Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1997-10-17
1999-10-05
Ambrose, Michael G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514100, 514107, 548113, 548414, 549220, 549 6, 558158, 558159, 562 12, 562 13, A61K 31675, A61K 31665, A61K 3166, C07F 96541
Patent
active
059624388
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel estrogen derivatives having carriers to bone which are useful for treating or preventing diseases caused by estrogen deficiency, and pharmaceutically acceptable salts thereof.
BACKGROUND ART
Estrogens are steroid or non-steroid estrogenic hormones, and various substances including not only natural substances but also synthetic substances are known as estrogens (Environmental Health Perceptives, Vol. 61, pp. 97-110 (1985)). Natural human estrogen is 17.beta.-estradiol produced mainly in ovary and this hormone plays an important role in the development of female secondary sexual character, the proliferation of endometrium, the control of sexual functions, the control of metabolism in bone, the control of lipid metabolism, etc. Therefore, when the estrogen in the body is deficient owing to aging or ovary malfunction, there are caused specific medical symptoms such as osteoporosis, menopausal disorders, lipid metabolism abnormality and vasomotor syndrome associated with menopause, atrophic vaginitis, kraurosis vulvae, premenstrual tension syndrome, female hypogonadism, etc. Estrogen supplementation therapy is applied to these diseases. The prophylactic effect of estrogen on fracture due to coronary cardiopathy or osteoporosis has recently been elucidated in postmenopausal women (Annals of Internal Medicine, Vol. 117, pp. 1038-1041 (1992)). Estrogen accelerates gonadotropin inhibition and is used also as a contraceptive in combination with progestogens (e.g. progesterone), other female sex hormones. However, since long-term administration of estrogen produces adverse side effects such as mastodynia, dysfunctional genital bleeding, corpulence, endometrial hyperplasia, endometrioma, mammary cancer, myocardial infarction, thromboembolism, cerebrovascular diseases, etc., a therapeutic agent Medicine, Vol. 94, pp. 646-650 (1993)!.
There have already been reported the following compounds obtained by combining each of various estrogens with a compound having a specific molecular structure which is considered to be rich in affinity for osseous tissue (a compound having affinity for bone) by a covalent bond through a spacer in order to incorporate the estrogen selectively into bone:
1) Compounds obtained by bonding a poly-(malonic acid) derivative as a compound having affinity for bone to the hydroxyl group of a 17.beta.-estradiol derivative or the like by a carbamate linkage (Japanese Patent Unexamined Publication No. 2-36145).
2) Compounds obtained by bonding a bisphosphonic acid derivative as a compound having affinity for bone to the hydroxyl group of 17.beta.-estradiol by an ester linkage or a carbamate linkage (Japanese Patent Application Kohyo No. 6-500777).
3) Compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of a steroid compound such as 17.beta.-estradiol by a carbamate linkage, thiocarbamate linkage or carbonate linkage (Japanese Patent Unexamined Publication No. 4-352795).
4) Compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of a steroid compound such as 17.beta.-estradiol by an ester linkage or a carbamate linkage (Japanese Patent Unexamined Publication No. 5-286993).
5) Specific compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of 17.beta.-estradiol by an ester linkage (Japanese Patent Unexamined Publication No. 6-100576).
6) Compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of 17.beta.-estradiol or the like by an ether linkage (Japanese Patent Unexamined Publication Nos. 5-230086 and 6-329697).
7) Compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of 17.beta.-estradiol or the like by an ether linkage or a carbamate linkage (Japanese Patent Unexamined Publication No. 5-345791).
8) Compounds obtained by bonding a bisphosphonic acid derivative directly to the basic skeleton of an estrogen compound such as a hexestrol derivative or 2-phenylindole derivative through an alkylene group (J
REFERENCES:
Heiman, Daniel F. et al, Estrogen Receptor Based Imaging Agents. 1. Synthesis and Receptor Binding Affinity of Some Aromatic and D-Ring Halogenated Estrogens, Journal of Medicinal Chemistry, Sep. 1980, vol. 23, No. 9, pp. 994-1002.
Patent Abstracts of Japan, vol. 095, No. 002, Mar. 31, 1995.
Harada Hideyuki
Katsumata Takashi
Sasaki Akira
Tsushima Naomi
Yamamoto Michihiro
Ambrose Michael G.
Sumitomo Pharmaceuticals Company Limited
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