Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-21
2001-12-04
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S131000, C546S134000
Reexamination Certificate
active
06326388
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to substituted 1,3,4-oxadiazole compounds, the method of reducing levels of tumor necrosis factor a and increasing cAMP levels and treating inflammatory and autoimmune diseases and cancer in a mammal through the administration thereof, and to pharmaceutical compositions of such derivatives.
BACKGROUND OF THE INVENTION
Tumor necrosis factor-&agr; (TNF&agr;) is a cytokine which is released primarily by cells of immune systems in response to certain immunostimulators. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation, cachexia, and acute phase responses similar to those seen during acute infections, inflammatory diseases, and shock states. Excessive or unregulated TNF&agr; production has been implicated in a number of disease conditions. These include endotoxemia and/or toxic shock syndrome [Tracey, et al.,
Nature
330, 662-664 (1987) and Hinshaw, et al.,
Circ. Shock
30, 279-292 (1990)], rheumatoid arthritis, inflammatory bowel disease, cachexia [Dezube, et al.,
Lancet
, 335 (8690), 662 (1990)], and lupus. TNF&agr; concentration in excess of 12,000 pg/mL have been detected in pulmonary aspirates from Adult Respiratory Distress Syndrome (ARDS) patients [Millar, et al.,
Lancet
2(8665), 712-714 (1989)]. Systemic infusion of recombinant TNF&agr; resulted in changes typically seen in ARDS [Ferrai-Baliviera, et al.,
Arch. Surg
. 124(12), 1400-1405 (1989)].
TNF&agr; appears to be involved in a number of bone resorption diseases, including arthritis. When activated, leukocytes will produce bone-resorption. TNF&agr; apparently contributes to this mechanism. [Bertolini, et al.,
Nature
319, 516-518 (1986) and Johnson, et al.,
Endocrinology
124(3), 1424-1427 (1989)]. TNF&agr; also has been shown to stimulate bone resorption and inhibit bone formation in vitro and in vivo through stimulation of osteoclast formation and activation combined with inhibition of osteoblast functions. Another compelling link with disease is the association between production of TNF&agr; by tumor or host tissues and malignancy associated hypercalcemia [
Calci. Tissue Int
. (
US
) 46(Suppl.), S3-10 (1990)]. In Graft versus Host Reactions, increased serum TNF&agr; levels have been associated with major complication following acute allogenic bone marrow transplants [Holler, et al.,
Blood
, 75(4), 1011-1016 (1990)].
Validation of TNF-&agr; inhibition as a clinical therapy has been demonstrated by the therapeutic use of TNF-&agr; antibodies and soluble TNF-&agr; receptors. TNF&agr; blockage with monoclonal anti-TNF&agr; antibodies has been shown to be beneficial in rheumatoid arthritis [Elliot, et al.,
Int. J. Pharmac
. 1995 17(2), 141-145]. High levels of TNF&agr; are associated with Crohn's disease [von Dullemen, et al.,
Gastroenterology
, 1995 109(1), 129-135] treatment with soluble TNF&agr; receptor treatment gave clinical benefits.
Cerebral malaria is a lethal hyperacute neurological syndrome associated with high blood levels of TNF&agr; and the most severe complication occurring in malaria patients. Elevated levels of serum TNF&agr; correlated directly with the severity of disease and the prognosis in patients with acute malaria attacks [Grau, et al.,
N. Engl. J. Med
. 320(24), 1586-1591 (1989)].
TNF&agr; plays a role in the area of chronic pulmonary inflammatory diseases. The deposition of silica particles leads to silicosis, a disease of progressive respiratory failure caused by a fibrotic reaction. Antibodies to TNF&agr; completely blocked the silica induced lung fibrosis in mice [Pignet, et al.,
Nature
, 344, 245-247 (1990)]. High levels of TNF&agr; production (in the serum and in isolated macrophages) have been demonstrated in animal models of silica and asbestos induced fibrosis [Bissonnette, et al.,
Inflammation
13(3), 329-339 (1989)]. Alveolar macrophages from pulmonary sarcoidosis patients have also been found to spontaneously release massive quantities of TNF&agr; as compared with macrophages from normal donors [Baughman, et al.,
J. Lab. Clin. Med
. 115(1), 36-42 (1990)].
