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Wnt signal channel inhibitor and application thereof

A technique for signaling pathways and inhibiting activity, applied in the field of medicine

Active Publication Date: 2015-09-02
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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  • Wnt signal channel inhibitor and application thereof
  • Wnt signal channel inhibitor and application thereof
  • Wnt signal channel inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 This example provides a synthetic method for heterocyclic compounds B1-B32

[0048] (1) Heterocyclic compound B1, which is synthesized by the following method:

[0049]

[0050] 1) Synthesis of Intermediate B1-2:

[0051] Dissolve B1-1 (1.2g, 6.98mmol) and triethylamine (800mg, 8.37mmol) in dichloromethane (30mL), slowly add chloroacetyl chloride (960mg, 8.37mmol) under ice-cooling, and stir at room temperature for 12 hours, add water (50mL), extract with ethyl acetate (50mL*3), combine the organic phases, wash with saturated brine (30mL*2), dry over anhydrous sodium sulfate, concentrate under reduced pressure and go through column chromatography (petroleum Ether:ethyl acetate=3:1) to obtain a pale yellow solid (800mg, 47%).

[0052] 2) Synthesis of Intermediate B1-3:

[0053] B1-2 (120 mg, 0.48 mmol) and p-bromophenol (92 mg, 0.53 mmol) were dissolved in acetone (8 mL), and potassium carbonate (80 mg, 0.58 mmol) and potassium iodide (8 mg, 0.048 mmol) w...

Embodiment 2

[0238] Example 2 Determination of Inhibition Ability of Heterocyclic Compounds B1-B32 to Wnt Signaling Pathway

[0239] L Wnt3A cells (CRL-2647, ATCC) were cultured in DMEM medium (Gibico) containing 10% fetal bovine serum (Hyclone). HEK293 STF stable clone cells (HEK293 cells transfected with "Super-Top Flash" TCF fluorescent reporter plasmid) were cultured in complete medium (containing 4mM L-glutamine, 1.5g / L sodium bicarbonate, 4.5g / L glucose , 6 μg / mL blasticidin and 10% fetal bovine serum in DMEM medium). When L Wnt3A cells and HEK293 STF stable clone cells were cultured 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 with DMSO, and then diluted to the desired concentration with DMEM medium. 20 μL of the compound solutio...

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PUM

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Abstract

The invention relates to heterocyclic compounds with Wnt signal channel inhibition activity, particularly including compounds, pharmaceutically acceptable salts, various isotopes, various isomers or various crystal structures thereof having a structure represented by a general formula I (shown in the specification). By the compounds and a composition of the compounds, a Wnt signal channel can be effectively inhibited and diseases related to the Wnt signal channel can be treated or prevented.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a heterocyclic compound with Wnt signaling pathway inhibitory activity. Background technique [0002] The earliest discovery of the Wnt signaling pathway came from the study of oncogenic viruses and the developmental mechanism 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 subsequently found to be an orthologous gene with the wingless gene of Drosophila, and the combination of the two was named Wnt gene (Clevers et al., Cell. 2006127: 469-480). 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 sign...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D213/30C07D401/12C07D213/40C07D213/56C07D405/12C07D401/04C07D413/14A61K31/497A61K31/4418A61K31/443A61P35/00A61P35/02A61P7/06A61P7/00A61P11/00A61P13/12A61P1/16A61P3/10A61P27/02A61P33/00A61P33/12A61P33/06
CPCC07D213/30C07D213/40C07D213/56C07D401/04C07D401/12C07D401/14C07D405/12C07D413/14Y02A50/30
Inventor 张小虎
Owner SUZHOU YUNXUAN PHARMA
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