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Nitrogen-containing macrocyclic compound as well as preparation method and medicinal composition and application thereof

A technology for macrocycles and compounds, applied in the field of nitrogen-containing macrocycles, can solve the problems of weak binding between bromodomains and acetylated proteins, and the influence of druggability.

Inactive Publication Date: 2018-05-25
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +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 macrocyclic compound as well as preparation method and medicinal composition and application thereof
  • Nitrogen-containing macrocyclic compound as well as preparation method and medicinal composition and application thereof
  • Nitrogen-containing macrocyclic compound as well as preparation method and medicinal composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 4003

[0679] Example 4003: 6-(4-fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-5-oxo-2,4,5,6-tetrahydrobenzo[b]pyrrole And[3,4-d]azepine-3-carbonitrile

[0680]

[0681] Step 1: 1-(Methylsulfonemethyl)-4-nitrobenzene

[0682]

[0683] 4-Nitrobenzyl bromide (10.0 g, 46.4 mmol) was dissolved in N,N-dimethylformamide (25 mL), then sodium methylsulfinate (7.10 g, 69.6 mmol) was added. The reaction solution was stirred at 65°C for 1 hour, cooled to room temperature, diluted with water, continued to stir for 10 minutes, filtered and dried to give the title compound (9.7 g, 97%) as a white solid.

[0684] Step 2: 4-(Methylsulfonemethyl)aniline

[0685]

[0686] Dissolve 1-(methylsulfonemethyl)-4-nitrobenzene (9.7g, 45.1mmol), iron powder (12.6g, 225.6mmol) and ammonium chloride (28.4g, 451.1mmol) in ethanol (120mL) and water (60 mL), and stirred at 90°C for 2 hours. The solids were filtered off and the filtrate was concentrated. The residue was redissolved in ethyl acetate (5...

Embodiment 4001

[0716] Example 4001: 6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-5-oxo-2,4,5,6-tetrahydrobenzo[b]pyrrole And[3,4-d]azepine-3-carboxamide

[0717]

[0718] 6-(4-fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-5-oxo 2,4,5,6-tetrahydrobenzo[b]pyrrolo[3, 4-d] Azepine-3-carbonitrile (42mg, 0.099mmol) and potassium carbonate (41mg, 0.297mmol) were dissolved in dimethylsulfoxide (2mL), then 30% aqueous hydrogen peroxide (0.5mL) was added , and the reaction solution 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 (17.7 mg, 40%) was obtained as a white solid. LCMS(ESI)[M+H] + = 442.1; 1 H NMR (400MHz, DMSO-d 6 )δ7.54(s,1H),7.46-7.25(m,3H),7.23-7.13(m,3H),7.10-7.01(m,2H),6.9...

Embodiment 4004

[0719] Example 4004: 6-(4-fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4 -d]azepine-3-carbonitrile

[0720]

[0721] 6-(4-fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-5-oxo 2,4,5,6-tetrahydrobenzo[b]pyrrolo[3, 4-d] Azepine-3-carbonitrile (50mg, 0.118mmol) was dissolved in tetrahydrofuran (5mL), and borane (1M solution in tetrahydrofuran, 0.5mL) was added at 0°C under nitrogen protection, and then warmed to room temperature Stir for 1 hour. Methanol (5 mL) was added to the reaction solution, the reaction solution was concentrated, and the residue was separated and purified by preparative-HPLC to obtain the title compound (14.6 mg, 30%) as a white solid. LCMS(ESI)[M+H] + = 410.1; 1 H NMR (400MHz, DMSO-d 6 )δ7.84(s,1H),7.62(s,1H),7.25-7.19(m,2H),6.98(t,J=7.2Hz,3H),6.76-6.70(m,2H),4.48(s ,2H),3.88(t,J=4.4Hz,2H),3.75(s,3H),3.01(t,J=4.4Hz,2H),2.96(s,3H).

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Abstract

The invention discloses a nitrogen-containing macrocyclic compound as well as a preparation method and a medicinal composition and application thereof. The invention provides the nitrogen-containing macrocyclic compound shown in the formula III-0, as well as a tautomer, an optical isomer, a hydrate, a solvent and pharmaceutical acceptable salts or predrug of the nitrogen-containing macrocyclic compound. The compound can be effectively combined with the bromodomain of BRD4, BRD3, BRD2 and BRDT in BET family so as to regulate and control the transcription of the downstream gene c-myc and relatedtarget genes thereof, and further a signaling pathway of the downstream is adjusted and a specific role is played, including treatment of diseases such as inflammatory diseases, cancer and AIDS (Acquired Immune Deficiency Syndrome). (The formula is shown in the description).

Description

technical field [0001] The invention relates to a nitrogen-containing macrocyclic 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): C07D487/04C07D471/14C07D471/04C07D471/10A61K31/55A61K31/551A61P35/00A61P35/02
CPCC07D471/04C07D471/10C07D471/14C07D487/04A61P29/00A61P35/00A61P35/02A61K31/55A61K31/551C07D487/14
Inventor 胡永韩朱久香蔡冬梅董平董加强王铁林
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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