14.alpha., 16.alpha.-ethanoand 14.alpha., 16.alpha.-etheno-estra

Details 14.alpha., 16.alpha.-ethanoand 14.alpha., 16.alpha.-etheno-estra 14.alpha., 16.alpha.-ethanoand 14.alpha., 16.alpha.-etheno-estra

1994-03-18

1995-08-08

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

514182, 552510, C07J 5300, A61K 31565

Patent

active

054399025

DESCRIPTION:

BRIEF SUMMARY
This application is a continuation of PCT/EP92/00945 filed Apr. 30, 1992.
The invention relates to 14.alpha.,16.alpha.-ethano- and 14.alpha.,16.alpha.-etheno-estratrienes of general formula I, ##STR3## in which A-B means a C-C single bond or C-C double bond, atoms and ##STR4## in which R.sub.2 represents a hydrogen atom or an acyl group with 1-12 carbon atoms, these compounds, as well as their use for production of pharmaceutical agents.
As acyl groups R.sub.1 and R.sub.2, radicals of organic carboxylic acids with 1-12 carbon atoms are suitable. They are derived from aliphatic, cycloaliphatic, aliphatic-cycloaliphatic, cycloaliphatic-aliphatic and aromatic monocarboxylic acids with 1-12 carbon atoms. The number of carbon atoms in the ring varies from 3 to 5. As radicals R.sub.1 and R.sub.2, the acyl groups of acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, caproic acid, heptylic acid, caprylic acid, pelargonic acid, decanoic acid, undecanoic acid, dodecanoic acid, 3-cyclopentylpropionic acid and benzoic acid are preferred. The acyl radicals of carboxylic acids with 2-7 carbon atoms are especially preferred.
The new 14.alpha.,16.alpha.-ethano- and 14.alpha.,16.alpha.-etheno-estratrienes are very strong estrogens. In the Allen-Doisy test, the compounds of general formula I are even more active than estradiol, especially after oral administration. Surprising is above all the far better action of the 17.alpha.-hydroxy compounds according to the invention in comparison with the naturally occurring estradiol with 17.alpha.-hydroxy group (17.alpha.-estradiol) as can be seen from table 1.


TABLE 1 __________________________________________________________________________ Compound Allen-Doisy Test Allen-Doisy Test Estrogen- s.c. .mu.g/animal/ p.o. .mu.g/animal/ receptor day [ED.sub.50 ] day [ED.sub.50 ] test (KF) Tabelle 1 Allen-Doisy-Test s.c. Allen-Doisy-Test p.o. Estrogen-Rezeptor- Verbindung .mu.g/Tier/Tag [ED.sub.50 ] .mu.g/Tier/Tag [ED.sub.50 ] Test [KF] __________________________________________________________________________ Estradiol 0.2-0.5 50-100 1.0 17.alpha.-Estradiol 100 >1000 46.0 14.alpha.,16.alpha.-Ethano-estra- 0.1-0.3 3-10 0.5 1,3,5(10)-trien-3,17.alpha.-diol 14.alpha.,16.alpha.-Etheno-estra- 1.5 1,3,5(10)-trien-3,17.alpha.-diol 14.alpha.,16.alpha.-Ethano-estra- 0.1-0.3 1.0 1.0 1,3,5(10)-trien-3,17.beta.-diol __________________________________________________________________________
In the Allen-Doisy test, an evaluation of vaginal smears in ovariectomized rats is performed on days 3-5 (d3-d5) after the one-time administration on day 1 (d1) of the test substance. The following cycle stages are distinguished:
After oral or subcutaneous administration, estrogenically active substances result in the proliferation of the vaginal epithelium and the hornification of superficial cell layers. As a threshold value, that amount of an estrogen is indicated in which 50% of the animals reach stage 3. Further, estrogens cause an increase of the uterus weight.
By the example of the 14.alpha.,16.alpha.-ethano-estra-1,3,5(10)-triene-3,17.alpha.-diol according to the invention, it is shown in FIG. 1 that after subcutaneous administration of only 0.3 .mu.g in the rat, the threshold value is already exceeded.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the results of administration of various amounts of 14.alpha., 16.alpha.-ethano-estra-1,3,5(10)-triene-3,17.alpha.-diol in the Allen-Doisy test on the rat, s.c., on the percentage of animals having a positive vaginal reaction, as indicated by vaginal smear. FIG. 1B shows the effect of administration of various amounts of this compound on the moist weight of the rat uterus.
The invention thus also relates to compounds of general formula I for use in the treatment of estrogen deficiency symptoms and for birth control in the female.
The compounds according to the invention can be formulated and used in the same way as ethinyl estradiol, which is the most used estrogen. They a

REFERENCES:
patent: 4407753 (1983-10-01), Groen
patent: 4789671 (1988-12-01), Bull et al.
Bull et al. J Chem. Soc. Perkins Trans. 1, 19, 2545-2553.

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