Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1994-06-24
1996-03-26
Kestler, Kimberly J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
552626, A61K 31565, C07J 100
Patent
active
055020461
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/02210 filed Sep. 24, 1992, now abandoned.
This invention relates to 11.beta.-substituted 14,17-ethanoestratrienes of general formula I ##STR2## in which R.sup.1 stands for a hydrogen atom, a C.sub.1 -C.sub.12 alkanoyl, a benzoyl, a straight-chain or branched-chain C.sub.1 -C.sub.12 alkyl, a C.sub.3 -C.sub.7 cycloalkyl or a C.sub.4 -C.sub.8 alkylcycloalkyl group, R.sup.2 stands for a hydrogen atom or a C.sub.1 -C.sub.12 alkanoyl group and R.sup.3 stands for a grouping ##STR3## in which n is 0, 1 or 2, and R.sup.4 and R.sup.5 independently of one another, mean a hydrogen atom or a straight-chain or branched C.sub.1 -C.sub.8 alkyl group, which can also be present partially fluorinated, a process for their production, pharmaceutical preparations containing these compounds, as well as their use for the production of pharmaceutical agents.
If R.sup.1 and/or R.sup.2 stand for an alkanoyl group, first of all an acetyl or propionyl group is considered; for R.sup.1 in the meaning of an alkyl group, above all the methyl or ethyl groups are suitable As cycloalkyl group for substituent R.sup.1 for example, the cyclopropyl, cyclopentyl and cyclohexyl group and as alkylcycloalkyl group, the methylcyclopropyl and methylcyclopentyl group are to be mentioned.
As partially fluorinated alkyl groups R.sup.4 and R.sup.5, first of all radicals 2,2,3,3,4,4,4-heptafluorobutyl and 4,4,5,5,5-pentafluoropentyl are suitable.
Within the meaning of the invention, especially preferred compounds are: acid-(N-methyl-N-isopropyl)-amide, acid-(N-methyl-N-2,2,3,3,4,4,4-heptafluorobutyl)amide, 1,3,5(10)-triene-3,17-diol, 5,5,5-pentafluoropentyl-sulfoxide, acid-(N-methyl-N-isopropyl)-amide, acid-(N-methyl-N-isopropyl)-amide, undecanoic acid-(N-methyl-N-isopropyl)-amide,
11-(14,17-ethano-17-hydroxy-3-methoxyestra-1,3,5(10)-trien-11.beta.-yl)-und ecanoic acid-(N-methyl-N-isopropyl)-amide.
Steroidal antiestrogens, which are essentially free of an estrogenic residual effect (pure antiestrogens), follow from EP-A 0 138 504 and EP 0 384 842. From the plurality of substances described in EP-A 0 138 504, especially the 11-(3,17.beta.-dihydroxy-1,3,5(10)-estratrien-7.alpha.-yl)-undecanoic acid-(N-butyl-N-methyl)amide is to be emphasized.
An increase of the estrogenic effectiveness relative to estradiol in peroral administration by introducing a 14,17-ethano bridging-over was observed in the 14,17-ethanoestratrienes described in international patent application WO 88/01 275, which carry two hydrogen atoms each as substituents on the C-7 and C-11 atom.
It has now been found that the compounds of general formula I according to the invention exhibit an especially high affinity to the estrogen receptor and, in the case of peroral administration, they are pure antiestrogens with very strong antiestrogenic effect.
The compounds according to the invention thus are suitable for treatment of estrogen-dependent diseases, for example, anovulatory infertility, prostatic hyperplasia, breast cancer, endometrial cancer and melanoma.
The daily dose for treating said diseases is typically 0.1 to 25 mg/kg; in humans, this corresponds to a daily dose of 5 to 1250 mg. According to the invention, a dosage unit contains 5 to 500 mg of one or more compounds of general formula I.
The compounds according to the invention are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredient one or more of the compounds according to the invention, optionally in a mixture with other pharmacologically or pharmaceutically effective substances. The production of the pharmaceutical agents takes place in a known way, and the known and usual pharmaceutical adjuvants as well as other usual vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmacy, cosmetics and related fields: Ullmans Encyklopa/ die der technischen
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Bohlmann Rolf
Kunzer Hermann
Muhn-Seipoldy Hans-Peter
Nishino Yukishige
Schneider Martin
Kestler Kimberly J.
Schering Aktiengesellschaft
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