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Inhibitors of transcription factor NF-kappaB

a transcription factor and inhibitor technology, applied in the field of salicylanilide inhibitors of transcription factor nfb, can solve problems such as organ destruction

Inactive Publication Date: 2006-02-16
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013] An object of the present invention is to provide a method for treating diseases which may be therapeutically modified by altering the activity of transcription factor NF-κB.

Problems solved by technology

Such mediators are known to play a role in the recruitment of leukocytes at sites of inflammation and in the case of iNOS, may lead to organ destruction in some inflammatory and autoimmune diseases.

Method used

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  • Inhibitors of transcription factor NF-kappaB

Examples

Experimental program
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Effect test

example 1

Preparation of N-(4-Acetylphenyl)-2-hydroxy-5-iodocarboxamide

[0099] A solution of iodosalicylic acid (1.9 g, 7.4 mmol) and 4-aminoacetophenone (0.97 g, 7.4 mmol) in chlorobenzene (40 mL) was treated with PCl3 (0.323 mL, 3.7 mmol). The solution was heated at reflux under an argon atmosphere. After 2 h. the solution was filtered hot and the filtrate was left standing at RT. After 18 h solution was filtered and the solid was recrystallized from MeOH to give the title compound (0.095 g, 5% yield): 1H NMR (400 MHz, DMSO-d6) δ 2.5-2.6 (s, 3H), 6.8-8.2 (m, 7H), 10.1-10.2 (s, 1H).

example 2

Preparation of N-(2,4-Difluorophenyl)-2-hydroxy-5-nitrophenylcarboxamide

[0100] A solution of 5-nitrosalicylic acid (1.4 g, 7.7 mmol) and 2,4difluoroaniline (0.8 mL, 7.7 mmol) in chlorobenzene (40 mL) was treated with PCl3 (0.338 mL, 3.8 mmol). The solution was heated at reflux under an argon atmosphere. After 2 h. the solution was filtered hot and the filtrate was left standing at RT. After 18 h the solution was filtered and the solid was recrystallized from MeOH to give the title compound (0.733 g, 35% yield): 1H NMR (400 MHz, DMSO-d6) δ 2.5-2.6 (s, 3H), 7.1-8.9 (m, 6H), 10.6-10.7 (s, 1H)

example 3

Preparation of N-(2,4-Difluorophenyl)-2-hydroxy-5-iodophenylcarboxamide

a) 5-Iodosalicylic acidchloride

[0101] 5-Iodosalicylic acid (2.0 g, 7.58 mmol) in toluene was treated with SOCl2 (1.66 mL, 22.7 mmol) and catalytic DMF at reflux for 1 h. The reaction mixture was evaporated to dryness and the acid chloride used in the next step without purification.

b) 2,4-Difluorophenyl)-2-hydroxy-5-iodophenylcarboxamide

[0102] The compound of Example 3(a) (3.79 mmol) and 2,4-difluoroaniline (380 uL, 3.79 mmol) in toluene was heated at reflux for 24 h. The reaction mixture was evaporated, the residue washed with ether and the solid residue recrystallized from MeOH to give 159 mg of N-(2,4-difluorophenyl)-2-hydroxy-5-iodophenylcarboxamide. ES MS (M+H)− m / e 373.7.

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Abstract

The present invention provides pharmaceutical compositions of salicylanilide inhibitors of transcription factor NF-κB, and methods for treating diseases in which activation of NF-κB is implicated. More specifically, the present invention provides methods of treatment of a variety of diseases associated with NF-κB activation including inflammatory disorders; particularly rheumatoid arthritis, inflammatory bowel disease, and asthma; dermatosis, including psoriasis and atopic dermatitis; autoimmune diseases; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; cancer, including Hodgkin's disease; certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia Telangiestasia by administering to a patient in need thereof a compound of the present invention.

Description

FIELD OF THE INVENTION [0001] This invention relates in general to salicylanilide inhibitors of transcription factor NF-κB. Such compounds are particularly useful for treating diseases in which activation of NF-κB is implicated. More specifically, these compounds inhibit IκB phosphorylation and subsequent degradation. Such compounds are useful in the treatment of a variety of diseases associated with NF-κB activation including inflammatory disorders; particularly rheumatoid arthritis, inflammatory bowel disease, and asthma; dermatosis, including psoriasis and atopic dermatitis; autoimmune diseases; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; cancer, including Hodgkins disease; and certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia Telangiestasia. BACKGROUND OF THE INVENTION [0002] Recent advances in scientific understanding of the mediators involved in acute and chronic inflammatory diseases and cancer have le...

Claims

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Application Information

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IPC IPC(8): A61K31/165A61K31/167A61P1/00A61P9/00A61P9/10A61P11/06A61P17/00A61P17/06A61P19/02A61P19/10A61P25/28A61P29/00A61P31/18A61P35/00A61P37/02A61P37/04A61P37/06A61P43/00C07C235/64
CPCC07C235/64A61K31/165A61P1/00A61P11/06A61P17/00A61P17/06A61P19/02A61P19/10A61P25/28A61P29/00A61P31/18A61P35/00A61P37/02A61P37/04A61P37/06A61P43/00A61P9/00A61P9/10A61K31/16
Inventor CALLAHAN, JAMES F.CHABOT-FLETCHER, MARIE C.
Owner SMITHKLINE BECKMAN CORP
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