Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1993-11-15
1995-05-23
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
552510, C07J 5300
Patent
active
054182271
DESCRIPTION:
BRIEF SUMMARY
This invention relates to 14,16.beta.-ethano-15.beta.,16.sup.1 -cyclo-14.beta.-estra-1,3,5(10)-trienes of general formula I ##STR2## in which R.sup.1 means a hydrogen atom, a C.sub.1 to C.sub.9 alkyl or C.sub.1 to C.sub.9 acyl radical, C.sub.2 to C.sub.9 alkenyl or alkinyl radical and process for their production, pharmaceutical preparations which contain these compounds as well as their use for the production of pharmaceutical agents. and consequently R.sup.3 can be present in 17.beta.-position or 17.alpha.-position.
As acyl radical R.sup.1 and for the acyl radical in acyloxy radical R.sup.3, 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 to 12 carbon atoms. The number of carbon atoms in the ring varies from 3 to 7. For radicals R.sup.1, R.sup.2, R.sup.3, and the acyl groups of acetic, propionic, butyric, isobutyric, pivalic, caproic, acrylic, crotonic, heptanoic, caprylic, pelargonic, decanoic, undecanoic, dodecanoic, 3-cyclopentylpropionic and benzoic acid are preferred.
In particular, acyl radicals R.sup.1, R.sup.2 and acyloxy radical R.sup.3 are to be derived from those carboxylic acids which have 2 to 8 carbon atoms.
Acyl groups R.sup.1, R.sup.2 and R.sup.3 can also come from dicarboxylic acids with up to 6 carbon atoms; here, in particular, succinic acid is meant.
If R.sup.1 is an alkyl radical, above all the methyl radical is meant; also, ethyl, propyl and isopropyl radicals are of special importance.
As a cycloalkyl radical, the cyclopentyl radical is preferred for R.sup.1.
Within the scope of this invention, the following compounds are to be emphasized: -cyclo-14.beta.-estra-1,3,5(10)-triene-3,17.beta.-diol, -cyclo-14.beta.-estra-1,3,5(10)-triene-3,17.alpha.-diol, -cyclo-14.beta.-estra-1,3,5(10)-trien-3-ol, -cyclo-14.beta.-estra-1,3,5(10)-trien-3-ol, -cyclo-14.beta.-estra-1,3,5,(10)-trien-3-ol, -cyclo-14.beta.-estra-1,3,5(10)-trien-3-ol.
The compounds of general formula I according to the invention exhibit a great affinity to the estrogen receptor and they have high estrogenic activity also after peroral administration.
As compounds with high estrogenic activity, for example, the natural estrogens estradiol and estriol (E. Schroder, C. Rufer and R. Schmiechen, Pharmazeutische Chemie [Pharmaceutical Chemistry], 1982, Georg Thieme Verlag, Stuttgart-New York, p. 568 ff) are known. But they are not metabolically stable and, after oral administration, are broken down by oxidation of the 17-hydroxy group to the corresponding, less effective estrone derivative.
By introducing, for example, an ethinyl group on the 17-C atom (ethinylestradiol, loc. cit., p. 574), the oxidation of the 17-hydroxy group can be prevented and the corresponding derivatives consequently have at their disposal high estrogenic activity after peroral administration,
Only recently has it been possible to obtain estrogen compounds with high peroral activity not by variations of the substituents in the steroid skeleton but by modification of the steroid skeleton itself. Thus, the bridging of the 14- and 17-carbon atoms of the estradiol with an etheno or ethano bridge blocks the oxidation of the 17.beta.-hydroxy group (J. Chem. Commun., 1986, 451-453 or international patent application PCT/DE87/00361) .
Obviously, the oxidation of the 17-hydroxy group is also impeded in the compounds according to the invention by the double bridging (despite the presence of a hydrogen atom on the 17-C atom).
The estrogenic activity of the compounds according to the invention is documented by the results of the estrogen receptor-binding test. In this known in vitro test, tissue from rat uteri is prepared and radioactively labeled .sup.3 H-estradiol is used as a reference substance. The compounds, according to the invention (16.sup.1 S)-14,16.beta.-ethano-15.beta.,16.sup.1 -cyclo-14.beta.-estra-1,3,5(10)-triene-3,17.beta.-diol (A) and (16.sup.1 S)-14,16.beta.-ethano-15.beta.,16.sup.1 -cycl
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Bull et al., "Cycloaddition Route to 14,17-Ethano-and 14-Alkyl-19-norsteroids", Journal of The Chemical Society. Perkin Transactions 1., No. 2 (Feb. 1990), pp. 241-251.
Bull James R.
Chwalisz Krzysztof
Elger Walter
Fritzemeier Karl-Heinrich
Kestler Kimberly J.
Reamer James H.
Schering Aktiengesellschaft
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