Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-19
2003-09-16
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S525000
Reexamination Certificate
active
06620838
ABSTRACT:
FIELD OF THE INVENTION
This invention is generally directed to benzopyranone compounds, compositions comprising the benzopyranone compounds and methods for treating a bone-resorbing disease, cancer, arthritis or an estrogen-related condition, comprising administering an effective amount of a benzopyranone compound to a patient in need thereof.
BACKGROUND OF THE INVENTION
The estrogen hormone has a broad spectrum of effects on tissues in both females and males. Many of these biological effects are positive, including maintenance of bone density, cardiovascular protection, central nervous system (CNS) function, and the protection of organ systems from the effects of aging. However, in addition to its positive effects, estrogen also is a potent growth factor in the breast and endometrium that increases the risk of cancer.
Until recently, it was assumed that estrogen binds to a single estrogen receptor (ER) in cells. As discussed below, this simple view changed significantly when a second ER (ER-&bgr;) was cloned (with the original ER being renamed ER-&agr;), and when co-factors that modulate the ER response were discovered. Ligands can bind to two different ERs which, in the presence of tissue-specific co-activators and/or co-repressors, bind to an estrogen response element in the regulatory region of genes or to other transcription factors. Given the complexity of ER signaling, along with the tissue-specific expression of ER-&agr; and ER-&bgr; and its co-factors, it is now recognized that ER ligands can act as estrogen agonists and antagonists that mimic the positive effects, or block the negative effects, of estrogen in a tissue-specific manner. This has given rise to the discovery of an entirely new class of drugs, referred to as Selective Estrogen Receptor Modulators or SERMs. These drugs have significant potential for the prevention and/or treatment of cancer and osteoporosis, as well as cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
Bone-resorbing diseases, such as osteoporosis, are debilitating conditions which affect a wide population, and to which there is only limited treatment. For example, osteoporosis affects about 50% of women, and about 10% of men, over the age of 50 in the United States. In individuals with osteoporosis, increased loss of bone mass results in fragile bones and, as a result, increased risk of bone fractures. Other bone-resorption diseases, such as Paget's disease and metastatic bone cancer, present similar symptoms.
Bone is a living tissue which contains several different types of cells. In healthy individuals, the amount of bone made by the osteoblastic cells is balanced by the amount of bone removed or resorbed by the osteoclastic cells. In individuals suffering from a bone-resorbing disease, there is an imbalance in the function of these two types of cells. Perhaps the most well known example of such an imbalance is the rapid increase in bone resorption experienced by postmenopausal women. Such accelerated bone lose is attributed to estrogen deficiency associated with menopause. However, the mechanism of how the loss of estrogen results in increased bone resorption has long been debated.
Recently, investigators have suggested that an increase in bone-resorbing cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), may be responsible for postmenopausal bone loss (Kimble et al.,
J. Biol. Chem
. 271:28890-28897, 1996), and that inhibitors of these cytokines can partially diminish bone loss following ovariectomy in rodents (Pacifici,
J. Bone Miner Res
. 11: 1043-1051, 1996). Further, discontinuation of estrogen has been reported to lead to an increase in IL-6 secretion by murine bone marrow and bone cells (Girasole et al.,
J. Clin. Invest
. 89:883-891, 1992; Jilka et al.,
Science
257:88-91, 1992; Kimble et al.,
Endocrinology
136:3054-3061, 1995; Passseri et al.,
Endocrinology
133:822-828, 1993), antibodies against IL-6 can inhibit the increase in osteoclast precursors occurring in estrogen-depleted mice (Girasole et al, supra), and bone loss following ovariectomy does not occur in transgenic mice lacking IL-6 (Poli et al.,
EMBO J
. 13:1189-1196, 1994).
