Application of dihydroartemisinin and quinolone conjugate in preparation of Wnt signaling pathway agonist

A technology of quinolone conjugates and dihydroartemisinin, which is applied in the direction of drug combinations, medical preparations containing active ingredients, organic active ingredients, etc., to achieve the effect of broadening the use of pharmaceuticals

Pending Publication Date: 2019-11-15
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Quinolones (such as ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin) are currently the drugs of choice for the treatment of extensively multidrug-resistant tuberculosis (MDR-TB), which are highly effective against Mycobacterium tuberculosis. Good inhibitory or killing effect, and no obvious cross-resistance with non-quinolone anti-tuberculosis drugs, no inhibitory effect on the activity of these drugs when used in combination, but long-term use of quinolone drugs will promote resistance to marketed quinolone drugs Mycobacterium tuberculosis

Method used

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  • Application of dihydroartemisinin and quinolone conjugate in preparation of Wnt signaling pathway agonist
  • Application of dihydroartemisinin and quinolone conjugate in preparation of Wnt signaling pathway agonist
  • Application of dihydroartemisinin and quinolone conjugate in preparation of Wnt signaling pathway agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1. Preparation of target compound

[0036] 1. Synthesis of the target compound TM1 series

[0037] The target compounds TM1 series (TM1-1~TM1-12) were prepared according to the method described in Chinese patent 104418864B (conjugates of dihydroartemisinin and quinolones and their preparation methods and applications).

[0038]

[0039]

[0040] 2. Synthesis of the target compound TM9 series

[0041] 1) Synthesis of intermediate IM3

[0042] The intermediate IM3 was prepared according to the method described in Chinese patent 104418864B (conjugates of dihydroartemisinin and quinolones and its preparation method and application).

[0043] 2) Synthesis of target compound TM9 series

[0044]

[0045] Add IM3 (1mmol) and 3mL of dichloromethane (DCM) into a 100mL reaction flask, stir at -10°C to 0°C, and partially dissolve, then add N,N'-diisopropylethylamine (DIPEA, 1.5mmol) in sequence , Pivaloyl chloride (1.5mmol), -10 ℃ ~ 0 ℃ continue to stir the ...

Embodiment 2

[0079] Example 2. The Wnt signaling pathway agonistic activity test of the target compound

[0080] The Wnt signaling pathway activating activity of the target compound was tested by the Open Innovation Drug Discovery (OIDD) program of Eli Lilly and Company. Firstly, a single-concentration primary screening (Primary SP) was performed, and then a multi-concentration test (Primary CRC) was performed on the potential molecules screened out initially. . The test results of the Wnt signaling pathway agonist activity of some compounds are shown in Table 3 and Table 4.

[0081] Table 3 Wnt signaling pathway agonistic activity test results-1

[0082]

[0083]Table 1 tested the activity of the target compound TM1 series at different concentrations to promote the expression of β-catenin protein in the nucleus in mouse myoblast C2C12 (cultured in Wnt-conditioned medium), and the target compound TM1 series promoted C2C12 cells under Wnt3a stimulation. The median effect concentration ...

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Abstract

The invention discloses an application of a dihydroartemisinin and the quinolone conjugate represented by a formula I in preparation of a Wnt signaling pathway agonist, which broadens its pharmaceutical use.

Description

technical field [0001] The invention belongs to the technical field of medical application of compounds, and relates to the application of a kind of dihydroartemisinin and quinolone conjugates in the preparation of Wnt signaling pathway agonists. Background technique [0002] Dihydroartemisinin is an artemisinin derivative with high-efficiency and low-toxic antimalarial activity. Studies in recent years have shown that dihydroartemisinin and its derivatives also have various biological activities such as anti-tumor, anti-inflammation, and anti-fibrosis. [0003] Quinolones (such as ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin) are currently the drugs of choice for the treatment of extensively multidrug-resistant tuberculosis (MDR-TB), which are highly effective against Mycobacterium tuberculosis. Good inhibitory or killing effect, and no obvious cross-resistance with non-quinolone anti-tuberculosis drugs, no inhibitory effect on the activity of the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4709A61K31/496A61P35/00
CPCA61K31/4709A61K31/496A61P35/00
Inventor 范莉唐雪梅杨大成罗鹏周福委孙晓丽张书虹
Owner SOUTHWEST UNIVERSITY
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