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4'-demethylepipodophyllotoxin compounds and use thereof as anticancer agent

A technology for demethylepipodophyllotoxins and compounds, which is applied in the field of novel 4′-demethylepodophyllotoxins and can solve the problems of poor water solubility, easy metabolic inactivation, toxic side effects, and insufficient drug efficacy.

Active Publication Date: 2012-07-04
NEWISH TECH (BEIJING) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the drugs themselves have problems such as insufficient efficacy, poor water solubility, easy drug resistance, easy metabolic inactivation, and large toxic and side effects, which limit their clinical use.

Method used

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  • 4'-demethylepipodophyllotoxin compounds and use thereof as anticancer agent
  • 4'-demethylepipodophyllotoxin compounds and use thereof as anticancer agent
  • 4'-demethylepipodophyllotoxin compounds and use thereof as anticancer agent

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0078] The preparation of general formula compound I:

[0079]

[0080] a: MeSO 3 H / NaI; CH 2 Cl 2 , then p-nitroaniline, BaCO 3 , THF; b: Pb-C, H 2 ;c: HATU, DIEA, DCM

[0081] Dissolve norepipodophyllotoxin SM (4.000g, 10mmol) in 150ml of anhydrous dichloromethane, add NaI (2.235mg, 15mmol), dissolve in 150ml of anhydrous CH 2 Cl 2 , stirred for about 10min, added methanesulfonic acid (10ml, 15mmol) under ice-water bath conditions, stirred at room temperature for 2h, filtered, the filtrate was concentrated under reduced pressure, and directly added BaCO 3 (3.950g, 20mmol), p-nitroaniline (2.070mg, 15mmol), dissolved in 150ml of anhydrous dichloromethane, stirred at room temperature under nitrogen protection for 8h, filtered, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate, saturated thiosulfuric acid Sodium solution and saturated brine were washed successively, dried over anhydrous sodium sulfate, and separated by silica gel colum...

Embodiment 1

[0089] MS(ESI): 576[M+H] +

[0090] 1 H-NMR (300MHz, CDCl 3): 8.93 (s, 1H, -NH-CO-), 7.43 (d, J=8.7, 2H, ArH), 6.75 (s, 1H, 5-H), 6.51-6.54 (m, 3H, 8-H , ArH), 6.33 (s, 2H, 2', 6'-H), 5.96 (d, J=4.5, 2H, -OCH 2 O-), 5.46(s, 1H, -OH), 4.58-4.65(m, 2H, 1-H, 4-H), 4.38(t, J=7.8, 1H, 11-H), 4.12(t, J=9.0,1H,11-H), 3.79(s,6H,3',5'-OCH 3 ), 3.12, (dd, J=5.1, 13.8, 1H, 2-H), 3.06 (s, 2H, - CH 2 -N(CH 3 ) 2 ), 2.37(s, 6H, -N(CH 3 ) 2 )

Embodiment 2

[0092] MS(ESI):638[M+H] +

[0093] 1 H-NMR (300MHz, CDCl 3 ): 7.57 (d, J=8.7, 2H, ArH), 7.61 (s, 1H, -NH-CO-), 7.45 (d, J=8.4, 2H, ArH), 6.69-6.77 (m, 3H, ArH , 5-H), 6.50-6.56 (m, 3H, ArH, 8-H), 6.33 (s, 2H, 2', 6'-H), 5.96 (d, J=6.0, 2H, OCH 2 O-), 5.30(s, 1H, -OH), 4.57-4.65(m, 2H, 1-H, 4-H), 4.39(t, J=7.5, 1H, 11-H), 4.02(t, J=10.2,1H,11-H), 3.78(s,6H,3',5'-OCH 3 ), 3.16(dd, J=4.8, 14.1, 1H, 2-H), 3.04(s, 6H, -N(CH 3 ) 2 ), 2.88-3.01(m, 1H, 3-H)

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Abstract

The invention discloses new 4'-demethylepipodophyllotoxin compounds represented by compounds of a formula I and physiologically acceptable salts, solvates and crystalline forms thereof, medical preparation containing the compounds and use of the compounds in treatment of tumors in clinic.

Description

technical field [0001] The present invention relates to novel 4'-norepipodophyllotoxin compounds of general formula I and physiologically acceptable salts. The use of these compounds in the course of treating malignant tumors also relates to the method for treating them and the pharmaceutical composition containing the compounds. Background technique [0002] Etoposide (etoposide, 1) and teniposide (teniposide, 2) are demethyl epipodophyllotoxin derivatives obtained by semi-synthesis from the active natural product podophyllotoxin (podophyllotoxin, 3), which are topoisomerases II inhibitors are widely used clinically as tumor chemotherapy drugs, especially for the treatment of small cell lung cancer, testicular cancer, lymphoma and Kaposi's sarcoma. However, the drugs themselves have problems such as insufficient efficacy, poor water solubility, easy drug resistance, easy metabolic inactivation, and relatively large toxic and side effects, which limit their clinical use. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/02A61K31/5377A61K31/496A61K31/4525A61K31/365A61P35/00
Inventor 肖志艳孙华汤雁波王娅杰
Owner NEWISH TECH (BEIJING) CO LTD