Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-10
2004-04-20
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S309000, C546S141000
Reexamination Certificate
active
06723736
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to tricyclic compounds, namely, substituted isoquinolines, isochromanones and isothiochromanones that inhibit the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and/or interleukin-6 (IL-6) and/or the enzyme cyclooxygenase-2 (COX-2) and/or the cytokine interleukin-10 (IL-10). This invention also relates to compositions containing such compounds and methods using such compounds for treatment and/or prevention of inflammation, inflammatory diseases, immunologic diseases and other diseases mediated by TNF-alpha, IL-6, IL-10 and/or COX-2.
BACKGROUND OF THE INVENTION
The present invention is concerned with the modulation of cellular signaling pathways involving pro-inflammatory cytokines and cyclooxygenase-2 (COX-2). Cytokines are molecules secreted by immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the body's normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine tumor necrosis factor-alpha (TNF-alpha) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. TNF-alpha is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-alpha participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al.,
J Clin Invest,
83:444-55, 1989). At higher concentrations, TNF-alpha can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al.,
Eur J Immunol,
21:2575-79, 1991; Brennan et al.,
Lancet,
2:244-7, 1989). TNF-alpha also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-alpha mediates the cytokine cascade that leads to joint damage and destruction (Arend et al,
Arthritis Rheum,
38:151-60, 1995). Inhibitors of TNF-alpha, including soluble TNF receptors (etanercept) (Goldenberg,
Clin Ther,
21:75-87,1999) and anti-TNF-alpha antibody (infliximab) (Luong et al,
Ann Pharmacother,
34:743-60, 2000), have recently been approved by the U.S. Food and Drug Administration (FDA) as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-alpha have also been implicated in many other disorders and disease conditions, including cachexia (Fong et al.,
Am J Physiol,
256:R659-65, 1989), septic shock syndrome (Tracey et al,
Proc Soc Exp Biol Med,
200:233-9, 1992), osteoarthritis (Venn et al.,
Arthritis Rheum,
36:819-26, 1993), inflammatory bowel disease such as Crohn's disease and ulcerative colitis (Murch et al.,
Gut,
32:913-7, 1991), Behcet's disease (Akoglu et al.,
J Rheumatol,
17:1107-8,1990), Kawasaki disease (Matsubara et al.,
Clin Immunol Immunopathol,
56:29-36, 1990), cerebral malaria (Grau et al.,
N Engl J Med,
320:1586-91, 1989), adult respiratory distress syndrome (Millar et al.,
Lancet,
2:712-4, 1989), asbestosis and silicosis (Bissonnette et al.,
Inflammation,
13:329-39, 1989), pulmonary sarcoidosis (Baughman et al.,
J Lab Clin Med,
115:36-42, 1990), asthma (Shah et al.,
Clin Exp Allergy,
25:1038-44,1995), AIDS (Dezube et al.,
J Acquir Immune Defic Syndr,
5:1099-104, 1992), meningitis (Waage et al.,
Lancet,
1:355-7,1987), psoriasis (Oh et al.,
J Am Acad Dermatol,
42:829-30, 2000), graft versus host reaction (Nestel et al.,
J Exp Med,
175:405-13, 1992), multiple sclerosis (Sharief et al.,
N Engl J Med,
325:467-72,1991), systemic lupus erythematosus (Maury et al.,
Int J Tissue React,
11:189=93, 1989), and diabetes (Hotamisligil et al.,
Science,
259:87-91, 1993).
It can be seen from the references cited above that inhibitors of TNF-alpha are potentially useful in the treatment of a wide variety of diseases. Compounds that inhibit TNF-alpha have been described in U.S. Pat. Nos. 6,090,763; 6,080,580; 6,075,041; 6,057,369; 6,048,841; 6,046,319; 6,046,221; 6,040,329; 6,034,100; 6,028,086; 6,022,884; 6,015,558; 6,004,974; 5,990,119; 5,981,701; 5,977,122; 5,972,936; 5,968,945; 5,962,478; 5,958,953; 5,958,409; 5,955,480; 5,948,786; 5,935,978; 5,935,977; 5,929,117; 5,925,636; 5,900,430; 5,900,417; 5,891,883; 5,869,677 and others.
