Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-28
2002-05-14
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235800, C514S272000, C514S274000, C514S318000, C514S341000
Reexamination Certificate
active
06387898
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel use of imidazole compounds in the treatment of CNS injuries.
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.
Dinareilo,
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 CSAID™ cytokine suppressive binding compounds, or pharmaceutical compositions thereof in the treatment of CNS injuries, such as head trauma, and ischemia.
The preferred compounds for use as cytokine inhibitors are those compounds of Formula (I) as noted herein. The preferred method of inhibition is the inhibition of the CSBP/p38/RK kinase pathway.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is to the novel use of a cytokine inhibitor, in particular that of cytokine CSBP/p38, for treating, in an acute setting, as well as preventing, in those individuals deemed susceptible to, various CNS injuries. A preferred group of these cytokine suppressive compounds are described herein as compounds of Formula (I).
CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.
Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel. The role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
TNF-&agr; is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression. Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp 1481-88 (1994) whose disclosure is incorporated herein by reference.
Models of closed head injuries and treatment with mixed 5-LO/CO agents is discussed in Shohami et al., J. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp 99-107 (1992) whose disclosure is incorporated herein by reference. Treatment which reduced edema formation was found to improve functional outcome in those animals treated.
Compounds for use herein include the cytokine inhibitors as described in U.S. Ser. No. 08/091,491, published as WO95/02575; WO96/21452; U.S. Ser. Nos. 08/369,964; 08/473,396; 08/659,102; 08/764,003; WO96/40143; U.S. Ser. No. 08/473,398; WO96/21654; WO93/14081; U.S. Ser. No. 08/095,234; WO95/03297; U.S. Ser. No. 08/481,671; PCT/US97/00619; PCT/US97/00614; PCT/US97/00500; PCT/US97/00529; U.S. Ser. Nos. 60/013,357; 60/013,358; 60/013,359; WO93/14082: WO95/13067; and WO95/31451. Each of these references are incorporated by reference herein in their entirety.
Preferred compounds for use as cytokine inhibitors are those compounds of Formula (I) noted below. Synthetic chemistry and methods of pharmaceutical formulations thereof are also contained within each noted patent application. A description of the assay for inhibition of the cytokine specific binding protein (CSBP) is also found in WO95/07922, whose disclosure is incorporated by reference in its entirety.
Accordingly, the present invention provides for use of a compound of Formula (I):
wherein:
R
1
is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, which heteroaryl ring is optionally substituted independently one to three times with Y, NHR
a
, optionally substituted C
1-4
alkyl, halogen, hydroxyl, optionally substituted C
1-4
alkoxy, optionally substituted C
1-4
alkylthio, C
1-4
alkylsulfinyl, CH
2
OR
12
, amino, mono and di-C
1-6
alkyl substituted amino, or N(R
10
)C(O)R
b
;
Y is X
Dinner Dara L.
Kinzig Charles M.
Ramsuer Robert W.
Smithkline Beecham Corporation
Venetianer Stephen
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