ZA200107388B - 16-Hydroxyestratrienes as selective estrogens. - Google Patents

16-Hydroxyestratrienes as selective estrogens. Download PDF

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ZA200107388B
ZA200107388B ZA200107388A ZA200107388A ZA200107388B ZA 200107388 B ZA200107388 B ZA 200107388B ZA 200107388 A ZA200107388 A ZA 200107388A ZA 200107388 A ZA200107388 A ZA 200107388A ZA 200107388 B ZA200107388 B ZA 200107388B
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diol
triene
estra
chain
fluoro
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ZA200107388A
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Hermann Kuenzer
Monika Lessl
Christa Hegele-Hartung
Gerd Mueller
Rudolf Knauthe
Karl-Heinrich Fritzemeier
Ulf Boemer
Dirk Kosemund
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Schering Ag
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    • C07J53/002—Carbocyclic rings fused
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Description

_ 16-Hydroxyestratrienes as Selectively Active Estrogens
Field of the Invention
This invention relates to new compounds as pharmaceutical active ingredients, which have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably a preferential action on bone rather than the uterus, and/or pronounced action with respect to stimulation of the expression of SHT2a receptors and transporters, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds.
The chemical compounds are novel, steroidal, tissue- selective estrogens.
Background of the Invention
Established estrogen therapies for treatment of hormone- deficiency-induced symptoms and the protective action of estrogens on bones, brains, vessels and other organ systems. ' The efficiency of estrogens in the treatment of hormone- deficiency-induced symptoms such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the oo successful use of estrogen therapies for prevention of bone mass loss in peri- and postmenopausal women, is well documented and generally accepted (Grady et al. 1992, Ann Intern Med 117: 1016-
1037). It is also well documented that estrogen replacement therapy in postmenopausal women or in women with ovarian dysfunction that is caused in some other way reduces the risk of cardiovascular diseases compared to non-estrogen-treated women (Grady et al., loc. cit.).
In addition, more recent studies confirm a protective action of estrogens against neurodegenerative diseases, such as, e.g.,
Alzheimer’s disease (Henderson 1997, Neurology 48 (Suppl 7):
S27-S35; Birge 1997, Neurology 48 (Suppl 7): S36-S41), a protective action with respect to brain functions, such as memory and learning capacity (McEwen et al. 1997, Neurology 48 (Suppl 7): S8-S15; Sherwin 1997, Neurology 48 (Suppl 7): S21-S26), as well as against hormone-deficiency-induced mood swings (Halbreich 1997, Neurology 48 (Suppl 7): S16-S5S20).
In addition, estrogen replacement therapy has proven effective relative to the reduction of the incidence of colorectal carcinoma (Calle, E. F. et al., 1995, J Natl Cancer
Inst 87: 517-523).
In conventional estrogen or hormone replacement therapy (= HRT), natural estrogens, such as estradiol, and conjugated estrogens that consist of equine urine are used either by themselves or in combination with a gestagen. Instead of the natural estrogens, derivatives that are obtained by esterification, such as, e.g., 17R-estradiol-valerate, can also oo be used.
Because of the stimulating action of the estrogens that are used on the endometrium, which results in an increase of the risk
® of endometrial carcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166: 1986-1992), estrogen/gestagen combination preparations are preferably used in hormone replacement therapy. The gestagenic component in the estrogen/gestagen combination avoids hypertrophy of the endometrium, but the occurrence of undesirable intracyclic menstrual bleeding is also linked to the gestagen-containing combination.
Selective estrogens represent a more recent alternative to the estrogen/gestagen combination preparations. Up until now, selective estrogens have been defined as those compounds that have an estrogen-like effect on the brain, bones and vascular system, owing to their antiuterotrophic (i.e., antiestrogenic) partial action, but they do not have a proliferative effect on the endometrium.
A class of substances that partially meet the desired profile of a selective estrogen are the so-called "Selective
Estrogen Receptor Modulators" (SERM) (R. F. Kauffman, H. U.
Bryant 1995, DNAP 8 (9): 531-539). In this case, these are partial agonists of estrogen receptor subtype "ERwa." This substance type is ineffective, however, with respect to the therapy of acute postmenopausal symptoms, such as, e.g., hot flashes. As an example of a SERM, the raloxifene that was recently introduced for the indication of osteoporosis can be mentioned. oo
®
Estrogen Receptor Beta (ERB)
Estrogen receptor % (ERB) was recently discovered as a second subtype of the estrogen receptor (Kuiper et al. (1396),
Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996)
Febs Letters 392: 49-53; Tremblay et al. (1997), Molecular
Endocrinology 11: 353-365). The expression pattern of ERS differs from that of the ERa (Kuiper et al. (1996), Endocrinology 138: 863-870). ERR thus predominates over ERo in the rat prostate, while ERwa predominates over ER in the rat uterus.
Areas in which in each case only one of the two ER-subtypes is expressed were identified in the brain (Shugrue et al. (1996),
Steroids 61: 678-681; Li et al. (1997), Neuroendocrinology 66:63-67). ERR is expressed in, i.a., areas that are considered to be important for cognitive processes and "mood" (Shugrue et al. 1997, J Comparative Neurology 388: 507-525).
Molecular targets for ERB in these brain areas could be the
SHT2a receptor and the serotonin transporter (G. Fink &
B. E. H. Sumner 1996 Nature 383:306; B. E. H. Sumner et al. 1999
Molecular Brain Research, in press). The neurotransmitter serotonin (5-hydroxytryptamine) is involved in the regulation of a considerable number of processes, which can be impaired in menopause. In particular, the effects of menopause on mood and cognition are connected with the serotoninergic system. Estrogen replacement therapy has proven effective with respect to Co treatment of these estrogen deficiency-produced symptoms, possibly by modulation of serotonin receptor and transporter expression.
@®
Other organ systems with comparatively higher ERf-expression comprise the bones (Onoe, Y. et al., 1997, Endocrinology 138: 4509-4512), the vascular system (Register, T. C.; Adams, M. R. 1998, J Steroid Molec Biol 64: 187-191), the urogenital tract (Kuiper, G. J. M. et al. 1997, Endocrinology 138: 863-870), the gastrointestinal tract (Campbell-Thopson 1997, BBRC 240: 478- 483), as well as the testis (Mosselmann, S. et al. 1996 Febs Lett 392 49-53) including the spermatides (Shugrue et al. 1998,
Steroids 63: 498-504). The tissue distribution suggests that estrogens regulate organ functions via ERB. The fact that ERB is functional in this respect also follows by studies in ER«a- (ERKO) or ERR- (BERKO) -knockout mice: ovariectomy produces bone mass loss in ERKO-mice, which can be cancelled out by estrogen substitution (Kimbro et al. 1998, Abstract OR7-4, Endocrine
Society Meeting New Orleans). Estradiol in the blood vessels of female ERKO mice also inhibits vascular media and smooth muscle cell proliferation (Iafrati, M. D. et al. 1997, Nature Medicine 3: 545-548). These protective actions of estradiol are carried out in the ERKO mouse presumably via ERB.
Observations of RERKO mice provide an indication on a function of ERR in the prostate and bladder: in the case of older male mice, symptoms of prostate and bladder hyperplasia occur (Krege, J. H. et al. 1998, Proc Natl Acad Sci 95: 15677- 15682). In addition, female ERKO mice (Lubahn, D. B. et al. oo 1993, Proc Natl Acad Sci 90: 11162-11166) and male ERKO mice (Hess, R. A. et al. 1997, Nature 390: 509-512) as well as female
RBERKO mice (Krege, J. H., 1998) have fertility disorders.
