Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-09-03
2001-08-07
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S179000, C514S182000, C552S558000, C552S614000, C552S617000, C552S625000, C552S627000
Reexamination Certificate
active
06271220
ABSTRACT:
BACKGROUND OF THE INVENTION
Angiogenesis, the process of vascularization, has been implicated in a host of biological disorders including cancer, macular degeneration and arthritis. Spawned by the therapeutic potential associated with the inhibition of pathological angiogenesis, a flurry of activity has led to the discovery of a variety of antiangiogenic compounds which exhibit clinical utility. The discovery of 2-methoxyestradiol by Folkman et al has demonstrated evidence for potent antiangiogenic activity by the estrane steroid family and has provided the most potent endogenous mammalian inhibitor of tubulin polymerization yet discovered. (See U.S. Pat. No. 5,504,074.) Additionally, Fotsis et al have shown that of 2-methoxyestradiol exhibits in vitro anti-mitotic properties and reversible inhibition of cell proliferation while confluent cultures are unaffected. (See Fotsis, et. al. Nature 1994, 368, 237.) Preclinical and clinical trials have also shown 2-methoxyestradiol to be promising in the treatment of several angiogenic disorders.
2-Methoxyestradiol has been reported to exhibit antiangiogenic activity through the inhibition of tubulin polymerization by binding at the colchicine binding site. In contrast to 2-methoxyestradiol, colchicine exhibits minimal selectivity, is highly cytotoxic and as a result, its clinical use has been limited due to this low therapeutic index. Since the discovery of 2-methoxyestradiol, structure-activity relationship studies have yielded several 2-substituted estradiol derivatives that exhibit greater affinity for the colchicine binding site, as well as displaying greater cytotoxic responses in cancer cell lines. While the full clinical potential of 2-methoxyestradiol and these related compounds continues to be investigated, little remains known about the relationship between the observed antiangiogenic activity of 2-methoxyestradiol and its ability to bind to tubulin.
SUMMARY OF THE INVENTION
We have discovered that certain compounds within the scope of the general formulae set forth below in the claims are useful for treating mammalian diseases characterized by undesired cell mitosis. Without wishing to bind ourselves to any particular theory, such compounds generally inhibit microtubulic formation and tubulin polymerization and/or depolymerization. Compounds within the general formulae having said inhibiting activity are preferred. Preferred compositions may also exhibit a change (increase or decrease) in estrogen receptor binding, improved absorption, transport (e.g. through blood-brain barrier and cellular membranes), biological stability, or decreased toxicity. We have also discovered certain compounds useful in the method, as described by the general formulae of the claims.
A mammalian disease characterized by undesirable cell mitosis, as defined herein, includes but is not limited to excessive or abnormal stimulation of endothelia cells (e.g. atherosclerosis) solid tumors and tumor metastasis, benign tumors, for example, hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas, vascular malfunctions, abnormal wound healing, inflammatory and immune disorders, Bechet's disease, gout or gouty arthritis, abnormal angiogenesis accompanying rheumatoid arthritis, psoriasis, diabetic retinopathy and other ocular angiogenic diseases such as retinopathy of prematurity (retrolental fibroplastic), macular degeneration, corneal graft rejection, neovascular glaucoma and Osler Weber syndrome. Other undesired angiogenesis involves normal processes including ovulation and implantation of a blastula. Accordingly, the compositions described above can be used to block ovulation and implantation of a blastula or to block menstruation (induce amenorrhea).
Other features and advantages of the invention will be apparent from the following description of preferred embodiments thereof.
REFERENCES:
patent: WO 95/04535 (1995-02-01), None
Garst Michael E.
MacDonald Timothy L.
Allergan Sales Inc.
Baran Robert J.
Fisher Carlos A.
McKane Joseph K.
Murray Joseph
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