SK11302001A3 - 16-hydroxyestratrienes as selective estrogens - Google Patents

Abstract

3,16-Dihydroxy-1,3,5(10)-estratriene derivatives (I) are new. 3,16-Dihydroxy-1,3,5(10)-estratriene derivatives of formula (I) are new: [Image] thick black line in ring = single or double bond; R 1>H, halo, OH, Me, CF 3, OMe or OEt; R 2>H, halo, OH or 1-6C optionally saturated alkoxy; R 4>H, halo, 1-10C optionally saturated alkyl, CF 3, C 2F 5or 1-6C optionally saturated alkoxy; R 7>H, halo, 1-10C optionally saturated alkyl (optionally fully or partly fluorinated), 1-6C optionally saturated alkoxy or optionally substituted aryl or heteroaryl; R 8>H, , 1-10C optionally saturated alkyl (optionally fully or partly fluorinated) or CN; R 9>H, Me, Et, CF 3or C 2F 5; R 1>1>H, ONO 2, OH, SH, halo, CH 2Cl, 1-10C optionally saturated alkyl (optionally fully or partly fluorinated), 1-6C optionally saturated alkoxy, 1-6C optionally saturated alkylthio or optionally substituted aryl or heteroaryl; R 1>3>Me, Et, CF 3or C 2F 5; R 1>4>H or 1-10C optionally saturated alkyl (optionally fully or partly fluorinated); R 1>5>H, halo or 1-10C optionally saturated alkyl (optionally fully or partly fluorinated and optionally interrupted by O, S, SO, SO 2or NR 1>5>'); R 1>5>' : H or 1-3C alkyl; R 16>optionally saturated 1-10C alkyl (optionally partly or fully fluorinated), CF 3, or pentafluoroethyl, CN or H ; R 1>7>H, OH, halo or 1-10C optionally saturated alkyl (optionally fully or partly fluorinated); or R 1>4>+R 1>5>optionally mono- or dihalogenated methylene; wavy lines = alpha or beta configuration. Excluded are: 1,3,5(10)-estratriene-3,16alpha -diol (Ia); 1,3,5(10)-estratriene-3,16beta -diol (Ib); 1,3,5(10),7-estratetraene-3,16alpha -diol (Ic); and 1,3,5(10),7-estratetraene-3,16beta -diol (Id). Independent claims are also included for the following: (1) use of compounds (I), including (Ia)-(Id), for treating diseases caused by estrogen deficiency in women and men; (2) use of the partial structure of formula (II) as a component of the total structure of compounds exhibiting a dissociation in estrogenic activity in favor of bone over uterus. [Image] ACTIVITY : Gynecological; uropathic; antiulcer; hemostatic; osteopathic; cardiant; antiarteriosclerotic; nootropic; neuroprotective; antiinflammatory; antiinfertility; immunomodulatory. MECHANISM OF ACTION : Estrogen receptor ligand. The relative binding affinity (estradiol = 100) of (Ia) for rat prostate and uterus estrogen receptors was 50 and 9 respectively, and the ratio of its relative binding affinities for human estrogen receptors alpha and beta was 6 (estradiol = 1).

Description

Technical field

The present invention relates to novel pharmaceutical active compounds which exhibit in vitro a higher affinity for rat prostate estrogen receptor preparations than for rat uterine estrogen receptor preparations and in vivo exhibit advantageous preferential action on the bone over the uterus and / or exhibit a pronounced effect, with respect to stimulating the expression of the 5HT2α receptor and 5HT2α transporter, the preparation of these compounds, their therapeutic use and the pharmaceutical therapeutics containing them.

These compounds are novel stercidal estrogens with tissue selectivity.

BACKGROUND OF THE INVENTION

Existing estrogen therapy in the treatment of hormone deficiency problems and the protective effect of estrogens on bones, brain, vascular system and other organs

The positive effects of estrogens in the treatment of symptoms of hormonal insufficiency such as hot flashes, estrogen target organ atrophy and incontinence, as well as successful use of estrogen therapy to prevent bone loss in peri- and postmenopausal women, are well documented and generally accepted (Grade and et al., Ann. Intern Med., 117, 1016-1037 (1992)). It is equally well documented that estrogen replacement therapy in postmenopausal women or in women with otherwise caused ovarian dysfunction reduces the risk of circulatory diseases compared to estrogen-untreated women (Grády et al., 1992).

In addition, new studies have demonstrated the protective effect of estrogens against neurodegenerative diseases such as Al2 zheimer's disease (Henderson, Neurology 48 (Suppl. 7), 27-35 (1997); Birge, Neurology 48 (Suppl. 7), 36-41 ( 1997)), a protective effect on brain functions such as memory and learning ability (Mc Ewen et al., Neurology 48 (Suppl. 7), 8-15 (1997); Sherwin, Neurology 48 (Suppl. 7), 21 26 (1997)), as well as an effect against hormonal deficiency moodiness (Halbreich, Neurology 48 (Suppl. 7), 16-20 (1997)).

Estrogen replacement therapy has also been shown to be effective in reducing the incidence of colon and rectal cancer (Calle E. F. et al., J. Natl. Cancer Inst. 87, 517-523 (1995)).

Conventional estrogen or hormone replacement therapy (HRT) uses natural estrogens such as estradiol and conjugated estrogen from horse urine, either alone or in combination with gestagen. Instead of natural estrogens, derivatives obtained by esterification, such as e.g. 17.beta.-estradiol valerate.

Due to the stimulatory effect of the estrogens used on the endometrium, which may increase the risk of endometrial cancer (Harlap S., Am. J. Obstet. Gynecol. 166, 1986-1992 (1992)), combination preparations are preferably used in hormone replacement therapy. The gestagen component in the estrogen / gestagen combination prevents endometrial hypertrophy, but combinations containing the gestagen are associated with undesirable occasional bleeding.

A more recent alternative to estrogen / gestagen containing preparations is selective estrogens. To date, the term selective estrogens refers to those compounds which act estrogenically on the brain, bones and circulatory system due to their partial anti-uterotrophic (i.e., anti-estrogenic effect), but do not act proliferatively on the endometrium.

A group of compounds that partially meet the desired selective estrogen profile are the so-called selective estrogen receptor modulators (SERM) (RF Kaufmann, HU Bryant, DNAP 8 (9), 531-539 (1995)). )). They are partial agonists of the estrogen receptors of the ERα subtype. However, this type of compounds is ineffective in the treatment of acute postmenopausal conditions such as hot flushes. An example of a selective estrogen indicated in osteoporosis is Raloxifene.

Estrogen receptor β (ΕΡβ)

Recently, estrogen receptor β (ΕΡβ) has been discovered as a second subtype of estrogen receptor (Kuiper et al., Proc. Natl. Acad. Sci. 93, 5925-5930 (1996); Mosselman, Dijkema, FEBS Letters 392, 49-53 (1996) Tremblay et al., Molecular Endocrinology 11, 353-365 (1997)). The distribution of ΕΡβ receptor expression is different from that of the ERα receptor (Kuiper et al., Endocrinology 138, 863-870 (1996). The ERβ receptor predominates in the rat prostate, whereas in the rat uterus the ERα predominates over ΕΡβ. in which only one of the ER subtypes is always expressed (Shugrue et al., Steroids 61, 678-681 (1996); Li et al., Neuroendocrinology 66, 63-67 (1997)). cognitive processes and "mood" (Shugrue et al., J. Comparative Neurology 388, 507-525 (1997)).

The molecular target for βΡβ in these brain regions could be the 5HT2α-receptor and the serotonin transporter (G. Fink and B.E.

H. Sumner, Nature 383, 306 (1996); B.E. Sumner et al., Molecular Brain Research (1999), in press). The neurotransmitter serotonin (5-hydroxytryptamine) is involved in the regulation of many processes that may be adversely affected during menopause. The effect of menopause on mood and cognitive processes is particularly related to the serotonergic system. Proven efficacy of estrogen replacement therapy in the treatment of estrogen deficiency problems may be due to modulation of serotonin receptor and transporter expression.

Other systems with comparatively high ERP expression include bones (Onoe Y. et al., Endocrinology 138, 4509-4512 (1997)),

Vascular system (TC Register, Adams MR, J. Steroid. Molec. Biol. 64, 187-191 (1998)), urogenital tract (Kuiper GJM et al., Endocrinology 138, 863-870 (1997)), the gastrointestinal tract (Campbell-Thompson, BBRC 240, 478-483 (1997)) as well as the testes (Mosselman S. et al., FEBS Lett. 392, 49-53 (1996) including spermatides (Shugrue et al., Steroids 63, 498-504 (1998)). Tissue distribution suggests that estrogens regulate organ function through βΡβ. The fact that ΕΡβ works in this respect is also evident from the study on ERa- (ERKO) - or ΕΗβ- (βΕΡΚΟ) -knockout-mice: ovariectomy causes bone loss in ERKO-mice, which can be suppressed by estrogen replacement therapy ( Kimbro et al., Abstract OR7-4, Endocrine Society Meeting, New Orleans 1998). Likewise, estradiol in the blood vessels of ERKO-female mice prevents the proliferation of vascular and smooth muscle cells (Iafrati MD et al., Nature Medicine 3, 545-548 (1997). This protective action of estradiol is likely to occur through the ΕΡβ receptor in ERKO-mice. .

Studies on βΕΡΚΟ-πψέί3θή indicate the function of ΕΡβ in the prostate and bladder: older male mice experience symptoms of prostate and bladder hyperplasia (Krege JH et al., Proc. Natl. Acad. Sci. 95, 15677-15682 (1998) ). In addition, females (Lubahn DB et al., Proc. Natl. Acad. Sci. 90, 11162-11166 (1993)) and male ERKO-mice (Hess RA A et al., Nature 390, 509-512 (1997)), as well as female βΕΡΚΟ-πψέί (Krege JH, 1998) are characterized by impaired fertility. This demonstrates the important role of estrogens in maintaining testicular, ovarian and fertility functions.

Westerlind et al. (1998) describe the differential effect of 16α-hydroxyestrone on bones on the one hand and on reproductive organs on the other hand in female rats (Westerlind et al., J. Bone and Mineral Res. 13, 1023-1031 (1998)).

According to our own research, 16α-hydroxyestrone binds three times better to the human estrogen receptor ΕΡβ than to the human estrogen5 ·· · ·· ** -.

The new ERα receptor is a new ERα receptor. The RBA value of the compound for the estrogen receptor of the rat prostate is five times better than the RBA value for the estrogen receptor of the rat uterus. The dissociation effect of this compound described by Westerlind is believed to be due to its preference for βΗβ over ERα.

The selective effect of estrogens on certain target organs could be achieved due to the different distribution of both ER subtypes in different tissues or organs using ligands specific to these subtypes. Compounds with a greater preference for ΕΓβ than for ERα in an in vitro receptor binding assay have been described by Kuiper et al. (Kuiper et al., Endocrinology 138, 863-870 (1996).) The selective effect of ligands specific for estrogen receptor subtypes on estrogen-sensitive parameters in vivo has not been described so far.

It is therefore an object of the present invention to provide such compounds which exhibit in vitro dissociation of binding to estrogen receptor preparations from rat prostate and rat uterus, and which exhibit in vivo dissociation of a bone benefit compared to an uterine effect. Such compounds should have a higher affinity in vitro for rat prostate estrogen receptor preparations than for rat uterine estrogen receptor preparations and should preferably exhibit a protective effect against hormonal deficits due to bone loss in comparison with a uterine stimulatory effect and / or should be preferred in vivo. characterized by a pronounced effect in stimulating expression of the 5HT2α receptor and 5HT2α transporter.

Further, the present invention is intended to provide structure-activity relationship information giving access to compounds having said pharmacological profile, i.e., a better estrogenic effect on bones than on the uterus.

SUMMARY OF THE INVENTION

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It concerns preparation

This object is solved by the present invention.

16α and βδ-hydroxyestra-1,3,5 (10) -trienes of formula I

wherein the substituents R ¹ to R ¹⁷ independently of one another have the following meanings:

R ¹ is a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a hydrogen atom;

R ² is halogen, hydroxy, straight or branched, saturated or unsaturated alkoxy group with up to 6 carbon atoms, or hydrogen;

R ⁴ is a halogen atom, a straight or branched, saturated or unsaturated alkyl group having up to 10 carbon atoms, a trifluoromethyl group, a pentafluoroethyl group, a straight or branched, saturated or unsaturated alkoxy group having up to 6 carbon atoms, or a hydrogen atom;

R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy having up to 6 atoms a carbon atom, an optionally substituted aryl or heteroaryl radical, or a hydrogen atom;

R ⁸ is a hydrogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully

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a fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, or a cyano group in the α or β position;

R ⁹ is a hydrogen atom in the α or β position, the methyl group in the α or β position, the ethyl group in the α or β position, the trifluoromethyl group in the α or β position, or the pentafluoroethyl group in the α or β position;

R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group having up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group having up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical, or a hydrogen atom;

R ¹³ is a methyl group at the a or β position, an ethyl group at the a or β position, a trifluoromethyl group at the a or β position, or a pentafluoroethyl group at the a or β position;

and either

R ¹⁴ is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, or a hydrogen atom in the α or β position;

and

R ¹⁵ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, once or by multiple sulfoxide or sulfone groups or imino groups = NR ¹⁵ (R ¹⁵ is hydrogen, methyl, ethyl, propyl, isopropyl), or hydrogen;

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R ¹⁴ and R ¹⁵ together form a 14α, 15α-methylene or 14β, 15β-methylene group, which is optionally substituted with one or two halogen atoms;

R ¹⁶ is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group, or a hydrogen atom in the α or β position;

R ¹⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, a hydrogen atom or a hydroxyl group;

wherein the dotted lines (----) in circles B, C, and D indicate an optional one or more double bonds and the wavy lines () indicate that the substituent may be in the α or β position;

for the preparation of a medicament for the treatment or prophylaxis of diseases or conditions caused by estrogen deficiency.

According to one variant of the invention, the compounds of the formula I are preferred, wherein the substituents R ¹ to R ¹⁷ independently of one another have the following meanings:

R ¹ is a fluorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a hydrogen atom;

is a fluorine atom, a hydroxyl group, a methoxy group,

R ⁴

R ⁷

R ⁸

R ⁹

R ¹¹

R ¹³ and either

R ¹⁴ a

R ^{15 is an} ethoxy group or a hydrogen atom;

is a fluorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a hydrogen atom;

is a fluorine atom in the α or β position, a methyl group, an ethyl group, a propyl group or an isopropyl group in an a or β position, a trifluoromethyl group in an a or β position, or a hydrogen atom;

is a hydrogen atom in the α or β position, a methyl group in the α or β position, or an ethyl group in the α or β position;

is a hydrogen atom at the α or β position, a methyl group at the a or β position, an ethyl group at the a or β position, a trifluoromethyl group at the a or β position, or a pentafluoroethyl group at the a or β position;

is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a fluorine atom at position a or β, a chloromethyl group at position a or β, a methyl group at position a or β, a methoxy group at position a or β, phenyl or a 3-methylthien-2-yl group at the α or β position, or a hydrogen atom;

is a methyl group in the α or β position or an ethyl group in the α or β position;

is a hydrogen atom at the α or β position, or a methyl group at the α or β position;

is a fluorine atom at position a or β, a methyl group at semi-10

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he a or β, or a hydrogen atom;

or

R ¹⁴ and R ^{15 taken} together form a 14α, 15α-methylene or 14β, 15β-πβ-γ-yn group;

R ¹⁶ is methyl, ethyl, ethynyl, propynyl, or trifluoromethyl;

R ¹⁷ is a fluorine atom in the α or β-position, methyl, hydrogen or hydroxyl;

wherein the dotted lines (----) in rings B, C and D indicate an optional additional double bond between carbon atoms 9 and 11.

In addition to the stated use of the compounds of formula I, the present invention also relates to the compounds of formula I 'as such. They are compounds of the formula I with the exception of the following compounds: estra-1,3,5 (10) -triene-3,16a-diol, estra-1,3,5 (10) -triene-3, ββ-diol, estra -1,3,5 (10), 7-tetraene-3,16a-diol, estra-1,3,5 (10), 7-tetraene-3, ββ-diol, 16a-ethinylestra1,3,5 (10) ) -triene-3, ββ-diol and βδ-ethinylestra-1,3,5 (10) -triene-3,16α-diol. Said compounds are already known, but their selective estrogenic activity and their use in the sense of the present invention are not described.

16α-Hydroxy-17-methylenestrogens have been described as anti-inflammatory compounds that are useful in the treatment of immunological diseases, particularly autoimmune diseases (WO 97/08188).

The differentiated effect of 16α-hydroxyestrone has already been described by Westerlind et al. (1998), however, a differentiated effect on brain functions and the vascular system on the one hand and on the uterus on the other has not been described.

3,16a-Dihydroxyestratriene has been described by Stack and Gorski (1985) as a "short-acting estrogen, but on its use as

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Lecturous estrogen is not yet known.

3,16-Dihydroxyestratrienes, which are additionally substituted at the 16-position with an ethynyl group, are described in RF 5099. The β-β-ethynyl compound can be used as a cholesterol lowering agent.

In the compounds of the formulas I and I 'as well as the sub-structures II and II' below, a halogen atom can be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, with fluorine being always preferred.

The alkoxy groups in the compounds of formulas I and I ', as well as the sub-structures II and II' below, may contain 1 to 6 carbon atoms, with a methoxy, ethoxy, propoxy, isopropoxy or tert- butoxy group.

Examples of alkyl groups are, for example, methylthio, ethylthio and trifluoromethylthio.

For the purposes of the present invention, aryl is understood to mean phenyl, 1-naphthyl, 2-naphthyl, with phenyl being preferred.

Unless explicitly stated otherwise, the aryl moiety includes a heteroaryl moiety. Exemplary heteroaryl radicals are 2-, 3 or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, pyrazinyl , 2-, 4- or

5-pyrimidinyl, or 3- or 4-pyridazinyl.

A substituent on an aryl or heteroaryl radical may be, for example, methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, or the like. · ····· · · ··· · ··· · ····· · · ·················································· halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, mono (C 1-8 -alkyl) amino or di (C 1-8 -alkyl) amino in which the two alkyl groups are the same or different, or a di (aralkyl) amino group in which both alkyl groups are the same or different.

Examples of straight or branched alkyl groups having 1 to 10 carbon atoms are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or a decyl group, with methyl, ethyl, propyl and isopropyl being preferred.

The alkyl groups may be partially or fully fluorinated or substituted by 1 to 5 halogen atoms, hydroxyl groups or C _1-4 -alkoxy groups.

Perfluorinated alkyl groups are, for example, trifluoromethyl, pentafluoroethyl and nonafluorobutyl. Examples of partially fluorinated alkyl groups include, for example, 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 9,9,9,8,8,7,7,6,6-nonafluorohexyl, etc.

The 14,15-methylene group substituted with a halogen atom may be, for example, a monochloromethylene group, a monofluoromethylene group or a difluoromethylene group.

Other variants of the present invention pertain to one or more conjugated double bonds in rings B, C and D of the estradien backbone. These are, for example:

A double bond between carbon atoms 6 and 7, or between carbon atoms 7 and 8, or between carbon atoms 8 and 9, or between carbon atoms 9 and 11, or between carbon atoms 8 and 14, or between carbon atoms 14 and 15, or double bonds between atoms

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and between 8 and 9, between carbon atoms 8 and 9 and between 14 and 15, or between carbon atoms 6 and 7, 8 and 9 and 11, or between carbon atoms 6 and 7, 8 and 9 and 14 and 15.

One or both hydroxyl groups on carbon atoms 3 and 16 can be esterified with an aliphatic, saturated or unsaturated C 14 monocarboxylic or Ci_i ₄ -polykarboxylovou acid, straight or branched, or a-or β-amino acid.

Suitable such carboxylic acids are, for example, the following:

Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myrystic acid, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid , elaidinic acid.

Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, corkic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid, mesaconic acid.

Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and p-toluylic acid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, isonicotinic acid.

Suitable amino acids include those well known to those skilled in the art, for example, alanine, βalanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline, etc.

The 16-hydroxyl group in the compounds of the invention and in the sub-structures below may be in position or or β. Another variant of the present invention relates to compounds of formula I and I 'as well as to sub-structures of formula II' wherein

R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy having up to 6 atoms carbon, or an optionally substituted aryl or heteroaryl radical; while

R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are hydrogen atoms.