Consequently, the important function of estrogens with respect to maintaining testis and ovary functions as well as fertility is confirmed.
Westerlind et al., 1998, describe a differential action of 16x-hydroxyestrone on the bones, on the one hand, and reproductive organs of female rats, on the other (Westerlind et al. 1998, J Bone and Mineral Res 13: 1023-1031).
Some studies showed that 1l6a-hydroxyestrone binds three times better to the human estrogen receptor $ (ER{) than to the human estrogen receptor « (ERa). The RBA value of the substance on the rat prostate estrogen receptor is five times better than the RBA value of the substance on the rat uterus estrogen receptor. According to some findings, the dissociation of the substance that is described by Westerlind can be attributed to their preference for ERS rather than ERa.
It was possible to achieve a selective estrogen action on specific target organs by subtype-specific ligands based on the different tissue or organ distribution of the two subtypes of the
ERs. Substances with a preference for ERB compared to ERo in the in vitro receptor binding test were described by Kuiper et al. (Kuiper et al. (1996), Endocrinology 138: 863-870). A selective action of subtype-specific ligands of the estrogen receptor on estrogen-sensitive parameters in vivo was not previously shown.
The object of this invention is therefore to provide oo compounds that have in vitro a dissociation with respect to the binding to estrogen receptor preparations from rat prostates and rat uteri and that have in vivo preferably a dissociation with
® respect to bones rather than the uterus action. The compounds are to have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably a higher potency with respect to protection against hormone-deficiency- induced bone mass loss in comparison to uterus-stimulating action and/or pronounced action with respect to stimulation of the expression of S5HT2a receptors and transporters.
In the broader sense, a structure-action relationship, which allows for access to compounds that have the above-formulated pharmacological profile of better estrogenic action on bones than on the uterus, is to be made available by this invention.
According to the invention, the object above is achieved by the provision of 16a- and 16R-hydroxy-estra-1,3,5(10)-trienes of general formula I 13 RY oR 7 R'® i 8
RS £ 2] OH (1#) R™ Zs
HO = RT
Rr ey in which radicals R' to RY, independently of one another, have
® the following meanings:
R! means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;
R? means a halogen atom, a hydroxyl group, a straight- chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;
R* means a halogen atom, a straight-chain or branched- chain, saturated or unsaturated alkyl group with up to carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;
RY means a halogen atom in o- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or f-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
R® means a hydrogen atom in «o- or B-position, a straight- chain or branched-chain, saturated or unsaturated, oo optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or f-position, or a cyano group in o- or f-position;
®
RY means a hydrogen atom in «- or R-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in «- or R-position;
R"" means a nitrooxy group in o- or R-position, a hydroxyl or mercapto group in «- or R-position, a halogen atom in «- or R-position, a chloromethyl group in «- or B- position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
R'3 means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in «- or B-position; and either
R'* means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or R-position or a hydrogen atom in a- or RB-position and
R'> means a halogen atom in o- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl oo group with up to 10 carbon atoms in a- or B-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino
® groups = NR" (R"™ = hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom or
R' and R' together mean a 14a, 1S5c-methylene or 148,158- methylene group that is optionally substituted with one or two halogen atoms;
R'® means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or R-position, a trifluoromethyl or pentafluorocethyl group, a cyanomethyl group or a hydrogen atom in o- or
R-position;
R'"7 means a halogen atom in «- or R-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in «- or B-position, a hydrogen atom or a hydroxyl group and the dotted lines ------ in rings B, C and D optionally mean one or more double bonds, and the wavy lines mean the arrangement of the respective substituent in «- or B- position, for the production of a pharmaceutical agent for treatment and prophylaxis of estrogen-deficiency-induced diseases and Co conditions.
According to a variant of the invention, preferably compounds of general formula I are used,
® in which radicals R' to R', independently of one another, have the following meanings
R' means a fluorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;
R? means a fluorine atom, a hydroxyl group, a methoxy or ethoxy group or a hydrogen atom;
R* means a fluorine atom, a methyl, ethyl, trifluoromethyl, methoxy or ethoxy group or a hydrogen atom;
R7 means a fluorine atom in «- or R-position, a methyl, ethyl, propyl or i-propyl group in «o- or B-position, a trifluoromethyl group in «- or B-position or a hydrogen atom;
R® means a hydrogen atom in a- or f-position, a methyl or ethyl group in «- or R-position;
R’ means a hydrogen atom in o- or f#-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in o- or R-position;
R'"" means a nitrooxy group in «o- or R-position, a hydroxyl group in «- or R-position, a fluorine atom in a- or 8- position, a choromethyl group in a- or B-position, a methyl group in «- or R-position, a methoxy group in o- or B-position, a phenyl- or 3-methylthien-2-yl radical oo in o- or fB-position or a hydrogen atom;
R"> means a methyl or ethyl group in «o- or f-position; and either

Claims (1)

  1. ® Claims
    1. 3,16-Dihydroxyestra-1,3,5(10)-triene derivatives of general formula I : 13 RY R': 3 6 RY £5 OH SCG HO 7 HR R* (0 in which radicals R' to RY, independently of one another, have the following meanings: R! means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom; R? means a halogen atom, a hydroxyl group, a straight- chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom; : R* means a halogen atom, a straight-chain or branched- chain, saturated or unsaturated alkyl group with up to oo carbon atoms, a trifluoromethyl or pentafluorcethyl group, a straight-chain or branched-chain, saturated or
    ® unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;
    R’ means a halogen atom in o- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
    RE means a hydrogen atom in o- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or R-position or a cyano group in «- or B-position;
    Rr’ means a hydrogen atom in a- or f#-position, a methyl, ethyl, trifluoromethyl or pentafluorcethyl group in o- or R-position;
    R" means a nitrooxy group in a- or B-position, a hydroxyl or mercapto group in «- or f-position, a halogen atom in ao- or R-position, a chloromethyl group in a- or B- position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in oo o- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with yi up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
    R'> means a methyl, ethyl, trifluoromethyl ox pentafluoroethyl group in B-position;
    and either
    R' means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or R-position or a hydrogen atom in «- or f-position and
    R'> means a halogen atom in o- or B-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or R-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups = NR" (R"™ = hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom or
    R' and RY together mean a 1l4a,l5a-methylene or 148, 15R- methylene group that is optionally substituted with one or two halogen atoms;
    R'® means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely oo fluorinated alkyl group with up to 10 carbon atoms in a- or R-position, a trifluoromethyl or pentafluoroethyl
    ® group, a cyanomethyl group or a hydrogen atom in «o- or R-position; R' means a halogen atom in o- or R-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to carbon atoms in o- or B-position, a hydrogen atom or a hydroxyl group and the dotted lines ------ in rings B, C and D optionally mean one or more double bonds, and the wavy lines mean the arrangement of the respective substituent in o- or R-position, excluding the compounds estra-1,3,5(10)-triene-3,16a-diol, estra-1,3,5(10)-triene-3,168-diol, estra-1,3,5(10),7-tetraene- 3,16a-diol, estra-1,3,5(10),7-tetraene-3,168-diol, 1lé6a- ethinylestra-1,3,5(10) -triene-3,168-diol and 16B-ethinylestra- 1,3,5(10) -triene-3,16x-diol.
