Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1998-02-23
2000-01-25
Clardy, S. Mark
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C07J 1300
Patent
active
060180625
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP96/01069 filed Mar. 13, 1996.
This invention relates to 17-difluoromethylene-estratrienes, process for their production and the use of the latter for the production of pharmaceutical products (pharmaceutical agents).
The 17-difluoromethylene-estratrienes according to this invention are characterized by general formula I: ##STR2## in which R.sup.1 means a hydrogen atom or a C.sub.1 -C.sub.10 alkyl group, .alpha.- or .beta.-position, .alpha.- or .beta.-position, substituent pairs
G and R.sup.2, R.sup.2 and R.sup.4, R.sup.4 and A, A and R.sup.3, B and D, D and E mean a double bond.
The invention preferably relates to those compounds of general formula I, in which means a hydrogen atom in .beta.- or .alpha.-position, or G with R.sup.2 mean an additional bond and the others of these substituents each mean a hydrogen atom, or then A, B, D, E, G, R.sup.3 and R.sup.4 each stand for a hydrogen atom, or whereby then A, B, D, E, G and R.sup.2 and R.sup.4 each stand for a hydrogen atom.
The C.sub.1 -C.sub.10 alkyl or alkoxy groups that occur in radicals R.sup.1, R.sup.2 and R.sup.3 are a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl radical, or their higher straight-chain or branched-chain homologues or, in the case of R.sup.3, a corresponding alkoxy radical. The methyl or methoxy radical is preferred.
A hydrogen atom preferably stands for R.sup.1.
Primarily a methyl group is suitable for R.sup.5.
In addition, the compounds of general formula I in which A, B, D, E, G, R.sup.2, R.sup.3 and R.sup.4 are hydrogen atoms or in which A, B, D, E, R.sup.3 and R.sup.4 are hydrogen atoms and G with R.sup.2 means an additional bond are preferred.
The compounds mentioned below are especially preferred according to this invention:
The compounds that come closest in structure to these compounds are the 17-monohalomethylene-estratrienes that are described in EP-A 0 320 438.
BRIEF DESCRIPTION OF THE DRAWINGS
Various other features and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood when considered in conjunction with the accompanying drawings, wherein:
FIG. 1 shows the effect of 17.beta.-estradiol (10 .mu.mol) on the aorta of male rats, wherein the axis shows percent alteration of contraction caused by KCl or phenylephrines, in aortas with (+) and without (-) endothelium; and
FIG. 2 shows the effect of compound A of the invention (30 .mu.mol) on the aorta of male rats, wherein the axis shows percent alteration of contraction caused by KCl or phenylephrines, in aortas with (+) and without (-) endothelium.
The known 17-halomethylene-estratrienes show a lesser affinity to the estrogen receptors than estradiol and cause increased cell membrane and blood/lymphatic permeability in comparison with estradiol. These compounds are therefore especially well suited for treating symptoms that occur owing to failure of the second action of estradiol (menopausal symptoms).
The new 17-difluoromethylene-estratrienes according to the invention show new, completely unexpected pharmacological properties not described until now for the above-mentioned 17-monohalomethylene-estratrienes and other steroids.
The 17-difluoromethylene-estratrienes are very weak estrogens, as was possible to show based on standard bonding studies on the estrogen receptor and in transactivation assays, in which 17.beta.-estradiol was used in each case as a comparison substance (M. T. Bocquel et al., Nucleic Acid Research 17:2581-95; S. Green et al., Nucleic Acid Research 16:369, 1989; L. Tora et al., EMBO J. 8:1981-86, 1989; J. E. Burch et al., Mol Cell. Biol. 8:1123-31, 1988).
It has been found that the 17-difluoromethylene-estratrienes exhibit, surprisingly enough, antioxidative and vasculoprotective properties and are therefore suitable for treating and preventing the most varied diseases (e.g., Siegfried et al., JPET 260:668, 1992; Chao et al., J. Immunol. 149:2736, 1992; Corbett & McDaniel, Diabetes, 41:897, 1992; Siminiak et al., Intl. J. Cardiol.,
REFERENCES:
patent: 5124321 (1992-06-01), Jungblut et al.
patent: 5773432 (1998-06-01), Kauser et al.
Bohlmann Rolf
Rubanyi Gabor
Badio Barbara
Clardy S. Mark
Schering Aktiengesellschaft
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