Another variant of the present invention relates to compounds of formulas I and I 'as well as partial structures of formula II anywhere

R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; while

R ^1, R ^2, R ^4, R ^7, R ^8, R ^9, R ^14, R ^15, R ^1S and R ¹⁷ are hydrogen.

Another variant of the present invention relates to compounds of formulas I and I 'as well as partial structures of formula II', wherein

R ¹⁵ is a halogen atom in the α or β position, straight or branched 15

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saturated, saturated or unsaturated or partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, one or more sulphoxide or sulphone groups or imino groups = NR ¹⁵ (R ^{15) 15} is hydrogen, methyl, ethyl, propyl, isopropyl); while

R ¹ , R ² , R ⁴ , R ⁷ , R ⁸ , R ⁹ , R ¹⁴ , R ¹⁶ and R ¹⁷ are hydrogen atoms.

Another variant of the present invention relates to compounds of formulas I and I 'as well as partial structures of formula I', wherein

R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy having up to 6 atoms carbon, or an optionally substituted aryl or heteroaryl radical; and

R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; while

R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ¹¹ , R ¹⁵ , R ¹⁶ and R ¹⁷ are hydrogen atoms.

Another variant of the present invention relates to the compounds of the formulas I and I 'as well as the partial structures of the general formula I and I'. Formula II ', where:

R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy group up to 6 atoms carbon, or an optionally substituted aryl or heteroaryl radical; and

R ¹⁵ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, once or by multiple sulfoxide or sulfone groups or imino groups = NR ¹⁵ (R ¹⁵ is hydrogen, methyl, ethyl, propyl, isopropyl); while

R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁶ and R ¹⁷ are hydrogen atoms.

Another variant of the present invention relates to compounds of formulas I and I 'as well as partial structures of formula II', wherein

R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; and

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R ¹⁵ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, once or by multiple sulfoxide or sulfone groups or imino groups = NR ¹⁵ (R ¹⁵ is hydrogen, methyl, ethyl, propyl, isopropyl); while

R ¹ , R ² , R ⁴ , R ⁷ , R ⁸ , R ⁹ , R ¹⁴ , R ¹⁶ and R ¹⁷ are hydrogen atoms.

Another variant of the present invention relates to compounds of formulas I and I 'as well as partial structures of formula II', wherein:

R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy having up to 6 atoms carbon, or an optionally substituted aryl or heteroaryl radical;

R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; and

R ⁵ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or

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fully fluorinated alkyl group in the a or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, one or more sulfoxide or sulfone groups or imino groups = NR ¹⁵ (R ¹⁵ is hydrogen, methyl, ethyl a group, a propyl group, an isopropyl group); while

R ^1, R ^2, R ^4, R ^8, R ^9, R ^14, R ¹⁶ and R ¹⁷ are hydrogen.

In the above variations of the compounds of the formula I according to the invention, as well as the partial structures of the formula II ', the following meanings are preferred:

R ⁷ is a fluorine atom in the α or β position, a methyl group, an ethyl group, a propyl group or an isopropyl group in an a or β position, a trifluoromethyl group in an a or β position, or a hydrogen atom;

R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a fluorine atom at position a or β, a chloromethyl group at position a or β, a methyl group at position a or β, a methoxy group at position a or β, a phenyl or 3-methylthien-2-yl group at the α or β position, or a hydrogen atom; and

R ¹⁵ is a fluorine atom at the α or β position, a methyl group at the α or β position, or a hydrogen atom.

Preferred are the following compounds of the invention:

14a, 15a-metylénestra-l, 3,5 (10) -triene-3,16x-diol,

14β, Ιδβ-ιηείγΐέηββίβ-β, 3,5 (10) -triene-3,16a-diol,

14β, Ιδβ-πιείγΙέηβΒί ^-Ι, 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-3,16a-diol, • ·············· • estra-1,3,5 (10), 6,8-pentaene-3, 16α-diol, 7α-fluorestra-1,3,5 (10) -triene-3,16α-diol, β-methoxyestra-1,3,5 (10) -triene-3,16a-diol, 7α-methylestra- 1,3,5 (10) -triene-3,16a-diol, β-fluoroestra-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, 17β-trifluoroestra-1,3,5 (10) -triene-3,16a-diol , 18α-homo-estra-1,3,5 (10) -triene-3,16α-diol, 18α-homo-estra-1,3,5 (10), 8 (9) -tetraene-3,16a- diol, 18α-homo-14α, 15α-methyleneestra-1,3,5 (10) -triene-3,16α-diol, 18α-homo-14α, 15α-methyleneestra-1,3,5 (10), 8 ( 9) -tetraene-3,16a-diol, 18a-homo-14a, 15a-methyleneestra-1,3,5 (10), 6,8-pentaene-3,16a-diol, 14a, 15a-methyleneestra-1, 3,5 (10) -triene-3, ββ-diol, 14β, 15β- methyleneestra-1,3,5 (10) -triene-3, ββ-diol, 14β, 15β-πΐθίγ1έηβ3ίΓ3-1,3,5 (10), 8 (9) -tetraene-3, ββ-diol, estra-1 , 3,5 (10), 8 (9) -tetraene-3, ββ-diol, estra-1, 3,5 (10), 8 (14) -tetraene-3, ββ-diol, estra-1,3 , 5 (10), 6,8-pentaene-3, Ιββ-diol,

7 fluoroestra-1,3,5 (10) -triene-3, Ιββ-diol,

Ιΐβ-methoxyestra-l, 3,5 (10) -triene-3, Ιββ-diol,

7a-methyl-estr-l, 3,5 (10) -triene-3, Ιββ-diol,

Ιΐβ-fluoroestra-l, 3,5 (10) -triene-3, Ιββ-diol,

8a-estra-1,3,5 (10) -triene-3, ββ-diol, estra-1,3,5 (10) -triene-2,3,16a-triol,

17β-fluoroestra-1,3,5 (10) -triene-3, Ιββ-diol,

18a-homo-estra-3,5 (10) -triene-3, Ιββ-diol,

18a-homo-estra-3,5 (10), 8 (9) -tetraen-3, Ιββ-diol,

18a-homo-14, 15-metylénestra-l, 3,5 (10) -triene-3, Ιββ-diol,

18a-homo-14, 15-metylénestra-l, 3,5 (10), 8 (9) -tetraen-3, Ιββ-diol,

18a-homo-14, 15-metylénestra-l, 3,5 (10), 6,8-pentaene-3, Ιββ-diol,

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7α-ethylestra-1,3,5 (10) -triene-3,16a-diol, 7α-propylestra-1,3,5 (10) -triene-3,16a-diol, 7α-isopropylestra-1,3, 5 (10) -triene-3,16a-diol, 7a-isopropenylestra-1,3,5 (10) -triene-3,16a-diol, 7a-phenylestra-1,3,5 (10) -triene-3 , 16α-diol, 7α-methoxyestra-1,3,5 (10) -triene-3,16a-diol, 7α-thiomethylestra-1,3,5 (10) -triene-3,16a-diol, 7α-cyanomethylestra -1,3,5 (10) -triene-3,16a-diol, 7β-ethylestra-1,3,5 (10) -triene-3, ββ-diol, 7β-propylestra-1,3,5 (10) ) -triene-3,16a-diol, 7β-isopropylestra-1,3,5 (10) -triene-3,16a-diol, 7β-isopropenylestra-1,3,5 (10) -triene-3,16a- diol, 7β-phenylestra-1,3,5 (10) -triene-3,16a-diol, 7β-methoxyestra-1,3,5 (10) -triene-3,16a-diol, 73-thiomethylestra-1, 3,5 (10) -triene-3,16a-diol, 7β-cyanomethylestra-1,3,5 (10) -triene-3,16a-diol, 7a-ethylestra-1,3,5 (10) -triene -3, δδ-diol, 7α-propylestra-1,3,5 (10) -triene-3, δδ-diol, 7α-isopropylestra-1,3,5 (10) -triene-3, δδ-diol, 7a -isopropenylestra-1,3,5 (10) -trien-3, δδ-diol, 7α-phenylestra-1,3,5 (10) -triene-3, δδ-diol, 7α-methoxyestra-1,3,5 (10) triol n-3, δδ-diol, 7α-thiomethylestra-1,3,5 (10) -triene-3, δδ-diol, 7α-cyanomethylestra-1,3,5 (10) -triene-3, δδ-diol, 7β-ethylestra-1,3,5 (10) -triene-3, δδ-diol, 7β-propylestra-1,3,5 (10) -triene-3, δδ-diol, 7β-isopropylestra-1,3, 5 (10) -trien-3, δδ-diol, 7β-isopropenylestra-1,3,5 (10) -trien-3, δδ-diol, 73-phenylestra-1,3,5 (10) -trien-3 , Βδ-diol, 7β-methoxyestra-1,3,5 (10) -triene-3, δδ-diol, 7β-β-diol, 7β-β-diol, β 3-1,3,5 (10) -triene-3, δδ-diol,

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7β-cyanomethylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-methylestra-1,3,5 (10) -triene-3,16α-diol, 15α-ethylestra-1,3, 5 (10) -triene-3,16a-diol, 15a-propylestra-1,3,5 (10) -triene-3,16a-diol, 15a-allylestra-1,3,5 (10) -triene-3 , 16α-diol, 15α-isopropylestra-1,3,5 (10) -triene-3,16α-diol, 15α-isopropenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-methoxyestra -1,3,5 (10) -triene-3,16a-diol, 15a-thiomethylestra-1,3,5 (10) -triene-3,16a-diol, 15a-methylestra-1,3,5 (10) ) -triene-3, ββ-diol, 15α-ethylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-propylestra-1,3,5 (10) -triene-3, ββ- diol, 15α-allylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-isopropylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-isopropenylestra-1, 3,5 (10) -triene-3, ββ-diol, 15α-methoxyestra-1,3,5 (10) -triene-3, ββ-diol, 15α-thiomethylestra-1,3,5 (10) -triene -3, β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol, 15β-propylestra-1,3,5 (10) -triene-3,16a-diol, 15β-31γ1θ3ίΓ3-1,3,5 (10) -tri ene-3,16a-diol, 15β-isopropylestra-1,3,5 (10) -triene-3,16a-diol, 15β-β-β-β-β 3 -1, 3,5 (10) -triene-3,16a -diol, 15β-methoxyestra-1,3,5 (10) -triene-3,16a-diol, δδ-β-β-β-β-γ-β, 3,5 (10) -triene-3,16 α-diol, β-β-β-β-β-β , 3,5 (10) -triene-3, ββ-diol, 15β-βίγ1θ3ίΓ3-1,3,5 (10) -triene-3, ββ-diol, βδ-ρ ^ ργΙθΞύΓβ-1,3,5 (10) ) -triene-3, ββ-diol, 15β-31γ1θ3ίΓ3-1,3,5 (10) -triene-3, ββ-diol, 15β-isopropylestra-1,3,5 (10) -triene-3, ββ- diol, βδ-βζ-diol, 3,5 (10) -triene-3, ββ-diol,

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15β-methoxyestra-1,3,5 (10) -triene-3, ββ-diol, 15β-thiomethylestra-1,3,5 (10) -triene-3,16β-diol, 7α-trifluoromethyl-lipofluorestra- 1,3,5 (10) -triene-3,16a-diol, 7a-pentafluoroethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7a-ethyl-11β-fluoroestra- 1,3,5 (10) -triene-3, ββ-diol, 7α-propyl-lip-fluorestra-1,3,5 (10) -triene-3,16a-diol, 7α-isopropyl-lip-fluorestra- 1,3,5 (10) -triene-3,16a-diol, 7a-isopropenyl-HP-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7a-phenyl-lip-fluoroestra- 1,3,5 (10) -triene-3,16a-diol, 7a-methoxy-11β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7a-thiomethyl-lip-fluoroestra- 1,3,5 (10) -triene-3, ββ-diol, 7α-cyanomethyl-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7β-ethyl-lip-fluoroestra- 1,3,5 (10) -triene-3, ββ-diol, 7β-propyl-lip-fluoroestra-1,3,5 (10) -triene-3,16α-diol, 7β-isopropyl-β-fluoroestra- 1,3,5 (10) -trien-3, ββ-diol, 7β-isopropenyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7β-phenyl-lip-fluoroestra- 1,3,5 (10) -triene-3,16a-diol, 7β-methoxy-lip-fluoro stra-1,3,5 (10) -triene-3,16a-diol, 7β-thiomethyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7β-cyanomethyl-lip- fluoroestra-1,3,5 (10) -trien-3, ββ-diol, 7α-ethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16β-diol, 7α-propyl-11β- Fluoroestra-1,3,5 (10) -triene-3,16β-diol, 7α-isopropyl-lip-fluoroestra-1,3,5 (10) -triene-3,16β-diol, 7α-isopropenyl-lipol fluoroestra-1,3,5 (10) -triene-3,16β-diol, 7α-phenyl-lip-fluoroestra-1,3,5 (10) -triene-3,16β-diol, 7α-methoxy-lip- fluoroestra-1,3,5 (10) -triene-3, ββρ-diol, 7α-thiomethyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββρ-diol, 7α-cyanomethyl-11β- fluoroestra-1,3,5 (10) -triene-3,16β-diol, 7β-ethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16β-diol, 7β-propyl-11β- fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7β-isopropyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-diol,

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7β-isopropenyl-11β-fluoroestra-1,3,5 (10) -trien-3, ββ-diol, 7β-ββηγ1-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7β-methoxy-β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7β-thiomethyl-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7β -] <γ3ηοιηθίγ1-11β-Fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15α-methyl-1H-fluoroestra-1,3,5 (10) -triene-3,16a -diol, 15α-ethyl-1H-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15α-propyl-1H-fluoroestra-1,3,5 (10) -triene- 3,16a-diol, 1Sa-allyl-β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15a-isopropyl-1H-fluoroestra-1,3,5 (10) - triene-3,16a-diol, 15a-isopropenyl-1'-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15a-methoxy-1H-fluoroestra-1,3,5 (10) ) -triene-3,16a-diol, 15a-thiomethyl-1H-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15a-methyl-1H-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15α-ethyl-1H-fluorestra-1,3,5 (10) -trien-3, ββ-diol, 15α-propyl-1H-fluorestra-1, 3,5 (10) - triene-3, ββ-diol, 15α-allyl-1 H -fluores tra-1,3,5 (10) -triene-3, ββ-diol, 15α-isopropyl-1H-fluorestra-1,3,5 (10) -triene-3, ββ-diol, 15α-isopropenyl-1 N -fluorestra-1,3,5 (10) -triene-3, ββ-diol, 15α-methoxy-1β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15α-thiomethyl -1'-Fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β-methyl-11β-fluoroestra-1,3,5 (10) -triene-3,16α-diol, 15β- ethyl-11β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-propyl-11β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β- 31γ1-11β-Γ1υ0Γβ3ίΓ3-Ί, 3,5 (10) -triene-3,16a-diol, 15β-isopropyl-11β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β- isopropenyl-11β-fluoroestra-1,3,5 (10) -trien-3, ββ-diol, 15β-Inetoxy-11β-fluorestra-1,3,5 (10) -triene-3,16α-diol, 15β -thiomethyl-11β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-methyl-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β llβ-ethyl-l-fluoroestra, 3,5 (10) -triene-3, Ιββ-diol,

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15β-ρτοργ1-11β-Fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β-allyl-1β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol , 15β-ϊζορΓοργ1-11β-trifluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β--ζρροορθηγ1-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol , 15β-Methoxy-1H-fluoroestra-1,3,5 (10) -trien-3, ββ-diol, 15β-thiomethyl-1H-fluoroestra-1,3,5 (10) -trien-3, βββ -diol, 14α, 15α-methylene-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 14β, 15β-methylene-7α-phenylestra-1,3,5 (10) -triene -3,16a-diol, 14β, 15β-η-γ1έη-7α-βθηγ1θ3ίΓ3-1,3,5 (10), 8 (9) -tetraene-3,16α-diol, 7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3,16a-diol, 7a-phenylestra-1,3,5 (10), 8 (14) -tetraene-3,16a-diol, 7-phenylestra-1,3 5 (10), 6,8-pentaene-3,16a-diol, 1'-methoxy-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, β-fluoro-7a- phenylestra-1,3,5 (10) -triene-3,16a-diol, 7a-phenyl-8a-estra-1,3,5 (10) -triene-3,16a-diol, 7a-phenylestra-1, 3,5 (10) -triene-2,3,16a-triol, 17β-fluoro-7a-phenylestra-1,3,5 (10) - triene-3,16α-diol, 18α-homo-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 18α-homo-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3,16a-diol, 18a-homo-14a, 15a-methylene-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 18a-homo-14a, 15α-methylene-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3,16α-diol, 18α-homo-14α, 15α-methylene-7-phenylestra-1,3,5 ( 10), 6,8-pentaene-3,16-diol,

14a, 15a-methylene-7a-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 14β, 15β-β-γηθίγ1έη-7α-Γθηγ1β3 ^ 3-1,3,5 (10) -triene- 3, ββ-diol, 14β, 15β-methylene-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3, ββ-diol, 7α-phenylestra-1,3,5 (10) , 8 (9) -tetraene-3, ββ-diol, 7α-phenylestra-1,3,5 (10), 8 (14) -tetraene-3, ββ-diol, 7-phenylestra-1,3,5 ( 10), 6,8-pentaene-3,16a-diol, 1'-methoxy-7a-phenylestra-1,3,5 (10) -triene-3, ββ-diol,

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Β-Fluoro-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 7α-phenyl-8α-estra-1,3,5 (10) -triene-3, ββ-diol, 7α-phenylestra-1,3,5 (10) -triene-2,3, ββ-triol, 17β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 18a- homo-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 18α-homo-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3, βββ -diol, 18α-homo-14α, 15α-methylene-7α-phenylestra-1,3,5 (10) -triene-3,16β-diol,

18a-homo-14a, 15a-methylene-7a-Phenyl-l, 3,5 (10), 8 (9) -tetraen-3, Ιββ-diol,

18a-homo-14a, 15a-methylene-7-Phenyl-l, 3,5 (10), 6,8-pentaene-3, Ιββ-diol,

15α-methyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-ethyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-propyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-allyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-isopropyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-isopropenyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-methoxy-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-thiomethyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-methyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-ethyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-propyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-allyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-isopropyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-isopropenyl-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-methoxy-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-thiomethyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-methyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-ethyl-7α-phenylestra-1,3,5 (10) -trien-3, 16α-diol, 15β-propyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-allyl-7α-phenylestra-1,3,5 (10) -trien-3, 16-diol

• · · • · · • · · • ··· · • ·· ·· · · • · · • · · · · · • · • · • · · · • · ·· ·· • · · ··· ·· • · ·· • ·

15β-isopropyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-isopropenyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-Methoxy-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15β-β-α-diol, 7β-β-diol, 1,3β (1,3) (tri)-3,16α-diol, 153-methyl-7α-phenylestra-1,3,5 (10) -trien-3, β-diol, 15β-β-γ-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 153-propyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-allyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-β-diol, 15β-β-diol, 15β-β-diol, 15β-β-diol, 15β-β-diol, 15β-β-diol, 15β-β-diol, 15β-β-diol, 3β-diol, Ββ-diol, 15β-πΐθίοχγ-7α-dienylestra-1,3,5 (10) -triene-3, ββ-diol, 153-thiomethyl-7α-phenylestra-1,3,5 (10) -triene-3, Β-β-diol, 15α-β-γ-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-ethyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -diene-3,16a-diol, 15α-propyl-1H-fluoro-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15α-31γ1-11β-fluoro- 7-phenyl nylestra-1,3,5 (10) -triene-3,16a-diol, 15a-isopropyl-1H-fluoro-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15a -isopropenyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-methoxy-113-fluoro-7α-phenylestra-1,3,5 (10) -triene -3,16α-diol, 15α-thiomethyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-πΐθίγ1-11β-Fluoro-7α-phenylestra-1, 3,5 (10) -triene-3, ββ-diol, 15α-ethyl-1H-fluoro-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-propyl-lip -fluoro-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-allyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -trien-3, βββ -diol, 15α-isopropyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16β-diol, 15α-isopropenyl-11β-fluoro-7α-phenylestra-1,3,5 ( (10) -triene-3,16β-diol, 15α-methoxy-lip-fluoro-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol,

• ·· • · · • · · • ··· · • ·· ·· · · • · · • · · · · • · • · * · · · · ·· ·· • · · ··· ·· • · • ·