    2. Compounds according to claim 1, in which radicals R' to RY, independently of one another, have the following meanings R' means a fluorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom; R? means a fluorine atom, a hydroxyl group, a methoxy or ethoxy group or a hydrogen atom; oo R* means a fluorine atom, a methyl, ethyl, trifluoromethyl, methoxy or ethoxy group or a hydrogen atom;
    ®
    R7 means a fluorine atom in «- or R-position, a methyl, ethyl, propyl or i-propyl group in «o- or R-position, an optionally substituted aryl radical, a trifluoromethyl group in «- or R-position or a hydrogen atom;
    R® means a hydrogen atom in «- or f-position, a methyl or ethyl group in o- or R-position;
    R’ means a hydrogen atom in o- or f-position, a methyl, ethyl, trifluoromethyl or pentafluorocethyl group in o- or R-position;
    RY means a nitrooxy group in o- or R-position, a hydroxyl group in «- or R-position, a fluorine atom in a- or B- position, a choromethyl group in a- or R-position, a methyl group in o- or R-position, a methoxy group in a- or R-position, a phenyl- or 3-methylthien-2-yl radical in o- or RB-position or a hydrogen atom;
    R'> means a methyl or ethyl group in a- or R-position;
    and either R' means a hydrogen atom in a- or R-position or a methyl group in a- or f-position and
    R'> means a fluorine atom in a- or R-position, a methyl group in o- or f-position, or a hydrogen atom,
    or
    R' and R' together mean a 1l4c,l5a-methylene group or a oo 148, 15k -methylene group
    R'® means a methyl, ethyl, ethinyl, propinyl or trifluoromethyl group;
    ® RY means a fluorine atom in «- or R-position, a methyl group, a hydrogen atom or a hydroxyl group, and the dotted lines ----- in rings B, C and D optionally mean an additional double bond between carbon atoms 9 and
    11.
    3. Compounds of general formula I according to claim 1, in which R’ means a halogen atom in «- or f-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in «- or f#-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical and R', R?, R*, R8, R’, R", RY, R', R' and R' in each case mean a hydrogen atom.
    : 4. Compounds of general formula I according to claim 1, in which R'"" means a nitrooxy group in a- or R-position, a hydroxyl or mercapto group in «- or R-position, a halogen atom in a- or fR-position, a chloromethyl group in o- or B- position, a straight-chain or branched-chain, saturated : or unsaturated, optionally partially or completely oo fluorinated alkyl group with up to 10 carbon atoms in a- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with
    ® up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical, and rR', R?, R*, R7, R®, R’, RY, R", R'® and RY in each case mean a hydrogen atom.
    5. Compounds of general formula I according to claim 1, in which R'>S means a halogen atom in «- or B-position or a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or B-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups = NR" (R"™ = hydrogen atom, methyl, ethyl, propyl, i-propyl), and rR', R?, BR, R’, R®, R%, RY, R™, R' and R' in each case mean a hydrogen atom.
    6. Compounds of general formula I according to claim 1, in which rR’ means a halogen atom in o- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or oo an optionally substituted aryl or heteroaryl radical, R" means a nitrooxy group in a- or R-position, a hydroxyl or mercapto group in a- or R-position, a halogen atom
    ® in «- or R-position, a chloromethyl group in o- or R- position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or fB-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and R', R?, R*, R®, RY, RY, R", RY and RY in each case mean a hydrogen atom.
    7. Compounds of general formula I according to claim 1, in which R’ means a halogen atom in «- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or B-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, R'” means a halogen atom in o- or RB-position or a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or R-position that can be interrupted by one or more oxygen atoms, oo sulfur atoms, sulfoxide or sulfone groups or imino groups = NR" (R" = hydrogen atom, methyl, ethyl, propyl, i-propyl), and
    ® rR', ®2, R%, R%, RY, R'", RY, RY and R' in each case mean a hydrogen atom.
    8. Compounds of general formula I according to claim 1, in which R'" means a nitrooxy group in «- or R-position, a hydroxyl or mercapto group in «- or R-position, a halogen atom in o- or R-position, a chloromethyl group in o- or B- position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or fR-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, R'> means a halogen atom in o- or R-position or a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or R-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups = NR" (R™ = hydrogen atom, methyl, ethyl, propyl, i-propyl), and R', R?, R*, R’7, R%®, RJ R', RY, and R'Y in each case mean a hydrogen atom. a.
    9. Compounds of general formula I according to claim 1, in which
    ®
    R’ means a halogen atom in a- or B-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in «a- or B-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,
    R'"" means a nitrooxy group in o- or R-position, a hydroxyl or mercapto group in «- or R-position, a halogen atom in «- or R-position, a chloromethyl group in «- or f- position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or RB-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,
    R'"” means a halogen atom in «- or R-position, or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or R-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups = NR"™ (R"™ = hydrogen atom, methyl, ethyl, propyl, i-propyl), and r', R?, R%*, R®, R%, R", R' and RY in each case mean a hydrogen atom.
    ®
    10. Compounds according to claim 1, characterized in that the dotted lines mean one or more conjugated double bonds.
    11. Compounds according to claim 1, wherein there is a double bond between C atoms 6 and 7.
    12. Compounds according to claim 1, wherein there is a double bond between C atoms 7 and 8.
    13. Compounds according to claim 1, wherein there is a double bond between C atoms 8 and 9.
    14. Compounds according to claim 1, wherein there is a double bond between C atoms 9 and 11.
    15. Compounds according to claim 1, wherein there is a double bond between C atoms 8 and 14.
    16. Compounds according to claim 1, wherein there is a double bond between C atoms 11 and 12.
    17. Compounds according to claim 1, wherein there is a double bond between C atoms 14 and 15.
    18. Compounds according to claim 10, wherein there are double bonds between C atoms 6 and 7 and C atoms 8 and 9. :
    19. Compounds according to claim 10, wherein there are double bonds between C atoms 8 and 9 and C atoms 14 and 15.
    20. Compounds according to claim 10, wherein there are double bonds between C atoms 6 and 7, C atoms 8 and 9 and C atoms 11 and 12.
    21. Compounds according to claim 10, wherein there are oo double bonds between C atoms 6 and 7, C atoms 8 and 9 and C atoms 14 and 15.
    @
    22. Compounds according to claim 10, wherein there are double bonds between C atoms 6 and 7, C atoms 8 and 9, C atoms 11 and 12 and C atoms 14 and 15.
    23. Compounds according to one of claims 1 to 22, wherein one or both hydroxyl groups is (are) esterified at C atoms 3 and 16 with an aliphatic or aromatic carboxylic acid or with an o- or R-amino acid.
