4,5-substituted imidazolyl compounds for the treatment of...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S398000, C548S254000, C548S311700, C548S342100, C548S333500, C548S334500, C548S337100, C548S338100, C548S341100, C548S342500, C548S325500, C548S325100, C548S345100, C548S343500, C548S343100

Reexamination Certificate

active

06426360

ABSTRACT:

FIELD OF THE INVENTION
This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis.
BACKGROUND OF THE INVENTION
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG
2
, PGH
2
and PGE
2
, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDS) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H synthase II”) provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel imidazoles disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts. The invention compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects. The substituted imidazoles disclosed herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
U.S. Pat. No. 4,822,805, to Takasugi et al., describes pyridyl-imidazoles as antiinflammatory agents. Specifically, 2-[2-methoxy-4-(methylsulfonyl)phenyl-4-methyl-5-(3-pyridyl) imidazole is described.
U.S. Pat. No. 4,188,397, to Hill, describes 2,2-alkyldiylbis(thio)bis(imidazoles) with substituted phenyl radicals at the 4 and 5 positions of the imidazole rings as having antiinflammatory activity. Specifically, imidazoles having phenyl radicals substituted with methoxy, methylthio, trifluoromethylhalo and methylenedioxy are described.
T. Sharpe et al. [
J.Med. Chem
., 28, 1188 (1985)] describe antiarthritic activity of 4,5-diaryl-2-(substituted thio)-1H-imidazoles.
U.S. Pat. No. 4,686,231, to Bender et al., describes 4,5-diaryl-1H-imidazoles as inhibiting the 5-lipoxygenase pathway for the treatment of arthritis. 1-Methyl-4,5-bis(methoxyphenyl)-2-methylthio-1H-imidazole is specifically described.
Australian publication AU8665565 describes cyano-2,2-bis(imidazoles) as having antihypertensive agents.
WO 93/14082, published Jul. 22, 1993, describes 1-pyridyl-2-phenyl-imidazole derivatives for the treatment of interleukin-1 mediated diseases.
H. Greenberg et al. [
J.Org.Chem
., 31, 3951 (1966)] describe 4-(2-oxo-5-phenyl-4-imidazolin-4-yl)benzenesulfonamide in a study of the bromination reaction thereof.
T. van Es and O. Backeberg [
J. Chem. Soc
., 1363 (1963)] describe the synthesis of 4,4′-imidazol-4,5-diyl]bis(benzenesulfonamide) for use in a study of substitution reactions on phenyl radicals.
European publication EP 372,445, published Jun. 13, 1990, describes 4,5-diaryl-1H-imidazoles as having antihypercholesterolemic activity. N-C[[5-(4-Methylsulfonylphenyl)-4-phenyl-1H-imidazol-2-yl]thio]pentyl-N-octyl-N-heptylurea is specifically described. U.S. Pat. No. 5,364,875, to Wilde, describes substituted imidazoles for the treatment of atherosclerosis. U.S. Pat. No. 5,358,946, to Wilde, describes substituted imidazoles for the treatment of atherosclerosis. U.S. Pat. No. 5,310,748, to Billheimer et al., describes substituted imidazoles for the treatment of atherosclerosis. U.S. Pat. No. 5,166,214, to Billheimer et al., describes substituted imidazoles for the treatment of atherosclerosis. T. Maduskuie et al., [
J. Med. Chem
., 38, 1067 (1995)] describes substituted imidazoles as acyl-CoA:Cholesterol Acyltransferase inhibitors
U.S. Pat. No. 4,503,065, to Wilkerson, describes 4,5-diaryl-2-halo-1H-imidazoles as being antiinflammatory. Specifically, 1-(1-ethoxyethyl)-2-fluoro-4,5-bis(4-methylsulfonylphenyl)-1H-imidazole is described.
J. Lombardino (
J. Med. Chem
., 17, 1182 (1974)) describes trisubstituted imidazoles as being antiinflammatory, and specifically 4,5-bis(4-methoxyphenyl)-2-trifluoromethyl-1H-imidazole. Similarly, U.S. Pat. No. 3,707,475, to Lombardino, describes antiinflammatory 4,5-diarylimidazoles. Specifically, 4-chlorophenyl-5-(4-methylthiophenyl)-2-trifluoromethyl-1H-imidazole is described.
U.S. Pat. No. 4,472,422, to Whitney, describes 4,5-diaryl-1H-imidazole-2-methanamines as having antiinflammatory activity. Specifically, 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-&agr;,&agr;-bis(trifluoromethyl)-1H-imidazole-2-methanamine is described.
U.S. Pat. No. 4,372,964, to Whitney, describes 4,5-diaryl-1H-imidazole-2-methanols as having antiinflammatory activity. Specifically, 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-&agr;,&agr;-bis(trifluoromethyl)-1H-imidazole-2-methanol is described. Additionally, Whitney describes 1-[4,5-diaryl-1H-imidazol-2-yl]-2,2,2-trifluoro-1-ethanones as having antiinflammatory activity. Specifically, 1-[5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-1H-imidazol-2-yl]-2,2,2-trifluoro-1-ethanone is described.
U.S. Pat. No. 4,576,958, to Wexler, describes 4-phenyl-5-(4-methylsulfonylphenyl)-1H-imidazoles as having antiinflammatory activity. Specifically, 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-&agr;,&agr;-bis(trifluoromethyl)-1H-imidazole-2-methanol and 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-&agr;,&agr;-bis(trifluoromethyl)-1H-imidazole-2-methanol, acetate is described. U.S. Pat. No. 4,632,930, to Carini et al., claims cycloalkyl substituted imidazoles, and specifically 4-cyclopentyl-5-(4-methylsulfonyl)-&agr;,&agr;-bis(trifluoromethyl)-1H-imidazole-2-methanol, as having antihypertensive properties.
U.S. Pat. No. 3,901,908, to Fitzi, et al., describes 2-alkyl-4,5-bis(substituted phenyl)-1H-imidazoles. Specifically, 2-tert-butyl-4-(4-methylsulfonylphenyl)-5-phenyl-1H-imidazole is described. French patent 2,081,407 describes 4,5-phenyimidazoles as antiinflammatory agents.
4,5-Diarylimidazoles have been described in WO95/00501, published Jan. 5, 1995, as having antiinflammatory activity.
The invention's imidazolyl compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects.
DESCRIPTION OF THE INVENTION
A class of substituted imidazolyl compounds useful in treating inflammation-related disorders is defined by Formula I:
wherein R
1
is selected from alkyl, haloalkyl, aralkyl, heterocyclicalkyl, heteroaralkyl, acyl, cyano, mercapto, alkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, halo, hydroxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, cyanoalkyl, aralkenyl, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-alkyl-N-aryl-aminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, haloalkylcarbonyl, carboxyl, alkoxyalkyl, alkenyloxyalkyl, aminocarbonyl, alkylaminocarbonyl, alkylaminocarbonylalkyl, heteroaralkoxyalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl, aralkoxy, aralkylthio, heteroaralkoxy, heteroaralkylthio, heteroaryloxy, heteroarylthio, arylthioalkyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, aryloxyalkyl, arylthio, aryloxy, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl radicals are optionally substituted at a substitutab

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