Interleukin-6 (IL-6) is another pro-inflammatory cytokine that exhibits pleiotropy and redundancy of action. IL-6 participates in the immune response, inflammation and hematopoiesis. It is a potent inducer of the hepatic acute phase response and is a powerful stimulator of the hypothalamic-pituitary-adrenal axis that is under negative control by glucocorticoids. IL-6 promotes the secretion of growth hormone but inhibits release of thyroid stimulating hormone. Elevated levels of IL-6 are seen in several inflammatory diseases, and inhibition of the IL-6 cytokine subfamily has been suggested as a strategy to improve therapy for rheumatoid arthritis (Carroll et al.,
Inflamm Res,
47:1-7,1998). In addition, IL-6 has been implicated in the progression of atherosclerosis and the pathogenesis of coronary heart disease (Yudkin et al.,
Atherosclerosis,
148:209-14, 1999). Overproduction of IL-6 is also seen in steroid withdrawal syndrome, conditions related to deregulated vasopressin secretion, and osteoporosis associated with increased bone resorption, such as in cases of hyperparathyroidism and sex-steroid deficiency (Papanicolaou et al.,
Ann Intern Med,
128:127-37, 1998).
Since excessive production of IL-6 is implicated in several disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion. Compounds that inhibit IL-6 have been described in U.S. Pat. Nos. 6,004,813; 5,527,546 and 5,166,137.
Cyclooxygenase is an enzyme that catalyzes a rate-determining step in the biosynthesis of prostaglandins, which are important mediators of inflammation and pain. The enzyme occurs as at least two distinct isomers, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 isomer is constitutively expressed in the gastric mucosa, platelets and other cells and is involved in the maintenance of homeostasis in mammals, including protecting the integrity of the digestive tract. The COX-2 isomer, on the other hand, is not constitutively expressed but rather is induced by various agents, such as cytokines, mitogens, hormones and growth factors. In particular, COX-2 is induced during the inflammatory response (DeWitt DL,
Biochim Biophys Acta,
1083:121-34, 1991; Seibert et al.,
Receptor,
4:17-23, 1994). Aspirin and other conventional non-steroid anti-inflammatory drugs (NSAIDs) are non-selective inhibitors of both COX-1 and COX-2. They can be effective in reducing inflammatory pain and swelling, but since they hamper the protective action of COX-1, they produce undesirable side effects of gastrointestinal pathology. Therefore, agents that selectively inhibit COX-2 but not COX-1 are preferable for treatment of inflammatory diseases. Recently, a diarylpyrazole sulfonamide (celecoxib) that specifically blocks COX-2 has been approved by the FDA for use in the treatment of rheumatoid arthritis (Luong et al.,
Ann Pharmacother,
34:743-60, 2000; Penning et al.,
J Med Chem,
40:1347-65, 1997). COX-2 is also expressed in many cancers and precancerous lesions, and there is mounting evidence that selective COX-2 inhibitors may be useful for treating and preventing colorectal and other cancers (Taketo MM,
J Natl Cancer Inst,
90:1609-20, 1998; Fournier et al.,
J Cell Biochem Suppl,
34:97-102, 2000). In 1999, celecoxib was approved by the FDA as an adjunct to usual care for patients with familial adenomatous polyposis, a condition which, left untreated, generally leads to colorectal cancer.
Compounds that selectively inhibit COX-2 have been described in U.S. Pat. Nos.
Dey Debendranath
Nag Bishwajit
Neogi Partha
Sen Ananda
Sharma Somesh D.
Owens Amelia
Theracos, Inc.
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