    24. Compounds according to claim 1, namely 14a, 15a-Methylen-estra-1,3,5(10) -triene-3,1l6a-diol 148%, 15R8-Methylen-estra-1,3,5(10) -triene-3,16x-diol 14%, 15R8-Methylen-estra-1,3,5(10),8 (9) -tetraene-3,16a-diol, Estra-1,3,5(10),8(9)-tetraene-3,16a-diol, Estra-1,3,5(10),8(14)-tetraene-3,1l6x-diol, Estra-1,3,5(10),6,8-pentaene-3,16x-diol, 7a-Fluoro-estra-1,3,5(10)-triene-3,16a-diol, 11R-Methoxy-estra-1,3,5(10)-triene-3,16a-diol, 7a-Methyl-estra-1,3,5(10) -triene-3,16a-diol 118-Fluoro-estra-1,3,5 (10) -triene-3, 16a-diol, 8a-Estra-1,3,5(10) -triene-3,16a-diol Estra-1,3,5(10)-triene-2,3,16a-triol 17R-Fluoro-estra-1,3,5(10) -triene-3,16a-diol, 18a-Homo-estra-1,3,5(10) -triene-3, 1l6a-diol, 18a-Homo-estra-1,3,5(10),8(9)-tetraene-3,16a-diol, 18a-Homo-14«a, 15a¢-methylen-estra-1,3,5(10) -triene-3,16xa-diol, oo 18a-Homo-14¢, 15a¢-methylen-estra-1,3,5(10),8 (9) -tetraene- 3,16a-diol,
    ® l18a-Homo-1l4q¢, 15a-methylen-estra-1,3,5(10),6,8-pentaene-
    3,16x-diol, l4a,15a-Methylen-estra-1,3,5(10) -triene-3,168-diol 14%,15R-Methylen-estra-1,3,5(10) -triene-3,168-diol 14R,15R-Methylen-estra-1,3,5(10),8 (9) -tetraene-3,168-diol, Estra-1,3,5(10),8(9) -tetraene-3, 16R-diol, Estra-1,3,5(10),8(14)-tetraene-3,16R8-diol, Estra-1,3,5(10),6,8-pentaene-3,168-diol, 7x¢-Fluoro-estra-1,3,5(10)-triene-3,168-diol, 11R-Methoxy-estra-1,3,5(10) -triene-3,168-diol, 7a-Methyl-estra-1,3,5(10)-triene-3,16R8-diol 11R-Fluoro-estra-1,3,5(10) -triene-3,168-diol, 8a-Estra-1,3,5(10)-triene-3,168-diol Estra-1,3,5(10)-triene-2,3,16x-triol 17R-Fluoro-estra-1,3,5(10) -triene-3,168-diol, 18a-Homo-estra-1,3,5(10) -triene-3,168%-diol, 18a-Homo-estra-1,3,5(10),8 (9) -tetraene-3, 168-diol, 18a-Homo-14q, 15¢-methylen-estra-1,3,5(10) -triene-3,168-diol, 18a-Homo-140, 150-methylen-estra-1,3,5(10),8 (9) -tetraene-
    3,16R-diol, 18a-Homo-14¢, 15¢-methylen-estra-1,3,5(10),6,8-pentaene-
    3,168-diol, } 7a-Ethyl-estra-1,3,5(10)-triene-3,16a-diol 7a-Propyl-estra-1,3,5(10)-triene-3,16a-diol oo 7a-i-Propyl-estra-1,3,5(10)-triene-3,16x-diol 7a-i-Propenyl-estra-1,3,5(10)-triene-3,16a-diol 70-Phenyl-estra-1,3,5(10) -triene-3,16x-diol
    ®
    7u-Methoxy-estra-1,3,5(10) -triene-3,16x-diol 7x¢-Thiomethyl-estra-1,3,5(10)-triene-3,16a-diol 70~Cyanomethyl-estra-1,3,5(10)-triene-3,16xa-diol 7R-Ethyl-estra-1,3,5(10)-triene-3,16a-diol 7f-Propyl-estra-1,3,5(10)-triene-3,16a-diol 7-i-Propyl-estra-1,3,5(10)-triene-3,16xa-diol 78%-i-Propenyl-estra-1,3,5(10)-triene-3,16a-diol 78-Phenyl-estra-1,3,5(10)-triene-3,16a-diol 7R-Methoxy-estra-1,3,5(10) -triene-3,16x-diol 78-Thiomethyl-estra-1,3,5(10)-triene-3,16a-diol 7R-Cyanomethyl-estra-1,3,5(10)-triene-3,16a-diol 7a-Ethyl-estra-1,3,5(10)-triene-3,168-diol 7a-Propyl-estra-1,3,5(10)-triene-3,168-diol 7a-i-Propyl-estra-1,3,5(10) -triene-3,16R8-diol 7a-i-Propenyl-estra-1,3,5(10)-triene-3,168-diol 7a-Phenyl-estra-1,3,5(10)-triene-3,168-diol 7a-Methoxy-estra-1,3,5(10)-triene-3,168-diol 7a-Thiomethyl-estra-1,3,5(10) -triene-3,168-diol 7¢-Cyanomethyl-estra-1,3,5(10) -triene-3,168-diol 7R8-Ethyl-estra-1,3,5(10)-triene-3,168-diol 78-Propyl-estra-1,3,5(10)-triene-3,168-diol 7R-i-Propyl-estra-1,3,5(10) -triene-3,168-diol 7R-1i-Propenyl-estra-1,3,5(10)-triene-3,168-diol 78-Phenyl-estra-1,3,5(10)-triene-3,16R8-diol oo 7R%-Methoxy-estra-1,3,5(10) -triene-3,168-diol
    7R-Thiomethyl-estra-1,3,5(10)-triene-3,168-diol 78-Cyanomethyl-estra-1,3,5 (10) -triene-3,168-diol
    ® 15a-Methyl-estra-1,3,5(10)-triene-3,16a-diol 15«¢-Ethyl-estra-1,3,5(10)-triene-3,16a-diol 150-Propyl-estra-1,3,5(10) -triene-3,16a-diol 150¢-Allyl-estra-1,3,5(10)-triene-3,16a-diol 15a-i-Propyl-estra-1,3,5(10)-triene-3,16a-diol 150-i-Propenyl-estra-1,3,5(10)-triene-3,16x-diocl 15a-Methoxy-estra-1,3,5(10) -triene-3,16a-diol 150-Thiomethyl-estra-1,3,5(10)-triene-3,1l6a-diol 15¢-Methyl-estra-1,3,5(10)-triene-3,16R%-diol 150-Ethyl-estra-1,3,5(10)-triene-3,168-diol 150-Propyl-estra-1,3,5(10)-triene-3,16%-diol 15a-Allyl-estra-1,3,5(10)-triene-3,168-diol 15¢-i-Propyl-estra-1,3,5(10)-triene-3,168-diol 15x-i-Propenyl-estra-1,3,5(10)-triene-3,168-diol 15x¢-Methoxy-estra-1,3,5(10) -triene-3,168-diol 15¢-Thiomethyl-estra-1,3,5(10)-triene-3,168-diol 15R8-Methyl-estra-1,3,5(10) -triene-3,16x-diol 15R8-Ethyl-estra-1,3,5(10) -triene-3,16a-diol 15R8-Propyl-estra-1,3,5(10)-triene-3,16x-diol 158-Allyl-estra-1,3,5(10)-triene-3,16a-diol 15R8-i-Propyl-estra-1,3,5(10)-triene-3,16a-diol 15R-i-Propenyl-estra-1,3,5(10)-triene-3,16a-diol 15R-Methoxy-estra-1,3,5(10) -triene-3,16x-diol 158-Thiomethyl-estra-1,3,5(10)-triene-3,16a-diol oo 15R8-Methyl-estra-1,3,5(10) -triene-3,16R8-diol 15R-Ethyl-estra-1,3,5(10) -triene-3,168-diol 15R-Propyl-estra-1,3,5(10)-triene-3,168%-diol
    ® 15R-Allyl-estra-1,3,5(10)-triene-3,168%-diol 15R-i-Propyl-estra-1,3,5(10)-triene-3,168-diol 15R8-i-Propenyl-estra-1,3,5(10)-triene-3,16R8-diol 158 -Methoxy-estra-1,3,5(10)-triene-3,168-diol 15R-Thiomethyl-estra-1,3,5(10)-triene-3,168-diol Ja-Trifluoromethyl-11Rf-fluoro-estra-1,3,5(10)-triene-3,16a- diol 7q-Pentafluorcethyl-118-fluoro-estra-1,3,5(10) -triene-3,16a- diol
    70-Ethyl-118-fluoro-estra-1,3,5(10)-triene-3,16a-diol 7a-Propyl-11R-fluoro-estra-1,3,5 (10) -triene-3,l6a-diol
