Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-27
2003-11-18
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06649617
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the novel use of imidazole compounds in the treatment of stroke and stroke management.
BACKGROUND OF THE INVENTION
Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al.,
Rev. Infect. Disease
, 6, 51 (1984)]. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock, syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic &bgr; cells.
Dinarello,
J. Clinical Immunology
, 5 (5), 287-297 (1985), reviews the biological activities which have been attributed to IL-1. It should be noted that some of these effects have been described by others as indirect effects of IL-1.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.
Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have been applied to IL-8, such as neutrophil attractant/activation protein-1(NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration.
IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
There remains a need for the treatment, and for the prevention of CNS injuries which are related to the ability of compounds which are cytokine suppressive, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.
SUMMARY OF THE INVENTION
This invention relates to the use of substituted imidazole compounds, or pharmaceutical compositions thereof in the treatment of stroke, and stroke management.
The compounds for use herein are described in PCT[US97/09888 filed Jun. 6, 1997, and published Dec. 18, 1997 as WO 97/47618, Liverton et al., now U.S. Pat. No. 5,859,041 granted Jan. 12, 1999, whose disclosures are incorporated herein by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is to the novel use of the compounds described in WO 97/47618 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries.
Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/47899 (PCT/US98/07831), Dodd et al., for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/52937 (PCT/US98/10807), Anantanarayan et al., now U.S. Pat. No. 5,932,576, granted Aug. 3, 1999; U.S. Pat. No. 6,0874,96, and U.S. Pat. No. 6,335,336 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent and patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 99/03837 (PCT/US98/13419), Wachter et al., now U.S. Pat. No. 6,040,320 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/47892 (PCT/US98/07910), Beers et al., now U.S. Pat. No. 5,965,583 and U.S. Pat. No. 6,214,830 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 99/01449 (PCT/EP98/03930), Revesz et al., now U.S. Pat. No. 6,300,347 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/52941 (PCT/US98/11684), Hanson et al., now U.S. Pat. No. 6,087,381 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Ano
Criares Theodore J.
Dinner Dara L.
Furman Theodore R.
Kinzig Charles M.
SmithKline Beecham Corporation
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