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4-deoxyisopodophyllotoxin derivatives, preparation and medicinal uses thereof

A technology for deoxygenation of alien ghosts and toxins, which can be used in the fields of medicinal chemistry and pharmacology to solve problems such as bone marrow suppression and poor water solubility.

Inactive Publication Date: 2008-01-16
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the above two compounds have been used clinically, there are still problems such as bone marrow suppression and poor water solubility, which limit their application.

Method used

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  • 4-deoxyisopodophyllotoxin derivatives, preparation and medicinal uses thereof
  • 4-deoxyisopodophyllotoxin derivatives, preparation and medicinal uses thereof
  • 4-deoxyisopodophyllotoxin derivatives, preparation and medicinal uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: Compound III-4[(3S,4R)-3-(3-methoxy-4-methoxymethoxy-α-hydroxybenzyl)-4-(3,4,5-trimethyl Oxybenzyl)dihydrofuran-2-one] preparation:

[0061]

[0062] Under nitrogen protection, 0.34 ml (2.4 mmol) of diisopropylamine was dissolved in 20 ml of dry tetrahydrofuran (THF), cooled to -78°C, and 1.5 ml (2.4 mmol), then 10 milliliters of THF solution with 532 mg (2.0 mmol) of 4-(3,4,5-trimethoxybenzyl)-4,5-dihydrofuran-2-one was slowly added dropwise to the reaction In the system, 8 milliliters of THF solutions that are dissolved with 392 mg (2.0 mmol) of 3-methoxy-4-methoxybenzaldehyde are slowly added dropwise into the reaction flask, and after the addition is completed, it is naturally warmed up to At room temperature, saturated ammonium chloride solution (20 ml) was added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (15 ml×3), the organic phases were combined, and dried over anhydrous sodium sulfate. After filtration, ...

Embodiment 2

[0071] II-1a compound [C(7″)-αH]: Rf (ethyl acetate / petroleum ether: 1 / 1): 0.30; 1H NMR (400MHz, CDCl3): δ2.30-2.41(m, 2H, H- 7), 2.65(m, 1H, Hz, H-3), 2.86(m, 1H, H-4), 2.97(brs, 1H, OH-7″β), 3.50(s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.13 (brs, 1H, H-5β), 4.28 (t, 1H, J=8.4, 8.4Hz, H-5α), 5.22 (s, 2H, OCH20), 5.29 (brs, 1H, H-7″α), 6.36 (d, 1H, J=1.6Hz, H-2'), 6.42 (dd, 1H, J=8.0, 2.0Hz, H-6'), 6.65(d, 1H, J=8.0Hz, H-5'), 6.81(d, 1H, J=8.0Hz, H-5"), 6.90(d , 1H, J=2.0Hz, H-2″), 7.03 (dd, 1H, J=8.0, 2.0Hz, H-6″).

[0072] III-1b compound [C(7″)-βH]: Rf (ethyl acetate / petroleum ether: 1 / 1): 0.30; 1HNMR (400MHz, CDCl3): δ2.20(t, 2H, J=9.2, 7.2 Hz, H-7), 2.52(m, 1H, H-4), 2.63(t, 1H, J=4.4, 3.6Hz, H-3), 3.49(s, 3H, OCH3), 3.69(s, 3H , OCH3), 3.82(s, 3H, OCH3), 3.87(s, 3H, OCH3), 3.91(dd, 1H, J=5.2, 2.8Hz, H-5β), 4.09(t, 1H, J=8.4, 8.4Hz, H-5α), 4.81(d, 1H, J=8.0Hz, H-7″β), 5.26(s, 2H, OCH2O), 6.38(d, 1H, J=2.0Hz, H-2' ), 6.46 (dd, 1H, J=...