    7a-i-Propyl-11R-fluoro-estra-1,3,5(10)-triene-3,16a-diol 7a-i-Propenyl-118-fluoro-estra-1,3,5(10)-triene-3,16a-diol 7a-Phenyl-11f-Fluoro-estra-1,3,5(10)-triene-3,16a-diol 7a-Methoxy-118-fluoro-estra-1,3,5(10) -triene-3,16a-diol 7a-Thiomethyl-118-fluoro-estra-1,3,5(10)-triene-3,16a-diol 7a-Cyanomethyl-118-fluoro-estra-1,3,5(10) -triene-3,16a-diol 78-Ethyl-118-fluoro-estra-1,3,5 (10) -triene-3,16a-diol 7R-Propyl-11B8-fluoro-estra-1,3,5(10) -triene-3,16a-diol 7R-i-Propyl-118-fluoro-estra-1,3,5(10)-triene-3,16a-diol 7%-i-Propenyl-11R8-fluoro-estra-1,3,5 (10) -triene-3,16a-diol 78-Phenyl-118-fluoro-estra-1,3,5(10) -triene-3,16a-diol 7R8-Methoxy-118-fluoro-estra-1,3,5(10) -triene-3,16x-diol 7R-Thiomethyl-118-fluoro-estra-1,3,5(10)-triene-3,16a-diol oo 78-Cyanomethyl-11f-fluoro-estra-1,3,5(10) -triene-3, 16a-diol 7a-Ethyl-118-fluoro-estra-1,3,5(10)-triene-3,168-diol 7a-Propyl-118-fluoro-estra-1,3,5(10) -triene-3,168-diol
    ® 7a-i-Propyl-11R-fluoro-estra-1,3,5(10)-triene-3,168-diol 7a-1i-Propenyl-11f-fluoro-estra-1,3,5(10)-triene-3,16R8-diol 7a-Phenyl-118-fluoro-estra-1,3,5(10)-triene-3,168-diol 7a-Methoxy-11R-fluoro-estra-1,3,5(10) -triene-3,168-diol 70-Thiomethyl-11R-fluoro-estra-1,3,5(10)-triene-3,16R8-diol 7a-Cyanomethyl-118-fluoro-estra-1,3,5(10)-triene-3,168-diol 7R-Ethyl-118-fluoro-estra-1,3,5(10) -triene-3,168-diol 7R-Propyl-118-fluoro-estra-1,3,5 (10) -triene-3,168-diol 7R-i-Propyl-11R-fluoro-estra-1,3,5(10)-triene-3,16R8-diol 7&-i-Propenyl-11R8-fluoro-estra-1,3,5(10)-triene-3,168-diol 7R-Phenyl-11f-fluoro-estra-1,3,5 (10) -triene-3,168-diol 78-Methoxy-11R-fluoro-estra-1,3,5(10) -triene-3,168-diol 7R-Thiomethyl-11R-fluoro-estra-1,3,5(10)-triene-3,168-diol 78-Cyanomethyl-118-fluoro-estra-1,3,5 (10) -triene-3,168-diol 15a-Methyl-11Rf-fluoro-estra-1,3,5(10) -triene-3,1l6a-diol 15a-Ethyl-11R8-fluoro-estra-1,3,5(10) -triene-3,1l6a-diol 15¢-Propyl-11R8-fluoro-estra-1,3,5(10) -triene-3,16a-diol 15¢-Allyl-118-fluoro-estra-1,3,5 (10) -triene-3,16a~-diol 15¢-1i-Propyl-118-fluoro-estra-1,3,5(10)-triene-3,16a-diol 15¢-i-Propenyl-11R8-fluoro-estra-1,3,5(10) -triene-3,16a-diol 150-Methoxy-118-fluoro-estra-1,3,5(10) -triene-3,16x-diol 15a-Thiomethyl-118-fluoro-estra-1,3,5(10)-triene-3, 16a-diol 15a-Methyl-11R8-fluoro-estra-1,3,5(10) -triene-3,168-diol 15a-Ethyl-118-fluoro-estra-1,3,5(10)-triene-3,168-diol oo 150-Propyl-11f-fluoro-estra-1,3,5(10) -triene-3,168-diol 150-A1l1lyl-11R-fluoro-estra-1,3,5(10) -triene-3,168-diol 15¢-i-Propyl-1iR-fluoro-estra-1,3,5(10)-triene-3,168-diol
    ® 150-i-Propenyl-118-fluoro-estra-1,3,5(10) -triene-3,168-diol 15a-Methoxy-118-fluoro-estra-1,3,5(10)-triene-3,16R8-diol 15«¢-Thiomethyl-118-fluoro-estra-1,3,5(10) -triene-3,16R-diol 158-Methyl-11R-fluoro-estra-1,3,5(10)-triene-3,16a-diol 15R8~-Ethyl-11R-fluoro-estra-1,3,5 (10) -triene-3,1l6x-diol 15R8-Propyl-11R-fluoro-estra-1,3,5(10) -triene-3,16x-diol 15R-Allyl-11R-fluoro-estra-1,3,5 (10) -triene-3,16a-diol 15R-i-Propyl-11f8-fluoro-estra-1,3,5(10)-triene-3,1l6a-diol 15R8-i-Propenyl-11R-fluoroc-estra-1,3,5(10) -triene-3,16w-diol 15R-Methoxy-11R%-fluoro-estra-1,3,5(10)-triene-3,16a-diol 15R-Thiomethyl-11R-fluoro-estra-1,3,5(10) -triene-3,16x-diol 15R-Methyl-11R-fluoro-estra-1,3,5(10)-triene-3,168-diol 158-Ethyl-11R-fluoro-estra-1,3,5(10)-triene-3,168-diol 158-Propyl-11R-fluoro-estra-1,3,5(10)-triene-3,16R8-diol 158-Allyl-11R-fluoro-estra-1,3,5(10)-triene-3,168-diol 15R-i-Propyl-11R8-fluoro-estra-1,3,5(10)-triene-3,16R-diol 15R-i-Propenyl-1iR-fluoro-estra-1,3,5(10)-triene-3,168-diol 158-Methoxy-118-fluoro-estra-1,3,5(10)-triene-3,168-diol 158-Thiomethyl-11R-fluoro-estra-1,3,5(10)-triene-3,168-diol l4a,15a-Methylene-7a-phenyl-estra-1,3,5(10) -triene-3,16a- diol 148,158-Methylene-7«a-phenyl-estra-1,3,5(10)-triene-3,16c- diol 14f3,158-Methylene-7a-phenyl-estra-1,3,5(10),8 (9) -tetraene- oo 3,1l6a-diol, 7o¢-Phenyl-estra-1,3,5(10),8(9) -tetraene-3,16a-diol, 70¢-Phenyl-estra-1,3,5(10),8(14) -tetraene-3,16x-diol,
    ®
    7a-Phenyl-estra-1,3,5(10),6,8-pentaene-3,l6x-diol,
    11R%-Methoxy-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol,
    118-Fluoro-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol,
    7¢-Phenyl-8a-estra-1,3,5(10)-triene-3,16a-diol
    7a-Phenyl-estra-1,3,5(10)-triene-2,3,16a-triol
    178-Fluoro-7x-phenyl-estra-1,3,5(10) -triene-3,16a-diol,
    18a-Homo-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol,
    18a-Homo-7a-phenyl-estra-1,3,5(10),8(9)-tetraene-3,1l6a-diol,
    18a-Homo-1l4a,15a¢-methylene-7«-phenyl-estra-1,3,5(10)-triene- 3,16a-diol,
    18a-Homo-14«a, 15¢-methylene-7a-phenyl-estra-1,3,5(10),8(9)- tetraene-3,16a-diol,
    18a-Homo-1l4«a, 15¢-methylene-7c¢-phenyl-estra-1,3,5(10),6,8- pentaene-3,l6x-diol,
    140, 150-Methylene-7a-phenyl-estra-1,3,5(10)-triene-3,168%- diol
    148,158-Methylene-7a-phenyl-estra-1,3,5(10)-triene-3,168- diol
    148, 158-Methylene-7a-phenyl-estra-1,3,5(10),8 (9) -tetraene- 3,168-diol,
    7a-Phenyl-estra-1,3,5(10),8(9) -tetraene-3,168-diol,
    7a-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,168-diol,
    7a-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16R8-diol,
    11R-Methoxy-7a-phenyl-estra-1,3,5(10)-triene-3,168-diol, oo
    11R8-Fluoro-7a-phenyl-estra-1,3,5(10) -triene-3,168-diol,
    7a-Phenyl-8c-estra-1,3,5(10) -triene-3,16R8-dicl
    7¢-Phenyl-estra-1,3,5(10) -triene-2,3,16a-triol
    _
    178-Fluoro-7a-phenyl-estra-1,3,5(10)-triene-3,168-diol, 18a-Homo-7«-phenyl-estra-1,3,5(10)-triene-3,168-diol, 18a-Homo-7«-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16R8-diol, 18a-Homo-1l4w, l50-methylene-7a-phenyl-estra-1,3,5(10)-triene-
    3,16R-diol, 18a-Homo-14qa, 15a-methylene-7a-phenyl-estra-1,3,5(10),8 (9) -
    tetraene-3,16R-diol, 18a-Homo-1l4a, 15a¢-methylene-7a-phenyl-estra-1,3,5(10),6,8-
