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Derivative of Dysosma versipellis, and composition, preparation method and use thereof

A technology of derivatives and compounds, applied in the field of podophyllotoxin derivatives and compositions thereof, can solve the problems of interfering with DNA replication and the like

Inactive Publication Date: 2013-01-02
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, VP16 and VM26 are different from podophyllotoxin, mainly inhibiting DNA topoisomerase 2, thereby interfering with DNA replication

Method used

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  • Derivative of Dysosma versipellis, and composition, preparation method and use thereof
  • Derivative of Dysosma versipellis, and composition, preparation method and use thereof
  • Derivative of Dysosma versipellis, and composition, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexa Preparation of hydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxo-5-cycl-5-yl)-3-trifluoromethylbenzamide ( Compound 1)

[0063] 3-Trifluoromethylbenzoic acid (475mg, 2.5mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (525mg, 2.76mmol ), 1-hydroxybenzotriazole (350mg, 2.6mmol), were added into dichloromethane (10ml), stirred for 30min, then compound II (1.0g, 2.5mmol) was added, and reacted at 25-30°C for 4h. The reaction solution was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by column chromatography (eluent: dichloromethane / acetone gradient elution) to obtain compound 1 (728 mg) as a white solid. Melting point: 168.9-173.3°C. ESI-MS: 572 (M + +H), 594(M + +Na), 610(M + +K). 1 HNMR / (CDCl 3 ) δppm: 8.051 (1H, s, Ar-H), 7.979 (1H, d, ...

Embodiment 2

[0065] 2-Chloro-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a , 9-Hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxacyclo-5-yl)-3,4-dimethoxy Preparation of benzamide (compound 2)

[0066] 2-Chloro-3,4-dimethoxybenzoic acid (216 mg, 1 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (191 mg, 1 mmol), 1-hydroxybenzotriazole (135 mg, 1 mmol), were added to dichloromethane (5 ml). After stirring for 2h, compound II (399mg, 1mmol) was added and reacted at 25-30°C for 4h. The reaction solution was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by column chromatography (eluent: dichloromethane / acetone gradient elution) to obtain compound 2 (308 mg) as a white solid. Melting point: 132.1~136.2℃. ESI-MS: 598 (M + +H), 620(M + +Na), 1217 (2M + +Na). 1 HNMR / (CDCl 3 )δppm: 7.490 (1H, d, J = 8.4Hz, Ar-H)...

Embodiment 3

[0068] N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexa Hydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxacyclo-5-yl)-2,3,4-trimethoxybenzamide (Compound 3) Preparation

[0069] 2,3,4-trimethoxybenzoic acid (212mg, 1mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (191mg, 1 mmol), 1-hydroxybenzotriazole (135 mg, 1 mmol), was added to dichloromethane (5 ml). After stirring for 2h, compound II (399mg, 1mmol) was added and reacted at 25-30°C for 4h. The reaction solution was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting crude product was purified by column chromatography (eluent: dichloromethane / acetone gradient elution) to obtain compound 3 (298 mg) as a white solid. Melting point: 137.4-141.9°C. ESI-MS: 594 (M + +H), 616(M + +Na), 632 (M + +K). 1 HNMR / (CDCl 3 )δppm: 8.078 (1H, d, J = 6.8Hz, NH), 7.868 (1H, d, J = 9.2Hz,...

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Abstract

The invention discloses a derivative of Dysosma versipellis, and compositions, preparation methods and use thereof. The animal experiment proves that the derivative of Dysosma versipellis has good antitumor activity; can be used for the treatment of leukaemia, liver cancer, lung cancer and the similar diseases; has less toxicity; and can satisfy the clinical needs. The derivative of Dysosma versipellis is a compound of the following formula (I).

Description

technical field [0001] The present invention relates to podophyllin derivatives and their composition, preparation method and application, as well as the application of the composition in the preparation of antitumor medicaments. Background technique [0002] Tumor disease is a malignant disease caused by multiple factors. Interfering with a certain (some) important link may prevent tumor growth. [0003] This application project is to study the anti-tumor activity of podophyllin derivatives of small molecules, and provide new options for anti-tumor drugs. [0004] Podophyllotoxin has significant antitumor activity, but its application is limited due to its strong toxicity and side effects. Derivatives etoposide (etoposide, vepesid, etoposide, etoposide, VP16) and teniposide (teniposide, podophylloside, teniposide, VM26) obtained by structural modification of podophyllotoxin ) has become a representative anti-cancer drug for clinical application. They are effective agains...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61K31/365A61P35/00
Inventor 肖旭华孙文劼闫琪肖璘吴学军蔡立张瑱黄晓玲刘珉宇刘英邓轶方陈仁海汤生荣刘全海
Owner SHANGHAI INST OF PHARMA IND
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