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Nitrogen-containing heterocyclic ring compounds, and preparation method, pharmaceutical compositions and application thereof

A nitrogen heterocycle and compound technology, applied in the field of nitrogen-containing heterocycle compounds, can solve the problems of weak binding between bromodomain and acetylated protein, influence of druggability, etc.

Inactive Publication Date: 2018-05-25
KAIHUI SCI & TECH DEV SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, the conserved water molecules at the bottom of the pocket have a significant impact on druggability
Binding of bromodomains to acetylated proteins is generally weak (K D values ​​on the lower micromolar to millimolar scale), which also increases the likelihood of finding potential inhibitors

Method used

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  • Nitrogen-containing heterocyclic ring compounds, and preparation method, pharmaceutical compositions and application thereof
  • Nitrogen-containing heterocyclic ring compounds, and preparation method, pharmaceutical compositions and application thereof
  • Nitrogen-containing heterocyclic ring compounds, and preparation method, pharmaceutical compositions and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0368] Example 1: N-(4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2- c] pyridin-7-yl) phenyl) ethanesulfonamide (I-1)

[0369]

[0370] Step 1: 2-Bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene

[0371]

[0372] 2-Bromo-1-fluoro-4-nitrobenzene (6.60g, 30.00mmol), 2,4-difluorophenol (3.90g, 30.00mmol) and cesium carbonate (19.50g, 60.00mmol) were dissolved in dimethyl sulfoxide (70 mL) and stirred at 110°C for 2 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (60*3 mL). The organic phase was washed with water and brine, dried (anhydrous sodium sulfate), filtered and concentrated to give the crude title compound (9.90 g, 100%), which was directly used in the next reaction.

[0373] Step 2: 3-Bromo-4-(2,4-difluorophenoxy)aniline

[0374]

[0375] Compound 1A (9.9g, 30.00mmol), iron powder (8.40g, 150.00mmol) and ammonium chloride (3.21g, 60.00mmol) were dissolved in a mixture of tetrahydrofuran / ethanol / wate...

Embodiment 2

[0409] Example 2: N-(4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2- c] pyridin-7-yl) phenyl) -N-methylethanesulfonamide (I-2)

[0410]

[0411] Step 1: N-(4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy) Methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)-N-methylethanesulfonamide

[0412]

[0413] Compound 1L (100mg, 0.17mmol) was dissolved in N,N-dimethylformamide (2mL), slowly added dropwise to sodium hydride (60% oil dispersion, 14mg, 0.34 mmol) in N,N-dimethylformamide (2 mL) solution. The reaction solution was stirred at 0°C for 30 minutes, then methyl iodide (37 mg, 0.26 mmol) was added, and the mixture was raised to room temperature and stirred for 2 hours. Water was added to the reaction system and extracted with ethyl acetate, the ethyl acetate layer was separated, washed with water and saturated brine, dried (anhydrous sodium sulfate), filtered and concentrated in vacuo to give the title compound (120mg, 6...

Embodiment 3

[0417] Example 3: N-(4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3 ,2-c]pyridin-7-yl)phenyl)ethanesulfonamide (I-3)

[0418]

[0419] Step 1: 7-Bromo-4-methoxy-1-methyl-1H-pyrrolo[3,2-c]pyridine

[0420]

[0421] Compound 1G (400mg, 1.76mmol) was dissolved in tetrahydrofuran (4mL), and slowly added dropwise to a solution of sodium hydride (60% oil dispersion, 140mg, 3.52mmol) in tetrahydrofuran (4mL) at 0°C under nitrogen protection middle. The reaction solution was stirred at 0°C for 30 minutes, then iodomethane (374 mg, 2.64 mmol) was added, and stirring was continued at 0°C for 2 hours. Water was added to the reaction system and extracted with ethyl acetate, the ethyl acetate layer was separated, washed with water and saturated brine, dried (anhydrous sodium sulfate), filtered and concentrated in vacuo, the residue was separated and purified by flash chromatography (petroleum ether / ethyl acetate=10 / 1), the title compound (480 mg, 91%) was ...

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Abstract

The invention discloses nitrogen-containing heterocyclic ring compounds, and a preparation method, pharmaceutical compositions and application thereof. The nitrogen-containing heterocyclic ring compounds as shown in a formula II which is described in the specification can effectively bind to the bromodomains of BRD4, BRD3, BRD2 and BRDT in the BET family so as to regulate the transcription of thedownstream gene c-myc and related target genes thereof, thereby regulating downstream signal pathways and playing specific roles, including treatment of diseases such as inflammatory diseases, cancersand AIDS; and a part of the compounds have high activity, and good cell activity and metabolic stability, and thus can be used as effective drugs for treating tumors.

Description

technical field [0001] The invention relates to a nitrogen-containing heterocyclic compound, its preparation method, pharmaceutical composition and application. Background technique [0002] Tumor is one of the main causes of human death worldwide in recent years. The overall cure rate of tumors is low and the recurrence rate is high, so the treatment of tumors has important value. [0003] The abnormality of epigenetic regulation is one of the important factors leading to tumorigenesis. Epigenetics refers to changes in gene expression levels based on non-gene sequence changes, including DNA methylation, histone modification, chromosome remodeling and non-coding RNA regulation, etc., mainly through the regulation of gene transcription or translation process, affecting its functions and properties. Histones are the core of chromatin and participate in post-transcriptional modifications, mainly including acetylation, methylation, phosphorylation and ubiquitination. [0004...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D487/04A61K31/519A61K31/437A61K31/5377A61K31/551A61K31/496A61K31/444A61P11/00A61P29/00A61P37/06
CPCA61K31/395A61K31/437A61K31/444A61K31/496A61K31/519A61K31/5377A61K31/551A61P11/00A61P29/00A61P31/18A61P35/00A61P37/06C07D471/04C07D487/04
Inventor 胡永韩朱久香林凯文蔡冬梅董平黄玮李曼华董加强王铁林
Owner KAIHUI SCI & TECH DEV SHANGHAI
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