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Pyrrolotriazine compounds and applications thereof

A compound, pyrrole technology, applied in the direction of active ingredients of heterocyclic compounds, drug combination, organic chemistry, etc.

Active Publication Date: 2020-04-17
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] HDACs targets are a class of anti-tumor targets with promising applications. The existing HDACs inhibitors still cannot fully meet the clinical needs. It is yet to be discovered that structurally novel and selective HDACs inhibitors can be used to prevent and / or treat diseases associated with histone depletion. Diseases associated with uncontrolled activity of acetylases, especially neoplastic diseases

Method used

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  • Pyrrolotriazine compounds and applications thereof
  • Pyrrolotriazine compounds and applications thereof
  • Pyrrolotriazine compounds and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] N-(2-aminophenyl)-4-[[[4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4 ]triazin-2-yl]thio]methyl]benzamide (I-1)

[0096]

[0097] Step a: Preparation of 1-amino-1H-pyrrole-2-carboxylic acid methyl ester (1)

[0098] Preparation of monochloramine ether solution: at -25°C, slowly add ammonium chloride (8.00g, 0.150mol) to ether (100mL), add ammonia water (15mL), at -10°C, within 15min Slowly add sodium hypochlorite solution (100mL) dropwise, continue to stir for 15 minutes after the addition, stop the reaction, let it stand for 3 minutes, quickly separate the organic layer, and dry it with anhydrous magnesium sulfate at -25°C for 1 hour, this is the diethyl ether of monochloramine solution.

[0099] Dissolve methyl 1H-pyrrole-2-carboxylate (1.00g, 7.99mmol) in anhydrous tetrahydrofuran (15mL), react for 15min under nitrogen protection, add anhydrous tetrahydrofuran dissolved in sodium hydrogen (1.20g, 50.00mmol) The suspension (45 mL) was reacted at room te...

Embodiment 2

[0115] N-(2-amino-4-fluorophenyl)-4-[[[4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1 , 2,4] Triazin-2-yl] sulfur] methyl] benzamide (I-2)

[0116]

[0117] Step a: N-(2-amino-4-fluorophenyl)-4-[[[4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f ][1,2,4]triazin-2-yl]thio]methyl]benzamide (I-2)

[0118] Add 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared above into a 25mL eggplant-shaped bottle, add N,N-dimethylformamide (10mL), and then add N,N-diisopropyl Ethylamine (204 mg, 1.58 mmol) was stirred at room temperature for 1 h, then p-fluoro-o-phenylenediamine (55 mg, 0.43 mmol) was added, and stirring was continued at room temperature for 4 h. TLC detected that the reaction was complete. Add water (80mL) to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic layers, wash with saturated brine (50mL) and add anhydrous sodium sulfate to dry, let stand, filter, evaporate the solvent under reduced pressure, silica gel column After sep...

Embodiment 3

[0120] N-(2-aminophenyl)-4-[[[4-[(1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazine-2 -yl]sulfur]methyl]benzamide (I-3)

[0121]

[0122] Step a: 4-[[[4-[(1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]thio]methyl ] Preparation of ethyl benzoate (6b)

[0123] 5 (500 mg, 1.44 mmol) prepared above was dissolved in N,N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70° C. for 5 minutes. Then N,N-diisopropylethylamine (929mg, 7.19mmol) and 3-aminopyrazole (239mg, 2.88mmol) were added, reacted at 80°C for 36h, and the reaction was complete by TLC detection. Add water (80mL) to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic layers, wash with saturated brine (50mL) and add anhydrous sodium sulfate to dry, let stand, filter, evaporate the solvent under reduced pressure, silica gel column After separation by chromatography (petroleum ether: ethyl acetate = 3:1), 314 mg of white solid was obtai...

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Abstract

The invention belongs to the field of medical chemistry, and particularly relates to a class of lactam-based histone deacetylase inhibitors and a preparation method thereof, a pharmaceutical composition containing the histone deacetylase inhibitor, and applications of the inhibitors in drugs for preventing and / or treating diseases related to histone deacetylase activity out-of-control.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of histone deacetylase inhibitors having a pyrrolo[2,1-f][1,2,4]triazine structure, a preparation method, and a histone deacetylase inhibitor containing the histone deacetylase A drug combination of acetylase inhibitors, and the use of such inhibitors in drugs for the prevention and / or treatment of diseases related to uncontrolled histone deacetylase activity. Background technique [0002] The orderly transcriptional regulation of genes is the prerequisite for the cells of the body to maintain normal functions. If the transcriptional regulation of genes is dysfunctional, the cells may become cancerous. The acetylation and deacetylation of core histones are closely related to gene regulation, and responsible for histone acetylation and deacetylation is a pair of proteases with mutually antagonistic functions—histone acetyltransferases (HATs) and histone deacet...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61P35/02A61K31/53A61K31/5377
CPCC07D487/04A61P35/00A61P35/02A61K31/5377A61K31/53
Inventor 陆涛陈亚东朱雍李红玫耿爱新崔昊钮家琪戴炜辰
Owner CHINA PHARM UNIV
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