Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-18
2003-08-12
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S422000, C514S427000, C514S429000, C514S333000, C546S001000, C546S277400, C548S469000, C548S511000, C548S518000
Reexamination Certificate
active
06605634
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention comprises a new class of compounds useful in treating diseases, such as TNF-&agr;, IL-1&bgr;, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. This invention, in particular, relates to novel aryl and heteroaryl substituted fused pyrrole compounds, compositions containing such compounds and methods of use of such compounds. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
Interleukin-1 (IL-1) and Tumor Necrosis Factor alpha (TNF-&agr;) are proinflammatory cytokines secreted by a variety of cells including monocytes and macrophages in response to many inflammatory stimuli (e.g. lipopolysaccharide-LPS) or external cellular stress (e.g. osmotic shock, peroxide). Elevated levels of TNF-&agr; and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic &bgr; cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-&agr;.
Elevated levels of IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis; anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome. Viruses sensitive to TNF-&agr; inhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.
TNF-&agr; and IL-1 appear to play a role in pancreatic &bgr; cell destruction and diabetes. Pancreatic &bgr; cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic &bgr; cells often accompanies type I diabetes. Pancreatic &bgr; cell functional abnormalities may occur in patients with type II diabetes. Type II diabetes is characterized by a functional resistance to insulin. Further, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production. Glucagon is a regulatory hormone that attenuates liver gluconeogenesis inhibition by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue. Thus glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety). By antagonizing the glucagon receptors, it is thought that insulin responsiveness in the liver will improve, thereby decreasing gluconeogenesis and lowering the rate of hepatic glucose production.
Several approaches have been taken to block the effects of TNF-&agr;. One approach involves utilizing soluble receptors for TNF-&agr; (e.g., TNFR-55 or TNFR-75) which have demonstrated efficacy in animal models of TNF-a mediated disease states (for a PEG dimer of TNFR-55 see Edwards CHI Meeting Nov. 13-15 (1995) and rhu sTNFR:Fc p-75 see Moreland). A second approach to neutralizing TNF-a utilizing a monoclonal antibody specific to TNF-a, cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al Immunological Reviews p. 195-223 (1995)).
The above approaches block the effects of TNF-a and IL-1 by either protein sequesterazation or receptor antagonism, but an additional approach to blockade is to intervene in the cellular production and secretion of IL-1 and/or TNF. There are numerous points for intervention between the extracellular stimulus and the secretion of IL-1 and TNF-a from the cell including interfering with transcriptional processes, interfering with translational processes, blocking signal transduction which may alter protein translation and/or transcription; and blocking release of the proteins from the cells. The most reliable effect to document is upon applying a given stimulus to a cell in vitro (e.g. monocyte), a certain amount of TNF or IL-1 (note: quantitated by enzyme linked immunoabsorbent assay, ELISA) is secreted over basal levels in the culture medium. Evidence as to the nature of intervention between the extracellular stimulus and the secretion of IL-1 and TNF-a from the cell can be provided by in vitro biochemical experiments, but it does not preclude the fact that the compounds may be intervening at a yet undetermined point on the pathway between extracellular stimulus and secretion of protein. Pentoxifylline is an example of a compound that is believed to intervene at the transcriptional level of IL-1 protein synthesis. Evidence suggests that the anti-inflammatory glucocorticoids block at both the transcriptional and translational levels (Lee et al Circulatory Shock 44:97-103 (1995)) of inflammatory mediators. Chloroquine (CQ) and hydroxychloroquine (HCQ) accumulate in lysosomes of monocytes (Borne Handbook of Cardiovascular and Anti-Inflammatory Agents p27-104 (1986)). CQ and HCQ inhibit cartilage cathepsin B and cartilage chondromucoprotease, and they may have membrane stabilizing effects on the lysozomes.
Since TNF-a is upstream in the cytokine cascade of inflammation wherein elevated levels of TNF-a lead to elevated levels of other cytokines including IL-1, IL-6 and IL-8, inhibiting the production of TNF-a may also reduce levels of other cytokines including but not limited to IL-1, IL-6 or IL-8. IL-8 is implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8 including but not limited to the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, reduction in IL-8 levels would lead to diminished neutrophil infiltration. Evidence has been reported that suggests P-38 plays a role in TNF induced transcriptional activation of IL-6 production (see: Walter Fiers EMBO Journal 1996, vol. 15, p 1914-23) and of IL-8 production (Dinarello, Proc. Nat. Acad. Sci. 1995 Vol 92, 12230-4).
In rheumatoid arthritis, both IL-1 and TNF-a induce synoviocytes and chondrocytes to produce collagenase and neutral proteases which leads to tissue destruction within the arthritic joints. In a model of arthritis, collagen-induced arthritis (CIA) in rats and mice, intraarticular administration of TNF-a either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al Lymphokine Cytokine Res. (11):253-256, (1992); and Cooper Clin. Exp. Immunol. 898:244-250, (1992)).
It has been reported that TNF-a plays a role in head trauma, stroke, and ischemia. For instance, in animal models of head trauma (rat), TNF-a levels increased in the contused hemisphere (Shohami et al J. Cereb. Blood Flow Metab. 14:615-619 (1994)). In
Mantlo Nathan B.
Rizzi James P.
Tarlton, Jr. Eugene
Zablocki Jeffery A.
Amgen Inc.
Levy Ron K.
Patel Sudhaker B
Person Richard V.
Raymond Richard L.
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