15α-Chloro-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15β-methyl-1H-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-ethyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-propyl-11β-fluoro-7α-phenylestra- 1,3,5 (10) -triene-3,16a-diol, 15β-81γ1-11β-fluoro-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-isopropyl- 11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-isopropenyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -trien-3, 16α-diol, 15β-methoxy-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-thiomethyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-methyl-11β-fluoro-7a-phenylestra-1,3,5 (10) -trien-3, δδ-diol, 15β-ethyl-11β-fluoro-7a -phenylestra-1,3,5 (10) -trien-3, δδ-diol, 15β-propyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -trien-3, δδ-diol, 15β -3,11β-Fluoro-7α-phenylestra-1,3,5 (10) -triene-3, βόβ-diol, 15β-isopropyl-11β-fluoro-7α-phenylestra-1,3,5 ( 10) -triene-3,16β-diol, 15β-isopropenyl-113-flu ór-7α-phenylestra-1,3,5 (10) -triene-3,16β-diol, 15β-methoxy-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16β- ηίο1,15β-thiomethyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16β-α1,11β- (3-methylthien-2-yl) estra-1,3,5 ( 10) -triene-3,16a-diol, 11β- (3-methylthien-2-yl) estra-1,3,5 (10) -triene-3,16β-η 1, 13a-estra-1,3,5 (10) -triene-3,16α-diol, 13α-estra-1,3,5 (10) -triene-3,16β-diol, 14β-estra-1,3,5 (10) -triene-3, 16α-diol, 14α-estra-1,3,5 (10) -triene-3,16β-α1,

Β-methylestra-1,3,5 (10) -triene-3,16α-diol, β-methylestra-1,3,5 (10) -triene-3,16β-α1,11,6-methyl-18α-homo -estra-1,3,5 (10) -triene-3,16a-diol, 1'-methyl-18a-homo-estra-1,3,5 (10) -triene-3, δδ-diol, ··· ········································

Ιΐβ-ethylestra-l, 3,5 (10) -triene-3,16x-diol,

Β-Ethylestra-1,3,5 (10) -trien-3, ββ-diol, 1 H -ethyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol, 1 β-ethyl-18α-homo-estra-1,3,5 (10) -trien-3, ββ-diol,

Ιΐβ-vinyl ester-l, 3,5 (10) -triene-3,16x-diol,

Β-vinylestra-1,3,5 (10) -trien-3, ββ-diol,

113-vinyl-18a-homo-estra-1,3,5 (10) -triene-3,16a-diol, 1H-vinyl-18a-homo-estra-1,3,5 (10) -triene-3 , Ιββ-diol,

Ιΐβ-etinylestra-l, 3,5 (10) -triene-3, Ιβα-diol,

Β-ethinylestra-1,3,5 (10) -triene-3, ββ-diol, lip-ethynyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol, lip- ethinyl-18a-homo-estra-3,5 (10) -triene-3, Ιββ-diol,

9a-methyl-estr-l, 3,5 (10) -triene-3,16x-diol,

9a-methyl-estr-l, 3,5 (10) -triene-3, Ιββ-diol,

9a-methyl-18a-homo-estra-3,5 (10) -triene-3,16x-diol,

9a-methyl-18a-homo-estra-3,5 (10) -triene-3, Ιββ-diol,

7a-methyl-18a-homo-estra-3,5 (10) -triene-3,16x-diol,

7a-methyl-18a-homo-estra-3,5 (10) -triene-3, Ιββ-diol,

7-ethyl-18a-homo-estra-3,5 (10) -triene-3,16x-diol,

7-ethyl-18a-homo-estra-3,5 (10) -triene-3, Ιββ-diol,

7, Ιΐβ-dimethylestra-l, 3,5 (10) -triene-3,16x-diol,

7, Ιΐβ-dimethylestra-l, 3,5 (10) -triene-3, Ιββ-diol,

7α, 1β-dimethyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol,

7a, lip-dimethyl-18a-homo-estra-1,3,5 (10) -triene-3, ββ-diol,

16β-ethynyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol,

16a-ethynyl-18-homo-estra-3,5 (10) -triene-3, Ιββ-diol,

7α-methyl-16β-ethinyl · estra-3,5 (10) -triene-3,16x-diol,

7a-methyl-16a-etinylestra-l, 3,5 (10) -triene-3, Ιββ-diol,

7a-methyl-16β-ethinyl · -18a-homo-estra-3,5 (10) -triene-3,16-diol;

7a-methyl-16a-ethynyl-18-homo-estra-3,5 (10) -triene-3, Ιββ-diol,

ΙΙβ-ΐϊΐθίγΙ-βββ-θίίηγΙθΒίΓθ-Ι, 3,5 (10) -triene-3,16a-diol,

• · · • ·· · · • • · ·· · • • • ··· · • · • • · • • · • e • • • ·· ·· · · · • · · · • ·

N, N-methyl-16α-ethynylestra-1,3,5 (10) -triene-3, ββ-diol, N, N-methyl-16β-ethynyl-18α-homo-estra-1,3,5 (10) - triene-3,16α-diol, N 1 -methyl-16α-ethynyl-18α-homo-estra-1,3,5 (10) -triene-3, ββ-diol.

Of the above compounds, the following are particularly preferred:

7 fluoroestra-1,3,5 (10) -triene-3,16x-diol,

7a-methyl-estr-l, 3,5 (10) -triene-3, Ιββ-diol,

7a-methyl-estr-l, 3,5 (10) -triene-3,16x-diol,

18a-homo-estra-3,5 (10) -triene-3,16x-diol,

7-Phenyl-l, 3,5 (10) -triene-3, Ιββ-diol,

7β-ίθηγ1θ3όΓ3-1,3,5 (10) -triene-3, Ιββ-diol,

7.beta.-Phenyl-l, 3,5 (10) -triene-3,16x-diol,

7-ethylestra-l, 3,5 (10) -triene-3, Ιββ-diol,

7p-ethylestra-l, 3,5 (10) -triene-3,16x-diol,

7p-ethylestra-l, 3,5 (10) -triene-3, Ιββ-diol.

Another aspect of the invention relates to the use of a partial structure of formula II

(II) as part of the overall structure of compounds that are characterized by dissociation in favor of an estrogenic effect on bone compared to an effect on the uterus.

Possible substituents on carbon atoms 7, 8, 9, 11, 13, 14, and 17 may be in the α or β position. The dotted lines (----) in rings B, C and D indicate any one or more double bonds between the corresponding carbon atoms.

• ·· • ·· · · • 9 ·· é · • • · · 9 9 9 • · · • · • ··· · • · · · • • • · • · · • · ·· ·· ··· ·· · · • ·

sub

The present invention preferably relates to such structures of formula II '

(II ') wherein the substituents R ^x ' to R ¹⁷ 'independently of one another have the following meaning:

R ¹ 'is halogen, hydroxyl, methyl, trifluoromethyl, methoxy, ethoxy, or hydrogen;

R ² is halogen, hydroxy, straight or branched, saturated or unsaturated alkoxy group with up to 6 carbon atoms, or hydrogen;

R ⁴ 'is a halogen atom, a straight or branched, saturated or unsaturated alkyl group having up to 10 carbon atoms, a trifluoromethyl group, a pentafluoroethyl group, a straight or branched, saturated or unsaturated alkoxy group having up to 6 carbon atoms, or a hydrogen atom;

R ⁷ 'is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the a or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy group containing up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical, or a hydrogen atom;

R ⁸ 'is a hydrogen atom in the α or β-position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the a or β-position containing Up to 10 carbon atoms, or a cyano group in the α or β position; · až až až až až až až až až až;

R ⁹ 'is a hydrogen atom at position a or β, a methyl group at position a or β, an ethyl group at position a or β, a trifluoromethyl group at position a or β, or a pentafluoroethyl group at position a or β;

R ¹¹ 'is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, an optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy- or alkylthio group of up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical, or a hydrogen atom;

R ¹³ 'is a methyl group at position a or β, an ethyl group at position a or β, a trifluoromethyl group at position a or β, or a pentafluoroethyl group at position a or β;

and either

R ¹⁴ 'is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, or a hydrogen atom in the α or β position;

and

R * ⁵ 'is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms , one or more sulfoxide or sulfone groups; or

• · · • ·· ·· · • · • · • • • • ··· · • · • • · • • · • · • • • ·· ·· ··· ·· · · · ·

imino = NR ¹⁵ (R ¹⁵ 'is hydrogen, methyl, ethyl, propyl, isopropyl), or hydrogen;

or

R ¹⁴ 'and R ¹⁵ ' taken together form a 14α, 15α-methylene or 14β, 15β-methylene group, which is optionally substituted with one or two halogen atoms;

R ¹⁶ 'is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group, or a hydrogen atom in the α or β position;

R ¹⁷ 'is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, a hydrogen atom or a hydroxyl group;

wherein the dotted lines (---) in circles B, C and D indicate any one or more double bonds and the wavy lines () indicate that the substituent may be in the α or β position.

The present invention relates to novel selective estrogen structures which are characterized by in vitro dissociation of binding to estrogen receptor preparations of rat prostate and rat uterus, and which exhibit in vivo advantageous dissociation of the effect on the bone compared to the effect on the uterus. To a large dose range, these compounds act to protect the bones without having a stimulating effect on the uterus. Within the same dosage range, their effect on the liver is only minor. In addition, these compounds have an estrogenic effect on the vascular system and brain functions.

The present invention also relates to pharmaceutical compositions,

• · · • · e • ·· · · • · · ·· · • • • ··· · • · • · • • • · • a • e • • · ·· · · · · · • · · ·

which contain at least one compound of formula I (or a physiologically acceptable organic or inorganic acid addition salt thereof), and the use of these compounds for the preparation of medicaments, in particular in the indications below.

The compounds may be administered orally or parenterally in the indications below.

The novel selective estrogens of the present invention can be used in the medicaments either alone or in combination, especially with antiestrogens and gestagens. Particularly preferred is the combination of selective estrogens with ERα-selective antiestrogens or estrogens which act peripherally selectively, i. j. that do not cross the blood-brain barrier.

The compounds and medicaments containing them are particularly suitable for the treatment of perimenopausal and postmenopausal conditions, particularly hot flushes, sleep disorders, irritability, mood swings, incontinence, vaginal atrophy or psychological disorders due to hormone deficiency. The compounds are also useful as hormone replacement and for the treatment of hormonal deficiency disorders in ovarian dysfunction following surgery or medical intervention. They can also be used to prevent bone loss in postmenopausal women or in women who have been treated with LHRH agonists or LHRH antagonists.

The compounds are also useful in alleviating the symptoms of andropause and menopause, i. j. as a hormone replacement hormone therapy (HRT) in men and women, both for prevention and therapy, for treatment of dismenorrhoea complaints and for the treatment of acne.

In addition, the compounds of the invention may be used to prevent hormonal deficits induced by bone loss and osteoporosis, to prevent cardiovascular diseases, particularly vascular diseases such as atherosclerosis, to suppress proliferation of smooth muscle arterial cells, to treat primary pulmonary hypertension, to prevent neurodegenerative diseases caused by hormone deficiency such as Al34

• ·· • ·· · · · • · · • · • • • ··· · • · • • · • • · • · • • • ·· ·· · · · · · · · · ·

zheimer's disease or memory or learning disabilities.

Furthermore, the compounds of the invention may be used for anti-inflammatory therapy and for the treatment of diseases of the immune system, in particular autoimmune diseases such as rheumatoid arthritis.

The compounds of the invention can also be used for the treatment of fertility disorders in men and for the treatment of prostate diseases.

The compounds of the invention may also be used in combination with natural vitamin D3 or calcitriol analogues for bone building or as adjunctive therapy in bone loss therapies (e.g. glucocorticoid therapy, chemotherapy).

Finally, the compounds of formula I may be used in conjunction with progesterone receptor antagonists, particularly in hormone replacement therapy, and in the treatment of gynecological disorders.

A medicament comprising estrogen and pure antiestrogen for simultaneous, sequential or separate administration in selective estrogen therapy of perimenopausal or postmenopausal conditions is described in EP-A 0 346 014.

The doses of the compounds of formula I vary widely and can cover any effective amount. Depending on the condition to be treated and the route of administration, the daily dose of the compound administered may be 0.01 µg / kg to 10 mg / kg body weight, preferably 0.04 µg / kg to 1 mg / kg body weight.

In humans, this amount corresponds to a dose of 0.8 µg to 800 mg, preferably 3.2 µg to 80 mg per day.

A single dose of the present invention comprises from 1.6 mg to 200 mg of one or more compounds of Formula I.

The compounds of the invention and their addition salts are suitable for the preparation of pharmaceutical compositions and medicaments.

• ·· • ·· ·· · • · · ·· · · · • · · • · · • · · • • ··· · • · · · · • • · • · · · • ·· ·· ··· ·· · · · ·

The pharmaceutical compositions or medicaments contain as active ingredient one or more compounds of the invention or their acid addition salts, optionally in admixture with other pharmacologically or pharmaceutically active substances. The medicament is prepared in a known manner, using conventional pharmaceutical excipients, carriers and diluents.

Suitable carriers and excipients are, for example, those described or recommended as excipients for pharmacy, cosmetics and related fields in the following publications: Ullmans Encyklopédie der technischen Chemie, Vol. 4, p. 1 to 39 (1953); Journal of Pharmaceutical Sciences, Vol. 52, p. 918 et seq. (1963); H. von Czetsch-Lindenwald, Hilfstoffe für Pharmazie und angrenzende Gebiete; Pharm. Ind., Workbook 2, p. 72 et seq. (1961); Dr. H. P. Fiedler, Lexikon der Hilfstoffe für Pharmazie, Kosmetik und Angrenzende Gebiete, Cantor KG, Aulendorf in Wirttemberg 1971.

The compounds may be administered orally or parenterally, for example, intraperitoneally, intramuscularly, subcutaneously or percutaneously. They can also be implanted into tissues.

For oral administration, capsules, pills, tablets, dragees, etc. are suitable. Single doses may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier such as starch, sugar, sorbitol, gelatin, glidant, silicic acid, talc, etc.

For parenteral administration, the active compounds may be dissolved or suspended in a physiologically acceptable solvent. Oils with the addition of a solubilizer, a surfactant, a suspending agent or an emulsifier are often used as a diluent. Examples of oils used include olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

The compounds can also be used in the form of depot injections or implanted compositions which can be formulated so as to provide slow release of the active ingredient.

• · · • · · • · • · · ·· · · • • • · • · · • · · • · • ··· · • · · • · • • · • · · • • ·· ·· ··· ·· • · • ·

As inert substances in the implants, for example, biodegradable polymers or synthetic silicones, such as silicone rubber, can be used. For percutaneous administration, the active compounds may also be incorporated into patches.

Various polymers, such as silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene, are suitable for the preparation of intravaginal (e.g. vaginal rings) or intramaterial (e.g. pessaries, spirals, IUS, Mirena® ⁵ ) systems for topical use prepared with active compounds of Formula I.

In order to achieve better bioavailability of the active ingredient, the compounds may also be formulated as cyclodextrin clathrates. To this end, the compounds are reacted with α-, β- or γ-cyclodextrin or its derivatives (PCT / EP95 / 02656).

According to the invention, the compounds of the formula I can also be encapsulated with liposomes.

techniques

Study of binding to estrogen receptors

The binding affinity of the novel selective estrgens is evaluated in competitive assays using 3H-estradiol as a ligand on estrogen receptor preparations from the prostate and uterus of the rat. Preparation of prostatic cytosol and testing of estrogen receptors using prostatic cytosol is performed according to the method described by Testas et al. (Testas J. et al., Endocrinology 109, 1287-1289 (1981)).

The preparation of the uterine uterine cytosol from the rat uterus and receptor testing using an ER-containing cytosol are essentially performed as described by Stack and Gorski (Stack, Gorski, Endocrinology 117, 2024-2032 (1985)) with some modifications described by Fuhrman (Fuhrman U. and et al., Contraception 51, 45-52 (1995)).

• · · • · · • ·· ·· · · ·· • · • · • · · • · · • · • ··· · • · · • · • • · • · · • • • · ·· ··· ·· · · • ·

The compounds of the present invention exhibit a higher binding affinity for the estrogen receptor from the rat prostate than to the estrogen receptor from the rat uterus. It is assumed that in rat prostate, ERα prevails over ERβ. As shown in Table 1, the rat ratio of prostate receptor to uterine receptor in rats is qualitatively consistent with the ratio of relative binding affinities (RBA) for human ERP and ERα (Kuiper et al., Endocrinology 138, 863-870 (1996)).

The predictive capability of the ER-prostate versus ER-uterine test system for the selective effect on tissues was further confirmed by in vivo studies. As for the in vivo effect on bones and uterus, the effect of compounds with a preference for prostate ER is dissociated in favor of the effect on bones (Table 2).

Bone effect study

Three month old female rats are ovariectomized and given the test compound once daily for 28 days immediately after surgery. It is administered subcutaneously in peanut oil / ethanol medium. The animals are sacrificed the day after the last application and the tibia and uterus are dissected. The uterus is weighed, fixed, and prepared for histological studies. Bone density determination is performed ex vivo on prepared long bones using pQCT (Quantitative Computer Tomography).

The measurement is performed at a distance of 4 to 6 mm from the articular head of the proximal tibia.

Ovariectomy reduces trabecular bone density over a measured range from about 400 mg Ca ²⁺ / cm ³ to about 300 mg Ca ²⁺ / cm ³ . By applying a compound of formula I according to the present invention, bone density reduction is prevented or inhibited. Bone density is measured on proximal tibia.

Table 2 shows the results for the compound of the invention.

estra-1,3,5 (10) -triene-3,16a-diol, the compounds of Examples 3, 4, 9,

• ·· • ·· ·· · · ·· • · • · • · · • · · • · • ··· · • · · • · · • · • · · • · ·· ·· ··· ·· · · · ·

and the compounds 7β-ethylestra-1,3,5 (10) -trien-3, ββ-diol, 7α-ethylestra-1,3,5 (10) -trien-3, ββ-diol, 7β-phenylestra-1, 3,5 (10) -triene-3, ββ-diol, 7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 7β-phenylestra-1,3,5 (10) -triene -3, ββ-diol and 7β-ethylestra-1,3,5 (10) -trien-3, ββ-diol.

The results obtained show that these compounds have a higher binding affinity for the estrogen receptor from the rat uterus; for estra-1,3,5 (10) -triene-3, ββ-diol ER (RBA) for rat prostate is 50 and ER (RBA) for rat uterus is 9. In vivo, this situation is reflected in a strongly differentiating the amount of estra-1,3,5 (10) -triene-3,16a-diol, which causes 50% bone protection (3 µg / animal) and 50% uterine stimulation (30 gg / animal) respectively for bone loss found 28 days after ovariectomy in ovariectomized rats not treated with the test substance. Unlike animals in which only a simulated ovariectomy-free operation was performed, this decrease is measurable.

The effect of the compounds of the invention on the vascular system is determined in an ApoE-knockout-mouse model as described by Elhage et al. (Elhage et al., Arteriosclerosis, Thrombosis and Vascular Biology 17, 2679-2684 (1997)).

To demonstrate the effect of estrogens on brain functions, mRNA-expression of the oxytocin receptor is used as a surrogate parameter (Hrabovszky E. et al., Endocrinology 139, 2600-2604 (1998)). Ovariectomized rats are dosed with test substance or vehicle (subcutaneous or oral, 6 times daily) for 7 days. On day 7 after the first administration, the animals are decapitated, the uterine weight is determined, and the level of oxytocin receptor mRNA is examined on appropriate brain sections by in situ hybridization. ED values were determined for ₅ of the stimulation of uterus growth and induction of the oxytocin receptor mRNA.

Another possibility for demonstrating the in vivo dissociated estrogenic effect of the compounds of the invention is that sweat is present in the pot. A single dose of the compounds of the invention is administered by cannula and the effect on 5HT2-receptor and serotonin-transporter protein expression and mRNA levels in the can be measured. areas of the brain that are rich in ERp. The effect on LH secretion is measured compared to the effect of serotonin receptor and serctonin transporter expression.

Substances with stronger binding to the estrogen receptor of the rat prostate than to the estrogen receptor of the rat uterus are more effective in increasing the expression of the serotonin receptor and the serotonin transporter compared to their positive effect on the distribution of LH. Serotonin receptor and serotonin transporter densities are determined on brain sections using radioactive ligands and corresponding mRNA by in situ hybridization. The method is described in the literature (G. Fink and B.E.H. Sumner, Nature 383, 306 (1996); B.E.H. Sumner et al., Molecular Brain Research (1999)).

