Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-10
2002-07-09
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S256000
Reexamination Certificate
active
06417202
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel pyridylpyrrole compounds, processes for the preparation thereof, the use thereof in treating cytokines mediated diseases and/or cell adhesion molecules mediated diseases, and pharmaceutical compositions for use in such therapy.
BACKGROUND ART
Cytokines possess a multitude of regulatory and inflammatory effects. 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.
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 (RA), osteoarthritis (OA), endotoxemia and/or toxic shock syndrome, other acute and chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease (IBD), tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links IL-1 activity to diabetes.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including RA, rheumatoid spondylitis, OA, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome (ARDS), cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfision 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), ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyresis. The concept of anti-TNF therapy has been validated by the demonstration that soluble TNF receptor and neutralizing monoclonal antibodies (MAbs) against TNF showed therapeutic efficacy in a variety of preclinical and clinical studies (e.g., Elliott, M. J. et al.,
The Lancet
, 1994, 344, 1125. Dullemen, H. M. V. et al.,
Gastroenterology
, 1995, 109, 129.)
Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types including neutrophils, mononuclear cells, fibroblasts, endothelial cells, epithelial cells and keratinocytes. Elevated IL-8 levels have been reported in joint fluids in RA, gouty arthritis, psoriatic scale and ARDS. Its production from endothelial cells is induced by IL-1, TNF or lipopolysachharide (LPS). IL-8 has been shown to have chemoattractant properties for neutrophils, T-lymphocytes and basophils. In addition, it promote angiogenesis as well as neutrophil activation, including lysozomal enzyme release and respiratory burst. IL-8 has also been shown to increase the surface expression of Mac-1 (CD 11b/CD18) on neutrophils, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased IL-8 production would benefit by compounds which are suppressive of IL-8 production.
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.
Cellular movement and adhesion are a fundamental biological response to external stimuli. During an inflammatory response, leukocytes must leave the plasma compartment and migrate to the point of antigenic insult. The mechanism of this migratory event is a complex interplay between soluble mediators and membrane-bound cellular adhesion molecules. Soluble cellular chemotactic factors, which are produced in the damaged tissue by a variety of resident cells, set up a chemical concentration gradient out to the plasma compartment. Interaction of these factors with their receptors on leukocytes leads to a directional migration of the leukocytes toward increasing concentrations of the chemotactic factor. Simultaneously, various adhesion molecules are upregulated on the leukocyte which mediate the initial rolling on the endothelial tissue, binding to a specific ligand on the activated endothelial tissue, and finally migration between endothelial cells into the tissue. The steps in this cascade of events are mediated by the interaction of specific cell surface protein, termed “cell adhesion molecules (CAMs)”. E-selectin (ELAM-1, endothelial leukocyte adhesion molecule-1), ICAM-1 (intercellular adhesion molecule-1), and VCAM-1 (vascular cell adhesion molecule-1) are three major adhesion molecules whose expression on endothelial cells is upregulated upon treatment with inflammatory stimuli. ICAM-1 is expressed at low levels on resting endothelium and is markedly induced in response to cytokines such as IL-1, TNF and interferon-&ggr; (IFN-&ggr;). VCAM-1 is not expressed in resting endothelium but is induced by IL-1, TNF and IL-4. Induction of both ICAM-1 and VCAM-1 occurs 4 to 6 hours after cytokine treatment and cell surface expression remains elevated for up to 72 hours after treatment with cytokines. On the other hand, induction of transcription of the E-selectin gene by cytokines such as IL-1 and TNF results in an increase in the expression on the surface of endothelial cells peaking approximately 4-6 hours after challenge, and returns toward a basal level of expression by 24 hours.
The concept of anti-CAMs therapy has been validated by the demonstration that MAbs against ICAM-1 and antisense oligonucleotide against ICAM-1 showed therapeutic efficacy in a variety of preclinical and clinical studies (A. F. Kavanaugh et al.,
Arthritis Rhetun
, 1994, 37, 992; C. E. Haug et al.,
Transplantation
, 1993, 55, 766; and J. E. Jr. Sligh et al.,
Proc. Natl. Acad. Sci
., 1993, 90, 8529). Further support comes from the reports of the in vivo activity of sLeX and related carbohydrates, antagonists of E-selectin mediated adhesion (M. S. Mulligan et al.,
Nature
, 1993, 364, 149-151). Thus, the potential therapeutic targets for CAMs inhibitors range from, but are not limited to, RA, IBD and psoriasis to ischemia/reperfusion injury, autoimmune diabetes, organ transplantation, ARDS, tumor metastases and AIDS, as is evident from the many ongoing development activities. The regulation of the functions of CAMs is of benefit in controlling, reduction and alleviating many of these disease states. There remains a need for treatment, in this field, for compounds which are capable of inhibiting cytokines production and/or CAMs expression. The pyridylpyrroles of the present invention have been shown in an in vitro assay to inhibit cytokines production and/or CAMs expression.
International Publication No. WO 95/18122 discloses 2-heteroaryl-3-cyanopyrrole compounds having agrochemical activities.
British Patent No. GB1311336 discloses quaternary salts of pyrrolylpyridine compounds (e.g., 4,4′-(3,4-dimethylpyrrol-2,5-diyl)bis(1-n-heptylpyridinium bromide) having antibacterial and fungal properties.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides a compound of the formula:
and its pharmaceutically acceptable salts, wherein
R
1
is selected from the following:
(a) hydrogen, R
6
—, R
6
—NH—, hydroxy-R
6
— or R
6
—O—R
6
—;
(b) R
6
—CO—, R
6
—O—CO—R
6
—, carboxy-R
6
—, NH
2
—CO— or R
6
—NH—CO—; and
(c) Ar—, Ar—R
6
—, Ar—NH—or Ar—CO—;
wherein Ar is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, pyrrolyl, indolyl, benzothienyl and benzofuryl, the aryl or heteroaryl groups being optionally substituted wi
Kawai Akiyoshi
Kawai Makoto
Murata Yoshinori
Sakakibara Minoru
Takada Junji
Aulakh C. S.
Ginsburg Paul H.
Jacobs Seth H.
Pfizer Inc.
Richardson Peter C.
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