Embodiment 3

[0074] III-2a compound [C(7″)-αH]: Rf (ethyl acetate / petroleum ether: 1 / 1): 0.30; 1H NMR (400MHz, CDCl3): δ2.44 (dd, 1H, J=14.4, 8.8Hz, H-7α), 2.30(dd, 1H, J=10.4, 7.2Hz, H-7β), 2.64(dd, 1H, J=12.4, 3.6Hz, H-3), 2.82(m, 1H, H-4), 3.03(brs, 1H, OH-7″β), 3.48(s, 3H, OCH3), 3.78(s, 3H, OCH3), 3.80(s, 3H, OCH3), 3.83(s, 3H , OCH3), 4.07(brs, 1H, H-5β), 4.31(t, 1H, J=8.4, 8.0Hz, H-5α), 5.22(s, 2H, OCH20), 5.28(d, 1H, J= 5.6Hz, H-7″α), 6.36(d, 1H, J=8.0Hz, H-6’), 6.42(s, 1H, H-2’), 6.65(d, 1H, J=8.0Hz, H-5'), 6.80 (d, 2H, J=8.0 Hz, H-2", 5"), 7.08 (d, 1H, J=8.0 Hz, H-6").

[0075] III-2b compound [C(7″)-βH]: Rf (ethyl acetate / petroleum ether: 1 / 1): 0.30; 1H NMR (400MHz, CDCl3): δ2.21(t, 2H, J=9.2, 4.4Hz, H-7), 2.50(m, 1H, H-4), 2.61(t, 1H, J=4.4, 3.6Hz, H-3), 3.49(s, 3H, OCH3), 3.80(s, 3H, OCH3), 3.83(s, 3H, OCH3), 3.89(s, 3H, OCH3), 3.95(dd, 1H, J=11.2, 9.2Hz, H-5β), 4.13(t, 1H, J=9.2 , 8.0Hz, H-5α), 4.84 (d, 1H, J=8.0Hz, H-7″β), 5.21 (s, 2H, OCH2O), 6.38 (d, 1H, J=8.0Hz, H-6 ...

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Abstract

The invention relates to 4-deoxidized-iso-podophyllotoxin derivatives displayed by formula (1) and the intermediate series of compounds of 4-deoxidized-iso-podophyllotoxin derivatives or the pharmaceutical salt or solvates of the 4-deoxidized-iso-podophyllotoxin derivatives. The invention also relates to the preparation method, the drug combinations, and the pharmaceutical applications of compounds in the formula (1). The compounds possess strong activity in inhibiting tumor cell growth, some of which having stronger cytotoxic activity to human body tumor cell lines in vitro than etoposide, the prior first class anti-tumor drug, thereby the compounds are expected to serve the purpose of such cancer drugs as anti-lung cancer drugs, anti-hepatoma drugs, and anti-cerbical cancer drugs; since the cytotoxicity of the related compounds to KB cells and PC-3 cells is approximate to or equivalent to etoposide, and meanwhile the compounds have strong etoposide to CNE cells, the compounds are expected to used in anti-tumor drugs, such as, anti-oral epithelial carcinoma drugs, nasopharyngeal carcinoma drugs, and prostate cancer drugs.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and pharmacology. Specifically, the present invention relates to two series of derivatives of 4-deoxyisopodophyllotoxin and its preparation method and for the effects of these derivatives on eight kinds of tumor cell lines such as human prostate cancer cell (PC-3), nasopharyngeal carcinoma cells (CNE), oral epithelial carcinoma cells (KB), human lung cancer cells (A549), human liver cancer cells (BEL-7404), human cervical cancer cells (Hela), human myeloid leukemia cells (HL-60) and Screening for tumor cell growth inhibitory activity in mouse lymphoid tumor (P388D1). These derivatives are found to have strong activity of inhibiting tumor cell growth, and can be expected to be used as antitumor drugs. Background technique [0002] At present, due to environmental pollution and other problems brought about by industrial development, the quality of human living environment is continuous...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/92A61K31/365A61K9/00A61P35/00
Inventor 赵昱丁红霞吕伟白骅
Owner ZHEJIANG UNIV
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