Preparation of Compounds of the Invention

For the preparation of the compounds of the invention, i. j. modified or substituted estra-1,3,5 (10) -triene-3,16? -diol derivatives, in particular, two generally applicable synthetic strategies are used.

The first strategy is characterized in that the 3,16-protected derivatives of estra-1,3,5 (10) -triene-3, ββξ-diols, or possibly free diols, are subjected to modification at individual positions of the skeleton.

A typical example is the synthesis of 11-nitrate esters. Yours. the pedestrian compound is the known estra-1,3,5 (10) -triene-3, ββ-diol diacetate (J. Biol. Chem. 213, 343 (1955)), which is first oxidized at the C (9) and C positions (11) by the method of Syks and co-workers (Tetrahedron Lett. 1971, 3393). Reductive removal of the benzyl hydroxyl group on C (9) affords directly estra-1,3,5 (10) -triene-3,11β, ββ-triol protected as diacetate. Inversion of the C (16) -hydroxyl group after saponification affords the epimeric 11-nitrate ester of estra-1,3,5 (10) -triene-3,16a-diol. However, the above procedure can also be carried out in the reverse direction, namely: By using estra-1,3,5 (10) -triene-3, β-α-diol diacetate as starting compound. In this way, the 16α-hydroxyl series 11-nitrate ester is obtained first. Other compounds resulting from intermediates, such as estra-1,3,5 (10) -triene-3,9,11β, ββξ-tetraol 11-nitrate esters, are also obtained after cleavage of the protecting groups at C (3) and C ( 16).

The second way is offered by correspondingly modified estrone analogs. Many of these have been prepared by known procedures (characteristic but not limiting synthetic procedures necessary to obtain representative substitution patterns on the estrone skeleton as well as a combination of multiple substituents can be found in the following publications: for C (1) J. Chem. Soc. 1968, 2915, for C (7) Steroids 54, 71 (1989), for C (8a) Tetrahedron Lett, 1991, 743, for C (8β) Tetrahedron Lett, 1964, 1763, Tetrahedron 25, 4011 (1969); J. Org Chem 35: 468 (1970);

C (II) J. Steroid. Biochem. 31, 549 (1988); Tetrahedron 33, 609 (1977); J. Org. Chem. 60, 5316 (1995); for C (9) DE-OS 2,035,879; J. Chem. Soc., Perkin 1 1973, 2095; for C (15) J. Chem. Soc.

Perkin 1 1996, 1269; for C (13a) Mendeleev Commun. 1994, 187; for Ο (14β) Z. Chem. 23, 410 (1983)). Transfer of oxygen function (Z.

Chem. 1970, 221) in these corresponding estrone analogs from C (17) to C (16) means a flexible approach to the compounds of the invention. However, novel estrone derivatives are also suitable for this purpose.

When a substituent is introduced into the 7-position of the steroid skeleton, mixtures of 7a- and 7β-3ΓεΓθοίζοιηέΓον are mostly formed. These can be separated into the individual isomers by methods known to those skilled in the art, for example by chromatography.

Case C (3) -methyl 8α-estra-1,3,5 (10) -trien-17-one (Bull. Soc. Chim. France 1967, 561) is described in detail as an example. The conversion of the ketone to the sulfonylhydrazone, by the simplest reaction with phenylsulfonylhydrazide, is followed by the degradation reaction to olefin C (16) -C (17) (Z. Chem. 10, 221-222 (1970); Liebigs

Ann. Chem. 1981, 1973-1981), to which the region and stereoselek ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 41 · ^π * · · · · · · · · · · · · · · • ··· tive it requires hypobromous acid. Reductive dehalogenation and deprotection at C (3) yields the ββ-alcohol, which can be converted to the 16α-epimer by known methods.

Another variant for introducing a hydroxyl group to the C (16) atom is the hydroboration of the C (16) -C (17) -double bond by sterically demanding boranes. This reaction is known to result in 16-oxidized products (Indian J. Chem. 9, 287-288 (1971)). Accordingly, the reaction of 3-methoxyestra-1,3,5 (10), 16-tetraene and 3-methoxy-18α-homo-estra-1,3,5 (10), 16-tetraene with 9-borabicyclo [3.3.1] Nonane] followed by oxidation with alkaline hydrogen peroxide provides the corresponding 16α-hydroxyestratrienes. In this reaction, epimeric 16β-hydroxysteroids are also formed to a small extent. Cleavage of the 3-methoxy group yields estra-1,3,5 (10) -3,16a-diols. By inverting the configuration at atom C (16), for example by the Mitsuncbu reaction (Synthesis 1980, 1), δδ-hydroxyestratrienes are again obtained.

The broad applicability of these synthetic pathways may be demonstrated by other examples, for example, 3-methoxy-7α-methylestra-1,3,5 (10) -trien-17-one (Helv. Chim. Acta 1967, 281) or at 1, 3-methoxy-7? 3-dimethoxyestra-1,3,5 (10) -trien-17-one (J. Crg. Chem. 32, 4078 (1967)).

The preparation of intermediate C (16) -C (17) olefinic intermediates is not limited to the arylsulfonylhydrazone method. In the event that the steroid backbone carries substituents that do not tolerate the alkaline reaction conditions of the olefin, other methods are also contemplated, in particular the conversion of C (17) ketones to vinyl iodides (Tetrahedron 1988, 147) or enoltriflates (Tetrahedron Lett. 1984, 4821) and their subsequent reduction.

If a pathway through C (16) -ketoderivatives is selected, which is subsequently converted to C (16β) -alcohols or by inversion to C (16a) -alcohols, then C (17) -> C (16) transposition may also be chosen ketone group. Reference is made to the specific case (J. Chem. Soc., Perkin 1 1976, 1350).

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The 16-hydroxyestratrienes according to the invention fluorinated on carbon atoms C (15) and C (17) can be prepared by hydroboration of 15-fluoroestra-1,3,5 (10), 16-tetraenes and 17-fluoroestra-1,3,5 (10), respectively. ), 16-tetraenes by sterically demanding boranes and subsequent oxidation with alkaline hydrogen peroxide. For example

15-Fluoroestra-1,3,5 (10), 16-tetraenes can be synthesized from

15-hydroxyestra-1,3,5 (10) -trien-17-one. First, the secondary hydroxyl group on carbon C (15) must be replaced by a fluorine atom. To this end, for example, 15α-hydroxyestrone (available as described in U.S. Pat. No. 3,375,174) can be converted in a known manner to 15β-fluoroestrone by reaction with diethylaminosulfurtrifluoride, and the corresponding 15α-mesylate is treated with tetra-nane. butylammonium fluoride (J. Chem. Res. (M) 1979, 4728-4755). The 15β-fluoroestra-1,3,5 (10) -trien-17-ones thus available are converted to tosylhydrazones which, by Bamford-Stevens reaction, give 15-fluoroestra-1,3,5 (10), 16-tetraenes which are necessary for implementation

16-hydroxyl group. 17-Fluorinated 16-hydroxyestratetraenes, which are the starting compounds for 17-fluorinated

16-hydroxyestratrienes are available by known methods. The corresponding ketones can be converted to geminal difluorides by reaction with sulfurtetrafluoride (J. Org. Chem. 36, 818-820 (1971)) or with dialkylaminosulfurtrifluorides (US-PS 3 976 691). Of these geminal difluorides, hydrogen fluoride can be eliminated by heating with alumina in an inert solvent according to U.S. Pat. No. 3,413,321 to obtain fluoroolefins. Moreover, these fluoroolefins are available directly from ketones by reaction with diethylaminosulfurtrifluoride in polar solvents in the presence of strong acids such as fuming sulfuric acid (US-PS 4,212,815).

17-Fluorestra-1,3,5 (10), 16-tetraen-3-ol, described in U.S. Pat. No. 3,413,321, can be converted to 17β-fluoro-ether after reaction with sterically demanding borane and subsequent oxidation with alkaline hydrogen peroxide. 1,3,5 (10) -triene-3,16x-ol.

As a further modification, the introduction of twins may be appropriate

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ties. In addition to being pharmacologically important as selective estrogens within the meaning of the present invention, these unsaturated derivatives are valuable intermediates for the synthesis of novel 16-hydroxyestra-1,3,5 (10) -trienes. The synthetic route for the introduction of a C (9) -C (11) double bond is as follows: aromatic ring A steroids are converted to 9α-hydroxysteroids by reaction with dimethyldioxirane; dehydration of these 9α-hydroxysteroids leads to estra-1,3,5 (10), 9 (11) -tetraene (Tetrahedron 50, 10709-10720 (1994)). By treating the 18α-homo-estra-1,3,5 (10) -triene-3,16α-diyldiacetate in situ generated dimethyldioxirane, the corresponding 9α-hydroxy compound can be prepared. Dehydration of this tertiary alcohol results in 18α-homo-estra-1,3,5 (10), 9 (11) -tetraene-3,16α-diyldiacetate. Its saponification yields 18α-homo-estra-1,3,5 (10), 9 (11) -tetraene-3,16α-diol.

The compounds of the formula I according to the invention are prepared as described in the Examples. Other compounds of formula (I ') can be obtained by analogous procedures using reagents that are homologous to those described in the Examples.

The etherification and / or esterification of the free hydroxyl groups is carried out by methods customary for the skilled person.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

8a-estra-3,5 (10) -triene-3, Ιββ-diol

3-Methoxy-8a-estra-3,5 (10) -trien-17-one-17-fenylsulfonylhydrazón

To a suspension of 3.68 g (20 mmol) of 3-methoxy-8α-estra-1,3,5 (10) -trien-17-one and 4.30 g (25 mmol) of benzenesulfonic acid hydrazide in 70 ml of ethanol are added 3 drops of concentrated hydrochloric acid and the mixture is vigorously stirred at a bath temperature of 80-90 ° C for 3 hours. After cooling, the reaction mixture is eliminated

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The hydrazone is filtered off with suction, washed with a little cold ethanol and dried under vacuum. Yield: 8.10 g (92%). t. 183-185 ° C.

3-Methoxy-8α-estra-1,3,5 (10), 16-tetraene

A suspension of 8.10 g (18.5 mmol) of the hydrazone from the previous experiment in 140 mL of dry ether was cooled in an ice bath to 0 ° C with the exclusion of moisture (argon atmosphere). Then, 36 ml (57 mmol) of a solution of methyl lithium in ether was added dropwise, the cooling bath was removed and the reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched by cooling the reaction mixture to 0 ° C and carefully adding saturated aqueous ammonium chloride solution (30 mL) with vigorous stirring. Ethyl acetate is added, the organic phase is washed with water and brine and dried over sodium sulfate. The crude product was chromatographed on silica gel with hexane-ethyl acetate (95: 5). 3.60 g (72%) of the product are obtained.

17-Bromo-3-Merox-8a-estra-3,5 (10) -trien-ΐββ-οΐ

To a solution of 3.40 g (12.67 mmol) of the olefin from the previous preparation in 75 mL of dimethylsulfoxide was added 5 mL of water and then 2.80 g (15.75 mmol) of N-bromosuccinimide was added in one portion with vigorous stirring. After 4.5 hours at room temperature, the reaction mixture was poured into water and the product was extracted with ethyl acetate (300 mL). The organic phase is washed first with water and brine and dried over sodium sulphate. The crude product was chromatographed on silica gel with toluene-acetone (9: 1). 3.50 g (75%) of product are obtained in the form of an oil.

3-Methoxy-8a-estra-3,5 (10) -trien-ΐββ-οΐ

3.50 g (9.60 mmol) of 17α-3-methoxy-8α-estra-1,3,5 (10) -trien-16β-ol, 3.50 g (12.03 mL) of tributyltin hydride and 50 mg of azobisisobutyronitrile in 30 ml of dry tetrahydrofuran was stirred and refluxed under argon for 2 hours with stirring. The reaction mixture was allowed to cool, concentrated in vacuo on a rotary evaporator, and the residue taken up in ethyl acetate (300 mL). The organic phase was

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Wash with dilute hydrochloric acid, water and brine and dry over sodium sulfate. The evaporation residue is chromatographed on silica gel with dichloromethane-ethyl acetate (9: 1). Yield: 2.70 g (98%).

8a-Estra-1,3,5 (10) -triene-3, ββ-diol (1)

A solution of 1.10 g (3.80 mmol) of the methyl ester from the previous experiment in 35 ml of a 1.2 M solution of diisobutylaluminium in toluene was refluxed for 4 hours under exclusion of moisture in an argon atmosphere. The reaction mixture was then cooled in an ice bath and quenched with stirring by carefully adding a mixture of water and acetic acid.

tovej. A precipitate formed the aspirated, washed thoroughly etyla- Cetate and organic phase the concentrated in vacuo. acquired raw product the crystallizes from acetone-hexane mixtures. yield 679 mg (65%) t. t. Mp 181-182 ° C. opt rot rotation: [α] _D + 13.6 ° (c 0.52; CH ₃ OH).

Example 2

8a-estra-3,5 (10) -triene-3,16x-diol

3-Methoxy-8a-estra-3,5 (10) -trien-16-ol ·

To a mixture of 1.50 g (5.24 mmol) of 3-methoxy-8α-estra-1,3,5,10) -trien-16β-ol, 2.06 g (7.85 mmol) of triphenylphosphine and 0.3 g. ml of formic acid in 10 ml of toluene was slowly added dropwise with stirring 1.22 ml (7.85 mmol) of diethyl azodicarboxylate in 2 ml of toluene. The reaction mixture was then stirred for 2 hours at room temperature. Ethyl acetate (300 ml) was then added, the organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the crude product is chromatographed on silica gel with hexane-acetone (gradient up to 4: 1). 1.40 g of 16α-formate is obtained, which is saponified by treatment with 50 ml of 3% methanolic potassium hydroxide at room temperature for 1 hour. The mixture is then acidified with dilute hydrochloric acid, the product is taken up in ethyl acetate (300 ml), the organic phase is washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the crude product is chromatographed on silica gel with dichloromethane-ethyl acetate (gradient up to 7: 3). Yield 940 mg (63%).

8a-Estra-1,3,5 (10) -triene-3,16a-diol (2)

A solution of 740 mg (2.58 mmol) of the methyl ester from the previous experiment in 25 mL of a 1.2 M solution of diisobutylaluminium in toluene was refluxed for 4 hours (bath temperature 130 ° C) under exclusion of moisture in an argon atmosphere. The reaction mixture was then cooled in an ice bath and carefully quenched by the addition of a mixture of water and acetic acid. The resulting precipitate is filtered off with suction, washed thoroughly with ethyl acetate and the organic phase is concentrated in vacuo. The crude product obtained is recrystallized from acetone-hexane. Yield 323 mg (46%), mp 239-240 ° C; [α] _D + 19.8 ° (c 0.52; CH ₃ OH).

Example 3

7-methyl-estr-l, 3,5 (10) -triene-3,16-diol

17-Fenylsulfonylhydrazór. 3-methoxy-7α-methylestra-1,3,5 (10) -trien-17-one

From 4.70 g (15.75 mmol) of 3-methoxy-7α-methylestra-1,3,5 (10) -trien-17-one gave 4.70 g (66%) of the corresponding phenylsulfonylhydrazone, which upon cooling of the reaction the mixture crystallizes; t. Mp 167-170 ° C.

3-Methoxy-7-methylestra-3,5 (10), 16-tetraene

Olefination of 4.40 g (9, 2 ⁷ mmol) fenylsulfonylhydrazónu the previous experiment to give 2.35 g (85%) of the olefin which is subjected to chromatography on silica gel with hexane-ethyl acetate (9: 1) and crystallization from ethanol to form white flakes, mp 114-116 ° C.

17-Bromo-3-methoxy-7-methylestra-3,5 (10) -trien-16.beta.-ol

This bromohydrin was prepared from 2.00 g (7.08 mmol) of the olefin from the previous experiment. Yield 2.14 g (80%) of product, m.p. t. 145-146 ° C (dec.) (Ether-pentane).

3-Methoxy-7α-methylestra-1,3,5 (10) -triene-ββ-οΐ

From 1.94 g (5.12 mmol) of bromide from the previous experiment, 1.40 g (91%) of the amorphous product was prepared by reductive dehalogenation.

7a-Methylestra-1,3,5 (10) -triene-3, ββ-diol (3)

Cleavage of 1.40 g (4.66 mmol) of the methyl ether prepared in the previous experiment gave 1.25 g (92%) of the diol, mp 209-210 ° C (acetone-hexane); [α] _D + 73.8 ° (c 0.50; CH ₃ OH).

Example 4

7a-Methylestra-1,3,5,10-triene-3,16a-diol (4)

From 0.74 g (2.58 mmol)

3,16β ßο1η is prepared by epimerization and saponification on C (16) to prepare 0,434 g (59%)

16-derivative,

t.

217-219 ° C (acetone-hexane); [α] _D + 84.4 ° (c 0.52; CH 3 OH).

Example 5

1-Methoxyestra-1,3,5,12) -trien-3, ββ-diol

17-Phenylsulfonylhydrazone 1,3-dimethoxyestra-1,3,5 (10) -trien-

17-one

From 3.14 g (10 moles) of 1,3-dimethoxyestra-1,3,5 (10) -trien-17-one, 4.0 g (85%) of 17-phenylsulphonylhydrazone are obtained according to the general hydrazone generic formula. , which crystallizes from the reaction mixture, i. t. 200-202 ° C.

1,3-Dimethoxyestra-1,3,5 (10), 16-tetraene

Olefination of 4.0 g (8.54 mmol) of the hydrazone from the previous preparation gave 1.96 g (76%) of the tetraene which was chromatographed

· Recrystallize from ethanol; t. Mp 109-111 ° C.

1,3-Dimethoxyestra-1,3,5 (10) -trien-ββ-οΐ

From 1.50 g (5.03 mmol) of the olefin from the previous preparation, 0.872 g (55%) of β-beta-alcohol is obtained by conversion to bromohydrin and dehalogenation.

1,3-Dimethoxyestra-1,3,5 (10) -trien-16a-ol

Inversion of 0.50 g (1.58 mmol) of βδ-alcohol gives 0.46 g (92%) of the 16α-epimer.

1-Methoxyestra-1,3,5 (10) -triene-3,16-beta1 (5)

From 0.25 g (0.79 mmol) of the 1,3-dimethoxy derivative, 0.18 g (75%) of methoxydiol was obtained by monodemethylation. After trituration in toluene, the product melts at 90-93 ° C.

Example 6

1-Methoxyestra-1,3,5 (10) -triene-3,16a-diol (6)

Demethylation of 0.35 g (1.11 mmol) of the dimethoxy derivative in 16a-row afforded 0.218 g (65%) of the monomethyl ether, m.p. t. 240-242 ° C (acetone-chloroform).

Example 7

3,11β, Ιύβ-Trihydroxyestra-l, 3,5 (10) -trien-II nitrate

3,16β-ϋί3θθίγ1οχγβ3 ^ 3-1,3,5 (10) -triene

To a mixture of 8.00 g (29.4 mmol) of estra-1,3,5 (10) -triene-3, β-beta-diol and 50 ml of pyridine is added at room temperature with stirring 10 ml of acetic anhydride and the mixture is allowed to react through night. The reaction mixture was then poured into ice water (3 L), whereupon the product precipitated as a precipitate. This is suctioned off on a frit, washed thoroughly with distilled water, dried and dissolved in dichloromethane.

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(500 mL). The organic phase is washed with dilute sodium bicarbonate solution and water and dried over sodium sulphate. The evaporation residue is recrystallized from acetone-hexane. Yield 8.40 g (80%).

3,16-diacetyloxy-9, Ιΐβ -dihydroxyestra-l, 3,5 (10) -trien-II nitrate

To a suspension of 7.85 g (22.0 mmol) of 3,16β-β5-α-α-β-1,3,5 (10) -triene in 200 ml of dilute (90%) acetic acid was added portionwise over 10 minutes with stirring. 60.31 g (110 mmol) of ceramononitrate are added. The steroid starting material is dissolved during the reaction. After 5 hours, the reaction mixture is poured into ice water (6 L) and the yellow-red precipitate is filtered off with suction and air-dried. The crude product was then dissolved in acetic acid (600 mL), the organic phase was washed with water and brine, and dried over sodium sulfate. The red-brown crude product was chromatographed on silica gel with dichloromethane-ethyl acetate (9: 1). Yield 5.10 g (53%), m.p. t. 173-175 ° C (acetone-hexane).