    pentaene-3,168-diol, 15a¢-Methyl-7«-phenyl-estra-1,3,5(10)-triene-3,16a-diol 15a-Ethyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 15a-Propyl-7a-phenyl-estra-1,3,5(10)-triene-3,16xa-diol 150¢-Allyl-7a-phenyl-estra-1,3,5(10) -triene-3,16a-diol 15¢-1i-Propyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 15¢-1i-Propenyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 15a-Methoxy-7a-phenyl-estra-1,3,5 (10) -triene-3,16a-diol 15¢-Thiomethyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 15a-Methyl-7a-phenyl-estra-1,3,5(10)-triene-3,168-diol 15a¢-Ethyl-70-phenyl-estra-1,3,5(10) -triene-3,168-diol 15a-Propyl-7a-phenyl-estra-1,3,5 (10) -triene-3,168-diol 15a-Allyl-7a-phenyl-estra-1,3,5(10) -triene-3,168-diol 15a¢-1i-Propyl-7«a-phenyl-estra-1,3,5(10)-triene-3,168-diol 150-i-Propenyl-7a-phenyl-estra-1,3,5(10)-triene-3,168-diol 15a-Methoxy-7a-phenyl-estra-1,3,5 (10) -triene-3,168-diol oo 15a¢-Thiomethyl-7a-phenyl-estra-1,3,5(10)-triene-3,16R8-diol 15f-Methyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 158-Ethyl-7a-phenyl-estra-1,3,5(10)-triene-3,16x-diol
    ® 15R-Propyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 15R-Allyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 15R%-i-Propyl-7a-phenyl-estra-1,3,5(10) -triene-3,16a-diol 15R-i-Propenyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 15R-Methoxy-7a-phenyl-estra-1,3,5(10)-triene-3,1l6x-diol 15R-Thiomethyl-7a-phenyl-estra-1,3,5(10)-triene-3,16a-diol 158-Methyl-7a-phenyl-estra-1,3,5(10)-triene-3,16%-diol 15R-Ethyl-7«-phenyl-estra-1,3,5(10) -triene-3,168-diol 15R3-Propyl-7a-phenyl-estra-1,3,5(10)-triene-3,16-diol 15R-Allyl-7a-phenyl-estra-1,3,5(10) -triene-3,168-diol 15R-i-Propyl-7a-phenyl-estra-1,3,5(10) -triene-3,16R8-diol 15R-i-Propenyl-7a-phenyl-estra-1,3,5(10)-triene-3,168-diol 15R-Methoxy-7a-phenyl-estra-1,3,5(10) -triene-3,168-diol 15R-Thiomethyl-7a-phenyl-estra-1,3,5(10)-triene-3,16R8-diol 150-Methyl-118-fluoro-7o-phenyl-estra-1,3,5(10) -triene- 3,1l6x-diol 15¢-Ethyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene-3,16a- diol 15¢-Propyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16x-diol 15¢-Allyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene-3,16a- diol 15¢-i-Propyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16x-diol oo 15q-i-Propenyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16a-diol
    ® 15¢-Methoxy-11R-fluoro-7a-phenyl-estra-1,3,5 (10) -triene- 3,16a-diol 15a-Thiomethyl-11R-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16a-diol 150¢-Methyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16R-diol 15¢-Ethyl-11R#-fluoro-7a-phenyl-estra-1,3,5(10)-triene-3,168%- diol 15q-Propyl-11R-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16R-diol 150-Allyl-11R-fluoro-7a-phenyl-estra-1,3,5(10)-triene-3,168- diol 150-1i-Propyl-11R-fluoro-7«a-phenyl-estra-1,3,5(10)-triene- 3,16%3-diol 150-1i-Propenyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,168-diol 15a-Methoxy-11R8-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16R8-diol 15a-Thiomethyl-11Rf-fluoro-7«-phenyl-estra-1,3,5(10)-triene- 3,16R-diol 15R8-Methyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16a-diol 15R-Ethyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene-3, 16a- diol oo 158-Propyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16a-diol
    ®
    15R-Allyl-11R-fluoro-7a-phenyl-estra-1,3,5(10) -triene-3, l6a- diol
    15R-i-Propyl-11R-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,1l6a-diol
    15R8-i-Propenyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16a-diol
    15R-Methoxy-11R-fluoro-7a-phenyl-estra-1,3,5(10) -triene- 3,16x-diol
    15R-Thiomethyl-11R8-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,1l6x-diocl
    158-Methyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16R-diol
    15R-Ethyl-11R-fluoro-7a-phenyl-estra-1,3,5(10)-triene-3, 168- diol
    15R8-Propyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,168-diol
    158-A11yl-118-fluoro-7a-phenyl-estra-1,3,5(10) -triene-3,168- diol
    15R-i-Propyl-118-fluoro-7«a-phenyl-estra-1,3,5(10)-triene- 3,168-diol
    158-i-Propenyl-118-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16R-diol
    15R-Methoxy-11R8-fluoro-7a-phenyl-estra-1,3,5(10)-triene- 3,16R-diol oo
    15R-Thiomethyl-11R-fluoro-7«-phenyl-estra-1,3,5(10)-triene- 3,168-diol
    11R- [2- (3-Methylthien) -yl) -estra-1,3,5(10) -triene-3,16a-diol
    118-[2- (3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,168%-diol 13a-Estra-1,3,5(10)-triene-3,16x-diol 13¢-Estra-1,3,5(10) -triene-3,168-diol 14R-Estra-1,3,5(10) -triene-3,1l6x-diol 14R-Estra-1,3,5(10) -triene-3,163-diol 11R8-Methylestra-1,3,5(10)-triene-3,16a-diol 11R-Methylestra-1,3,5(10)-triene-3,168-diol 11R-Methyl-18a-homoestra-1,3,5(10)-triene-3,16a-diol 11R-Methyl-18a-homoestra-1,3,5(10)-triene-3,168-diol 11R-Ethylestra-1,3,5(10)-triene-3,16a-diol 11R-Ethylestra-1,3,5(10)-triene-3,168%-diol 11R-Ethyl-18a-homoestra-1,3,5(10)-triene-3,16a-diol 11R-Ethyl-18a-homoestra-1,3,5(10)-triene-3,168-diol 11R-Vinylestra-1,3,5(10)-triene-3,16a-diol 11f-Vinylestra-1,3,5(10)-triene-3,168-diol 118-Vinyl-18a-homoestra-1,3,5 (10) -triene-3,16a-diol 11%-Vinyl-18a-homoestra-1,3,5(10) -triene-3,168-diol 11R-Ethinylestra-1,3,5(10)-triene-3,16a-diol 11R-Ethinylestra-1,3,5(10)-triene-3,168-diol 11R-Ethinyl-18a-homoestra-1,3,5(10)-triene-3,16a-diocl 11R-Ethinyl-18a-homoestra-1,3,5(10) -triene-3,16R8-diol 9x-Methylestra-1,3,5(10)-triene-3,16a-diol 9a -Methylestra-1,3,5(10)-triene-3,168-diol 9a-Methyl-18a-homoestra-1,3,5(10) -triene-3,16a-diol B 90 -Methyl-18a-homoestra-1,3,5(10)-triene-3,16R8-diol 7a-Methyl-18a-homoestra-1,3,5(10) -triene-3,16a-diol 7x-Methyl-18a-homoestra-1,3,5(10) -triene-3,168-diol
