Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1998-02-02
2000-06-27
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514182, 540 47, 540113, 552510, 552539, 552548, 552552, 552554, 552555, 552558, 552610, 552611, 552618, 552626, 552650, A61K 3158, A61K 3156, C07J 4300, C07J 5300
Patent
active
060807350
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
This invention relates to new estra-1,3,5(10)-trien sulfamates.
Estrogens play a major role in hormonal contraception and climacteric hormone replacement therapy (HRT) as well as in the treatment of gynecological (e.g. mammary carcinoma) and andrological (e.g. prostate carcinoma) diseases.
In HRT and for contraception, estrogens are predominantly used in combination with a gestagen, e.g. levonorgestrel, desogestrel, gestodene, drospirorenone, norethisterone, cyproterone acetate, chlormadinone acetate and dienogest.
For contraception, estrogens are required for reliable suppression of follicular maturation and ovulation. They will also substitute for widely suppressed endogenic, ovarian secretion of estradiol. Such substitution is essential to maintenance of an artificial menstruation cycle and other functions of sexual organs, which would not be satisfactorily achievable by a gestagen alone.
Endogenic estrogens also have important central nervous and metabolic functions in the female organism.
Normal estrogen levels make a crucial contribution to individual comfort and wellbeing (L. Zichella; Clinical Management of the Menopausal Woman; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 15-22). Their presence, through various mechanisms, may help in preventing development of cardiovascular diseases, for example, by generating "favourable" lipoprotein patterns in the blood (G. Samsioe; Hormone Replacement Therapy and Cardiovascular Disease; Int. J. of Fertil. and Menop. Studies. 38, Suppl. 1 [1993], 23-29), inhibition of lipid incorporation into vascular walls (T. B. Clarkson; Experimental Effects of Progesterone versus Progestins on Arterial Wall; Gynecol. Endocrinol., 6: Suppl. 1 [1992], 15), reduction of blood pressure through favourable action on vascular tonus (R. A. Lobo; Estrogen and Cardiovascular Disease; Ann. New York Acad. Sciences, 592 [1990], 286-294), reduction of perfusion resistance in important vascular regions, attenuation of contractile stimuli on vascular muscle (C. Jiang et al.; Acute effect of 17.beta.-estradiol on rabbit coronary artery contractile responses to endothelin-1; Am. J. Physiol., 263 [1992], H271-H275). The inner vascular walls, under the impact of estrogens, release factors (prostacyclins) which counteract to the buildup of blood clots.
Estrogens are additionally indispensable to women for preservation of the bone structure. Their loss may cause osseous degradation (osteoporosis) (C. Christiansen; Prevention and Treatment of Osteoporosis with Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 45-54). These latter "central nervous" and "metabolic" effects of estrogens are major aspects in HRT.
Notwithstanding the numerous appreciable aspects of estrogen therapy, there still are certain unresolved problems which impose limitations on the therapeutic use of estrogens or may entail undesirable effects.
The bioavailability of natural estrogens (estradiol, estrone, estrone sulphate, esters of estradiol, estriol) tends to be minimised after oral application (K. B. Lokind et al.; Oral bioavailability of 17.beta.-estradiol and various ester prodrugs in the rat; Int. J. Pharmaceutics, 76 [1991], 177-182). That minimised amount is of high individual variability, and a dosage of general validity, consequently, cannot be recommended. The use of natural estrogens (estradiol) for hormonal contraception has been negatively assessed because of these pharmacokinetic restrictions (W. Kuhnz et al.; Pharmacokinetics of Estradiol, Free and Total Estrone in Young Women, following Single Intravenous and Oral Administration of 17.beta.-Estradiol; Arzneimittel-Forschung /Drug Res., 43(II), 9 [1993], 966-973). Rapid elimination of substances from blood is another problem. Estrogen substitution in HRT must repeatedly be readjusted to the individual recipient. Efforts so far have failed to develop estradiol prodrugs for improved oral bioavailability (K. B. Lokind et al.; see above).
Synthetic estrogens, too, are accompanied by serious drawba
REFERENCES:
patent: 5616574 (1997-04-01), Reed et al.
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Elger Walter
Lucas, heir by Margit
Reddersen Gudrun
Schneider Birgitt
Schwarz Sigfrid
Coleman Brenda
JENAPHARM GmbH & Co. KG
Shah Mukund J.
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