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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 problems such as weak binding between bromodomain and acetylated protein, and influence on druggability

Inactive Publication Date: 2018-05-25
KAIHUI SCI & TECH DEV SHANGHAI +1
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  • 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

[0292] Example 1: N-(4-(2,4-Difluorophenoxy)-3-(1-oxoisoindolin-5-yl)phenyl)ethylsulfonamide (II-1)

[0293]

[0294] Step 1: 2-Bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene

[0295]

[0296] Dissolve 2-bromo-1-fluoro-4-nitrobenzene (6.60g, 30.00mmol), 2,4-difluorophenol (3.90g, 30.00mmol) and cesium carbonate (19.50g, 60.00mmol) in dimethyl Sulfoxide (70 mL) and stirred at 110 °C for 2 h. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (60*3 mL). The organic phase was washed with water and brine, dried (anhydrous sodium sulfate), filtered and concentrated to obtain the crude title compound (9.90 g, 100%), which was directly used in the next reaction.

[0297] Step 2: 3-bromo-4-(2,4-difluorophenoxy)aniline

[0298]

[0299] 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 / water (45mL / 45mL / 15mL) , Stir at 100°C for 2h. The solid was fi...

Embodiment 2

[0305] Example 2: N-(4-(2,4-Difluorophenoxy)-3-(1-oxoisoindolin-4-yl)phenyl)ethylsulfonamide (II-2)

[0306]

[0307] Step 1: N-(4-(2,4-Difluorophenoxy)-3-(1-oxoisoindolin-4-yl)phenyl)ethylsulfonamide

[0308] Compound 1C (100mg, 0.26mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)isoindolin-1-one (85mg, 0.33mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20mg, 0.03mmol) and potassium carbonate (88mg, 0.64mmol) dissolved in 1, In 4-dioxane (2mL), and stirred overnight at 110°C under nitrogen protection. The reaction solution was concentrated, and the residue was separated and purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) using the residue to obtain the title compound (80 mg, 71%) as a white solid. MS(ESI): m / z=391.2[M+1] + . 1 H NMR(400MHz, DMSO-d 6 )δ9.81(s,1H),8.63(s,1H),7.67(s,1H),7.56(s,2H),7.30(t,J=19.9Hz,3H),7.02(d,J=24.7 Hz, 3H), 4.33 (s, 2H), 3.14 (s, 2H), 1.22 (s, 3H).

Embodiment 3

[0309] Example 3: N-(4-(2,4-Difluorophenoxy)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6- (Yl)phenyl)ethylsulfonamide (II-3)

[0310]

[0311] Step 1: 4-(2,4-Difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)aniline

[0312]

[0313] Compound 1B (3.00g, 10.00mmol), pinacol diborate (5.18g, 20.00mmol), 1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (732mg ,1.00mmol) and potassium acetate (3.00g, 30.00mmol) were dissolved in 1,4-dioxane (50mL), and the reaction solution was stirred at 100°C under nitrogen protection for 2h. The reaction solution was concentrated, and the residue was separated and purified by flash chromatography (ethyl acetate / petroleum ether = 1 / 9) to obtain the title compound (3.50 g, 90%) as a yellow oil. LCMS(ESI)[M+H] + =348.2.

[0314] Step 2: 6-Bromo-3-methyl-3,4-dihydroquinazolin-2(1H)-one

[0315]

[0316] To a solution of 3-methyl-3,4-dihydroquinazolin-2(1H)-one (1.0g, 61.7mmol) in dichloromethane (25mL) was slowly added N-br...

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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] Tumors are one of the main causes of human death worldwide in recent years. The overall tumor cure rate is low and the recurrence rate is high, so the treatment of tumors has important value. [0003] Abnormal epigenetic regulation is one of the important factors leading to tumorigenesis. Epigenetics refers to changes in gene expression levels based on changes in non-gene sequences, including DNA methylation, histone modification, chromosome remodeling, and non-coding RNA regulation. It mainly affects the process of gene transcription or translation. Its functions and characteristics. Histones are the core of chromatin and participate in post-transcriptional modification, including acetylation, methylation, phosphorylation and ubiquitination. [0004] The bromodomain is an evolutionarily high...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D209/48C07D239/80C07D209/46A61K31/517A61K31/437A61K31/5025A61K31/404A61P11/00A61P29/00A61P37/06
CPCA61K31/404A61K31/437A61K31/5025A61K31/517A61P11/00A61P29/00A61P37/06C07D209/46C07D209/48C07D239/80C07D471/04C07D487/04
Inventor 胡永韩蔡冬梅董平朱久香林凯文黄玮李曼华董加强王铁林
Owner KAIHUI SCI & TECH DEV SHANGHAI
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