Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-10-27
1998-02-17
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514312, 514314, 514340, 514374, 514376, 546152, 546153, 546176, 546180, 546275, 548215, 548225, 548235, C07D41306, A61K 3142, A61K 3147
Patent
active
057191638
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is in the field of anti-inflammatory 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.sub.2, PGH.sub.2 and PGE.sub.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). Recently, the sequence of another heretofore unknown enzyme in the human arachidonic acid/prostaglandin pathway has been reported by T. Hla and K. Nielson, Proc. Natl. Acad. Sci, USA, 89, 7384 (1992) and named "cyclooxygenase II (COX II)" or "prostaglandin G/H synthase II". The discovery of an inducible enzyme associated with inflammation provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. Cyclooxygenase II is inducible by cytokines or endotoxins and such induction is inhibited by glucocortoids (J. Masferrer, et al, Proc. Natl. Acad. Sci, USA, 89, 3917 (1992)). The 6-methoxy-2-napthylacetic acid metabolite of nabumetone has been found by E. Meade et al to selectively inhibit the COX II enzyme (J. Biol. Chem., 268, 6610 (1993)). In addition, Futaki et al (Prostaglandins, 47, 1 (1994)) have reported that N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide inhibits the COX II enzyme.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel oxazoles 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 oxazolyl compounds disclosed herein preferably selectively inhibit cyclooxygenase II over cyclooxygenase I.
2,3-Diaryl-5-halo thiophenes are described in U.S. Pat. No. 4,590,205 as analgesic or antiinflammatory agents. More particularly, 2,3-diaryl-5-bromo thiophenes are described in U.S. Pat. No. 4,820,827 as having antiinflammatory and prostaglandin synthetase inhibitory activity for use in the treatment of inflammation and dysmenorrhea. Copending application Ser. No. PCT/US94/466 describes 4,5-substitutedphenylthiophenes as having antiinflammatory activity.
Pyrazole derivatives having antiinflammatory activity are described in U.S. Pat. No. 5,134,142, to Matsuo et al.
U.S. Pat. No. 3,578,671, to K. Brown, describes antiinflammatory 4,5-diphenyloxazoles substituted in the 2-position by a saturated or unsaturated aliphatic acid. U.S. Pat. No. 4,051,250, to J. Dahm et al, describes oxazole, imidazole and thiazole compounds, including 2-mercapto-4-(4-methylmercaptophenyl)-5-(4-chlorophenyl)oxazole, as having antiphlogistic, analgesic and antipyretic activity. Other related diphenyloxazole disclosures include U.S. Pat. No. 4,001,228, to G. Mattalia, for antiaggregating activity and U.S. Pat. No. 3,895,024, to R. Hafeli, for intermediates in the production of antiinflammatory agents. U.S. Pat. No. 4,489,084, to F. Haviv and F. Kerdesky, describes diphenyloxazolyl hydrazinoalkyl nitrile compounds for use as
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Lee Len F.
Masferrer Jaime L.
Norman Bryan H.
Talley John J.
G.D. Searle & Co.
McKane Joseph
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