.), so the structural modification of the C ring is of great scientific significance to mention its druggability, but because of the bluntness of the skeleton, the C ring of this type of compound is just difficult to modify

Method used

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  • Abietane compound with C-ring combined lactone ring novel skeleton as well as preparation method and application of abietane compound
  • Abietane compound with C-ring combined lactone ring novel skeleton as well as preparation method and application of abietane compound
  • Abietane compound with C-ring combined lactone ring novel skeleton as well as preparation method and application of abietane compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Weigh 10g (34mmol) of tanshinone IIA raw material in a reaction flask, add 100ml of tetrahydrofuran, add 3.4g (34mmol) of succinic anhydride, 9.5g of DMAP, and 6.6g of zinc powder while stirring, heat to reflux under nitrogen protection, and stir for 3 hours. TLC monitored the completion of the reaction. The zinc powder was removed by filtration, the filtrate was evaporated to dryness, recrystallized with methanol, and dried to obtain 9.6 g of the product (compound 1), with a yield of 75%. Its chemical structure is confirmed by spectral analysis and X-single crystal diffraction as follows:

[0058]

[0059] The spectral data of compound 1 are as follows:

[0060] ESI–MS: m / z=379.6[M+H] + .

[0061] 1 H NMR (600MHz, DMSO-d 6 )δ12.43(s,1H),8.03(d,J=8.8Hz,1H),7.91(d,J=1.2Hz,1H),7.69(d,J=8.8Hz,1H),4.54(t, J=4.6Hz,1H),3.38–3.31(m,2H), 3.25(dd,J=17.2,5.6Hz,1H),3.14(dd,J=17.2,5.6Hz,1H),2.35(d,J =1.2Hz,3H), 1.92–1.79(m,2H),1.77–1.64(m,2H),1.35(s,3H),1.34(s,3H); 13 C ...

Embodiment 2

[0063] Weigh 10g (34mmol) of Tanshinone IIA raw material in the reaction flask, add 100ml tetrahydrofuran,

[0064] While stirring, 3.88 g (34 mmol) of glutaric anhydride, 7.8 g of DMAP, and 5.9 g of iron powder were added, and heated to reflux under the protection of nitrogen. After stirring for 6 hours, the reaction was complete as monitored by TLC. The iron powder was removed by filtration, and the filtrate was evaporated to dryness, recrystallized with acetone, and dried to obtain 10.8 g of the product (compound 1), with a yield of 81%. Its chemical structure was confirmed by spectral analysis as follows:

[0065]

[0066] The spectral data of compound 2 are as follows:

[0067] ESI-MS: m / z=391.30[M-H] - .

[0068] 1 H NMR (500MHz, Acetone-d 6 )δ8.09(d, J=8.8Hz, 1H), 7.80(d, J=1.2Hz, 1H), 7.72(d, J=8.8Hz, 1H), 4.39(dd, J=8.5, 3.5Hz, 1H), 3.43(t, J=6.4Hz, 2H), 2.47(d, J=1.0Hz, 3H), 2.44–2.31(m, 3H), 1.94–1.87(m, 2H), 1.75(dd,J =12.1, 6.2Hz, 2H), 1.38(d, J=3.7Hz, 6...

Embodiment 3

[0070] Weigh 1.0g (2.55mmol) of the raw material of compound 2 into a reaction flask, add 30ml of dichloromethane, add 1.2g of DMAP, 0.6g of DCC, and 0.2ml of triethylamine while stirring, heat to reflux under nitrogen protection, and stir for 5 hours , TLC monitors that the reaction is complete. The reaction was quenched with ice water, extracted with dichloromethane (20ml×3), combined, the organic phase was concentrated, and separated by silica gel column to obtain 0.59 g of the product (compound 3), with a yield of 59%. Its chemical structure was confirmed by spectral analysis as follows:

[0071]

[0072] The spectral data of compound 3 are as follows:

[0073] ESI-MS: m / z=391.28]M-H] - .

[0074] 1 H NMR (500MHz, Acetone-d 6 )δ10.66(1H,br.s),8.11(d,J=8.7Hz,1H),7.79(s,1H),7.63(d,J=8.7Hz,1H),4.55(dd,J=9.7 ,2.9Hz,1H),3.42–3.39(m,1H),3.26 (d,J=16.3Hz,1H),2.62–2.47(m,2H),2.42–2.36(m,4H),2.02–1.95( m,2H),1.39(s,3H),1.36(s,3H); 13 C NMR (125MHz, Acetone-d 6 )δ178.19,...

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Abstract

The invention discloses an abietane compound with a C-ring combined lactone ring novel skeleton, which is prepared by condensing an abietane diterpenoid quinone compound serving as a raw material andanhydride under the action of a metal catalyst. According to the novel abietane compound constructed by the invention, the non-planarity of the compound is effectively improved, the structure is novel, the corresponding biological activity is also remarkably improved, and the compound has greater patent medicine potential.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an abietane compound with a novel skeleton of a C-ring parallel lactone ring and a preparation method and application thereof. Background technique [0002] The research on abietic diterpenoids was first studied in the early 19th century, when Ellingson discovered the first abietic diterpene compound abietic acid from colophony (Ellingson, E.O.Abietic acid and some of its salts. Journal of the American Chemical Society .1914,36,325-335.), studies have shown that it has various pharmacological effects such as antibacterial and anti-gastric acid secretion (San Feliciano, A.; Gordaliza, M.; Salinero, M.A. et al. Abietane acids: sources, biological activities, and therapeutic uses. Planta Medica. 1993, 59, 485-90.). After that, it attracted widespread attention. In nature, abietane diterpenoids mainly exist in higher plants such as Labiatae, Pinaceae, Compositae, Euphorbiaceae, F...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07D307/77A61K31/365A61K31/37A61P35/00A61P9/00A61P9/10
CPCA61P9/00A61P9/10A61P35/00C07B2200/13C07D307/77C07D493/04
Inventor 周长新曾林伟侯阿芳甘礼社高玉丽
Owner 杭州禾橼医药科技有限公司
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