Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-05
2003-09-02
Solola, Taofiq (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S399000, C514S314000, C514S341000, C514S396000, C514S398000, C514S400000, C544S139000, C546S184000, C546S334000, C548S311400, C548S315100, C548S315400, C548S323500, C548S325500
Reexamination Certificate
active
06613789
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.
Diaryl oxazoles have been described in WO patent publication WO94/27980 as having antiinflammatory activity. Substituted 4,5-diarylimidazoles have been described in WO95/00501 and in copending U.S. application Ser. No. 08/281,903.
2-Alkylimidazoles have been described as having angiotensin II activity. For example, see U.S. Pat. No. 5,185,351 and WO 91/00277.
U.S. Pat. No. 5,207,820 to Wriede et al. describes 1-arylimidazole carboxylic esters as herbicide safeners. Specifically, ethyl [1-[2,6-dinitro-4-(methylsulfonyl)phenyl]-2-methyl-1H-imidazol-3-yl]carboxylate is described.
WO 93/14082, published Jul. 22, 1993, describes 1-pyridyl-2-phenyl-imidazole derivatives for the treatment of interleukin-1 mediated diseases. 1-(4-Pyridyl)-2-(4-fluorophenyl)-4-methylimidazole is described. WO 95/02591, published Jan. 26, 1995, describe tri-substituted imidazoles for the treatment of cytokine mediated diseases.
U.S. Pat. No. 3,487,087, to Sarett et al., describes a method of nitration of imidazoles and specifically 1-methyl-2-[4-(methylsulfonyl)phenyl]-5-nitroimidazole.
U.S. Pat. No. 5,112,532, to Ninomiya et al., describes imidazoles as an organic non-linear optical material. Specifically, 4-(4-hydroxyphenyl)-2-[2-formyl-4-(methylsulfonyl)phenyl]imidazole is described.
U.S. Pat. Nos. 3,682,949 and 3,719,759, to Sarett et al., describe 2-aryl-nitroimidazoles as agents for the treatment of parasites and bacteria. Specifically, 1-(2-hydroxyethyl)-2-(4-sulfonamidophenyl)-5-nitroimidazole is described.
U.S. Pat. No. 4,822,805, to Takasugi et al., describes pyridylimidazoles as antiinflammatory agents. Specifically, 2-[2-methoxy-4-(methylsulfonyl)phenyl]-4-methyl-5-(3-pyridyl)imidazole is described.
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
and R
2
are independently selected from aryl, cycloalkyl, cycloalkenyl and heterocyclo, wherein R
1
and R
2
are optionally substituted at a substitutable position with one or more radicals independently selected from alkylsulfonyl, aminosulfonyl, haloalkylsulfonyl, halo, alkylthio, alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, haloalkoxy, amino, alkylamino, arylamino and nitro;
wherein R
3
is a radical selected from hydrido, alkyl, haloalkyl, aralkyl, heterocycloalkyl, acyl, cyano, alkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylthio, cycloalkylthioalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, cycloalkyloxy, cycloalkyloxyalkyl, haloalkylsulfonyl, arylsulfonyl, halo, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, cyanoalkyl, azidoalkyl, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-alkyl-N-arylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, haloalkylcarbonyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, alkylaminocarbonylalkyl, heteroarylalkoxyalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, aralkoxy, aralkylthio, heteroaralkoxy, heteroaralkylthio, heteroarylalkylthioalkyl, heteroaryloxy, heteroarylthio, arylthioalkyl, aryloxyalkyl, arylthio, aryloxy, aralkylthioalkyl, aralkoxyalkyl, aryl and heterocyclo;
wherein R
4
is a radical selected from hydrido, alkyl and fluoro; wherein R
5
is selected from hydroxyl and alkoxy; and wherein R
6
is hydrido; or wherein R
5
and R
6
together form a double bond; provided at least one of R
1
and R
2
is substituted with alkylsulfonyl or aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin-related conditions such as psoriasis, eczema, burns and dermatitis. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis, and for the prevention or treatment of cancer, such as colorectal cancer. Compounds of the invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. The compounds would also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis, conjunctivitis, and of acute injury to the eye tissue. The compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders such as cortical dementias including Alzheimers disease. The compounds of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin sho
Collins Paul W.
Huff Renee M.
Khanna Ish K.
Koszyk Francis J.
Partis Richard A.
G. D. Searle & Co.
Solola Taofiq
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