Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-13
2004-03-02
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S357000, C514S408000, C514S520000, C514S602000, C514S709000, C546S268100, C546S339000, C546S329000, C546S330000, C548S413000, C548S577000, C564S084000, C564S085000, C564S086000, C568S029000, C568S028000
Reexamination Certificate
active
06699884
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of anti-inflammatory pharmaceutical agents and generally relates to compounds, compositions and methods for treating cyclooxygenase-2 mediated disorders, such as inflammation and inflammation-related disorders. The invention particularly relates to fluoro-substituted benzenesulfonyl compounds, compositions and methods for treating cyclooxygenase-2 mediated disorders.
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. Common non-steroidal antiinflammatory drugs (“NSAIDs”) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are, however, 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.
Recently, there has been significant research into some of the roles of cyclooxygenase-2. It has been found that COX-2 is upregulated in benign and malignant tumors (K. Subbaramaiah et al.,
Proc. Soc. Exp. Biol. Med.,
216, 201 (1997)) including lung cancer (T. Hida et al.,
Anticancer Res.,
18, 775-82 (1998)), Barrett's esophagus (K. Wilson,
Cancer Res.,
58, 2929-34 (1998)) and skin cancer (S. Buckman et al.,
Carcinogenesis,
19, 723-29 (1998)). It is expressed in airway cells with implication in asthma (P. Barnes et al.,
Lung Biol. Health Dis.,
114, 111-27 (1998)). COX-2 also has a role in pre-term labor, angiogenesis (M. Tsujii et al.,
Cell,
93, 705-16 (1998)), vascular rejection (M. Bustos,
J. Clin. Invest.,
100, 1150-58 (1997)), HIV induced apoptosis (G. Bagetta et al.,
Biochem. Biophys. Res. Commun.,
244, 819-24 (1998)), neurodegeneration (T. Sandhya et al.,
Brain Res.,
788, 223-31 (1998)), inflammatory bowel disease, colitis, (I. Singer et al.,
Gastroenterology,
115, 297-306 (1998)), cerebral ischemia (S. Nogawa et al.,
Proc. Natl. Acad. Sci.,
95, 10966-71 (1998)), and hypertension (A. Nasjletti,
Hypertension,
31, 194-200 (1997)), among others.
Drugs that inhibit cyclooxygenase affect colon cancer (T. Kawamori et al.,
Cancer Res.,
58, 409-12 (1998)), allergic neuritis (K. Miyamoto et al.,
Neuro. Report,
9, 2331-34 (1998)), dementia, burn infections (M. Shoup,
J. Trauma: Inj., Infec., Crit. Care,
45, 215-21 (1998)), cytomegalovirus infectivity (E. Speir et al.,
Circ. Res.,
83, 210-16 (1998)), and lumbago (H. Bosch,
Curr. Med. Res. Opin.,
14, 29-38 (1997)), among others.
The references below disclose compounds having antiinflammatory activity and show that efforts are continuing to find a safe and effective antiinflammatory agent. WO96/19463 describes oxazoles substituted with a [(2- or 3)-halo-4-(alkylsulfonyl, aminosulfonyl or alkylaminosulfonyl)]phenyl group that selectively inhibit cyclooxygenase-2. U.S. Pat. No. 5,380,738 describes 4-fluoro-phenyl and 4-methylsulfonyl substituted oxazoles that selectively inhibit cyclooxygenase-2. U.S. Pat. No. 5,719,163 describes substituted oxazoles that selectively inhibit cyclooxygenase-2. WO96/36617 describes oxazoles that selectively inhibit cyclooxygenase-2. WO96/19462 describes oxazoles that selectively inhibit cyclooxygenase-2. WO98/11080 describes 3,4-diaryl-oxazolones that selectively inhibit cyclooxygenase-2.
EP 799,823 A1 describes 1- or 2-[3-halo-4-(methylsulfonyl, aminosulfonyl or substituted aminosulfonyl)phenyl]-pyrroles that selectively inhibit cyclooxygenase-2. U.S. Pat. No. 5,935,990 describes substituted pyrroles that selectively inhibit cyclooxygenase-2.
