Pharmaceutically active isoindoline derivatives

Details Pharmaceutically active isoindoline derivatives Pharmaceutically active isoindoline derivatives

2000-11-14

2002-10-01

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S201000

Reexamination Certificate

active

06458810

ABSTRACT:

The present invention pertains to non-polypeptide isoindoline derivatives that decrease the levels of tumor necrosis factor alpha (TNF&agr;) and to the treatment of disease states mediated thereby. The compounds inhibit angiogenesis and are useful in the treatment of cancer, inflammatory, and autoimmune diseases. For example, compounds that selectively inhibit TNF&agr; are useful in treating inflammation and effecting relaxation of airway smooth muscle with a minimum of unwanted side effects, e.g., cardiovascular or anti-platelet effects. The present invention also relates to methods of treatment and pharmaceutical compositions utilizing such compounds.
BACKGROUND OF THE INVENTION
Tumor necrosis factor &agr;, or TNF&agr;, is a cytokine which is released primarily by mononuclear phagocytes in response to a number immunostimulators. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute 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. 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, Crohn's disease, IBD, cachexia {Dezube et al.,
Lancet,
335 (8690), 662 (1990)} and Adult Respiratory Distress Syndrome 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 osteoblast formation and activation combined with inhibition of osteoblast function. Although TNF&agr; may be involved in many bone resorption diseases, including arthritis, a most 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 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)}.
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)}.
Unregulated angiogenesis is pathologic and sustains progression of many neo-plastic and non-neoplastic diseases including solid tumor growth and metastases, arthritis, some types of eye disorders, and psoriasis. See, e.g., 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; Folkman et al., 1983,
Science
221:719-725; and Folkman and Klagsbrun, 1987,
Science
235:442-447. In addition, 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.
Angiogenesis thus is encountered in various disease states, tumor metastasis, and abnormal growth by endothelial cells. Pathological states created by unregulated angiogenesis have been grouped together as angiogenic dependent or angiogenic associated diseases. Control of the angiogenic processes could lead to the mitigation of these conditions.
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. Endothelial cells exposed to a medium containing suitable growth factors can be induced to evoke some or all of the angiogenic responses. Polypeptides with in vitro endothelial growth promoting activity 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. Folkman et al., 1995, N. Engl. J. Med., 333:1757-1763.
Inhibitory influences predominate in the naturally occurring balance between endogenous stimulators and inhibitors of angiogenesis. Rastinejad et al., 1989,
Cell
56:345-355. In those 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.
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 suggest TNF&agr; is a candidate for inducing angiogenesis in inflammation, wound repair, and tumor growth.
TNF&agr; production also has been independently associated with cancerous conditions, particularly induced tumors {Ching et al.,
Brit. J. Cancer,
(1955) 72, 339-343, and Koch,
Progress in Medicinal Chemistry,
22, 166-242 (1985)}. Whether or not involved with TNF&agr; production, angiogenesis is prominent in solid tumor formation and metastasis and angiogenic factors have been found associated with several solid tumors such as rhabdomyosarcomas, retinoblastoma, Ewing sarcoma, neuroblastoma, and osteosarcoma. Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and pyogenic granulomas. Independent of its action on TNF&agr; production, the prevention of angiogenesis could halt the growth of these tumors and the resultant damage to the animal due to the presence of the tumor. Angiogenesis has been associated with blood-born tumors such as leukemias and various acute or chronic neoplastic diseases of the bone marrow. In such conditions, unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen.
Angiogenesis also is involved in tumor metastasis. Thus angiogenesis stimulation occurs in vascularization of the tumor, allowing tumor cells to enter the blood stream and circulate throughout the body. After the tumor cells have left the primary site, and have settled into the secondary, metastasis site, angiogenesis must occur before the new tumor can grow and expand.
All of the various cell types of the body can be transformed into benign or malignant tumor cells. The most frequent tumor site is lung, followed by colorectal, breast, prostate, bladder, pancreas, and then ovary. Other prevalent types of cancer include leukemia, central nervous system cancers, including brain cancer, melanoma, lymphom

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