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Amino-five-membered heterocyclic compound with Wnt signal channel inhibitory activity and application thereof

A technology of signaling pathway and inhibitory activity, applied in the field of medicine

Active Publication Date: 2018-03-06
SUZHOU YUNXUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Dysregulation of Wnt signaling also contributes to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakiness, and neovascularization

Method used

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  • Amino-five-membered heterocyclic compound with Wnt signal channel inhibitory activity and application thereof
  • Amino-five-membered heterocyclic compound with Wnt signal channel inhibitory activity and application thereof
  • Amino-five-membered heterocyclic compound with Wnt signal channel inhibitory activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] This example provides amino five-membered heterocyclic compounds D1-D16 with Wnt signaling pathway inhibitory activity and their synthesis methods.

[0065] (1) Amino five-membered heterocyclic compound D1 having Wnt signaling pathway inhibitory activity, which is prepared by the following method:

[0066]

[0067] 1) Synthesis of intermediate D1-2:

[0068] Copper bromide (446mg, 2mmol) and isoamyl nitrite (234mg, 2mmol) were dissolved in acetonitrile (5mL), D1-1 (180mg, 1mmol) was added, heated to 60°C and stirred for 2 hours. After cooling to room temperature, saturated brine (30 mL) was added. Extracted with diethyl ether (50mL×3), washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (petroleum ether:ethyl acetate=50:1) to obtain a white Solid (120 mg, 50%), its mass spectrum data is: ESI-MS (m / z): 244.7 [M+H] + .

[0069] 2) Synthesis of intermediate D1-3:

[00...

Embodiment 2

[0134] In this example, the inhibitory ability of the amino five-membered heterocyclic compounds D1-D16 with Wnt signaling pathway inhibitory activity prepared in Example 1 on the Wnt signaling pathway was determined.

[0135] LWnt3A cells (CRL-2647, ATCC) were cultured in DMEM medium (Gibico) containing 10% fetal bovine serum (Hyclone). HEK293STF stable clone cells (HEK293 cells transfected with "Super-TopFlash" TCF fluorescent reporter plasmid) were cultured in complete medium (containing 4mML-glutamine, 1.5g / L sodium bicarbonate, 4.5g / L glucose, 6μg / L mL blasticidin and 10% fetal bovine serum in DMEM medium). When LWnt3A cells and HEK293STF stable clone cells were cultivated to 90% confluency, they were harvested separately and mixed at a ratio of 1:1. 100 μL / well of the mixed cell culture solution was added to a 96-well plate to make the final cell concentration 12,000 cells / well, and then cultured for another 24 hours. The compounds to be tested were serially diluted wi...

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Abstract

The invention provides an amino-five-membered heterocyclic compound with the Wnt signal channel inhibitory activity. The amino-five-membered heterocyclic compound with the Wnt signal channel inhibitory activity and pharmaceutically acceptable salt thereof have the structure shown in the general formula I, wherein the general formula I is defined in the description. The invention also provides a pharmaceutical composition, and the pharmaceutical composition comprises the amino-five-membered heterocyclic compound with the Wnt signal channel inhibitory activity as a component. The invention alsoprovides the amino-five-membered heterocyclic compound with the Wnt signal channel inhibitory activity and the pharmaceutically acceptable salt thereof and application of the pharmaceutical composition in preparing medicine for treating or preventing Wnt-signal-channel abnormal disease. By means of the amino-five-membered heterocyclic compound with the Wnt signal channel inhibitory activity, a Wntsignal channel can be effectively antagonized, and disease caused when the Wnt signal channel is abnormal can be treated or prevented.

Description

technical field [0001] The invention relates to an amino five-membered heterocyclic compound with Wnt signaling pathway inhibitory activity and application thereof, belonging to the technical field of medicine. Background technique [0002] The earliest discoveries of the Wnt signaling pathway came from studies of oncogenic viruses and the developmental mechanisms of Drosophila. The Wnt gene was discovered in 1982 and was initially identified as a preferential integration site for mouse mammary tumor virus. This gene can transmit proliferation and differentiation information between cells. It is an oncogene and was named Int gene at that time ( Mouse Int-1 and Int-3). It was later found that it belongs to the same orthologous gene as the wingless gene of Drosophila, so the combination of the two was named Wnt gene. So far, 19 members of the Wnt gene family have been discovered and cloned, and the signal transduction pathway mediated by the Wnt gene is called the Wnt signal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14C07D471/04A61K31/444A61K31/4709A61K31/541A61P35/00
CPCC07D417/14C07D471/04
Inventor 张小虎
Owner SUZHOU YUNXUAN PHARMA
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