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Inhibitors of bromodomains as modulators of gene expression

A group and alkyl technology, applied in the field of inhibitors of bromodomain proteins as regulators of gene expression, can solve problems such as unfavorable hyperactivation

Inactive Publication Date: 2014-01-29
MT SINAI SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While p53 activation has been recognized to have therapeutic potential in cancer treatment, its hyperactivation can also be detrimental in normal and defective pathologies

Method used

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  • Inhibitors of bromodomains as modulators of gene expression
  • Inhibitors of bromodomains as modulators of gene expression
  • Inhibitors of bromodomains as modulators of gene expression

Examples

Experimental program
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preparation example Construction

[0158] Preparation of compounds may involve protection and deprotection of various chemical groups. The need for protection and deprotection and the choice of suitable protecting groups can be readily selected by one skilled in the art. The chemistry of protecting groups can be found, for example, in: Protecting Group Chemistry, First Edition, Oxford University Press, 2000; and March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience Publication, 2001 (each of which is incorporated herein by reference in its entirety).

[0159] The reaction can be monitored by any suitable method in the art, for example product formation can be monitored by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (UV-visible), mass spectrometry; or by chromatography, such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) ...

Embodiment 1

[0290] Embodiment 1. Preparation of the compound represented by formula (1).

[0291] A. Steps for preparing building blocks and intermediates of compounds represented by formula (1).

[0292]

[0293] Reference: BMCL 2008, 18(23)6093-6096

[0294] A solution of 2-aminopyridine (1.0 g, 10.6 mmol) in pyridine (5 mL) was cooled to 0°C and treated in portions with p-iodobenzenesulfonyl chloride (3.37 g, 11.2 mmol). The solution was heated to 60°C for 1 hour and then cooled to 25°C. Most of the solvent was removed under vacuum, and the residue was dissolved in a small amount of MeOH (20 mL) and H 2 O (100mL) suspended. The white solid that had formed was collected by suction filtration. The solid is dissolved in a small amount of CH 2 Cl 2 , and precipitated by adding hexane to give the final compound as a white solid (3.34 g, 87%) which was used without further purification. 1 H NMR (600MHz, DMSO-d 6 )δ7.97(1H,d,J=4.8Hz),7.91(2H,d,J=8.4Hz),7.75(1H,t,J=7.2Hz),7.61(2H,d,...

Embodiment CM278

[0303]

[0304] Will be in DMF:Et 3 A solution of starting material (0.807 g, 2.24 mmol, 1.1 equiv, iodide) in N (6.0 mL) was treated with Pd(OAc) 2 (0.091g, 0.406mmol, 0.02 equivalent), P-(o-tolyl) 3 (0.371g, 1.22mmol, 0.06eq) and the alkene product (0.508g, 2.03mmol, 1eq) worked up. The solution was heated to 100° C. for 2 hours in a microwave tube. The resulting solution was then filtered, concentrated in vacuo and purified by flash chromatography (0-3% MeOH-CH 2 Cl 2 ) to give CM278 (1.11 g, 99%) as a clear oil. 1 H NMR (600MHz, CDCl 3 )δ8.36(1H,d,J=5.4Hz),7.89(2H,d,J=8.4Hz),7.71(1H,t,J=7.8Hz),7.53(2H,d,J=8.4Hz) ,7.45(1H,d,J=9.0Hz),7.30(1H,s),7.16(1H,d,J=16.2Hz),6.86(1H,d,J=16.2Hz),6.83(1H,t, J=6.0Hz),6.52(1H,s),2.18(3H,s),1.51(9H,s).LCMS m / z482.1496([M+H + ],C 25 h 27 N 3 o 5 S requires 482.1744).

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Abstract

This disclosure relates generally to compounds and compositions comprising one or more diphenylethylene, diphenylethylyne, and azobenzene analogs. These compounds are useful for treating diseases associated with NF-kB and p53 activity, such as cancer and inflammatory disease.

Description

[0001] Cross references to related patent applications [0002] This patent application claims priority to US Application No. 61 / 445,859, filed February 23, 2011, which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federal Funding for Research or Development [0004] The United States Government has certain rights in this invention pursuant to Grant No. R01HG004508-03 issued by the National Institutes of Health / National Human Genome Research Institute. technical field [0005] In general, the present invention relates to compounds and compositions comprising one or more stilbene, diphenylethylene and azobenzene analogs. These compounds are useful in the treatment of diseases associated with NF-κB and p53 activity, such as cancer and inflammatory diseases. Background technique [0006] Cardiovascular disease continues to be an epidemic in the United States and Western countries. Myocardial ischemia is primarily due to coronary syndromes,...

Claims

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Application Information

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IPC IPC(8): A01N27/00A61K31/015
CPCA61K31/18C07D213/76A61K45/06C07C311/44A61K2300/00
Inventor M·M·周迈克尔·奥尔迈尔希拉兹·穆杰塔巴亚历山大·普洛特尼科夫大卫·卡斯特里斯基G·T·张
Owner MT SINAI SCHOOL OF MEDICINE
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