Elevated levels of TNF&agr; are implicated in reperfusion injury, the inflammatory response which follows reperfusion, and is a major cause of tissue damage after blood flow loss [Vedder, et al.,
PNAS
87, 2643-2646 (1990)]. TNF&agr; also alters the properties of endothelial cells and has various pro-coagulant activities, such as producing an increase in tissue factor pro-coagulant activity, suppressing the anticoagulant protein C pathway, and down-regulating the expression of thrombomodulin [Sherry, et al.,
J. Cell Biol
. 107, 1269-1277 (1988)]. TNF&agr; has pro-inflammatory activities which together with its early production (during the initial stage of an inflammatory event) make it a likely mediator of tissue injury in several important disorders including but not limited to, myocardial infarction, stroke and circulatory shock. TNF&agr;-induced expression of adhesion molecules, such as intercellular adhesion molecules (ICAM) or endothelial leukocyte adhesion molecules (ELAM) on endothelial cells may be especially important [Munro, et al.,
Am. J. Path
. 135(1), 121-132 (1989)].
It has been reported that TNF&agr; is a potent activator of retrovirus replication including activation of HIV-1. [Duh, et al.,
Proc. Nat. Acad. Sci
. 86, 5974-5978 (1989); Poll, et al.,
Proc. Nat. Acad. Sci
. 87, 782-785 (1990); Monto, et al.,
Blood
79, 2670 (1990); Clouse, et al.,
J. Immunol
. 142, 431-438 (1989); Poll, et al.,
AIDS Res. Hum. Retrovirus
, 191-197 (1992)]. At least three types or strains of HIV (i.e., HIV-1, HIV-2 and HIV-3) have been identified. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T-lymphocyte requires T-lymphocyte activation. Other viruses, such as HIV-1, HIV-2 infect T-lymphocytes after T-cell activation. This virus protein expression and/or replication is mediated or maintained by this T-cell activation. Once an activated T-lymphocyte is infected with HIV, the T-lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication. Cytokines, specifically TNF&agr;, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T-lymphocyte activation. Therefore, interference with cytokine activity such as prevention or inhibition of cytokine production, notably TNF&agr;, in an HIV-infected individual assists in limiting the maintenance of T-lymphocyte caused by HIV infection.
Monocytes, macrophages, and related cells, such as kupffer and glial cells, also have been implicated in maintenance of the HIV infection. These cells, like T-cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [Rosenberg, et al.,
The immunopathogenesis of HIV Infection, Advances in Immunology
, 57 (1989)]. Cytokines, such as TNF&agr;, have been shown to activate HIV replication in monocytes and/or macrophages [Poli, et al.,
Proc. Natl. Acad. Sci
., 87, 782-784 (1990)], therefore, prevention or inhibition of cytokine production or activity aids in limiting HIV progression for T-cells. Additional studies have identified TNF&agr; as a common factor in the activation of HIV in vitro and have provided a clear mechanism of action via a nuclear regulatory protein found in the cytoplasm of cells [Osborn, et al.,
PNAS
86 2336-2340]. This evidence suggests that reducing TNF&agr; synthesis may have an antiviral effect in HIV infections, by reducing transcription and thus virus production.
AIDS viral replication of latent HIV in T-cell and macrophage lines can be induced by TNF&agr; [Folks, et
Man Hon-Wah
Muller George W.
Celgene Corporation
Higel Floyd D.
Mathews, Collins Shepherd & Gould P.A.
Saeed Kamal
LandOfFree
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