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Imidazole derivative containing indazole structure as well as preparation method and application thereof

A technology of imidazole derivatives, applied in the field of imidazole derivatives and their preparation, can solve the problem of low level of mesenchymal characteristics, and achieve excellent results

Active Publication Date: 2021-01-26
YANBIAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Previous research also found that tumor samples from glioblastoma patients who responded to treatment and had a longer time before relapse had lower levels of mesenchymal signatures

Method used

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  • Imidazole derivative containing indazole structure as well as preparation method and application thereof
  • Imidazole derivative containing indazole structure as well as preparation method and application thereof
  • Imidazole derivative containing indazole structure as well as preparation method and application thereof

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preparation example Construction

[0082] The present invention also provides a preparation method of the imidazole derivatives described in the above technical scheme, comprising the following steps:

[0083] 1) Mixing the compound shown in formula A with an organometallic lithium reagent or a Grignard reagent for an ion exchange reaction to obtain a compound substituted by lithium or a Grignard reagent, and performing an addition reaction with anhydrous DMF on the compound substituted by the lithium or Grignard reagent, Obtain 1H-indazole-5-carbaldehyde; The X is a halogen element;

[0084]

[0085] 2) Mix 1H-indazole-5-carbaldehyde with diphenyl (6-methylpyridin-2-yl)-aniline methyl phosphate, carry out condensation reaction under alkaline conditions, add acid for hydrolysis reaction, and obtain 2-(1H-indazol-5-yl)-1-(6-methylpyridin-2-yl)ethanone;

[0086] 3) 1-methyl-1H-indazole-5-formaldehyde and aniline are carried out condensation reaction to generate imine compound, and described imine compound and...

Embodiment 1

[0153] Preparation of compound 2

[0154] 6.00 g of 5-bromo-1hydro-indazole (compound 1, 30.46 mmol) was taken into a 250 mL round-bottom flask, and 120 mL of tetrahydrofuran was added thereto to dissolve the raw materials. After the solution was cooled at -50°C for 20 min, n-butyllithium (48 mL, 76.15 mmol) was slowly added dropwise at this temperature and stirred for 2 h. Anhydrous DMF (4.7 mL, 60.92 mmol) was added at this temperature and stirring was continued for 30 min. The reaction mixture was quenched with water and left at room temperature. The reaction solution was extracted three times with ethyl acetate, and the organic phases were combined. The combined organic phases were washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate=4:1) to obtain solid compound 2.

[0155] Compound 21H-Indazole-5-carbaldehyde

...

Embodiment 2

[0159] Preparation of compound 3

[0160] Take 5.20 g of compound 2 (35.58 mmol) into a 250 mL round-bottomed flask, add a 4:1 mixed solvent of tetrahydrofuran and isopropanol (100 mL) to it, stir well, and then add diphenyl (6-methylpyridin-2-yl) )-anilino methyl phosphate (20 g, 46.25 mmol) and cesium carbonate (15 g, 46.25 mmol) were reacted at room temperature for 12 h, the solution changed from colorless to pale yellow, and became clear and cloudy. Then, 1N HCl (150 mL) was added, and the solution became clear from turbidity. The reaction was stirred at room temperature for 1 h, then methyl tert-butyl ether (75 mL) was added, and the reaction was stirred for 30 min. The water and methyl tert-butyl ether layers were separated with a separatory funnel, and the aqueous layer was washed with saturated NaHCO in an ice-water bath. 3 The pH of the solution was adjusted to neutral. The reaction solution was extracted three times with ethyl acetate, and the organic phases were c...

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Abstract

The invention relates to an imidazole derivative containing an indazole structure as well as a preparation method and application of the imidazole derivative, and belongs to the technical field of medicine synthesis. The imidazole derivative disclosed by the invention is an imidazole compound containing an indazole structure as shown in a structural formula (I) and pharmaceutically acceptable saltor hydrate thereof. The imidazole derivative containing the indazole structure has inhibitory activity on transforming growth factor beta1 receptor kinase (ALK5), can inhibit a TGF -beta induced EMT-like process, has a potential anti-cancer effect on malignant glioma, and can be used for treating human glioma related to an epithelial-mesenchymal transition (EMT)-like process.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to imidazole derivatives containing indazole structures and a preparation method and application thereof. Background technique [0002] Transforming growth factor (TGF-β) is a protein with multiple functions and multi-directional regulation, belonging to a class of cytokine superfamily, including TGF-βs (TGF-β1, TGF-β2, TGF-β3), activin ( activins), inhibins and bone morphogenetic proteins (BMPs). [0003] TGF-β signaling requires two types of single-transmembrane serine (serine) / threonine (threonine) receptor kinases, which are type I receptors and type II receptors (referred to as type II receptors). , TβR-I and TβR-II). First, TGF-β binds to the type II receptor as a dimer, and then recruits two type I (or activin receptor-like kinase 5, abbreviated, ALK5) receptors. Type II receptors activated by TGF-β hyperphosphorylate ALK5 at serine and threonine residues in the GS ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/4439A61P35/00A61P35/04
CPCA61P35/00A61P35/04C07D401/14
Inventor 金学军金成华郭振王晶莹
Owner YANBIAN UNIV
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