Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-17
2002-04-30
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S479000
Reexamination Certificate
active
06380239
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to 1-oxo- and 1,3-dioxo-isoindolines substituted in the 4- or 5-position of the isoindoline ring, the method of reducing levels of inflammatory cytokines such as tumor necrosis factor-&agr; and treating inflammatory diseases, autoimmune diseases, tumors, and cancers 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 mononuclear phagocytes in response to a number of immunostimulators. It is a key cytokine in the inflammation cascade causing the production and/or release of other cytokines and agents. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and phase responses similar to those seen during acute infections and shock states. Excessive or unregulated TNF&agr; production thus has been implicated in a number of disease conditions such as alloreactions such as graft-versus-host disease (GVHD), demyelinating diseases, hypotension, hypertriglyceridaemia, diabetes, osteolysis, neoplasia, leukemia, osteomyelitis, pancreatitis, thrombotic disease, inflammatory bowel disease, scleroderma, rheumatoid arthritis, osteoarthritis, and vasculitis. Anti-TNF&agr; treatments have validated TNF&agr; inhibition in rheumatoid arthritis, inflammatory bowel diseases, endotoxemia and toxic shock syndrome {Tracey et al.,
Nature
330, 662-664 (1987) and Hinshaw et al.,
Circ. Shock
30, 279-292 (1990)}; cachexia {Dezube et al.,
Lancet,
335 (8690), 662 (1990)} and Adult Respiratory Distress Syndrome (ARDS) where TNF&agr; concentration in excess of 12,000 pg/mL have been detected in pulmonary aspirates from ARDS patients {Millar et al.,
Lancet
2(8665), 712-714 (1989)}. Systemic infusion of recombinant TNF&agr; also 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 bone resorption diseases, including arthritis. When activated, leukocytes will produce bone-resorption, an activity to which the data suggest TNF&agr; contributes. {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 function. In Graft versus Host Reaction, 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)}.
Parasitic infections can be controlled by TNF&agr; like malaria or Legionella infection. 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. 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)}.
Angiogenesis, the process of new blood vessel development and formation, plays an important role in numerous physiological events, both normal and pathological. Angiogenesis occurs in response to specific signals and involves a complex process characterized by infiltration of the basal lamina by vascular endothelial cells in response to angiogenic growth signal(s), migration of the endothelial cells toward the source of the signal(s), and subsequent proliferation and formation of the capillary tube. Blood flow through the newly formed capillary is initiated after the endothelial cells come into contact and connect with a preexisting capillary.
Macrophage-induced angiogenesis is known to be mediated by TNF&agr;. Leibovich et al. {
Nature,
329, 630-632 (1987)} showed TNF&agr; induces in vivo capillary blood vessel formation in the rat cornea and the developing chick chorioallantoic membranes at very low doses and suggested that TNF&agr; is a candidate for inducing angiogenesis in inflammation, wound repair, and tumor growth. TNF&agr; production also has been associated with cancerous conditions such as tumor lysis syndrome, reoccurrence of bladder cancer, and particularly induced tumors {Ching et al.,
Brit. J. Cancer,
(1955) 72, 339-343, and Koch,
Progress in Medicinal Chemistry,
22, 166-242 (1985)}.
The naturally occurring balance between endogenous stimulators and inhibitors of angiogenesis is one in which inhibitory influences predominate. Rastinejad et al., 1989,
Cell
56:345-355. In those rare instances in which neovascularization occurs under normal physiological conditions, such as wound healing, organ regeneration, embryonic development, and female reproductive processes, angiogenesis is stringently regulated and spatially and temporally delimited. Under conditions of pathological angiogenesis such as that characterizing solid tumor growth, these regulatory controls fail.
Unregulated angiogenesis becomes pathologic and sustains progression of many neoplastic and non-neoplastic diseases. A number of serious diseases are dominated by abnormal neovascularization including solid tumor growth and metastases, arthritis, some types of eye disorders, and psoriasis. See, e.g., reviews by Moses et al., 1991,
Biotech.
9:630-634; Folkman et al., 1995,
N. Engl. J. Med.,
333:1757-1763; Auerbach et al., 1985,
J. Microvasc. Res.
29:401-411; Folkman, 1985,
Advances in Cancer Research,
eds. Klein and Weinhouse, Academic Press, New York, pp. 175-203; Patz, 1982,
Am. J. Opthalmol.
94:715-743; and Folkman et al., 1983,
Science
221:719-725. In a number of pathological conditions, the process of angiogenesis contributes to the disease state. For example, significant data have accumulated which suggest that the growth of solid tumors is dependent on angiogenesis. Folkman and Klagsbrun, 1987,
Science
235:442-447.
The maintenance of the avascularity of the cornea, lens, and trabecular meshwork is crucial for vision as well as to ocular physiology. See, e.g., reviews by Waltman et al., 1978,
Am. J. Ophthal.
85:704-710 and Gartner et al., 1978,
Surv. Ophthal.
22:291-312. Currently, the treatment of these diseases, especially once neovascularization has occurred, is inadequate and blindness often results.
An inhibitor of angiogenesis could have an important therapeutic role in limiting the contributions of this process to pathological progression of the underlying disease states as well as providing a valuable means of studying their etiology. For example, agents that inhibit tumor neovascularization could play an important role in inhibiting metastatic tumor growth.
The components of angiogenesis relating to vascular endothelial cell proliferation, migration and invasion, have been found to be regulated in part by polypeptide growth factors. Experiments in culture, indicate that endothelial cells exposed to a medium containing suitable growth factors can be induced to evoke some or all of the angiogenic responses. Several polypeptides with in vitro endothelial growth promoting activity have been identified. Examples include acidic and basic fibroblast growth factors, transforming growth factors &agr; and &bgr;, platelet-derived endothelial cell growth factor, granulocyte colony-stimulating factor, interleukin-8, hepatocyte growth factor, proliferin, vascular endothelial growth factor and placental growth factor. See, e.g., review by Folkman et al., 1995,
N. Engl. J. Med.,
333:1757-1763.
Several kinds of compounds have been used to prevent angiogenesis. Taylor et al. have used protamine to inhibit angiogenesis, see Taylor et al.,
Nature
297:307 (1982). The toxicity of protamine limits its practical use as a therapeutic. Folkman et al. have disclosed the use of heparin and steroids to control angiogenesis. See Folkman et al.,
Science
Muller George W.
Stirling David
Buckwalter Brian L.
Celgene Corporation
Mathews, Collins Shepherd & McKay, P.A.
Murray Joseph
Ramsuer Robert W.
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