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Heterocyclic compound with Wnt signal path inhibitory activity and application thereof

A technology of heterocyclic compounds and signaling pathways, applied in the field of medicine

Inactive Publication Date: 2016-01-20
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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  • Heterocyclic compound with Wnt signal path inhibitory activity and application thereof
  • Heterocyclic compound with Wnt signal path inhibitory activity and application thereof
  • Heterocyclic compound with Wnt signal path inhibitory activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] This example provides heterocyclic compounds A1-A48 with Wnt signaling pathway inhibitory activity and their synthesis methods.

[0048] (1) Heterocyclic compound A1, which is synthesized by the following method:

[0049]

[0050] 1) Synthesis of Intermediate A1-2:

[0051] Add compound A1-1 (6.9g, 40mmol), bis-pinacol borate (11.2g, 44mmol), KOAc (7.8g, 80mmol), Pd(dppf) in a 250mL round bottom flask 2 Cl 2 (1.63g, 2.0mmol) and tetrahydrofuran (100mL), nitrogen replacement, reflux stirring overnight, cooling to normal temperature, suction filtration with diatomaceous earth, the filtrate was spin-dried to obtain a black oily crude product (15.6g, content: 27%), directly use in the next step.

[0052] 2) Synthesis of intermediate A1-3:

[0053] The crude intermediate A1-2 (8g, 27%, 9.86mmol) was dissolved in dioxane / water (100mL / 20mL), p-bromobenzylamine (1.65g, 8.88mmol), potassium carbonate (2.72g, 19.73 mmol), Pd(dba) 2 (567mg, 0.99mmol) and SPhos (810mg, 1.9...

Embodiment 2

[0361] In this example, the ability of the heterocyclic compounds A1-A48 prepared in Example 1 to inhibit the Wnt signaling pathway to inhibit the Wnt signaling pathway was determined.

[0362] 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 with DMSO, and then diluted to the ...

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PUM

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Abstract

The invention provides a heterocyclic compound with Wnt signal path inhibitory activity. The heterocyclic compound and chemically acceptable salt, isotope, isomer and a crystal structure thereof are provided with a structure shown as the general formula I (see the formula in the description). The invention further provides application of the heterocyclic compound with the Wnt signal path inhibitory activity. The heterocyclic compound with the Wnt signal path inhibitory activity serves as effective antagonist of a Wnt signal path, and can be used for treating or preventing diseases caused by abnormity of the Wnt signal path.

Description

technical field [0001] The invention relates to a 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 signaling pathway. The Wnt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D471/04C07D417/14C07D405/14C07D403/12C07D401/04C07D513/04A61P35/00A61P7/06A61P7/00A61P35/02A61P11/00A61P13/12A61P1/16A61P3/10A61P27/02A61P33/00A61P33/12A61P33/06
CPCC07D401/04C07D401/12C07D401/14C07D403/12C07D405/14C07D417/14C07D471/04C07D513/04Y02A50/30
Inventor 张小虎
Owner SUZHOU YUNXUAN PHARMA
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