    ® 7q-Ethyl-18a-homoestra-1,3,5(10) -triene-3,16a-diol 70-Ethyl-18a-homoestra-1,3,5(10) -triene-3,16%-diol 7a,11R-Dimethylestra-1,3,5(10) -triene-3,16a-diol 7q,11R-Dimethylestra-1,3,5(10)-triene-3,168-diol 70, 11R-Dimethyl-18a-homoestra-1,3,5(10) -triene-3, 16a-diol 7a,11R8-Dimethyl-18a-homoestra-1,3,5(10) -triene-3,16a-diol 16R-Ethinyl-18a-homoestra-1,3,5(10)-triene-3,1l6a-diol 16-Ethinyl-18a-homoestra-1,3,5(10)-triene-3,168-diol 7¢-Methyl-16R8-ethinylestra-1,3,5(10)-triene-3,16a-diol 7a-Methyl-16c-ethinylestra-1,3,5(10) -triene-3,16R8-diol 7q-Methyl-168-ethinyl-18a-homoestra-1,3,5(10)-triene-3,16x- diol 7a-Methyl-16a-ethinyl-18a-homoestra-1,3,5(10)-triene-3,168%- diol 11R-Methyl-168-ethinylestra-1,3,5(10) -triene-3,16a-diol 11R-Methyl-16a-ethinylestra-1,3,5(10) -triene-3,16R8-diol 11R-Methyl-16R8-ethinyl-18a-homoestra-1,3,5 (10) -triene-3,16a- diol 11R%-Methyl-16a-ethinyl-18a-homoestra-1,3,5 (10) -triene-3,16%- diol.
    25. Compounds according to claim 24, namely 7a-Fluoro-estra-1,3,5(10) -triene-3,16a-diol, 7a-Methyl-estra-1,3,5(10)-triene-3,168-diol 7a-Methyl-estra-1,3,5(10)-triene-3,16a-diol oo 18x-Homo-estra-1,3,5(10)-triene-3,16a-diol 7a-Phenyl-estra-1,3,5(10) -triene-3,168-diol 7%-Phenyl-estra-1,3,5(10) -triene-3,16R8-diol
    ® 7R-Phenyl-estra-1,3,5(10) -triene-3,16x-diol 7Ja-Ethyl-estra-1,3,5(10)-triene-3,168-diol 78-Ethyl-estra-1,3,5(10) -triene-3,16a-diol 7R-Ethyl-estra-1,3,5(10) -triene-3,168-diol.
    26. Use of the 3,16-dihydroxyestra-1,3,5(10)-triene derivatives of general formula I’ RI R13 RY R' R' 2 PR R RR OH HO R’ R* I) in which radicals R' to RY, independently of one another, have the following meanings: R! means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom; R? means a halogen atom, a hydroxyl group, a straight- chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom; R* means a halogen atom, a straight-chain or branched- oo chain, saturated or unsaturated alkyl group with up to carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight-chain or branched-chain, saturated or
    ® unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;
    R’ means a halogen atom in o- or R-position, a straight - chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in o- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
    RE means a hydrogen atom in «- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in «- or R-position or a cyano group in o- or B-position;
    rR’ means a hydrogen atom in a- or f-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in a- or R-position;
    R'" means a nitrooxy group in o- or B-position, a hydroxyl or mercapto group in «- or R-position, a halogen atom in a- or f-position, a chloromethyl group in «- or B- position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in oo a- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
    R'> means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in «- or f-position;
    and either
    R' means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in a- or R-position or a hydrogen atom in «- or B-position and
    R'” means a halogen atom in o- or B-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in «- or fR-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups = NR" (R"™ = hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom or
    R'™ and RY together mean a 1l4c,lS5a-methylene or 148%, 158- methylene group that is optionally substituted with one or two halogen atoms;
    R'® means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely oo fluorinated alkyl group with up to 10 carbon atoms in a- or R-position, a trifluoromethyl or pentafluorocethyl
    ® group, a cyanomethyl group or a hydrogen atom in a- or RB-position; R' means a halogen atom in «- or R-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to carbon atoms in «o- or R-position, a hydrogen atom or a hydroxyl group and the dotted lines ------ in rings B, C and D optionally mean one or more double bonds, and the wavy lines mean the arrangement of the respective substituent in o- or B- position, for the production of a pharmaceutical agent for treatment of estrogen-deficiency-induced diseases and conditions in women and in men.
    27. Use according to claim 26 for the treatment of peri- and post-menopausal symptoms.
    28. Use according to claim 26 for treatment of peri- and post-male-menopausal symptoms.
    29. Use according to claim 27 for prevention and treatment of hot flashes, sleep disturbances, irritability, mood swings, incontinence, vaginal atrophy, and hormone-deficiency-induced emotional diseases.
    30. Use according to claim 29 for prevention and treatment oo of diseases in the urogenital tract.
    31. Use according to claim 26 for prevention and therapy of gastrointestinal diseases.
    eo
    32. Use according to claim 31 for prevention and therapy of ulcers and hemorrhagic diatheses in the gastrointestinal tract.
    33. Use according to claim 32 for prevention and therapy of neoplasias.
    34. Use according to claim 26 for in-vitro treatment of male infertility.
    35. Use according to claim 26 for in-vivo treatment of male infertility.
    36. Use according to claim 26 for in-vitro treatment of female infertility.
    37. Use according to claim 26 for in-vivo treatment of female infertility.
    38. Use according to claim 26 for hormone replacement therapy (HRT).
    39. Use according to claim 26 for the therapy of hormone- deficiency-induced symptoms in the case of surgical, medicinal or ovarian dysfunction that is caused in some other way.
