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Azaindole compound and application thereof

A technology of azaindole and compounds, applied in the field of medicinal chemistry, can solve problems such as non-existence and side effects

Active Publication Date: 2020-09-01
GUANGZHOU MEDICAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the steps of tumor invasion and metastasis, transforming growth factor β (TGF-β) plays a tumor-promoting role. Due to the pleiotropic effects and complex functions of TGF-β, its inhibition may lead to side effects, while the downstream mediators of TGFβ signaling Because SMAD3 contains a DNA-binding domain, it can directly bind to the promoter in the target gene to regulate transcription, but SMAD2 and SMAD4 do not have these functions

Method used

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  • Azaindole compound and application thereof
  • Azaindole compound and application thereof
  • Azaindole compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Embodiment 1: the synthesis of compound 5a-5j

[0097]

[0098] Synthesis of Intermediate 4a:

[0099]

[0100] Put NaH (192mg, 4.8mmol) in the reaction flask, replace nitrogen, add 7mL of anhydrous DMF to dissolve, add methyl phosphonoacetate diethyl phosphonoacetate under the condition of ice-water bath, stir for 0.5 hours, add compound 3a dropwise ( 636mg, 3.973mmol) in 7.5mL DMF solution, stirred at room temperature for 8 hours. Sampling point plate, the reaction is basically completed, quenched the reaction with water, stirred for 2 hours, extracted three times with ethyl acetate, washed with saturated brine, dried and filtered, concentrated and purified by silica gel column to obtain yellow solid compound n1 (520 mg, 60.5%); compound n1 (520mg, 2.4mmol) dissolved in THF / MeOH / H 2 O (5mL / 8mL / 8mL) mixed solution was added NaOH (288mg, 7.2mmol) and stirred at room temperature for 4 hours. Sampling point plate, the reaction is basically completed. HCl (1M) wa...

Embodiment 2

[0166] Embodiment 2: the synthesis of compound 9

[0167]

[0168] Compound 6 (208mg, 1mmol) and AlCl 3 (667mg, 5mmol) was placed in a reaction flask, replaced with nitrogen, dissolved in 20mL of DCM, and stirred at room temperature for 1 hour. Add methyl 2-chloro-2-oxoacetate (122mg, 1mmol), stir at 0°C for 0.5 hours, then warm to room temperature, and 2 Stir overnight under protective conditions. Sampling point plate, the reaction is basically completed, extraction, DCM extraction three times, combined organic phase, dried, filtered, concentrated, purified by silica gel column chromatography to obtain yellow solid compound 7 (270 mg, 92%); 1 H NMR (400MHz, CDCl 3 )δ8.71(d, J=7.8Hz, 1H), 8.49(d, J=4.7Hz, 1H), 7.63–7.53(m, 3H), 7.48(d, J=5.7Hz, 2H), 7.35( dd,J=7.8,4.8Hz,1H),3.74(s,3H),3.24(s,3H). 13 CNMR (100MHz, CDCl 3 )δ177.5, 162.6, 149.1, 144.0, 137.7, 132.1, 119.8, 119.2, 112.7, 52.9.

[0169] Put compound 7 (270mg, 0.92mmol) and LiOH (66mg, 2.76mmol) in a react...

Embodiment 3

[0171] Embodiment 3: the synthesis of compound 12

[0172]

[0173] Put NaH (112mg, 2.8mmol) in the reaction flask, replace nitrogen, add 5mL of anhydrous DMF to dissolve, add methyl phosphonoacetate diethyl phosphonoacetate (555mg, 2.2mmol) under the condition of ice-water bath, stir for 0.5 hours, A DMF solution of compound 10 (451 mg, 2.0 mmol) was added dropwise and stirred at room temperature for 8 hours. Sampling and spotting the plate, the reaction was basically completed, quenched the reaction with water, stirred for 2 hours, extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated, and purified on a silica gel column to obtain yellow intermediate n7 (542 mg, 84%).

[0174] Intermediate n7 (542 mg, 1.68 mmol) was dissolved in CH 2 Cl 2 (9mL) and TFA (2mL) in a mixed solution, stirred overnight at room temperature, sampled and plated, the reaction was basically completed, and compound 11 (550mg, crude yield) was obtained....

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PUM

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Abstract

The invention provides an azaindole compound with a structure shown as a formula (I) and application of the azaindole compound. The azaindole compound can effectively inhibit SMAD3-phosphorylation andhas good anti-tumor activity in a rat LCC induced tumor model. Compared with a compound SIS3, part of the azaindole compound provided by the invention is obviously improved in water solubility. The azaindole compound provided by the invention is expected to become an effective drug for preventing and treating tumors.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an azaindole compound and its application. Background technique [0002] Tumor growth and metastasis are the main causes of death in cancer patients. In the steps of tumor invasion and metastasis, transforming growth factor β (TGF-β) plays a tumor-promoting role. Due to the pleiotropic effects and complex functions of TGF-β, its inhibition may lead to side effects, while the downstream mediators of TGFβ signaling Because SMAD3 contains a DNA-binding domain, it can directly bind to the promoter in the target gene to regulate transcription, but SMAD2 and SMAD4 do not have these functions. In addition, SMAD3 has the ability to regulate the expression of key target proteins in tumor immunotherapy. For example, SMAD3 can up-regulate the expression of programmed death receptor 1 (PD-1) on T cells, but SMAD2 cannot up-regulate the expression of PD-1; target The silencing o...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D487/04C07D401/06A61K31/4725A61K31/519A61K31/437A61K31/496A61K31/506A61K31/45A61K31/444A61K31/497A61P35/00
CPCA61P35/00C07D401/06C07D471/04C07D487/04
Inventor 余细勇蓝辉耀胡文辉杨忠金武楠楠
Owner GUANGZHOU MEDICAL UNIV
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