Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-16
2003-04-29
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S364000, C548S137000, C548S145000
Reexamination Certificate
active
06555563
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical agents. In particular, the present invention relates to compounds, pharmaceutical formulations, and methods useful for treating inflammation and inflammation-related disorders, such as, for example, arthritis.
BACKGROUND OF THE INVENTION
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used pharmacological agents worldwide. They are commonly prescribed for the relief of pain, stiffness, and joint swelling for patients with osteoarthritis and rheumatoid arthritis, conditions estimated to affect 12.1% and 1.0%, respectively, of adults in the United States (Lawrence R C, Helmick C G, Arnett F C, et al. “Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States”
Arthritis Rheum
(1998) 41 (5): 778-99).
Although NSAIDs are generally well tolerated, upper gastrointestinal adverse events are frequently associated with their use. Symptoms range from dyspepsia, nausea, and abdominal pain to more serious complications of mucosal ulceration such as bleeding and perforation. Such upper gastrointestinal complications are the most frequent serious complication of NSAID use and are probably contributory to most NSAID-related deaths. Approximately 16,500 NSAID-related deaths are estimated to occur annually in the US (among 13 million patients exposed to the drugs, see Singh G., Triadafilopoulos G., “Epidemiology of NSAID induced gastrointestinal complications”
J. Rheumatol
., (1999) 26 Suppl. 56: 18-24).
NSAIDs act by inhibiting the activity of the enzyme cyclo-oxygenase (COX), and thereby prostaglandin and thromboxane production. COX exists as two isoforms, COX-1 and COX-2. The gastrointestinal adverse events associated with long term NSAID use are believed to result from the inhibition of COX-1. Other less frequent adverse events such as bleeding complications, fluid and electrolyte disorders, acute renal failure, and renal papillary necrosis have also been attributed to inhibition of this enzyme. In contrast, the anti-inflammatory and analgesic effects of NSAIDs are thought to result from inhibition of COX-2.
Certain 1, 2, 4- and 1, 3, 4-thiadiazoles bearing tert-butylphenol moieties and other structurally related compounds are known to provide activity as inhibitors of cyclooxygenase and/or 5-lipoxygenase (see, for example, U.S. Pat. No. 5,510,361 to Scherz; Song Y., Conner D. T., Sercel A. D., Sorenson R. J., Doubleday R.,
J. Med. Chem
. Vol. 42 (1999), pp. 1161-1169; Mullican M. D., Wilson M. W., Connor D. T., Kostlan C. R., Schrier D. J., Dyer R. D.,
J. Med. Chem
., Vol. 36 (1993), pp. 1090-1099). However, there are very few known compounds that are able to selectively inhibit COX-2 in the presence of COX-1 (see U.S. Pat. No. 5,616,601 to Khanna, et al.).
Accordingly, there is a need for compounds and pharmaceutical compositions useful for selectively inhibiting COX-2 in the presence of COX-1, thereby minimizing the pathological side effects associated with NSAID use while maximizing the desired anti-inflammatory and analgesic effects provided by NSAIDs.
SUMMARY OF THE INVENTION
In accordance with the present invention, there are provided compounds and pharmaceutical compositions useful for the selective inhibition of COX-2 in the presence of COX-1. As a result, invention compounds and compositions provide anti-inflammatory relief to a subject in need thereof while dramatically reducing the occurrence of side effects in the subject. Compounds contemplated for use in the practice of the present invention are substituted heterocyclic compounds containing amidinyl and imidazolyl groups.
In accordance with additional embodiments of the present invention, there are provided methods for treating inflammation related conditions, methods for treating pathological conditions of the skin, methods for reducing side effects associated with anti-inflammatory agents, and methods for selectively inhibiting COX-2 in the presence of COX-1.
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Battistini et al., “Cox-1 and Cox-2: Toward the Development of More Selective NSAIDs,” DN&P, 7(8), 501-512, 1994.
Clemett et al., “Celecoxib: A Review of its Use in Osteoarthritis, Rheumatoid Arthritis and Acute Pain,” Drugs, 59(4), 957-980, 2000.
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Koguro et al., “Novel Synthesis of 5-Substituted Tetrazoles from Nitriles,” Synthesis, 910-914, 1998.
Lawrence et al., “Estimates of the Prevalence of Arthritis and Selected Musculoskeletal Disorders in the United States,” Arthritis & Rheumatism, 41(5), 778-799, 1998.
Le et al., “From Tetrazoles via Hydrazonoyl Chlorides to 1,3,4-Thiadiazole Oligomers,” Tetrahedron Letters, 41, 9407-9411, 2000.
Mullican et al., “Design of 5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles,1,3,4-oxadiazoles, and -1,2,4-thiazoles as Orally-Active, Nonulcerogenic Antiinflammatory Agents,” J.Med.Chem, 36, 1090-1099, 1993.
Singh et al., “Epidemiology of NSAID Induced Gastrointestinal Complications,” Journal of Rheumatology, 26, Supplement 56, 18-24, 1999.
Song et al., “Synthesis, Structure-Activity Relationships, and in Vivo Evaluations of Substituted Di-tert-butyl- Phenols as a Novel Class of Potent, Selective, and Orally Active Cyclooxygenase-2 Inhibitors 2. 1,3,4- and 1,2,4-Thiadiazole Series,” J. Med. Chem., 42, 1161-1169, 1999.
Vane, “Towards a Better Aspirin,” Nature, 367, 215-216, 1994.
Le Van-Duc
Salazar Jean-Frédérick
Foley & Lardner
McKane Joseph K.
Medinox Inc.
Reiter Stephen E.
Saeed Kamal
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