    40. Use according to claim 26 for prophylaxis and therapy of a hormone-deficiency-induced bone mass loss.
    41. Use according to claim 40 for prophylaxis and therapy of osteoporosis.
    42. Use according to claim 26 for prevention and therapy of cardiovascular diseases.
    43. Use according to claim 26 for prevention and treatment oo of vascular diseases.
    ‘44. Use according to claim 43 for prevention and treatment of arteriosclerosis.
    45. Use according to claim 43 for prevention and treatment of neointimal hyperplasias.
    46. Use according to claim 26 for prevention and treatment of hormone-deficiency-induced neurodegenerative diseases.
    47. Use according to claim 26 for prevention and treatment of Alzheimer’s disease and hormone-deficiency-induced impairment of memory and learning capacity.
    48. Use according to claim 26 for treatment of inflammatory diseases and diseases of the immune system.
    49. Use according to claim 26 for prevention and treatment of benign prostate hyperplasia (BPH).
    50. Use of the structural part of formula II 3 b3 Hr Jo —0Q (10) as a component of the total structure of compounds that have a dissociation in favor of their estrogenic action on bone rather than the uterus.
    ®
    51. Use of the structural part of general formula II’ according to claim 50 =: °F 3 EF (RE = Ls Re Fe hh = rR" RS —0 IN 7 R* (11%) in which radicals RY to R'’, independently of one another, have the following meanings: RY means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom; rR? means a halogen atom, a hydroxyl group, a straight- chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom; RY means a halogen atom, a straight-chain or branched- chain, saturated or unsaturated alkyl group with up to oo carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight-chain or branched-chain, saturated or e unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;
    R”' means a halogen atom in o- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in «o- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, an optionally substituted aryl or hetercaryl radical or a hydrogen atom;
    RY means a hydrogen atom in «o- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in «- or R-position or a cyano group in o- or R-position;
    RY means a hydrogen atom in «- or RB-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in o- or B-position;
    RY means a nitrooxy group in o- or R-position, a hydroxyl or mercapto group in o- or R-position, a halogen atom in a- or R-position, a chloromethyl group in o- or B- position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in oo a- or R-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with
    ® up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
    R'' means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in o- or R-position;
    and either
    R'Y means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in ®- or R-position or a hydrogen atom in o- or R-position and
    R'”’ means a halogen atom in «- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in «- or B-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups = NR" (R"™ = hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom or
    R™ and R"' together mean a 14a, 15a-methylene group or a 148, 158-methylene group that is optionally substituted with one or two halogen atoms;
    R'® means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely oo fluorinated alkyl group with up to 10 carbon atoms in
    » a- or R-position, a triflucromethyl cor pentafluoroethvl group, a cyanomethyl group or a hydrogen atom in o- or R-position; R'" means a halogen atom in z- or R-position, a straight- chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl, group with up to 10 carbon atoms in «- or R-position, a hydrogen atom or a hydroxyl group, and the dotted lines ---- in rings B, C and D optionally mean one or more double bonds, and the wavy lines mean the arrangement of the respective substituent in «o- or B-position.
    52. Pharmaceutical compositions that contain at least one compound according to one of claims 1 to 25 as well as a pharmaceutically compatible vehicle.
    53. A substance or composition for use in a method for treatment of estrogen-deficiency-induced diseases and conditions in women and in men, said substance or composition comprising a compound as defined in claim 26, and said method comprising administering said substance or composition.
    54. A substance or composition for use in a method of treatment according to claim 53 for the treatment of peri- and post-menopausal symptoms.
    55. A substance or composition for use in a method of treatment according to claim 53 for treatment of peri- and post-male-menopausal symptoms. : AMENDED SHEET rs 132
    56. A substance or composition for use in a method of Creatment according to claim 54 for prevention and treatment of hot flashes, sleep disturbances, irritability, mood swings, incontinence, vaginal atrophy, and hormone-deficiency-induced emotional diseases.
    57. A substance or composition for use in a method of Creatment according to claim 56 for prevention and treatment of diseases in the urogenital tract.
    58. A substance or composition for use in a method of treatment according to claim 53 for prevention and therapy of gastrointestinal diseases.
    59. A substance or composition for use in a method of treatment according to claim 58 for prevention and therapy of ulcers and hemorrhagic diatheses in the gastrointestinal tract.
    60. A substance or composition for use in a method of treatment according to claim 59 for prevention and therapy of neoplasias.
    61. A substance or composition for use in a method of treatment according to claim 53 for in-vitro treatment of male infertility.
    62. A substance or composition for use in a method of treatment according to claim 53 for in-vivo treatment of male infertility.
    63. A substance or composition for use in a method of treatment according to claim 53 for in-vitro treatment of female infertility. AMENDED SHEET oR
    64. A substance or composition for use in a method of treatment according to claim 53 for in-vive treatment of female infertility.
    65. A substance or composition for use in a method of treatment according to claim 53 for hormone replacement therapy (HRT).
    66. A substance or composition for use in a method of treatment according to claim 53 or the therapy of hormone- deficiency-induced symptoms in the case of surgical, medicinal or ovarian dysfunction that is caused in some other way.
    67. A substance or composition for use in a method of treatment according to claim 53 for prophylaxis and therapy of a hormone-deficiency-induced bone mass loss.
    68. A substance or composition for use in a method of treatment according to claim 67 for prophylaxis and therapy of Osteoporosis.
    69. A substance or composition for use in a method of treatment according to claim 53 for prevention and therapy of cardiovascular diseases.
    70. A substance or composition for use in a method of treatment according to claim 53 for prevention and treatment of vascular diseases.
    71. A substance or composition for use in a method of treatment according to claim 53 for prevention and treatment of arteriosclerosis.
    72. A substance or composition for use in a method of treatment according to claim 70 for prevention ad treatment of neointimal hyperplasias. AMENDED SHEET
    A 134
    73. A substance or composition for use in a method of treatment according to claim 53 for prevention and treatment of hormone-deficiency-induced neurodegenerative diseases.
    74. A substance or composition for use in a method of treatment according to claim 53 for prevention and treatment of Alzheimer's disease and hormone-deficiency-induced impairment of memory and learning capacity.
    75. A substance or composition for use in a method of treatment according to claim 53 for treatment of inflammatory diseases and diseases of the immune system.
    76. A substance or composition for use in a method of Creatment according to claim 53 for prevention and treatment of benign prostate hyperplasia (BPH) .
    77. Use of the structural part of formula II as defined in claim 50, in the manufacture of a preparation which includes the total structure of compounds that have a dissociation in favor of their estrogenic action on bone rather than the uterus, wherein the structural part of formula II forms a component of the total structure.
    78. Use according to claim 77 of the structural part of general formula II' as defined in claim 51.
    79. A compound according to claim 1, substantially as herein described and illustrated.
    80. Use according to claim 26, claim S50 or claim 77, substantially as herein described and illustrated.
    81. A composition according to claim 52, substantially as herein described and illustrated. AMENDED SHEET
    ) 82. A substance or composition for use in a method of treatment according to claim 53, substantially as herein described and illustrated.
    83. A new compound, a new use of a compound as defined in claim 26 or claim 50, a new composition, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
ZA200107388A 1999-02-09 2001-09-06 16-Hydroxyestratrienes as selective estrogens. ZA200107388B (en)

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