Androstane derivative, preparation method and applications thereof

A derivative, androstane technology, applied in the field of medicine

Active Publication Date: 2019-09-17
TIANJIN CHASE SUN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When there is no Hh signal, Ptch binds to Smo and inhibits the action of Smo, resulting in the inhibition of the transcriptional activity of its downstream transcription factor Gli

Method used

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  • Androstane derivative, preparation method and applications thereof
  • Androstane derivative, preparation method and applications thereof
  • Androstane derivative, preparation method and applications thereof

Examples

Experimental program
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preparation example Construction

[0028] The present invention provides the preparation method of the androstane derivative described in the above scheme, comprising the following steps:

[0029] (1) subjecting the compound having the structure shown in formula II to Sven oxidation reaction to obtain the compound having the structure shown in formula III;

[0030]

[0031] (2) hydrolyzing the compound having the structure shown in formula III to obtain the compound having the structure shown in formula IV;

[0032]

[0033] (3) performing quaternization reaction on the compound having the structure shown in formula IV and allyl bromide to obtain the androstane derivative having the structure shown in formula I.

[0034] In the present invention, the compound having the structure shown in formula II is subjected to Sven oxidation reaction to obtain the compound having the structure shown in formula III;

[0035]

[0036] The source of the compound having the structure shown in formula II is not partic...

Embodiment 1

[0061] The androstane derivative with the structure shown in formula I is prepared according to the following reaction scheme:

[0062]

[0063] (1) Under stirring conditions, add dichloromethane (500mL) and oxalyl chloride (220mmol) into a 3000mL three-necked reaction flask in sequence, and after cooling down to -60°C, add dichloromethane-DMSO mixed solution (440mmol DMSO dissolved in 100 mL of dichloromethane). After stirring at the same temperature for 10 minutes, a dichloromethane solution (500 mL) of a compound having a structure represented by formula II (15.6 g, 32 mmol) was added dropwise, and after stirring at -60°C for 15 minutes, the reaction solution was cooled to -78°C, and then triethyl ether was added Amine (860 mmol). Stirring was continued at the same temperature for 30 min, and the reaction ended. After the reaction solution was slowly raised to room temperature, it was washed with saturated NaCl solution and extracted with dichloromethane. The organic l...

Embodiment 2

[0079] (1) Under stirring conditions, add dichloromethane (500mL) and oxalyl chloride (160mmol) into a 3000mL three-necked reaction flask in sequence, and after cooling down to -70°C, add dichloromethane-DMSO mixed solution (320mmol DMSO dissolved in 100 mL of dichloromethane). After stirring at the same temperature for 20 minutes, a dichloromethane solution (500 mL) of a compound (15.6 g, 32 mmol) having a structure represented by formula II was added dropwise. After stirring at -70°C for 15 minutes, the reaction solution was cooled to -78°C, and then triethyl ether was added. Amine (800 mmol). Stirring was continued at the same temperature for 60 min, and the reaction ended. After the reaction solution was slowly raised to room temperature, it was washed with saturated NaCl solution and extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 8...

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Abstract

The invention provides an androstane derivative, a preparation method and applications thereof, and belongs to the technical field of medicine. According to the present invention, the androstane derivative has good inhibitory effect on Hedgehog signaling pathway so as to provide an effective treatment drug for patients with chronic myelogenous leukemia; the results of the embodiments show that the androstane derivative has the Hedgehog pathway signaling inhibition average IC50 value measured by using mouse [s12] and human [MZ24] Gli reporter cell lines of 0.020 [mu]m while the average IC50 value of the existing FDA-approved Hedgehog pathway inhibitor is 0.022 [mu]M, such that the androstane derivative has Hedgehog signaling pathway inhibition effect, and further achieve the effect comparable to Vismodegib.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an androstane derivative and a preparation method and application thereof. Background technique [0002] The study of molecularly targeted anticancer drugs is the main trend and trend in the field of current anticancer drug research. In recent years, antitumor drugs targeting the Hedgehog (Hh) signaling pathway have become a new research hotspot in this field. The Hedgehog (Hh) signaling pathway plays an important role in the occurrence and development of tumors, and is closely related to about one-third of human tumors. Abnormal activation of Hh signaling will lead to the occurrence of various tumors such as medulloblastoma, breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, and ovarian cancer. Hedgehog is a segmented gene discovered during the study of the development of Drosophila. The Hh signal is mainly transmitted intracellularly through the trans...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61P35/02
CPCA61P35/02C07J43/003
Inventor 魏增泉李宝齐郭嘉林刘登科孔凯董凯姚小青
Owner TIANJIN CHASE SUN PHARM CO LTD
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