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Etoposide compound with hydroxamic acid structure and preparation method and usage thereof

A technology of hydroxamic acid and epipodophyllotoxin, which is applied to medical preparations containing active ingredients, organic chemistry, pharmaceutical formulations, etc., can solve the problems of easy drug resistance and single action target, and achieve good resistance The effect of tumor activity

Inactive Publication Date: 2013-12-25
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to blocking multiple pathways of tumor cell survival, this small molecule drug can overcome the shortcomings of traditional drugs that are prone to drug resistance
For example, the first-generation tyrosine kinase inhibitor imatinib has a single target, mainly inhibiting the tyrosine kinase Bcr-Abl
Patients tend to develop drug resistance after taking imatinib for a period of time

Method used

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  • Etoposide compound with hydroxamic acid structure and preparation method and usage thereof
  • Etoposide compound with hydroxamic acid structure and preparation method and usage thereof
  • Etoposide compound with hydroxamic acid structure and preparation method and usage thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 1.1 Preparation of Compound 2

[0037] Dissolve 5 g of 4-bromobutyric acid in 100 mL of methanol, add 3.3 mL of thionyl chloride dropwise at room temperature, continue the reaction for 1 hour after the drop is complete, and remove the solvent and excess thionyl chloride under reduced pressure to obtain 5.4 g of a colorless liquid . Yield 99.6%.

Embodiment 2

[0039] 1.2 Preparation of compound 3

[0040] At room temperature, add 4.52 g of potassium carbonate to the N,N-dimethylformamide solution containing 3.79 g of p-nitrophenol, stir for half an hour, add 5.4 g of methyl 4-bromobutyrate, and react at 100°C for 12 hours. After cooling to room temperature, add 100 mL of water, extract with 100 mL of ethyl acetate, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain a yellow oil. Diethyl ether was added to the oil, and a large amount of solid was precipitated. After filtering, it was washed with a small amount of diethyl ether, and after drying, 3.3 g of light yellow solid was obtained, with a yield of 46.0%.

Embodiment 3

[0042] 1.3 Preparation of Compound 4

[0043] At room temperature, dissolve 2.1 g of methyl 4-(4-nitrophenoxy)butyrate in 10 mL of tetrahydrofuran, add 5 mL of 3M aqueous sodium hydroxide solution, reflux for 2 hours, and then cool to room temperature. Add 20 mL of 1M hydrochloric acid, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain 1.9 g of a yellow solid with a yield of 96.0%.

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Abstract

The invention provides a novel etoposide derivative with a hydroxamic acid structure as showed in the general formula I, a pharmaceutically-acceptable salt of the etoposide derivative, a preparation method of the etoposide derivative and usage of the etoposide derivative. In the general formula I, X is -NH-, -O-, -S-, -NH-CH2-, -O-CH2- or -S-CH2-; Y is aromatic ring, substituted aromatic ring, aromatic hyterocyclic ring or substituted aromatic hyterocyclic ring; Z is -O-, -NHCO- or -CONH-; and B is C1-C8 alkyl, C2-C8 alkenyl, alkynyl or cycloalkyl. The compound provided by the invention has good antitumor activity and can be applied clinically by oral administration, intravenous injection or intramuscular injection.

Description

technical field [0001] The invention relates to a class of multi-target inhibitors acting on topoisomerase II and histone deacetylase, as well as the preparation method and application of these compounds. More specifically, it relates to novel epipodophyllotoxin derivatives (I) having the following structures, their preparation methods and the application of these compounds in the antitumor field. [0002] Background technique [0003] DNA topoisomerase is an important class of anti-tumor targets, and podophyllotoxin (1) is a representative anti-tumor compound that acts on topoisomerase II. It is obtained from closely related plants such as lotus, Tibetan podophyllum, and mountain lotus leaf. It has significant antitumor and antiviral activities, but its application is limited due to its strong toxicity and side effects. [0004] Etoposide (VP-16) (2) and its phosphate (etoposide phosphate, or etopophos) and teniposide (VM-26) (3) derived from podophyllotoxin structural ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04A61K31/365A61P35/00
Inventor 吕伟张翾史培忠刘新桂叶智华罗宇陈奕李佳李静雅丁健
Owner EAST CHINA NORMAL UNIV
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