3, ββ-Diacetyloxyestra-1,3,5 (10) -trien-lip-ol-11-nitrate

To a solution of 2.42 g (5.58 mmol) of 3, ββ-diacetyloxyestra-1,3,5 (10) -triene-9, ββ-diol-11-nitrate and 2.90 mL (18.31 mmol) of triethylsilane In 60 ml of dry dichloromethane cooled to -15 ° C, 5.0 ml of boron trifluoride etherate was added dropwise with stirring. The mixture was allowed to react for 1 hour at -15 ° C and then for an additional hour at 0 ° C. The reaction mixture was then poured into ice water containing sodium bicarbonate with stirring. The product mixture is extracted into dichloromethane, the organic phase is washed with water and dried over sodium sulfate. After evaporation, the crude product is chromatographed on silica gel with hexane-ethyl acetate (gradient up to 7: 3). Yield 1.58 g (68%), m.p. t. 188-190 ° C (acetone-hexane).

3,11β, ββ-Trihydroxyestra-1,3,5 (10) -triene-11-nitrate (7)

To a solution of 1.31 g (3.14 mmol) of the diacetate from the previous experiment in 60 ml of dichloromethane was added 20 ml of methanolic hyd50 solution.

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potassium hydroxide (3%) and the mixture was stirred under argon for 4 hours. Then 500 μΐ of acetic acid is added to the reaction mixture, diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate. The crude product was recrystallized from dichloromethane. Yield 874 mg (83%), m.p. t. 170-171 ° C (dec.); [α] D + 68.9 ° (c 0.52; CH 3 OH).

Example 8

3,11β, 16α-Trihydroxyestra-1,3,5 (10) -triene-11-nitrate (8)

To a solution of 820 mg (2.46 mmol) of 3,16β-diol in 25 ml of dry tetrahydrofuran is added 2.26 g (8.62 mmol) of triphenylphosphine and 325 μΐ of formic acid. Then 1.34 ml (8.62 mmol) of diethyl azodicarboxylate was slowly added dropwise to this solution at room temperature. After the addition, the reaction mixture was stirred for 30 minutes at room temperature, then poured into water and the product was extracted into ethyl acetate. The organic phase is washed with water and brine and dried over sodium sulfate. The crude product is then taken up in 20 ml of dichloromethane, 10 ml of methanolic potassium hydroxide solution (3%) is added to the solution, and the mixture is stirred for 2.5 hours at room temperature without air oxygen. It was then acidified with dilute hydrochloric acid, extracted with dichloromethane (200 ml), washed with water and dried over sodium sulfate. The crude product was chromatographed on silica gel with dichloromethane-acetone (gradient up to 4: 1). Yield 704 mg (= 5%) of the product as a foam; [a] _a + 71.4 ° (c 0 50, CH 3 OH).

Example 9

18a-homo-estra-3,5 (10) -triene-3,16x-diol

3-methoxy-18a-homo-estra-3,5 (10) -triene-3,16x-diol

To a solution of 7.41 g of 3-methoxy-18α-homo-estra-1,3,5 (10), 16-tetraene in 50 ml of anhydrous tetrahydrofuran is added under protective gas 6.6 g of 9-borabicyclo [3.3.1] ] nonane. The reaction mixture is then stirred at room temperature until complete reaction and then quenched with 75 ml of water. After gas evolution had ceased, 45 ml of 3M sodium hydroxide solution was added and 45 ml of hydrogen peroxide solution (30%) was slowly added dropwise with cooling. The mixture was stirred for 1 hour at room temperature and then extracted with ethyl acetate. Chromatography of the crude product on silica gel in cyclohexane-ethyl acetate (3: 1) afforded 6.03 g of 3-methoxy-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol, which upon crystallization from methanol to form colorless crystals, mp 109-111 ° C; [α] _D + 71 ° (c 1.02; chloroform).

18-Homo-estra-1,3,5 (10) -triene-3,16a-diol (9)

To a suspension of 2 g of 3-methoxy-18a-homo-estra-1,3,5 (10) -triene-3,16a-diol in 40 ml of toluene was added dropwise 26 ml of diisobutylaluminium hydride (30% v / v) solution under protective gas. ) in toluene, and the mixture is refluxed until the reaction is complete (approximately 10 hours). To the cooled reaction mixture was added 10.6 ml of ethanol and cautiously 32 ml of dilute (1: 1) hydrochloric acid was added while cooling. Extraction with ethyl acetate gave 1.85 g of crude 18α-homo-estra-1,3,5 (10) -triene-3,16α-diol. Crystallization from ethyl acetate gave 1.34 g of colorless crystals, mp 194-198 ° C; [α] _D + 69 ° (c 0.99, dioxane).

Example 10

18a-Homo-estra-1,3,5 (10) -triene-3, δδ-diol (10)

To a solution of 0.5 g of 18α-homo-estra-1,3,5 (10) -triene-3,16α-diol in 25 mL of toluene was added 3.66 g of triphenylphosphine and 3.42 g of 4-nitrobenzoic acid. 6.4 ml of a diethyl azodicarboxylate solution (40% solution in toluene) are then slowly added dropwise to the solution. After 48 hours at room temperature, the reaction mixture is diluted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution, water and brine, dried over sodium sulphate and concentrated. The product obtained is dissolved in 30 ml of Me52

• ·· • ·· ·· · ♦ • · * ·· • · • · • · • · · • ··· · • · · * A A • · · • · _e · ·· ·· »·· ·· • · • ·

of potassium carbonate and 4.82 g of potassium carbonate are added to the solution. The mixture is stirred at room temperature until saponification is complete. Most of the methanol was distilled off and the residue was taken up in ethyl acetate. The solution was washed with brine and dried over magnesium sulfate. After concentration, 0.45 g of crude 18α-homo-estra-1,3,5 (10) -triene-3, ββ-diol is obtained. Crystallization from ethyl acetate gave 0.26 g of colorless crystals, mp 210-213 ° C; [α] _D + 67.4 ° (c 1.01, dioxane).

Example 11

18a-homo-estra-3,5 (10), 9 (11) -tetraene-3,16-diol

18a-homo-estra-3,5 (10) -triene-3,16-diyl diacetate

A mixture of 1 g of 18α-homo-estra-1,3,5 (10) -triene-3,16α-diol, 4 ml of pyridine, 4 ml of acetic anhydride and 10 mg of dimethylaminopyridine is allowed to stand overnight. It is then poured onto ice and extracted with ethyl acetate. The combined extracts were washed with copper sulfate solution (10%) and saturated sodium chloride solution and dried over magnesium sulfate. 1.32 g of 18α-halo-estra-1,3,5 (10) -triene-3,16a-diyldiacetate are obtained in the form of a colorless foam; +50 DEG (c 1.08, chloroform).

18a-homo-estra-3,5 (10), 9 (11) -tetraene-3,16-diyl diacetate

To a mixture of 12 mL dichloromethane, 18 mL water, 15 mL acetone,

5.4 g of sodium bicarbonate and 12 mg of tetra-n-butylammonium hydrogen sulfate are added 1.32 g of 18α-homo-estra-1,3,5 (10) -triene-3,16α-diyldiacetate. After cooling to 10 ° C, 11.1 g of potassium monopersulfate (Caroat ') are added gradually. The reaction mixture was stirred at 10 ° C for 4.5 hours. The salts are separated by filtration through a frit and the organic phase of the filtrate is separated. The aqueous layer was extracted once more with dichloromethane and the combined extracts were dried over magnesium sulfate. Evaporation of the solvent gave 1.73 g of crude 9α-hydroxy-18α-hex-oestra-1,3,5 (10) -triene-3,16α-diyldiacetate. This was dissolved in 12 ml

~ ·· · • ·· ·· · · • í · ·:; • · • • ·? . • • ··· · f · ··· ·· • z · · · .Z · ·· ·· • ···

dichloromethane, cooled to 10 ° C and treated with 0.16 mL 70% sulfuric acid. After completion of the reaction, sodium hydrogen carbonate is added to the reaction mixture and the organic phase is separated. After drying and evaporation of the solvent, 1.33 g of a brown oil is obtained, which is chromatographed on silica gel with cyclohexane-ethyl acetate (3: 1). 0.63 g of 18a-homo-estra-1,3,5 (10), 9 (11) -tetraene-3,16a-diyldiacetate is obtained in the form of a colorless foam; [α] _D + 123 ° (c 1.02; chloroform).

18a-Homo-estra-1,3,5 (10), 9 (11) -tetraene-3,16a-diol (11)

To a solution of 0.63 g of 18α-homo-estra-1,3,5 (10), 9 (11) -tetraene-3,16α-diyldiacetate in 50 mL of methanol is added 4.72 g of potassium carbonate and the mixture is stirred at room temperature until complete saponification. Most of the methanol is then distilled off and the residue is taken up in ethyl acetate. The organic solution was washed with brine and dried over magnesium sulfate. After concentration, 0.49 g of 18α-homo-estra-1,3,5 (10), 9 (11) -tetraene-3,16α-diol is obtained in the form of yellowish crystals, mp 196-202 ° C; [α] _D + 163 ° (c 1; dioxane).

Example 12

Estra-1,3,5 (10), 9 (11) -tetraene-3,16-diol

Estra-1,3,5 (10), 9 (11) -tetraene-3,16-diyl diacetate

From 19.9 g (55.82 mmol) of estra-1,3,5 (10) -triene-3,16a-diyldiacetate was prepared 12.69 g (35.8 mmol; 64%) of estra-1,3, 5 (10), 9 (11) -tetraene-3,16a-diyldiacetate analogously to Example 11.

Estra-1,3,5 (10), 9 (11) -tetraene-3, beta-diol (12)

From 12.5 g (35.26 mmol) of estra-1,3,5 (10), 9 (11) -tetraene-3,16a-diyldiacetate, saponification analogously to Example 11 yields 9.53 g (35 g) of the title compound. 26 mmol (99%) estra-1,3,5 (10), 9 (11) 54

• ·· ·· · ·:! • · • · · • ··· · : í · · ·: i · 99 ·· ....... · ·

-tetraene-3,16a-diol in the form of almost colorless crystals. Crystallization from ethyl acetate gave colorless crystals, mp 237-2444 ° C; [α] _D -6 ° (c 0.94; chloroform).

Example 13

13-estra-3,5 (10) -triene-3,16x-diol

3-Methoxy-17-tozylhydrazono-13a-estra-3,5 (10) -triene

A mixture of 2.5 g (8.79 mmol) of 3-methoxy-13α-estra-1,3,5 (10) -trien-17-one and 1.96 g of tosylhydrazide was refluxed with 15 ml of ethanol for 6 hours. and glacial acetic acid (4: 1, v / v). The cooled reaction mixture was then quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. The dark brown oil obtained is chromatographed on silica gel (cyclohexane-ethyl acetate 4: 1). 2.49 g of a colorless amorphous solid are obtained; [ _{α] D} -58 ° (c 0.99, dioxane).

3-methoxy-13a-estra-3,5 (10), 16-tetraene

To a suspension of 2.43 g (5.37 mmol) of 3-methoxy-17-tosylhydrazono-13a-estra-1,3,5 (10) -triene in 20 mL of anhydrous tert-butyl methyl ether was slowly added dropwise 1.61 mL of 10 M solution of n-butyllithium in hexane. The reaction mixture is stirred for 1 hour at room temperature and then 50 ml of saturated ammonium chloride solution are added dropwise with cooling. After separation of the organic phase, the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The crude product (2.1 g of a brown oil) was chromatographed on silica gel to give 0.81 g of 3-methoxy-13a-estra-1,3,5 (10), 16-tetraene as a colorless oil; [.alpha.] ₌ -6 DEG (c 0.94, chloroform).

• ·· • ··. ** · ·::: · · • · • · · • ··· · : with · ·: : • · ·· ·· «·· * ·· ·· • ·

3-methoxy-13a-estra-3,5 (10) -trien-16-ol

3-Methoxy-13a-estra-1,3,5 (10), 16-tetraene (0.81 g; 3 mmol) was dissolved under shielding gas in 10 ml of anhydrous tetrahydrofuran and 0.73 g of 9-borabicyclo was added to the solution. [3.3.1] nonane. The mixture is stirred at room temperature until complete reaction. It is then quenched with 15 ml of water. After gas evolution had ceased, 7.8 ml of 3M sodium hydroxide solution was added. 7.8 ml of 30% hydrogen peroxide solution are then slowly added dropwise to the reaction mixture while cooling, the mixture is stirred for 1 hour at room temperature and extracted with ethyl acetate. The crude product was chromatographed on silica gel with cyclohexane-ethyl acetate (4: 1) to give 604 mg of 3-methoxy-13a-estra-1,3,5 (10) -trien-16a-ol as a colorless oil.

13a-Estra-1,3,5 (10) -triene-3,16a-diol (13)

3-Methoxy-13a-estra-1,3,5 (10) -trien-16a-ol (0.55 g) was dissolved in 10 ml of toluene under hot shielding gas. To this solution is added dropwise a mixture of 2.3 ml of diisobutylaluminium hydride and

5.5 ml of toluene and the mixture was refluxed until complete (about 4 hours). Ethanol (2.1 ml) was added to the cooled reaction mixture followed by dilute (1: 1) hydrochloric acid (6 ml) cautiously with cooling. After extraction with ethyl acetate, the organic phase is washed neutral and dried over magnesium sulphate. 362 mg of 13a-estra-1,3,5 (10) -triene-3,16a-diol are obtained, which after recrystallization from methanol forms colorless crystals, mp 224-231 ° C; [α] _D + 61 ° (c 1.13, pyridine).

Example 14

9p-estra-3,5 (10) -triene-3,16x-diol

3-Methoxy-17-tozylhydrazono-9?-Estra-3,5 (10) -triene

It is prepared analogously to Example 13. It is a colorless foam.

A

13th

• ·· • · · • · · • ·· ·· · · • · · * a · • · • · • · • · · · · • ··· · _t · ·· ·· • · · ··· ·· • · ·· • ·

3-Methoxy-9P ~ estra-3,5 (10), 16-tetraene

An oil was prepared analogously to the example.

It's colorless

3-methoxy-9?-Estra-3,5 (10) -trien-16-ol

Prepared analogously to oil.

Example

13th

It's colorless

9β-Estra-1,3,5 (10) -triene-3,16a-diol (14) Example

It is prepared analogously to

140-145 [deg.] C .; [α] _D -91 ° (c 0.98, dioxane).

13th

They are colorless crystals, i. t.

Example 15

3,16-Bis (benzyloxy) -18a-homo-estra-3,5 (10) -triene-l-one

3,16-Bis (benzyloxy) -18a-homo-estra-3,5 (10), 9 (11) -tetraene

To 32 ml of anhydrous N, N-dimethylformamide was added 4 g of sodium hydride (80% in paraffin oil) under a protective atmosphere;

25.52 mmol). To this mixture was added dropwise a solution of 7.67 g (26.97 mmol) of 18α-homo-estra-1,3,5 (10) -triene-3,16α-diol in 40 mL of tetrahydrofuran. After gas evolution was complete, 13.84 g (80.91 mmol) of benzyl bromide was added. After completion of the reaction, the reaction solution is slowly added dropwise to water (ca. 1 L). Extraction with ethyl acetate gave 14 g of a brown oil. Chromatography on silica gel gave 10.2 g (21.9 mmol; 81.3%) of 3,16α-bis (benzyloxy) -18α-homo-

-estra-1,3,5 (10), 9 (11) -tetraene as a colorless oil; [α] _D + 110 ° (c 1.01, chloroform).

3,16a-Bis (benzyloxy) -18a-homo-estra-1,3,5 (10) -trien-11a-ol

3,16a-Bis (benzyloxy) -18a-homo-estra-1,3,5 (10), 9 (11) -tetraene (10 g; 21.5 mmol) was dissolved in 60 ml of anhydrous tetrahydrofuran under shielding gas and then 12.9 g (107.61 mmol) of catecholborane and 0.99 g (43.1 mmol) of lithium borohydride are added. Po u57

• ·· • ·· ·· · · • · · · · • · • · · · 2 * ··· · • · ·· ·· • · · · • · · ··· ·· • · • · ·· · ·

At the end of the reaction, the reaction mixture was carefully quenched with 100 mL of water, 95 mL of 3 N sodium hydroxide was added and 95 mL of 30% hydrogen peroxide was added dropwise with cooling. The mixture was stirred for 1 hour at room temperature and then extracted with ethyl acetate. The crude product was chromatographed on silica gel with cyclohexane-ethyl acetate (4: 1) to give 8.73 g (18.08 mmol; 84%) of 3, β-α-bis (benzyloxy) -18α-homo-estra-1. 3,5 (10) -trien-11a-ol in the form of a colorless foam; [α] _D -48 ° (c 0.96, chloroform).

3,16-Bis (benzyloxy) -18a-homo-estra-3,5 (10) -triene-l-one

3,16a-Bis (benzyloxy) -18a-homo-estra-1,3,5 (10) -trien-11a-ol (0.89 g; 1.84 mmol) was dissolved in 20 mL of dichloromethane and added to the solution. 0.98 g (4.6 mmol) of pyridinium chlorochromate. The mixture was stirred for 4 hours, then diluted with carbon tetrachloride and filtered through silica gel. The filtrate was concentrated and the residue was chromatographed on silica gel with cyclohexane-ethyl acetate (4: 1). There was thus obtained 3,13a-bis (benzyloxy) -18a-homo-estra-1,3,5 (10) -trien-11-one as a colorless solid (0.63 g, 1.31 mmol; 71%). ; [α] _D + 177 ° (c 0.96, chloroform); IR ([nu] C-O): 1705 cm <^-1> .

Example 16

3,16-bis (benzyloxy) estra-1,3,5 (10) -triene-l-one

3,16-bis (benzyloxy) estra-1,3,5 (10), 9 (11) -tetraene

From 8.7 g (32.17 mmol) of estra-1,3,5 (10), 9 (11) -tetraene-3,16α-diol, 12.83 g (28.47 mmol; 88%) were prepared. Ββ-bis (benzyloxy) estra-1,3,5 (10), 9 (11) -tetraene analogously to Example 15; colorless oil; [α] _D + 96 ° (c 1, chloroform).

3,16-bis (benzyloxy) estra-1,3,5 (10) -trien-lla-ol

Analogous to Example 15, from 12.74 g (28.27 mmol)

• · · • · · ·· · · ·· • · • · • · · • ··· · Q · • · · • · · • · · • · • · · • · ·· ·· ··· ·· · · • ·

3,16a-bis (benzyloxy) estra-1,3,5 (10), 9 (11) -tetraene is prepared by

9.43 g (20.2 mmol; 71%) of 3,16a-bis (benzyloxy) estra-1,3,5 (10) -trien-11a-ol as a colorless solid; [α] _D -44 ° (c 1.02; chloroform).

3,16a-Bis (benzyloxy) estra-1,3,5 (10) -trien-11-one (16)

Analogously to Example 15, 1.91 g (4.09 mmol) was prepared from 3 g (6.4 mmol) of 3,16α-bis (benzyloxy) estra-1,3,5 (10) -trien-11a-ol; 64%) 3,16a-bis (benzyloxy) estra-1,3,5 (10) -trien-11-one; [α] _D + 197 ° (c 0.94, chloroform); IR ([nu] C-O): 1709 cm <^-1> .

Example 17

9a-Methyl-18a-homo-estra-3,5 (10) -triene-3,16x-diol

3,16-Bis (benzyloxy) -9a-methyl-18a-homo-estra-3,5 (10) -trien-11-one

Under shielding gas, a solution of 0.8 g (1.66 mmol) of 3,16a-bis (benzyloxy) -18a is added dropwise to a solution of 0.8 g (7.13 mmol) of potassium tert-butoxide in 2.26 ml of tert-butanol. -homo-estra-1,3,5 (10) -trien-11-one in 15.57 ml of methyl iodide. After 15 minutes, the reaction was quenched with 50 mL of saturated sodium chloride solution. Extraction with ethyl acetate and evaporation gave a yellow foam which was chromatographed on silica gel with cyclohexane-ethyl acetate (7: 1). 0.6 g (1.21 mmol; 73%) of 3,16α-bis (benzyloxy) -9α-methyl-18α-homo-estra-1,3,5 (10) -trien-11-one is obtained in the form of colorless foam; [α] _D + 216 ° (c 1.03, chloroform); IR ([nu] C-O): 1705 cm <^-1> .

