Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ether doai
Patent
1997-04-01
1998-05-12
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ether doai
A61K 31075
Patent
active
057505764
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/F195/00475 filed Sep. 6, 1995.
This invention relates to the use of certain triphenyiethylene compounds, that are devoid of significant antiestrogenic and estrogenic activity, for the prevention and treatment of osteoporosis.
Osteoporosis is one of the most common chronic diseases in postmenopausal women. It is characterized by rapid bone loss after the menopause resulting in bone fractures. One of the major factors in the pathogenesis of osteoporosis is increased bone resorption in association with estrogen-deficiency. Increased bone resorption results in decreased bone mass and decreased bone strength. The current preventive treatment includes the use of estrogen replacement therapy in postmenopausal women.
Estrogen and transforming growth factors-.beta. (TGF-.beta.) are key factors in bone remodelling and may have overlapping functions. They are both capable of inducing collagen and inhibiting bone resorption. It is still unclear whether estrogen functions through a pathway that regulates TGF-.beta. production.
Postmenopausal bone loss occurs when coupling between bone formation and bone resorption is no longer balanced. Estrogen replacement therapy results in decreased bone turnover, decreased bone resorption and decreased fracture occurrence in postmenopausal patients. However, results of in vitro experiments have not provided clear-cut clues to the mechanism by which estrogen exerts its effects on bone. Data suggest that estrogen may act on bone by several mechanisms, either directly through estrogen receptors, indirectly through other cells besides bone cells and/or in concert with other factors and hormones such as progesterones. A long-term use of estrogens is associated with potential side effects due to the increased risk for cancers of estrogen dependent tissues such as endometrium and breast.
Triphenylethylene group antiestrogens tamoxifen and toremifene have recently been shown to stimulate TGF-.beta. production by fibroblasts (Colletta et al., Br. J. Cancer, 62, 405-409, 1990. Tamoxifen has also been shown to have a positive effect on bone density (Jordan et al, Breast Cancer Res. Treatm, 10, 31-35, 1987). Tamoxifen and toremifene are both in a group of compounds that are used clinically for the treatment of estrogen receptor positive breast cancer. In patients with breast cancer these compounds primarily exert their antiestrogenic properties by blocking the estrogen receptors present in breast cancer cells, thus inhibiting cancer cell growth. Although their primary mode of action is inhibition of estrogen receptors they are also known to behave as estrogen agonists, particularly in uterine tissue in which they stimulate cell proliferation. Several reports have now suggested that tamoxifen may in fact induce secondary uterine tumors in women receiving long term tamoxifen therapy. The antiestrogenic triphenylethylenes also share many hormonal side effects in common with the estrogens, including hot flashes, nausea, menstrual irregularity and the potential for development of life-threatening thrombolic disorders.
While the clinical efficacy of tamoxifen as an agent to prevent and/or treat osteoporosis remains to be elucidated, the side effects of the antiestrogenic triphenylethylenes would be a particular disadvantage for type of long term, chronic therapy that is required to prevent osteoporosis. On the other hand agents, that had the ability to prevent osteoporosis but were devoid of hormone related side effects such us uterine hyperplasia, hot flashes, nausea and thromboembolic complications would be very useful clinically.
DESCRIPTION OF DRAWING
FIG. 1 illustrates the results of the measurements of ash weight of the epiphysis of rat tibia of compound A.
According to the invention a compound having formula (I) ##STR2## wherein R.sub.1 and R.sub.2 are independently H or OH, is used in the manufacture of a medicament for use in the prevention and treatment of osteoporosis. It has been found that the compounds of formula (I), which are devoid of significant
REFERENCES:
patent: 5605700 (1997-02-01), DeGregorio
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DeGregorio Michael
Harkonen Pirkko
Kangas Lauri
Laine Aire
Vaananen Kalervo
Criares Theodore J.
Orion-yhtyma Oy
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