WO99/64415 describes 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole; 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(hydrogen, cyano, nitro, trifluoromethyl or ethoxycarbonyl)-1H-pyrazole; 2-[(4-bromophenyl) or (3-methyl-4-bromophenyl)]-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole; 4-[2-(4-bromophenyl)-4-hydroxy-4-trifluoromethyl-1H-imidazol-1-yl]-2-fluorobenzene sulfonamide; 3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-2(5H)-furanone; 3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl or aminosulfonyl)phenyl]-5-methylisoxazole; 4-(4-bromophenyl)-5-[3-fluoro-4-(methylsulfonyl or aminosulfonyl)phenyl]-2-methyl-1,3-oxazole; and 4-(3-methyl-4-bromophenyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1,3-oxazole as intermediates used in the preparation of sulfonylbenzene compounds comprising an aryl or heteroaryl substituted phenyl moiety. WO99/64415 states that the disclosed sulfonylbenzene compounds are useful in the treatment of cyclooxygenase mediated diseases.
U.S. Pat. Nos. 5,466,823, 5,504,215, 5,508,426, 5,510,496, 5,516,907, 5,521,207 and 5,760,068 describe substituted pyrazolyl benzenesulfonamides that selectively inhibit cyclooxygenase-2. U.S. Pat. No. 5,475,018 describes 1,5-diphenyl pyrazoles that selectively inhibit cyclooxygenase-2. U.S. Pat. Nos. 5,486,534 and 5,756,529 describe 3,4-substituted pyrazoles that selectively inhibit cyclooxygenase-2. U.S. Pat. Nos. 5,401,765 and 5,639,777 describe 1,4,5-trisubstituted pyrazoles that selectively inhibit cyclooxygenase-2. U.S. Pat. Nos. 5,434,178 and 5,908,852 describe 1,3,5-trisubstituted pyrazoles that selectively inhibit cyclooxygenase-2.
WO94/15932 describes thiophene and furan derivatives that selectively inhibit cyclooxygenase-2. WO94/26731 describes thiophene compounds that selectively inhibit cyclooxygenase-2. WO97/16435 describes 3,4-diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs of compounds that are cyclooxygenase-2 inhibitors. GB 2,294,879 describes substituted furanones as cyclooxygenase-2 inhibitors.
U.S. Pat. No. 5,859,257 describes substituted isoxazoles that selectively inhibit cyclooxygenase-2. EP 745,596 describes substituted isoxazoles that selectively inhibit cyclooxygenase-2.
U.S. Pat. Nos. 5,344,991, 5,420,287 and 5,663,180 describe substituted cyclopentenes that selectively inhibit cyclooxygenase-2.
U.S. Pat. No. 5,418,254 describes substituted cyclopentadienyls that selectively inhibit cyclooxygenase-2.
U.S. Pat. No. 5,916,905 describes 2,3-substituted pyridines that selectively inhibit cyclooxygenase-2. U.S. Pat. No. 5,596,008 describes 3,4-diaryl substituted pyridines that selectively inhibit cyclooxygenase-2. WO98/03484 describes substituted pyridines that selectively inhibit cyclooxygenase-2.
U.S. Pat. Nos. 5,393,790 and 5,736,579 describe substituted spiro compounds that selectively inhibit cyclooxygenase-2.
U.S. Pat. Nos. 5,670,510, 5,672,626 and 5,672,627 describe spirodienes that selectively inhibit cyclooxygenase-2.
U.S. Pat. No. 5,668,161 describes substituted thiazoles that selectively inhibit cyclooxygenase-2.
U.S. Pat. No. 5,616,601 describes 1,2-substituted imidazoles that selectively inhibit cyclooxygenase-2. WO96/03387 describes 4,5-substituted imidazoles that selectively inhibit cyclooxygenase-2. WO96/03388 describes 1,2-substituted imidazoles that selectively inhibit cyclooxygenase-2. U.S. Pat. Nos. 5,521,193 and 5,534,521 describe benzimidazoles that selectively inhibit cyclooxygenase-2.
WO94/13635 describes 5-methanesulfonamido-1-indanones th
Brown David L.
Graneto Matthew J.
Ludwig Cindy L.
Molyneaux John M.
Talley John J.
Davis Zinna Northington
Pharmacia Corporation
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