3,16-Bis (benzyloxy) -9a-methyl-18a-homo-estra-3,5 (10) -triene

To a mixture of 0.76 g (1.54 mmol) of 3,16α-bis (benzyloxy) -9α-methyl-18α-homo-estra-1,3,5 (10) -trien-11-one and 5 ml of triethylene glycol was added. a solution of 2.16 g (38.15 mmol) of potassium hydroxide in 15 ml of triethylene glycol and 1.54 g (30.8 mmol) of hydrazine hydrate are added. The resulting mixture is heated to a temperature of 4 hours for 4 hours. 210 ° C. Saturated sodium chloride solution was added to the mixture and the mixture was extracted with ethyl acetate. The organic phase is washed with dilute hydrochloric acid, water and brine. After evaporation, the crude product is chromatographed on silica gel with cyclohexane-ethyl acetate (14: 1). There was thus obtained 3,16α-bis (benzyloxy) -9α-methyl-18α-homo-estra-1,3,5 (10) -triene as a colorless oil, 0.66 g (1.37 mmol; 89%), [α] _D + 47 ° (c 0.93, chloroform).

9α-Methyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol (17)

To a solution of 0.65 g (1.37 mmol) of 3,16α-bis (benzyloxy) -9α-methyl-18α-homo-estra-1,3,5 (10) -triene in 20 mL of tetrahydrofuran is added 0.65 g. g of palladium on carbon (10% Pd) and the mixture was subjected to hydrogenation. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was concentrated to give 0.4 g (1.33 mmol; 97%) of 9α-methyl-18α-homo-estra-1,3,5 (10) -trien-3, 16α-diol, which recrystallized from methanol to form colorless crystals, mp 210-215; [α] _D + 72 ° (c 0.99, dioxane).

Example 18

9a-methyl-estr-l, 3,5 (10) -triene-3,16x-diol

3,16-Bis (benzyloxy) -9a-methylestra-3,5 (10) -triene-l-one

In an analogous manner to Example 17, 0.379 g (0.78 mmol) was obtained from 0.497 g (1.06 mmol) of 3,16α-bis (benzyloxy) estra-1,3,5 (10) -trien-11-one. %) 3,16a-bis (benzyloxy) -9a-methylestra-1,3,5 (10) -trien-11-one as a colorless foam; [α] _D + 231 ° (c 1.03; chloroform); IR ([nu] C-O): 1709 cm <^-1> .

3,16-Bis (benzyloxy) -9a-methylestra-3,5 (10) -triene

Analogous to Example 17, from 0.715 g (1.48 mmol)

3,16α-bis (benzyloxy) -9α-methylestra-1,3,5 (10) -trien-11-one gives: • • • • • · ·

0.458 g (0.98 mmol; 66%) of 3,16α-bis (benzyloxy) -9α-methylestra-1,3,5 (10) -triene as a colorless oil; [α] _D + 61 ° (c 1.16, chloroform).

9a-Methylestra-1,3,5 (10) -triene-3,16a-diol (18)

Analogous to Example 17, 0.292 g (1 mmol; 99%) of 9a was obtained from 0.476 g (1.01 mmol) of 3, .beta.-bis (benzyloxy) -9a-methylestra-1,3,5 (10) -triene. -methylestra-1,3,5 (10) -triene-3,16a-diol, which crystallizes to give colorless crystals, mp 182-186 ° C; [α] _D + 77 ° (c 0.99, dioxane).

Example 19 11β-Methyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol

3,16α-Bis (benzyloxy) -1α-methyl-18α-homo-estra-1,3,5 (10) -trien-11β-ο1

3,16a-Bis (benzyloxy) -18a-homo-estra-1,3,5 (10) -trien-11-one (0.6 g, 1.25 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran under shielding gas . The solution was cooled to -15 ° C and 4.17 mL of a 3 M methylmagnesium bromide solution was added. After complete reaction, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The crude product was chromatographed on silica gel with cyclohexane-ethyl acetate (6: 1) to give 0.59 g (1.18 mmol; 95%) of 3,16a-bis (benzyloxy) -1a-methyl-18a-homo. -estra-1,3,5 (10) -trien-β-ol as a colorless oil; [α] _D -1 (c 0.99, chloroform).

3, Ιβα-bis (benzyloxy) -lip-methyl-18a-homo-estra-3,5 (10) -triene

3,16-Bis (benzyloxy) lla-methyl-18a-homo-estra-3,5 (10) -

-triene-β-οΐ (0.5 g; 1 mmol) was dissolved under shielding gas in dichloromethane and 1.75 g (2.4 mL; 15.3 mmol) of triethylsilane was added. The mixture was cooled to -10 ° C and added

• · · ·

5.69 g (5 mL; 40 mmol) of boron trifluoride etherate. After completion of the reaction, the mixture was washed with saturated sodium bicarbonate solution and extracted. The crude product was purified by chromatography on silica gel (cyclohexane-ethyl acetate 9: 1). 0.327 g (0.68 mmol; 58%) of 3,16a-bis (benzyloxy) -β-methyl-

-18a-homo-estra-1,3,5 (10) -triene as a colorless oil; [α] _D + 119 ° (c 0.99, chloroform).

lip-Methyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol (19)

Dissolve 3,16α-Bis (benzyloxy) -lip-methyl-18α-homo-estra-1,3,5 (10) -triene (0.45 g; 0.93 mmol) in 20 mL of tetrahydrofuran to the obtained solution 0.45 g of palladium on carbon (10% Pd) was added and hydrogenated. The catalyst was then filtered off and the filtrate was evaporated to give 0.264 g (0.87 mmol; 94%) of lip-methyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol. Crystallization from ethyl acetate gave colorless crystals, mp 244-251 ° C; [a] _of + 197 ° (c 1.07, dioxane).

Example 20 lip-Methyl-18α-homo-estra-1,3,5 (10) -triene-3,16β-ύΐο1 (20)

To a solution of 0.1 g (0.33 mmol) of lip-methyl-18α-homc-estra-1,3,5 (10) -triene-3,16α-diol in toluene is added 0.35 g (1.33) mmol) triphenylphosphine and 0.22 g (1.33 mmol) acid

4-nitrobenzoic acid. 0.6 ml (1.33 mmol) of a solution of diethyl azodicarbonylate (40% solution in toluene) is then slowly added dropwise, the mixture is heated at 50 ° C until complete, then diluted with ethyl acetate and the organic phase is washed with a bicarbonate solution. sodium sulfate, water and brine, dried over magnesium sulfate and evaporated to give the crude product.

The product thus obtained was dissolved in 20 ml of methanol and 0.81 g (5.85 mmol) of potassium carbonate was added. The mixture is stirred at room temperature until complete saponification. The larger in methanol is distilled off and the residue is taken up in ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel with cyclohexane-ethyl acetate (2: 1) to give 0.79 g (0.26 mmol; 78%) of lip-methyl-18α-homo-estra-1,3,5 ( 10) -triene-3,16a-diol, which upon crystallization from ethyl acetate forms colorless crystals, mp 175-188 ° C; [α] _D + 148 ° (c 0.95, dioxane).

Example 21

ΙΙβ -methyl-estr-l, 3,5 (10) -triene-3,16x-diol

3,16-Bis (benzyloxy) -Ιΐβ-methylestra-3,5 (10) -trien-ΐΐβ-οΐ

The compound was prepared in analogy to the procedure described in the Example

19. Colorless oil; [α] _D + 2 ° (c 0.92; chloroform).

3,16-Bis (benzyloxy) -Ιΐβ-methylestra-3,5 (10) -triene

The compound was prepared in analogy to the procedure described in the Example

19. Colorless oil; [α] _D + 112 ° (c 1, chloroform).

Β-Methylestra-1,3,5 (10) -triene-3,16a-diol (21)

The compound was prepared in analogy to the procedure described in the Example

19. Crystallization from tert-butyl methyl ether gives colorless crystals, mp 243-250 ° C; [α] _D + 172 ° (c 0.96, dioxane).

Example 22

Β-Methylestra-1,3,5 (10) -triene-3,16β-β1 (22)

The compound was prepared in analogy to the procedure described in the Example

20. Crystallization from cyclohexane-ethyl acetate gave colorless crystals, mp 194-199 ° C; [α] _D + 177 ° (c 0.97, dioxane).

Example 23 1'-Ethyl-18a-homo-estra-1,3,5 (10) -triene-3,16a-diol

3,16-Bis (benzyloxy) ethyl-lla-18a-homo-estra-3,5 (10) -trien-11β-ο1

The compound was prepared in analogy to the procedure described in the Example

19. Colorless oil.

3,16a-Bis (benzyloxy) -1'-ethyl-18a-homo-estra-1,3,5 (10) -triene

The compound was prepared in analogy to the procedure described in the Example

19. Colorless oil.

1H-Ethyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol (23)

The compound was prepared in analogy to the procedure described in the Example

19. Colorless crystals, mp 242-255 ° C; [α] _D + 140 ° (c 0.99;

pyridine).

Example 24

ΙΙβ-Ethyl-1Sa-homo-estra-1,3,5 (10) -triene-3, ββ-diol (23)

The compound was prepared in analogy to the procedure described in the Example

20. Colorless crystals, mp 152-156 ° C; [α] _D + 148 ° (c 0.95, dioxane).

Example 25

ΙΙβ-ethylestra-l, 3,5 (10) -triene-3,16x-diol

3,16-Bis (benzyloxy) lla-ethylestra-1,3,5 (10) -trien-ΐΐβ-οΐ

The compound was prepared in analogy to Example 19. Colorless oil; [α] _D -3 ° (c 1; chloroform).

3,16-Bis (benzyloxy) lla-ethylestra-1,3,5 (10) -triene

The compound was prepared in analogy to the procedure described in the Example.

19. Colorless oil; [α] _D + 97 ° (c 1, chloroform).

1Ιβ-Ethylestra-1,3,5 (10) -triene-3,16a-diol (25)

The compound was prepared in analogy to the procedure described in the Example

19. After crystallization from ethyl acetate, it forms colorless crystals,

mp 245-250 ° C; [α] _D + 104 ° (c 1; dioxane).

Example 26

Β-Etylestra-1,3,5 (10) -trien-3, β-diol (26)

The compound was prepared in analogy to the procedure described in the Example

20. Amorphous solid.

Example 27

Β-Methoxyestra-1,3,5 (10) -triene-3,16α-diol 1 H -Methoxy-17-tosylhydrazonoestra-1,3,5 (10) -trien-3-ol

A mixture of 6 ml of ethanol, 4 ml of glacial acetic acid, 1 g (3.3 mmol) of 3-hydroxy-1H-methoxyestra-1,3,5 (10) -trien-17-ene and 0.7 g (3, Toluene-4-sulfonic acid hydrazide (8 mmol) was heated to reflux. After about 5 hours of boiling, the reaction mixture is cooled and the product isolated by dropwise addition to about 100 ml of water. The water contained in the crude product was removed by azeotropic distillation with n-hexane. Yield: 1.14 g (73%).

Β-Methoxyestra-1,3,5 (10), 16-tetraen-3-ol

To a solution of 469 mg (1 mmol) of 1'-methoxy-17-tosylhydrazonoestra-1,3,5 (10) -trien-3-ol in 15 ml of tetrahydrofuran is added at room temperature under inert gas and with vigorous stirring at room temperature. ml (10 mmol) of a solution of n-butyllithium (10 M solution in n-hexane). The reaction solution is heated to reflux. After about 10 minutes of reaction, the mixture was cooled and saturated 20 ml was added dropwise65

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solution of ammonium chloride and 30 ml of ethyl acetate. The organic phase is washed with brine and dried over sodium sulfate. The crude product was purified by chromatography on silica gel (cyclohexane-ethyl acetate 1: 1). Yield: 170 mg (60%).

1'-Methoxy-3-triethylsilyloxyestra-1,3,5 (10), 16-tetraene

To 284 mg (1 mmol) of β-methoxyestra-1,3,5 (10), 16-tetraen-3-ol in 10 ml of tert-butyl methyl ether and 1 ml of pyridine was added 0.6 ml of triethyl bromosilane. After 1 hour, 30 mL of water was added to the reaction suspension. The organic phase is separated, washed, dried and concentrated in vacuo. The oily product thus obtained is used immediately in the next step (hydroboration). Yield 380 mg (95%).

ΙΙβ-Methoxyxy-1,3,5 (10) -triene-3,16a-diol (27)

To a solution of 380 mg (0.95 mmol) of 1'-methoxy-3-triethylsilyloxyestra-1,3,5 (10), 16-tetraene in 20 ml of tetrahydrofuran is added under an inert gas atmosphere 464 mg (3.8 mmol) 9. -borabycyclo- [3.3.1] nonane and the resulting solution is stirred at room temperature until complete reaction. Then 5 ml of science is added dropwise. After gas evolution had ceased, 2 ml of 5 N sodium hydroxide solution and 2 ml of 30% hydrogen peroxide were added dropwise. The mixture was stirred for 1 hour at room temperature and the product was extracted with ethyl acetate. The crude product obtained is purified by chromatography on n-hexane-chloroform-methanol (45: 45: 10) and recrystallized from ethyl acetate-n-hexane. The product obtained (230 mg; 80%) is colorless crystals, mp 212-222 ° C; [.alpha.] D @ ₂₀ + 101 DEG (c 0.53; dioxane).

Example 28

Β-Methoxyestra-1,3,5 (10) -triene-3, β-diol (28)

To a solution of 229 mg (0.76 mmol) of β-methoxyestra-1,3,5 (10) -triene-3,16α-diol in 30 ml of toluene was added 1.8 g (6.8 mmol) of trife. ·· · · · · · · · ·

• · · · · • ·· · • • • • · • · • • • • • · • · • • • • · • • • • · · · · · · · · · ·

nylphosphine and 1.14 g (6.8 mmol) of 4-nitrooenzoic acid. Then 2.7 ml (6.8 mmol) of diethyl azodicarboxylate solution (40% solution in toluene) was added dropwise. The mixture is allowed to react for 24 hours at room temperature, then diluted with ethyl acetate and the organic phase is washed with sodium bicarbonate solution, water and sodium chloride solution. The organic phase is concentrated, the product is taken up in methanol, 2.5 g of potassium carbonate are added to the solution, and the resulting suspension is heated to reflux until complete saponification. Most of the methanol was distilled off and the residue was taken up in ethyl acetate. The extract was washed with water and brine and the solvent was evaporated. Crystallization from chloroform-cyclohexane gave 195 mg (85%) of nearly colorless crystals, mp 195-200 ° C; [α] _D ^- + 86 ° (c 1.18, dioxane).

Example 29

Β-Phenylestra-1,3,5 (10) -triene-3,16a-diol 1 H -phenyl-17-tosylhydrazonoestra -1,3,5 (10) -trien-3-ol

3-Hydroxy-1H-phenylestra-1,3,5 (10) -trien-17-one (590 mg;

1.71 mmol) was reacted with toluene-4-sulfonic acid hydrazide. In this case, part of the product falls out of the reaction solution after cooling. The solid is filtered off with suction, washed with ethanol and dried. 450 mg (51%) of a yellowish crystalline product are obtained. An additional portion of the product (303 mg; 38%) contained in the mother liquors can be obtained by extraction and corresponding chromatographic work-up.

Β-Phenylestra-1,3,5 (10), 16-tetraen-3-ol 11-Phenyl-17-tosylhydrazonoestra-1,3,5 (10) -trien-3-ol (515 mg; 1 mmol · ) was treated with 1 ml (10 mmol) of n-butyllithium solution analogously to Example 28. 450 mg of crude product was obtained, which was used in the next stage of triethylsilyl ether.

• ·· • ·· · · • · · ·· · · • • · · • · · • · · • · • ··· · • · · · • • • · • · · • · ·· ·· ··· ·· · · · ·

lip-Phenyl-3-triethylsilylestra-1,3,5 (10), 16-tetraene

Β-Phenylestra-1,3,5 (10), 16-tetraen-3-ol (crude product) was converted to triethylsilyl ether analogously to Example 28. The product was purified by chromatography on silica gel using cyclohexane-ethyl acetate (6: 1). 1) and the solution is concentrated in vacuo. Yield 320 mg oily substance (72% based on 515 mg lip-phenyl-17-tosylhydrazonoestra-1,3,5 (10) -trien-3-ol).

Β-Phenylestra-1,3,5 (10) -triene-3,16α-diol (29)

The hydroboration of 320 mg (0.72 mmol) of lip-phenyl-3-triethylsilylestra-1,3,5 (10), 16-tetraene was carried out analogously to Example 27. Isolation, chromatography on silica gel in toluene-ethyl acetate ( 0: 30) and crystallization from methanol gave 183 mg (73%) of the product, mp 254-261 ° C; [α] ^ ₀ -103 ° (c 0.09, dioxane).

Example 30

Β-Phenylestra-1,3,5 (10) -triene-3,16b-diol (30)

Inversion of the 16-hydroxyl group was carried out as described in Example 28. From 36 mg (0.1 mmol) of β-phenylestra-1,3,5 (10) -triene-3,16α-diol was chromatographed on silica gel with toluene. -ethyl acetate (70:30) after crystallization from toluene gave 25 mg (69%) of colorless crystals, mp 241-247 ° C; [α] D ²⁰ -103 ° (c 0.09; dioxane).

Example 31

16a-ethinyl-18a-homo-estra-3,5 (10) -triene-3,16b-diol

3-hydroxy-18a-homo-estra-3,5 (10) -trien-16-one

18a-Homo-estra-1,3,5 (10) -triene-3,16a-diol (2.4 g) was dissolved in 60 ml of acetone with the addition of 2.5 ml of dichloromethane. The resulting solution is cooled to 10 ° C and added dropwise to the solution.

4.2 ml of chromosulphuric acid (8 mol / l CrCl3). After completion of the reaction, sodium bisulfite solution was added to the reaction mixture, and most of the acetone was distilled off. Approximately

100 ml of water and the precipitated steroid product is aspirated. After drying, 2.02 g of 3-hydroxy-18α-homo-estra-1,3,5 (10) -trien-16-one is obtained as colorless crystals, mp 264-266 ° C; [α] D ₌ -115 ° (c 0.743;

pyridine).

16α-Ethinyl-18α-homo-estra-1,3,5 (10) -triene-3,16β-diol (31)

At about 0 ° C, 30 mL of tetrahydrofuran is saturated with acetylene. 3.4 ml (8.4 mmol) of a solution of n-butyllithium (2.5 M in toluene) are then added to this solution with cooling and stirring. The temperature should be about 0 ° C. A solution of 141 mg (0.5 mmol) of 3-hydroxy-18-ahomo-estra-1,3,5 (10) -trien-16-one in 10 ml of tetrahydrofuran was added to the suspension of lithium acetylide thus prepared. After a reaction time of 30 minutes at about 0 ° C, the reaction solution is quenched with dilute hydrochloric acid. After the tetrahydrofuran is distilled off, the residue is taken up in toluene, the phases are separated and the organic phase is washed with water. The crude product is obtained by concentrating the solution in vacuo and purified by chromatography on silica gel (toluene / acetone 7: 1). Subsequent crystallization from toluene gave 131 mg (85%) of crystalline product, mp 197-202 ° C; [ _{α] D} + 100 ° (c 1.06; dioxane).

Example 32

16β-Ethinyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol (32)

The preparation of 16β-ethynyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-dicl was carried out in an analogous manner to that described in Example 31. Increasing the temperature to room temperature yielded a larger proportion of 16β-ethynyl product which can be isolated by chromatography on silica gel in cyclohexane-ethyl acetate (3: 1); yield 20%, mp 213-219 ° C; [α] _D ²⁰ +48 ° (c 1.04; dioxane).

• ·······················

Example 33 1 H -Fluoro-7α-methylestra-1,3,5 (10) -trien-3, δδ-diol and β-fluoro-7α-methylestra-1,3,5 (10) -trien-3,16a 1-Di-fluoro-7α-methylestr-4-ene-3,17-dione

To a suspension of copper (I) iodide (15.2 g, 79.8 mmol) in dry tetrahydrofuran (70 mL) cooled to 0 ° C was added

28.7 g (330 mmol) of lithium bromide and 27.8 ml of DMPU. The mixture was stirred for 30 minutes at 0 ° C and then cooled to -30 ° C. 52 ml of a solution of methylmagnesium bromide in diethyl ether (3M solution) are added with stirring. The mixture was stirred for an additional 30 minutes and then a solution of 10.0 g (34.7 mmol) of β-fluoroestra-4,6-diene-3,17-dione, 24.3 mL of DMPU and 23 mL was added to the gray-colored suspension. trimethylsilyl chloride in 60 mL of dichloromethane. After the addition, the reaction mixture is stirred for a further 1.5 hours at a temperature between -30 ° C to -10 ° C, the cooling bath is removed and 35 ml of ethyl acetate are carefully added to the reaction solution at room temperature with vigorous stirring. The organic layer was washed with a saturated aqueous ammonium chloride solution until the copper was removed and dried over sodium sulfate. The crude product was chromatographed on silica gel with hexane-ethyl acetate (gradient up to 1: 1). Yield 3.1 g (30%).

