Aromatic-ring-containing compound, preparation method thereof, pharmaceutical composition and application thereof

A compound and aromatic ring technology, applied in the field of aromatic ring-containing compounds, can solve problems such as the influence of druggability

Inactive Publication Date: 2018-07-24
KAIHUI SCI & TECH DEV SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, the conserved water molecules at the bottom

Method used

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  • Aromatic-ring-containing compound, preparation method thereof, pharmaceutical composition and application thereof
  • Aromatic-ring-containing compound, preparation method thereof, pharmaceutical composition and application thereof
  • Aromatic-ring-containing compound, preparation method thereof, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0358] Example 1: 6-(3,5-dimethylisoxazol-4-yl)-1-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[ d] imidazole-4-carbonitrile

[0359]

[0360] Step 1: 4-Methyl-N'-(phenyltetrahydro-2H-pyran-4-yl)methylene)benzenesulfonylhydrazide

[0361]

[0362] Phenyl(tetrahydro-2H-pyran-4-yl)methanone (1.9g, 10mmol) and 4-methylbenzenesulfonic acid (172mg, 1mmol) were dissolved in methanol (30mL), then 4-methyl Benzenesulfonyl hydrazide (1.99 g, 10.7 mmol). The reaction solution was stirred overnight at 50°C under nitrogen protection, then cooled to room temperature, and stirred for another 10 minutes. Filtration afforded the crude title compound (3.5 g, 93%) as a white solid. LCMS(ESI)[M+H] + =359.2.

[0363] Step 2: 2-Bromo-4-iodo-6-nitroaniline

[0364]

[0365] Dissolve 2-bromo-6-nitroaniline (5.65g, 26.0mmol) in acetic acid (40mL), then add N-iodosuccinimide (5.4g, 31.2mmol), and stir the reaction solution at 50°C overnight , then cooled to room temperature. Water...

Embodiment 2

[0381] Example 2: 6-(3,5-dimethylisoxazol-4-yl)-1-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[ d] imidazole-4-carboxamide

[0382]

[0383] Step 1: 6-(3,5-Dimethylisoxazol-4-yl)-1-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d ]imidazole-4-carboxamide

[0384]

[0385] Example 1 (56 mg, 0.140 mmol) and potassium carbonate (50 mg, 0.362 mmol) were dissolved in dimethyl sulfoxide (2 mL), and then 30% aqueous hydrogen peroxide (0.5 mL) was added. The reaction was stirred at room temperature for 3 hours. The reaction was quenched with water 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 reverse phase prep-HPLC. The title compound (8.2 mg, yield 14%) was obtained as a white solid. LCMS(ESI)[M+H] + = 431.2; 1 H NMR (400MHz, DMSO-d 6 )δ9.11(d, J=3.6Hz, 1H), 9.05(s, 1H), 8.06(d, J=1.6Hz,...

Embodiment 3

[0386] Example 3: 3,5-Dimethyl-4-(1-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-4-(1H-pyrazol-4-yl)- 1H-Benzo[d]imidazol-6-yl)isoxazole

[0387]

[0388] Step 1: 3,5-Dimethyl-4-(1-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-4-(1H-pyrazol-4-yl)-1H -Benzo[d]imidazol-6-yl)isoxazole

[0389]

[0390] Compound 1F (112mg, 0.24mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) Isoxazole (70mg, 0.36mmol), sodium carbonate (104mg, 0.96mmol) and tetrakistriphenylphosphine palladium (56mg, 0.048mmol) were dissolved in 1,4-dioxane (6mL) and water (1.5mL) , microwave heated to 100°C, and stirred for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by preparative-HPLC to obtain the title compound (7.8 mg, 7%) as a white solid. LCMS(ESI)[M+H] + =...

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Abstract

The invention discloses an aromatic-ring-containing compound, a preparation method thereof, a pharmaceutical composition and application. The present invention provides the aromatic-ring-containing compound represented by a formula 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or a solvate thereof, and the aromatic-ring-containing compound can be effectively bounded to bromodomains of BRD4, BRD3, BRD2, and BRDT in BET family to regulate transcription of downstream gene c-myc and related target genes of the c-myc so as to regulate downstream signalingpathways to play specific roles including treatment of diseases such as inflammatory diseases, cancer, and AIDS. Some of the compounds have high activity, and have good cell activity and metabolic stability, so that the compounds can be an effective drug for treating tumors.

Description

technical field [0001] The invention relates to an aromatic ring-containing 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] The ...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D405/14C07D401/14C07D403/04C07D471/04A61K31/422A61K31/4192A61K31/4439A61K31/444A61K31/437A61P11/00A61P29/00A61P37/02A61P35/00A61P35/02A61P11/06A61P9/10A61P17/00A61P13/12A61P1/00A61P1/16A61P37/06A61P19/02A61P19/08A61P17/06A61P5/14A61P3/10
Inventor 胡永韩蔡冬梅朱久香董平李曼华林凯文董加强王铁林
Owner KAIHUI SCI & TECH DEV SHANGHAI
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