Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-21
2003-07-29
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S425000, C514S651000, C546S203000, C548S528000, C564S317000
Reexamination Certificate
active
06599921
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to non-steroidal compounds that demonstrate high-binding affinity for the estrogen receptor, while being devoid of any agonistic effects on reproductive tissues and to non-steroidal compounds that have a high binding affinity for the estrogen receptor while also having some agonistic activity specific to the skeletal and cardiovascular systems. More particularly, the present invention relates to novel non-steroidal ligands for the estrogen receptor as well as methods of making the same and their applications in treating a variety of disease states.
BACKGROUND OF THE INVENTION
Interfering with the activity of endogenously produced estrogens can modulate the course of many estrogen-dependent diseases. One approach has been to prevent estrogen biosynthesis using inhibitors of aromatase enzymes, which are responsible for the conversion of androgens to estrogens. Alternatively, estrogen activity may be interrupted at the receptor level using estrogen antagonists.
The involvement of estrogens in the development and progression of breast cancer has been known for over 100 years. In normal breast tissue, only 6% of the mammary epithelial cells express estrogen receptors (McDonnell et al.,
Ann. N. Y. Acad. Sci.
1996; 121-37), whereas over 60% of primary breast tumors are estrogen receptor positive and are dependent on estrogen for growth. However, it has been documented that other agents (e.g. growth factors) can activate estrogen receptors in the absence of estrogen (Pareczyk and Schneider,
J. Cancer Res. Clin. Oncol.
1996; 122:383-96). As a result, blocking activity at the estrogen receptor is potentially a more effective therapeutic strategy than inhibition of estrogen biosynthesis.
Tamoxifen, a triphenylethene derivative, is the most widely used anti-estrogen for the treatment of breast cancer. It is predominantly used as a first-line therapy in metastatic breast cancer to prolong survival. Unfortunately, resistance to tamoxifen usually develops within 15 months of therapy initiation. Nevertheless, the clinical efficacy of tamoxifen as a hormonal therapy for many types of breast cancer has led to the search for more potent estrogen receptor antagonists.
Several new antiestrogens including toremifene, droloxifene, idoxifene, TAT-59 and raloxifene are currently being evaluated in the laboratory and in the clinic for the treatment of estrogen related disorders (Gradishar and Jordan,
J. Clin. Oncol.
1997; 15(2):840-52). There has been considerable concern regarding the long-term use of tamoxifen due to an increase in incidences of endometrial cancer, deep venous thrombosis and pulmonary embolism for patients receiving the therapy (Rauschning and Pritchard,
Breast Cancer Res. Treat
1994; 31:83-94). Other more common side effects include, hot flushes, vaginal bleeding and blurred vision (Nicholson R I,
Bailliere and Tindall,
1987:60-87). Despite these side effects, results from one clinical study have demonstrated the utility of tamoxifen in the prevention of breast cancer in women at high risk of developing the disease (Fisher et al,
J. of the Nat'l Cancer Inst.
1998; Vol. 90; No. 18; 1371-1388). The FDA has approved tamoxifen for use as a prophylactic.
It has been suggested that the partially agonistic properties of some anti-estrogens are responsible for both their side-effect profile and the development of resistance to therapy (Nicholson et al.,
Ann. N. Y. Acad. Sci.
1996; 784:-325-35). Partial agonists are compounds for which the balance in the expression of antagonistic and agonistic activity depends on the dose administered, as well as on the species and target organ studied. More specifically, differences in agonistic/antagonistic responses depend on the presence of cell-specific proteins that can act as co-activators or transcription factors (Mitlak and Cohen,
Horm. Res.
1997; 48:155-63). In vitro and in vivo experiments have suggested that the agonistic properties of some anti-estrogens may become dominant through the course of therapy. This has been demonstrated in clinical settings where 10-30% of tamoxifen-resistant patients showed improvement of their diseases after withdrawal from tamoxifen therapy (Parczyk and Schneider,
J. Cancer Res. Clin. Oncol.
1996; 122:383-96).
“Pure” anti-estrogens are compounds that have exclusively antagonistic properties and lead to the formation of inactive ligand-receptor complexes. In contrast to partial agonists that stimulate the expression of estrogen receptors, pure anti-estrogens cause a down-regulation of cellular receptor protein levels (Parczyk and Schneider,
J. Cancer Res. Clin. Oncol.
1996; 122:383-96). Since the estrogen receptor is activated through estrogen-independent factors, the reduction in estrogen receptor levels obtained with pure anti-estrogens may offer clinical advantages over partial agonists and aromatase inhibitors. Clinical trials with pure anti-estrogens have shown efficacy against tamoxifen-resistant breast cancers where approximately two-thirds of tamoxifen-resistant patients responded to ICI 182780 (faslodex), and no significant adverse effects were observed (England and Jordan,
Oncol. Res.
1997; 9:397-402).
Many studies performed to date have suggested that anti-estrogens with partial agonistic activity have positive effects on cardiovascular and skeletal systems. For example, tamoxifen lowers total and LDL cholesterol, lowers lipoprotein (A) and preserves bone mass in postmenopausal women undergoing breast cancer treatment (Mitlak and Cohen,
Horm. Res.
1997; 48:155-63). Estrogens play an important role in the regulation and synthesis of lipids and therefore have a protective effect on the cardiovascular system. Following menopause, the risk of developing atherosclerosis and coronary disorders dramatically increases in women not undergoing hormone replacement therapy. In addition, estrogens are critically important in the maintenance of proper bone mass. As the circulating level of estrogen decreases, post-menopausal women experience an increase in the rate of bone turnover, resulting in net bone loss. Therefore, the positive effects of tamoxifen observed on skeletal and cardiovascular systems may be related to agonistic activity through the estrogen receptor present in those tissues (Mitlak and Cohen,
Horm. Res.
1997; 48:155-63).
Other partial agonists currently in development have demonstrated anti-estrogenic effects on reproductive tissues with increased protective effects or estrogenic activity on the skeletal and cardiovascular systems. These compounds are known as Selective Estrogen Receptor Modulators (SERMs). Examples of these include droloxifene, which is being developed as an anti-osteoporotic agent, and raloxifene, which has been approved by the FDA for prevention of osteoporosis in post-menopausal women.
Although anti-cancer agents fall into specific classifications, it is not uncommon for agents to act by multiple modes of action. For example, tamoxifen has been shown to have anti-proliferative activity on cancer cells and endothelial cells by an estrogen independent mechanism. Taxol, an anti-mitotic agent acting on microtubules has also demonstrated anti-angiogenic properties, possibly by inducing apoptosis through Bcl-2 phosphorylation. These are but a few examples and the fact that some anti-estrogens have demonstrated anti-angiogenic properties is of particular interest to many in this field of research. Such a possibility is not precluded in the present invention.
There thus remains a need to develop a series of non-steroidal compounds that demonstrate high-binding affinity for the estrogen receptor, while being devoid of any agonistic effects on reproductive tissues. Alternatively, non-steroidal compounds that have a high binding affinity for the estrogen receptor and have some agonistic activity specific to the skeletal and cardiovascular systems are also desirable. Therefore, either pure anti-estrogens or partial anti-estrogens with high binding affinity, low toxicity and prolonged efficacy would be of gre
Kwiatkowski Stefan
Lazarowych Natalie
Lowell Jeffry Lawrence
Mercure Julie
Pupek Krzysztof
Chang Ceila
Fulbright & Jaworski
NanoDesign, Inc.
LandOfFree
Non-steroidal estrogen receptor ligands does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Non-steroidal estrogen receptor ligands, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Non-steroidal estrogen receptor ligands will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3105150