^ l-fluoro-3-hydroxy-7a-methyl-estr-l, 3,5 (10) -trien-17-one

To 8.3 g (27.2 mmol) of β-fluoro-7α-methylestr-4-ene-3,17-dione in 260 mL of acetonitrile was added 7.0 g (31.3 mmol) of copper (I) bromide and the reaction mixture was stirred at room temperature. Stir for 7 hours at room temperature. Ethyl acetate is then added to the reaction solution, the organic phase is washed with aqueous ammonium chloride solution, sodium hydrogen carbonate solution and finally with water, and dried over sodium sulfate. The crude product was chromatographed on silica gel with toluene-ethyl acetate (gradient to 7: 3). yield

3.3 g (40%); [α] _D + 166.8 ° (c 0.5, methanol).

3-acetyloxy-l ^ -fluoro-7a-methylestra-3,5 (10) -trien-17-one

1Q

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lip-Fluoro-3-hydroxy-7α-methylestra-1,3,5 (10) -trien-17-one (3 g; 9.9 mmol) in 12 mL pyridine was allowed to stand with 6 mL acetic anhydride at room temperature through night. The reaction mixture was then poured into ice water with stirring. The precipitate is filtered off with suction and taken up in ethyl acetate. The organic phase is washed with dilute hydrochloric acid and water and dried over sodium sulphate. 3.4 g of product are obtained which is sufficiently pure for further use.

3-acetyloxy-lip-fluoro-7-methylestra-3,5 (10), 16-tetraene

To a solution of 2.7 g (7.9 mmol) of 3-acetyloxy-lip-fluoro-7α-methylestra-1,3,5 (10) -trien-17-one in 40 mL of dry dichloromethane was added 3.8 g ( 2,6-di-tert-butyl-4-methylpyridine (18.4 mmol) was cooled to 0 ° C under argon and trifluoromethanesulfonic anhydride (2.64 ml, 16 mmol) was added dropwise with stirring. The cooling bath is then removed and the mixture is stirred for 1.5 hours at room temperature. Ethyl acetate is added, the organic phase is washed with water and dried over sodium sulfate. To a solution of the crude product (6.0 g) in 15 ml of DMF was added 5.72 ml of tributylamine, 0.11 g (C, 15 mmol) of bis (acetate) bis (triphenylphosphine) palladium and 0.61 ml of acid at room temperature. The mixture was stirred under argon for 30 minutes at a bath temperature of 60 ° C. The mixture is then quenched with ice water, extracted with ethyl acetate, the organic phase is washed with dilute hydrochloric acid and water, and dried over sodium sulfate. The crude product is chromatographed on silica gel with heptane-acetic acid (gradient to 9: 1). Yield 1.71 g (66%).

lip-Fluoro-7α-methylestra-1,3,5 (10) -trien-3, ββ-diol (33a)

To a solution of 1.67 g (5.22 mmol) of 3-acetyloxy-1H-fluoro-7α-methylestra-1,3,5 (10), 16-tetraene in 30 mL of DMSO and 2.4 mL of water at RT N-bromosuccinimide (1.36 g) was added portionwise at 0 ° C with stirring. After the addition, the cooling bath was removed and the mixture was stirred for 45 minutes at room temperature. Then re71

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the reaction mixture is poured into ice water, extracted with ethyl acetate and the organic phase is washed with water and dried over sodium sulfate. The crude bromohydrin (2.3 g) was dissolved in dry tetrahydrofuran and 5 ml (18.6 mmol) of tributyltin hydride and a first portion of AIBN (total 200 mg; spatula tip over the entire reaction) were added to the solution. The reaction mixture is stirred for 10 hours at a bath temperature of 80 ° C under argon, then diluted with ethyl acetate, the organic phase is washed with dilute hydrochloric acid and water, and dried over sodium sulfate. The crude product is saponified with 2.0 g of potassium carbonate in 50 ml of methanol and 5 ml of dichloromethane. The reaction mixture was stirred for 1.5 hours under argon and then poured into ice water. After acidification with dilute hydrochloric acid, the product was extracted into ethyl acetate. The organic phase is washed with water and dried over sodium sulphate. The crude product was chromatographed on silica gel with chloroform-tert-butyl methyl ether (gradient to 95: 5). Yield 1.16 g (75%), mp 239-240 ° C (dec.); [α] _D + 96.8 ° (c 0.51, methanol).

Β-Fluoro-7α-methylestra-1,3,5 (10) -triene-3,16α-diol (33b)

To a solution of 0.60 g (2.0 mmol) of 1'-fluoro-7α-methylestra-1,3,5 (10) -triene-3,16betaine in 20 mL of dry tetrahydrofuran was added 1.82 g (9 mmol) of triphenylphosphine and 0.26 ml of formic acid. To this solution, 1.10 ml of DEAD was added dropwise with stirring under argon at room temperature. After 30 minutes, the reaction was quenched with water and dried over sodium sulfate. The crude product was purified by chromatography on silica gel with dichloromethane-ethyl acetate (gradient to 95: 5). The formates thus obtained are dissolved in 15 ml of dichloromethane, 7.5 ml of a 3% methanolic sodium hydroxide solution are added and the mixture is allowed to stand for 2 hours under argon at room temperature. The mixture is then quenched with an aqueous acetic acid solution, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. The crude product was purified by crystallization from acetone-hexane. Yield 0.45 g (75%), mp 221-222 ° C (dec.); [.alpha.] _D @ + 104.2 DEG (c 0.52; methanol).

The following compounds were prepared analogously to Examples 3 and 4:

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7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, m.p. t. 239-241 ° C (acetone-hexane);

7β-phenylestra-1,3,5 (10) -trien-3, ββ-diol, m.p. t. 171-173 ° C (acetone-hexane);

7β-5enylestra-1,3,5 (10) -triene-3,16a-diol, amorphous;

7a-ethylestra-1,3,5 (10) -triene-3,16a-diol, m.p. t. 192-193 ° C (acetone-hexane);

7α-ethylestra-1,3,5 (10) -triene-3, ββ-diol, amorphous;

7β-ethylestra-1,3,5 (10) -triene-3,16a-diol, m.p. t. 187-189 ° C (acetone-hexane);

7β-ethylestra-1,3,5 (10) -triene-3, ββ-diol, m.p. t. 156-157 ° C (dichloromethane-hexane);

· · ·

Table 1

Estrcgén structure hER a 3A hER β RBA * ERP / ER Rat uterus Prostate rats Prost.ER/ mater.ER Estradicl chiral 100 100 1 100 100 1 estrone Chiral _n 60 37 0, 6 3 2 0.8 17? estradiol · chiral 2H 58 11 0.2 2.4 1.3 0, 5 estriol &apos; .ri.ne .. XCR 14 21 1.5 4 20 5 5-Anarosténdiol chiral 6 17 3 0.1 5 50 genistein 5 36 / 0, 1 10 100 coumestrol / 3 H 94 185 n Å 1.3 24 18

* Kuiper et al., Endccrinology 138, 863-870 (1996)

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Table 2

Compound or Example structure ER (RBA) Uterine rats ER (RBA) Prostate rats 501 bone protection [pg / animal] 50% uterine stimulation [μα, animal] 16-Estradiol ..I b- 9 50 3 30 9 b- 5.3 59 10 XX? ABOUT-. - 13 7P ~ ethylestra-1,3,5 (10) - -trien-3,16β- diol ..riX 0 ^ ·· 0.2 2 7-Etylestra- 1,3,5 (10) - -trien-3,16β- diol ..xb? " 143 7β-Phenylestra — 1,3,5 (10) -triene-3,16β-diol · 0.7 14 'A-Phenylestra-1,3,5: 10) -triene-3,16β-diol U 2, 9 9

·· • ··

999

9 9

995 99 ·· · · · · ··· • ·

IM ··

Compound or Example structure ER (RBA) Rat uterus ER (RBA) Prostate rats 50% bone protection [gg / animal] 50% uterine stimulation [pg / animal] 7β-Phenylestra-1,3,5 (10) -triene-3,16a-diol \ 0’4 0 0.2 1.3 7p-ethylestra-1,3,5 (10) -triene-3,16x-diol .or 0.1 2.9 4 ..Xiŕ 29 200 3 xa ABOUT-" 5, 6 83

Claims (9)

