Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1993-10-29
1996-02-13
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
552510, A61K 3156, C07J 100
Patent
active
054911370
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of EP92/009946 filed Apr. 30, 1992.
The invention relates to new 14.alpha.,17.alpha.-(propano-and 17.sup.2 -propeno)-estratrienes of general formula I ##STR3## in which R.sup.1 means a hydrogen atom, a methyl or an acyl group with 1-12 carbon atoms, ##STR4## a C--C single or double bond.
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 and aromatic monocarboxylic acids. The number of carbon atoms in the ring varies from 3 to 5. As radicals R.sup.1 and R.sup.2, the acyl groups of acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, caproic acid, heptanoic acid, caprylic acid, pelargonic acid, decanoic acid, undecanoic acid, dodecanoic acid, 3-cyclopentylpropionic acid and benzoic acid are preferred.
14,17-Ethano-estratrienes are known from International Patent Application WO 88/01275. Although these compounds do not contain a 17.alpha.-ethinyl group, they are as estrogen effective as ethinyl estradiol even after oral administration. So far opinion has been that the 17.alpha.-ethinyl group is necessary to achieve an oral effectiveness.
It has now been found that the new 14.alpha.,17.alpha.-(propano-and 17.sup.2 -propeno)-estratrienes are also effective after oral administration and in this case surpass the effectiveness of ethinyl estradiol, as can be seen from table 1. The compounds of this application also contain no 17.alpha.-ethinyl group.
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. Regarded as a threshold value, is the amount of an estrogen at which 50% of the animals reach stage 3. Further, estrogens cause an increase of the uterus weight.
The compounds according to the invention can be formulated and used in the same way as ethinyl estradiol. They are processed to the usual forms of pharmaceutical agents with the additives, vehicles, and flavoring substances usual in galenic pharmaceutics according to methods known in the art. For oral administration, tablets, coated tablets, capsules, pills, suspensions or solutions are especially suitable. For parenteral administration, oily solutions, such as, for example, sesame oil or castor oil solutions are especially suitable, which optionally in addition can also contain a diluent, such as, for example, benzyl benzoate or benzyl alcohol.
The active ingredient concentration in the pharmaceutical compositions is a function of the form of administration and the field of use. Thus, for example, capsules or tablets for the treatment of estrogen deficiency symptoms can contain 0.001 to 0.05 mg of active ingredient, oily solutions for intramuscular injection per 1 ml about 0.01 to 0.1 mg of active ingredient and vaginal ointments about 0.1 to 10 mg per 100 ml of ointment. For contraception in the female, the estrogens according to the invention can be used in combination with gestagens. Tablets or coated tablets preferably are to contain 0.003 to 0.05 mg of the estrogen according to the invention and 0.05 to 0.5 mg of a gestagen.
The compounds according to the invention can be used in the case of estrogen deficiency symptoms of the female, such as, for example, amenorrhea, dysmenorrhea, sterility, frigidity, endometritis, colpitis and menopausal symptoms. Further, the compounds can be used as estrogen components in combination preparations with gestagens for contraceptives in the female.
The 14.alpha.,17.alpha.-(propano-and 17.sup.2 -propeno)-estratrienes of general formula I ##STR5## in which R.sup.1 means a hydrogen atom, a methyl or an acyl group with 1-12 carbon atoms, ##STR6## a C--C single or double bond. can be produced with the car
REFERENCES:
patent: 4789671 (1988-12-01), Bull et al.
CA 85: 21707, Kumar "Attempted Synthesis . . ." Diss Abstr. Int B 1976, 36(10) 5046-5047.
CA 88: 7191, Szeto "Potential Inhibitors . . . ", Diss Abstr. Int B 1977, 38(3) 1125-1126.
Bull James R.
Elger Walter
Fritzemeier Karl-Heinrich
Krattenmacher Rolf
Kilby Scalzo Catherine S.
Richter Johann
Schering Aktiengesellschaft
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