Existing treatments for slowing bone loss generally involves administration of compounds such as estrogen, bisphosphonates, calcitonin, and raloxifene. These compounds, however, are generally used for long-term treatments, and have undesirable side effects. Further, such treatments are typically directed to the activity of mature osteoclasts, rather than reducing their formation. For example, estrogen induces the apoptosis of osteoclasts, while calcitonin causes the osteoclasts to shrink and detach from the surface of the bone (Hughes et al.,
Nat. Med
. 2:1132-1136, 1996; Jilka et al.,
Exp. Hematol
. 23:500-506, 1995). Similarly, bisphosphonates decrease osteoclast activity, change their morphology, and increase the apoptosis of osteoclasts (Parfitt et al.,
J. Bone Miner Res
. 11: 150-159, 1996; Suzuki et al.,
Endocrinology
137:4685-4690, 1996).
Cytokines are also believed to play an important role in a variety of cancers. For example, in the context of prostate cancer, researchers have shown IL-6 to be an autocrine/paracrine growth factor (Seigall et al.,
Cancer Res
. 50:7786, 1999), to enhance survival of tumors (Okamoto et al.,
Cancer Res
. 57:141-146, 1997), and that neutralizing IL-6 antibodies reduce cell proliferation (Okamoto et al.,
Endocrinology
138:5071-5073, 1997; Borsellino et al.,
Proc. Annu. Meet. Am. Assoc. Cancer Res
. 37:A2801, 1996). Similar results have been reported for IL-6 with regard to multiple myeloma (Martinez-Maza et al.,
Res. Immunol
. 143:764-769, 1992; Kawano et al.,
Blood
73:517-526, 1989; Zhang et al.,
Blood
74:11-13, 1989; Garrett et al.,
Bone
20:515-520, 1997; and Klein et al.,
Blood
78:1198-12-4, 1991), renal cell carcinoma (Koo et al.,
Cancer Immunol
. 35:97-105, 1992; Tsukamoto et al.,
J. Urol
. 148:1778-1782, 1992; and Weissglas et al.,
Endocrinology
138:1879-1885, 1997), and cervical carcinoma (Estuce et al.,
Gynecol. Oncol
. 50:15-19, 1993; Tartour et al.,
Cancer Res
. 54:6243-6248, 1994; and Iglesias et al.,
Am. J. Pathology
146:944-952, 1995).
Furthermore, IL-6 is also believed to be involved in arthritis, particularly in adjuvant-, collagen- and antigen-induced arthritis (Alonzi et al.,
J. Exp. Med
. 187:146-148, 1998; Ohshima et al.,
Proc. Natl. Acad. Sci. USA
95:8222-8226, 1998; and Leisten et al.,
Clin. Immunol. Immunopathol
56:108-115, 1990), and anti-IL-6 antibodies have been reported for treatment of arthritis (Wendling et al.,
J. Rheumatol
. 20:259-262, 1993). In addition, estrogen has been shown to induce suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice (Jansson et al.,
Neuroimmunol
. 53:203-207, 1994)
The cytokine IL-6 has also been shown to be an important factor in inducing the formation of osteoclasts (Girasole et al., supra; Jilka et al. (1992), supra; Jilka et al. (1995), supra; Kimble et al. (1995), supra; Pacifici et al., supra; and Passeri et al., supra). Other investigators have shown that administration of the neutralizing antibody, antisense oligos, or the Sant 5 antagonist against IL-6, reduces the number of osteoclasts in trabecular bone of ovariectomized mice (Devlin et al.,
J. Bone Miner
13:393-399, 1998; Girasole et al., supra; Jilka et al. (1992), supra, and Schiller et al.,
Endocrinology
138:4567-4571, 1997), the ability of human giant cells to resorb dentine (Ohsaki et al.,
Endocrinology
131:2229-2234, 1993; and Reddy et al.,
J. Bone Min. Res
. 9:753-757, 1994), and the formation of osteoclasts in normal human bone marrow culture. It has also been found that estrogen downregulates the IL-6 promoter activity by interactions between the estrogen receptor and the transcription factors NF-&kgr;B and C/EBP&bgr; (Stein et al.,
Mol. Cell Biol
. 15:4971-4979, 1995).
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been suggested to play a role in the proliferation
Bhagwat Shripad S.
McKie Jeffrey A.
Missbach Martin
Renaud Johanne
McKane Joseph K.
Pennie & Edmonds LLP
Signal Pharmaceuticals Inc.
Wright Sonya
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