PATENT CLAIMS First 3,16-Dihydroxyestra-1,3,5 (10) -triene derivatives of the general formula I wherein the substituents R ¹ to R ¹⁷ independently of one another have the following meanings: R ¹ is a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a hydrogen atom; R ² is halogen, hydroxy, straight or branched, saturated or unsaturated alkoxy group with up to 6 carbon atoms, or hydrogen; R ⁴ is a halogen atom, a straight or branched, saturated or unsaturated alkyl group having up to 10 carbon atoms, a trifluoromethyl group, a pentafluoroethyl group, a straight or branched, saturated or unsaturated alkoxy group having up to 6 carbon atoms, or a hydrogen atom; R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the a or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy group having up to 6 atoms optionally substituted aryl or hetero77 R ⁹ R ¹¹ R ¹³ and either R ¹⁴ a R ¹⁵ · · ^{15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15} An aryl radical or a hydrogen atom; is a hydrogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, or a cyano group in the α or β position; is a hydrogen atom at the α or β position, a methyl group at the a or β position, an ethyl group at the a or β position, a trifluoromethyl group at the a or β position, or a pentafluoroethyl group at the a or β position; is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally partially or a fully fluorinated alkyl group containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group containing up to 6 carbon atoms, an optionally substituted aryl or non-heteroaryl radical, or a hydrogen atom; is a methyl group at the β-position, an ethyl group at the β-position, a trifluoromethyl group at the β-position, or a pentafluoroethyl group at the β-position; is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, or a hydrogen atom in the α or β position; is a halogen atom in the α or β position, straight or branched 78, a saturated or unsaturated or partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, one or more sulfoxide or sulfone groups or imino groups = NR ¹⁵ (R ¹⁵ is hydrogen, methyl, ethyl, propyl, isopropyl), or hydrogen; or R ¹⁴ and R ^{15 taken} together form a 14a, 15a-methylene or 14β, 15β-methylene group, which is optionally substituted by one or two halogen atoms; R ¹⁶ is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group, or a hydrogen atom in the α or β position; R ¹⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, a hydrogen atom or a hydroxyl group; wherein the dotted lines (----) in rings B, C and D indicate one or more double bonds and the wavy lines () indicate that the substituent may be in the α or β position; with the exception of the following compounds: estra-1,3,5 (10) -triene-3,16a-diol, estra-1,3,5 (10) -triene-3, ββ-diol, estra-1,3,5 (10), 7-tetraene-3,16a-diol, estra-1,3,5 (10), 7-tetraene-3, ββ-diol, • ··· ··· · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · 16a-Ethinylestra-1,3,5 (10) -triene-3, ββ-diol, and Ιββ-etinylestra-l, 3,5 (10) -triene-3,16x-diol. Compounds according to claim 1, wherein the substituents R ¹ to R 'independently of one another have the following meanings: R ¹ is a fluorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a hydrogen atom; R ² is fluoro, hydroxy, methoxy, ethoxy, or H; R ⁴ is a fluorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a hydrogen atom; R ⁷ is a fluorine atom in the α or β position, methyl, ethyl, propyl or isopropyl in the α or β position, optionally substituted aryl, a trifluoromethyl in the α or β position, or a hydrogen atom; R ³ is a hydrogen atom in the α or β position, a methyl group in the α or β position, or an ethyl group in the α or β position; R ⁹ is a hydrogen atom in the α or β position, the methyl group in the α or β position, the ethyl group in the α or β position, the trifluoromethyl group in the α or β position, or the pentafluoroethyl group in the α or β position; R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a fluorine atom at position a or β, a chloromethyl group at position a or β, a methyl group at position a or β, a methoxy group at position a or β, a phenyl group or a 3-methylthien-2-yl group at the a-position of the a-group; Or β, or a hydrogen atom; R ¹³ is a methyl group at the α or β position or an ethyl group at the α or β position; and either R ¹⁴ is a hydrogen atom at the α or β position, or a methyl group at the α or β position; and R ¹⁵ is a fluorine atom at the α or β position, a methyl group at the α or β position, or a hydrogen atom; or R ¹⁴ and R ^{15 taken} together form a 14α, 15α-methylene or 14β, 15β-πΐγγ1β group; R ¹⁶ is methyl, ethyl, ethynyl, propynyl, or trifluoromethyl; R ¹⁷ is a fluorine atom in the α or β-position, a methyl group, a hydrogen atom or a hydroxyl group; wherein the dotted lines (----) in rings B, C and D indicate an optional additional double bond between carbon atoms 9 and 11. Compounds of formula I according to claim 1, wherein R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; while • ·· • ·· · · • • e · ·· · • • • • · • · · • · • • • • ··· · • · • · • • • · • · • • • ··· ·· ··· ·· · · · · R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are hydrogen atoms. Compounds of formula I according to claim 1, wherein R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; while R ¹ , R ⁴ , R ⁴ , R ⁷ , R ³ , R ⁹ , R ¹⁴ , R ¹⁵ , R ¹⁰ and R ¹⁷ are hydrogen atoms. Compounds of formula I according to claim 1, wherein R ¹⁵ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, once or by multiple sulfoxide or sulfone groups or imino groups = NR ¹⁵ (R ⁵ is hydrogen, methyl, ethyl, propyl, isopropyl); while R ¹ , R ² , R ⁴ , R ⁷ , R ³ , R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁶ and R * ⁷ are hydrogen atoms. Compounds of formula I according to claim 1, wherein R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; and R- ¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, an optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group having up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; while R ^1, R ^2, R ^4, R ^8, R ^9, R ^14, R ^5, R ¹⁶ and R ¹⁷ are hydrogen. 7th Compounds of formula I according to claim 1, wherein r ' is a halogen atom in the α or β position, a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl residue; and R ' ⁵ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, one or more sulfoxide or sulfone groups or imino groups = NR ¹⁵ (R ¹³ is hydrogen, methyl, ethyl, propyl, isopropyl); while • · ··· · · ··· · .. · .. ··· ··· ·· • ···· ·····. . * · ····· ♦ ··· ·· ··· ·· ·· R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁶ and R ¹⁷ are hydrogen atoms. Compounds of formula I according to claim 1, wherein R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; and R ¹⁵ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, once or by multiple sulfoxide or sulfone groups or imino groups = NR ^-5 (R ¹⁵ is hydrogen, methyl, ethyl, propyl, isopropyl); while R ¹ , R ² , R ⁴ , R ⁷ , R ⁸ , R ⁹ , R ⁸ , R ¹⁰ and R ¹⁷ are hydrogen atoms. Compounds of formula I according to claim 1, wherein R is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the a or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy having up to 6 carbon atoms , or an optionally substituted aryl or heteroaryl residue; • ·· • ·· 99 • · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9,999 · • 9 9 9 9 9 • · 9 9 9 9 9 ·· ·· 999 99 99 99 R ¹¹ is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group containing up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical; and R ¹⁵ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, once or by multiple sulfoxide or sulfone groups or imino groups = NR ¹⁵ (R ^-5 is hydrogen, methyl, ethyl, propyl, isopropyl); while R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ^{13 14} , R ¹⁵ and R ¹⁷ are hydrogen atoms. Compounds according to claim 1, characterized in that the dotted lines (---) indicate the double bonds. Compounds according to claim 1, characterized in that they have a double bond between atoms 12. Compounds according to claim 1 having a double bond between atoms Compounds according to claim 1, having a double bond between atoms denoting one or more conjugates denoted by carbon 6 and 7. signify s and t ý m, carbon 7 and 8. signify s and t ý m, carbon 8 and 9. • ·· • ·· ·· · ·· · · · · • · • · · • · · · · • ··· · • · · · · · • · 9 ·· ·· 999 ·· · · Compounds according to claim 1, characterized in that they have a double bond between atoms 15. A compound according to claim 1 having a double bond between atoms denote carbon 9 and 11. by signify by carbon 8 and 14. Compounds according to claim 1, characterized in that they have a double bond between carbon atoms 11 12th Compounds according to claim 1, characterized in that they have a double bond between carbon atoms 15th Compounds according to claim 10, characterized in that they have double bonds between carbon atoms 6 and 7 and between carbon atoms 8 and 9. Compounds according to claim 10, characterized in that they have double bonds between carbon atoms 8 and 9 and between carbon atoms 14 and 15. Compounds according to claim 1 10, wherein the bonds between carbon atoms 7, between carbon atoms 8 and 9 and between carbon atoms 11 and 12. Compounds according to claim 1 10, characterized in that they have double bonds between carbon atoms 7, between carbon atoms 8 and 9 and between carbon atoms 14 and 15. Compounds according to claim 10, characterized in that they have double bonds between carbon atoms 6 and 7, between carbon atoms 8 and 9, between carbon atoms 11 and 12 and between carbon atoms 14 and 15. Compounds according to Claims 1 to 22, characterized in that one or both of the hydroxyl groups on the carbon atoms are as follows: · · · ··· · ······ · · · ······················ 3 and 16 are esterified with an aliphatic or aromatic carboxylic acid or an α- or β-amino acid. 24. Compounds according to claim 1, namely: 14a, 15a-metylénestra-l, 3,5 (10) -triene-3,16x-diol, 14β, 15?-Metylénestra-l, 3,5 (10) -triene-3,16x-diol, 14β, 15β-methylenestra-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-3,16a-diol, estra-1,3,5 (10), 6,8-pentaene-3,16a-diol, 7 fluoroestra-1,3,5 (10) -triene-3,16x-diol, Ιΐβ-methoxyestra-l, 3,5 (10) -triene-3,16x-diol, 7a-methylestra-1,3,5 (10) -triene-3,16a-diol, Ιΐβ fluoroestra-1,3,5 (10) -triene-3,16x-diol, 8a-estra-1,3,5 (10) -triene-3,16a-diol, estra-1,3,5 (10) -triene-2,3,16a-triol, 17? Fluoroestra-l, 3,5 (10) -triene-3,16x-diol, 18a-homo-estra-3,5 (10) -triene-3,16x-diol, 18a-homo-estra-3,5 (10), 8 (9) -tetraene-3,16x-diol, 18α-homo-14α, 15α-methyleneestra-1,3,5 (10) -triene-3,16α-diol, 18α-homo-14α, 15α-methyleneestra-1,3,5 (10), 8 (9) -tetraene-3,16a-diol, 18a-homo-14a, 15a-methyleneestra-1,3,5 (10), 6,8-pentaene-3,16a-diol, 14a, 15a-methyleneestra-1,3, 5 (10) -triene-3,16β-όίο1, 14β, 15?-Metylénestra-l, 3,5 (10) -triene-3,16β-όϊο1, 14β, 15β-methylenestra-1,3,5 (10), 8 (9) -tetraene-3,16β-όίο1, estra-1,3,5 (10), 8 (9) -tetraene-3,16β- diol, estra-1,3,5 (10), 8 (14) -tetraene-3,16β-όίο1, estra-1,3,5 (10), 6,8-pentaene-3,16β-όίο1, 7-fluoroestra-l, 3,5 (10) -triene-3,16β-όίο1, Ιΐβ-methoxyestra-l, 3,5 (10) -triene-3,16β-όϊο1, 7a-methyl-estr-l, 3,5 (10) -triene-3, Ιδβ-diol, • ·· • ·· ·· · • · · ·· · · * · · · • · · • · • ··· · • · · 9 · · • · • · · • · ·· ·· ··· ·· «· · · 11β-fluoroestra-1,3,5 (10) -triene-3, Ιββ-diol, 8a-estra-1,3,5 (10) -triene-3, ββ-diol, estra-1,3,5 (10) -triene-2,3,16a-triol, 17β-trifluoroestra-1,3, 5 (10) -triene-3, ββ-diol, 18α-homo-estra-1,3,5 (10) -triene-3, ββ-diol, 18α-homo-estra-1,3,5 (10) , 8 (9) -tetraene-3, ββ-dicl, 18α-homo-14a, 15α-methyleneestra-1,3,5 (10) -triene-3, ββ-diol, 18α-homo-14a, 15α-methylene ester -1,3,5 (10), 8 (9) -tetraene-3, ββ-diol, 18α-homo-14α, 15α-methylenestra-1,3,5 (10), 6,8-pentaene-3, Ββ-diol, 7α-ethylestra-1,3,5 (10) -trien-3, 10α-diol, 7α-propylestra-1,3,5 (10) -triene-3, 10α-diol, 7α-isopropylestra- 1,3,5 (10) -triene-3,16a-diol, 7a-isopropenylestra-1,3,5 (10) -triene-3,16a-diol, 7a-phenylestra-1,3,5 (10) -triene-3,1a-diol, 7a-methoxyestra-1,3,5 (10) -triene-3,1a-diol, 7a-thiomethylestra-1,3,5 (10) -triene-3,16a-dicl , 7α-cyanomethylestra-1,3,5 (10) -triene-3, 10α-diol, 7β-ethylestra-1,3,5 (10) -triene-3, 10α-diol, 7β-ρτοργ1θ3ίτ3-1,3 , 5 (10) -triene-3, 10α-diol, 7β-β-β-diol, 7β-β-diol, 7β-β-diol, 7β-β-β-diol, 7β-β-diol O) -triene-3,16a-diol, 7β-ηθγ1θ3ίΤ3-1,3,5 (10) -triene-3, 10α-diol, 7β-πiβίοχγθ3 ^ 3-1,3,5 (10) -triene-3 , 1α-diol, 7β-α-diol, 7β-α-diol, 7β-α-diol, 7β-α-diol, 7β-α-diol, 3,5 (10) -triene-3, 10α-diol, 7α-ethylestra-1,3,5 (10) -triene-3, ββ-diol, 7α-propylestra-1,3,5 (10) -triene-3, βόβ-diol, 7α-isopropylestra-1,3, 5 (10) -triene-3, β-diol, 7α-isopropenylestra-1,3,5 (10) -triene-3, ββ-diol, 7α-phenylestra-1,3,5 (10) -triene-3 , Ββ-diol, 7α-methoxyestra-1,3,5 (10) -trien-3, ββ-diol, 7α-thiomethylestra-1,3,5 (10) -trien-3, ββ-diol, 7α-cyanomethylestra-1,3,5 (10) -triene-3, ββ-diol, 7β-ethylestra-1,3, 5 (10) -triene-3, ββ-diol, 7β-propylestra-1,3,5 (10) -triene-3, ββ-diol, 7β-isopropyl · estra-1,3,5 (10) -triene -3, ββ-diol, 7β-isopropenyl · estra-1,3,5 (10) -triene-3, ββ-diol, 7β-phenylestra-1,3,5 (10) -triene-3, ββ-diol , 7β-methoxyestra-1,3,5 (10) -trien-3, ββ-diol, 7β-thiomethylestra-1,3,5 (10) -trien-3, ββ-diol, 7β-cyanomethylestra-1,3 5 (10) -triene-3, ββ-diol, 15α-methylestra-1,3,5 (10) -triene-3,16a-diol, 15α-ethylestra-1,3,5 (10) -triene- 3,16a-diol, 15a-propylestra-1,3,5 (10) -triene-3,16a-diol, 15a-allylestra-1,3,5 (10) -triene-3,16a-diol, 15a- isopropylestra-1,3,5 (10) -triene-3,16α-diol, 15α-isopropenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-methoxyestra-1,3,5 ( 10) -triene-3,16a-diol, 15a-thiomethylestra-1,3,5 (10) -triene-3,16a-diol, 15a-methylestra-1,3,5 (10) -triene-3, βββ -diol, 15α-ethylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-propylestra-1,3,5 (10) -triene-3, ββ-dio 1,15a-allylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-isopropylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-isopropenylestra-1, 3,5 (10) -triene-3, ββ-diol, 15α-methoxyestra-1,3,5 (10) -triene-3, ββ-diol, 15α-thiomethylestra-1,3,5 (10) -triene -3, ββ-diol, βδ-β-diol, 3,5 (10) -triene-3, ββ-diol, 15β-ethylestra-1,3,5 (10) -triene-3,16α-diol, 153-propylestra-1,3,5 (10) -triene-3,16a-diol, 15β-allylestra-1,3,5 (10) -triene-3, ββ-diol, βδ-ίζορΓοργΙθείΓβ-Ι, 3, 5 (10) -triene-3, Ιβα-diol, 15β-isopropenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-methoxyestra-1,3,5 (10) -triene-3,16a-diol, 15β-thiomethylestra-1,3, 5 (10) -triene-3,16a-diol, 15β-methylestra-1,3,5 (10) -triene-3, ββ-diol, 15β-ethylestra-1,3,5 (10) -trien-3 , Ββ-diol, 15β-propylestra-1,3,5 (10) -triene-3, ββ-diol, 15β-allylestra-1,3,5 (10) -triene-3, ββ-diol, 15β-isopropylestra -1,3,5 (10) -trien-3, ββ-diol, 15β-isopropenylestra-1,3,5 (10) -triene-3, ββ-diol, 15β-methoxyestra-1,3,5 (10) ) -triene-3, ββ-diol, 15β-thiomethylestra-1,3,5 (10) -triene-3, ββ-diol, 7α-trifluoromethyl-lip-fluorestra-1,3,5 (10) -triene- 3,16α-diol, 7α-pentafluoroethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16α-diol, 7α-ethyl-lip-fluoroestra-1,3,5 (10) -triene- 3,16α-diol, 7α-propyl-lip-fluoroestra-1,3,5 (10) -triene-3,16α-diol, 7α-isopropyl-lip-fluoroestra-1,3,5 (10) -triene- 3,16α-diol, 7α-isopropenyl-lip-fluoroestra-1,3,5 (10) -triene-3,16α-diol, 7α-phenyl-lip-fluoroestra-1,3,5 (10) -triene- 3,16α-diol, 7α-methoxy-lip-fluoroestra-1,3,5 (10) -triene-3,16α-diol, 7α-thiome ethyl-11β-fluoroestra-1,3,5 (10) -trien-3, ββα-diol, 7α-cyanomethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16α-diol, 7β- ethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7β-propyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7β- 11β-Fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7β-isopropenyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7β- phenyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7β-methoxy-β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7g- thiomethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7β-cyanomethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 7a- etvl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-dicl, 7α-propyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, • ·· • · · • · · • ··· I • ·· ·· · · • · · • · · é ·· • · • · • · • · ·· ·· * • · · ··· ·· • · ·· · · 7α-isopropyl-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7α-isopropenyl-1β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol , 7α-Γεηγ1-11β-Fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7α-methoxy-1H-fluoroestra-1,3,5 (10) -triene-3, ββ- diol, 7α-cyanomethyl-1H-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7α-cyanomethyl-1H-fluoroestra-1,3,5 (10) -trien-3 , Ββ-diol, 7β-ethyl-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 7β-ρτοργί-ββ-fluoroestra-1,3,5 (10) -trien-3 , Β-β-diol, 7β-β-diol, 7β-β-diol, 7β-β-diol, 7β-β-diol, 1,3β (10) -triene-3 , Ββ-diol, 7β-phenyl-11β-fluorestra-1,3,5 (10) -triene-3, ββ-diol, 7β-β-diol, 11β-fluorestra-1,3,5 (10) -trien-3 , Β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol, β-β-diol , Ββ-diol, 15α-methyl-1H-fluorestra-1,3,5 (10) -triene-3,16α-diol, 15α-β-γ-11β-Fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15a-propyl-1H-fluoroestra-1,3,5 (10) -triene-3,16a-diol , 15α-31γ1-11β-Fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15a-isopropyl-1H-fluoroestra-1,3,5 (10) -triene-3,16a- diol, 15α-isopropenyl-1H-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15α-methoxy-1H-fluoroestra-1,3,5 (10) -trien-3, 16α-diol, 15α-thiomethyl-1 H -fluorestra-1,3,5 (10) -triene-3,16a-diol, 15α-β-γ-11β-fluoroestra-1,3,5 (10) -triene-3 , Ββ-diol, 15α-βίγ1-11β-fluorestra-1,3,5 (10) -triene-3, ββ-diol, 15α-ρτοργ1-11β-Fluoroestra-1,3,5 (10) -trien-3 , Ββ-diol, 15α-allyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15α-βζ-diol, 15α-β-diolestra-1,3,5 (10) -triene-3 , Ββ-diol, 15α-β-diol, 15β-diol, 15α-methoxy-1 H -fluoroestra-1,3,5 (10) -triene-1,3,5 (10) -triene- 3, ββ-diol, 15α-thiomethyl-1 H -fluorestra-1,3,5 (10) -triene-3, ββ-diol, δδ-ιηβίνΙ-ββ-ΓΙυότθβίΓθ-3,5, 3,5 ( 10) -triene-3,16a-diol, · · · · · · · · · · · ··· ··· 15β-β-γ-11β-trifluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-propyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-allyl-11β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-isopropyl-11β-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-isopropenyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-methoxy-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-thiomethyl-lip-fluoroestra-1,3,5 (10) -triene-3,16a-diol, 15β-methyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β-ethyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β-propyl-lip-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β-allyl-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β-isopropyl-11β-fluoroestra-1,3,5 (10) -triene-3, ββ-diol, 15β-isopropenyl-lip-fluoroestra-1,3,5 (10) -trien-3, ββ-diol, 15β-methoxy-lip-fluoroestra-1,3,5 (10) -trien-3, ββ-diol, 15β-thiomethyl-lip-fluorestra-1,3,5 (10) -triene-3, ββ-diol, 14α, 15α-methylene-7α-phenylestra-1,3,5 (10) -triene-3,16a- diol, 14β, 15β-methylene-7α-phenylestra-1,3,5 (10) -triene-3,16 α-diol, 14β, 15β-methylene-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3,16α-diol, 7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3,16a-diol, 7a-phenylestra-1,3,5 (10), 8 (14) -tetraene-3,16a-diol, 7-Phenyl-1,3,5 (10), δ, 8-pentaene-3,16-diol, 1β-Methoxy-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, β-Fluoro-7α-phenylestra-1β, 3,5 (10) -triene-3,16α-diol , 7α-phenyl-8α-estra-1,3,5 (10) -triene-3,16α-diol, 7α-phenylestra-1,3,5 (10) -triene-2,3,16α-triol, 17β -fluoro-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 18a-homo-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 18a -homo-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3,16α-diol, 18α-homo-14α, 15α-methylene-7α-phenylestra-1,3,5 (10) ) -trien-3, loa-diol, 18a-homo-14a, 15a-methylene-7a-phenylestra-1,3,5 (10), 8 (9) -tetraene-3,16a-diol, • ·· · · ·· · · • · ♦ ♦ · · • · • • · · • · · ··· ·· • · 9 9 9 99 9 • ·································································· I · 18a-homo-14a, 15a-methylene-7-Phenyl-l, 3,5 (10), 6,8-pentaene-3, Ιβα-diol, 14α, 15α-methylene-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 14β, 15β-methylene-7α-phenylestra-1,3,5 (10) -triene-3, Β-β-diol, 14β, 15β-β-diol-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3, ββ-diol, 7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3, ββ-diol, 7α-phenylestra-1,3,5 (10), 8 (14) -tetraene-3, ββ-diol, 7-phenylestra-1,3,5 (10) , 6,8-pentaene-3, ββ-diol, 1β-methoxy-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, ββ-fluoro-7α-phenylestra-1,3 5 (10) -triene-3, ββ-diol, 7α-phenyl-8α-estra-1,3,5 (10) -triene-3, ββ-diol, 7α-phenylestra-1,3,5 (10) 1-Trien-2,3,16a-triol, 17β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 18α-homo-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 18α-homo-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3, ββ-diol, 18α-homo-14a, 15α- methylene-7-Phenyl-1,3,5 (10) -triene-3,16β-diol, 18α-homo-14α, 15α-methylene-7α-phenylestra-1,3,5 (10), 8 (9) -tetraene-3, ββ-diol, 18α-homo-14α, 15α-methylene-7-phenylestra-1,3,5 (10), 6,8-pentaene-3, ββ-diol, 15α-methyl-7α-phenylestra-1,3,5 (10) ) -triene-3,16a-diol, 15a-ethyl-7a-phenylestra-1,3,5 (10) -triene-3, δδ-diol, 15a-propyl-7a-phenylestra-1,3,5 (10) ) -triene-3,16a-diol, 15a-allyl-7a-phenylestra-1,3,5 (10) -triene-3,16a-dicl, 15a-isopropyl-7a-phenestra-1,3,5 (10) ) -triene-3,16a-diol, 15a-isopropenyl-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15a-methoxy-7a-phenylestra-1,3,5 (10) ) -triene-3,16a-diol, 15a-thiomethyl-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15a-methyl-α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-ethyl-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-propyl-7α-phenylestra-1,3,5 (10) ) -triene-3, Ιββ-diol, • ·· • ·· · · • • e ·· · • • • ··· · • · • · • • • · • · • • • e · ·· · · · • · · · • · 15α-allyl-7α-phenylestra-1,3,5 (10) -triene-3, ββ-dicl, 15α-isopropyl-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-isopropenyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-methoxy-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-Thiomethyl-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15β-methyl-7α-phenyl · estra-1,3,5 (10) -triene-3,16a- diol, 1β-ethyl-7α-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-propyl-7α-phenylestra-1,3,5 (10) -triene-3,16a- diol, 15β-allyl-7α-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-isopropyl-7α-phenylestra-1,3,5 (10) -triene-3,16a- diol, 15β-isopropenyl-7α-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-Inetoxy-7α-phenylestra-1,3,5 (10) -triene-3,16a- diol, 15β-thiomethyl-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-methyl-7α-phenylestra-1,3,5 (10) -triene-3, ββ- diol, 15β-ethyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-propyl-7α-phenylestra-1,3,5 (10) -trien-3, δδβ- diol, 15β-β1γ1-7α-Γenylestra-1,3,5 (10) -triene-3, ββ-diol, 15β-isopropyl-7α-phen ylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-isopropenyl-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-methoxy-7α- phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-β-β-diol, 7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-methyl-1β -fluoro-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15a-ethyl-lip-fluoro-7a-phenylestra-1,3,5 (10) -triene-3,16a -diol, 15α-propyl-1H-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-allyl-1H-fluoro-7α-phenylestra-1,3, 5 (10) -trien-3, ββ-diol, 15α-isopropyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-isopropenyl-1H-fluoro -7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15α-β-β-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol , 15α-thiomethyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 9 • ·· ·· · · · · · · 9 • • ··· · • · · · at • • · ·· ·· • · · ··· ·· • ·· • · · 15α-methyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15α-ethyl-lip-fluoro-7α-phenylestra-1,3,5 (10) - triene-3, ββ-diol, 15α-propyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-allyl-lip-fluoro-7α-phenylestra-1 3,5 (10) -triene-3, ββ-diol, 15α-isopropyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16β-diol, 15α-isopropenyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16β-diol; 15α-methoxy-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3, ββ-diol, 15α-thiomethyl-lip-fluoro-7α-phenylestra-1,3,5 (10) - triene-3, ββ-diol, 15β-methyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-ethyl-lip-fluoro-7α-phenylestra-1 , 3,5 (10) -triene-3,16a-diol, 15β-propyl-lip-fluoro-7a-phenylestra-1,3,5 (10) -triene-3,16a-diol, 15β-allyl-lip -fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-isopropyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16a diol, 15β-isopropenyl-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-methoxy-11β-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16α-diol, 15β-thiomethyl-lip-fluoro-7α-phenylestra-1,3,5 (10 ) -triene-3,16α-diol, 15β-methyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3, ββ-dicl, 15β-ethyl-lip-fluoro-7α-phenylestra -1,3,5 (10) -trien-3, ββ-diol, 15β-propyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-allyl -lip-fluoro-7α-phenylestra-1,3,5 (10) -trien-3, ββ-diol, 15β-isopropyl-lip-fluoro-4 α-phenylestra-1,3,5 (10) -zriene- 3,16β-diol, 15β-isopropenyl-lip-fluoro-7α-phenylestra-1,3,5 (10) -triene-3,16β-diol, 15ss-methoxy-lip-fluoro-7-Phenyl-l, 3,5 (10) -triene-3, Ιββ-diol, 15p-thiomethyl-llB-fluoro-7-Phenyl-1,3,5 (10) -triene-3, Ιββ-diol, 11β- (3-methylthien-2-yl) estra- 1,3,5 (10) -triene-3,16x-diol, 11β- (3-methylthien-2-yl) estra-1,3,5 (10) -triene-3, ββ-diol, 13α-estra-1,3,5 (10) -triene-3,16a-diol . 13-estra-3,5 (10) -triene-3, Ιββ-diol, 14β-θ3ίΓ3-1,3,5 (10) -triene-3,16x-diol, Κβ-βε ^ β-Ι, 3,5 (10) -triene-3, ββ-diol, f Β-methylestra-1,3,5 (10) -triene-3,16α-diol, ββ-methylestra-1,3,5 (10) -trien-3, ββ-diol, 1β-methyl-iea- homo-estra-1,3,5 (10) -triene-3,16a-diol, 1H-methyl-18a-homo-estra-1,3,5 (10) -triene-3, ββ-diol, β -etylestra-l, 3,5 (10) -triene-3,16x-diol, Ιΐβ-ethylestra-l, 3,5 (10) -triene-3, Ιββ-diol, Β-Ethyl-1α-homo-estra-1,3,5 (10) -triene-3,16a-diol, 1'-ethyl-18a-hmo-estra-1,3,5 (10) -trien-3 , Ιββ-diol, Β-vinylestra-1,3,5 (10) -triene-3,16α-diol, β-vinylestra-1,3,5 (10) -trien-3, ββ-diol, Β-vinyl-1Ba-homo-estra-1,3,5 (10) -triene-3,16a-diol, 1'-vinyl-18a-homo-estra-1,3,5 (10) -trien-3 , Ββ-diol, ββ-ethynylestra-1,3,5 (10) -triene-3,16α-diol, Β-Ethinylestra-1,3,5 (10) -triene-3, ββ-diol, 1 H -ethynyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol, 1 N-ethynyl-18α-homo-estra-1,3,5 (10) -trien-3, ββ-diol, 9α-methylestra-1,3,5 (10) -triene-3,16α-diol,. 9a-methyl-estr-l, 3,5 (10) -triene-3, Ιββ-diol, 9-methyl-18-homo- estra-3,5 (10) -triene-3,16x-diol, 9a-methyl-18a-homo-estra-3,5 (10) -triene-3, Ιββ-diol, 7α-methyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol, 7α-methyl-18α-homo-estra-1,3,5 (10) -triene-3, Ββ-diol, 7α-ethyl-18α-homo-estra-1,3,5 (10) -triene-3,16α-diol, 7α-ethyl-18α-homo-estra-1,3,5 (10) - triene-3, ββ-diol, 7α, ββ-dimethylestra-1,3,5 (10) -triene-3,16α-diol, 7α, ββ-dimethylestra-1,3,5 (10) -trien-3, Ιββ-diol, • ·· • · · • ·· ·· · · ·· • · • · • ··· · • · · • · · • · • · · ·· ·· * • · · ··· ·· • · ·· • · 7α, lip-dimethyl-18a-homo-estra-3,5 (10) -triene-3,16x-diol, 7α, lip-dimethyl-18a-homo-estra-3,5 (10) -triene-3,16-diol, 16.beta.-ethynyl-18-homo-estra-3,5 (10) -triene-3,16x-diol, 16a-ethynyl-18-homo-estra-3,5 (10) -triene-3, Ιββ-diol, 7a-methyl-16-p-etinylestra-l, 3,5 (10) -triene-3,16x-diol, 7a-methyl-16a-etinylestra-l, 3,5 (10) -triene-3,16 ~ -diol, 7-methyl-16.beta.-ethynyl-18-homo-estra-3,5 (10) -triene-3,16x-diol, 7α-methyl-16α-ethynyl-18α-homo-estra-1,3,5 (10) -triene-3, ββ-diol, lip-methyl-16β-ethinylestra-1,3,5 (10) -triene- 3,16α-diol, lip-methyl-16α-ethinylestra-1,3,5 (10) -triene-3, Ιόβ-diol, lip-methyl-16β-ethynyl-18α-homo-estra-1,3,5 (10) -triene-3,16a-diol, and lip-methyl-16a-ethynyl-18a-homo-estra-1,3,5 (10) -triene-3, ββ-diol. Compounds according to claim 24, characterized in that: 7 fluoroestra-1,3,5 (10) -triene-3,16x-diol, 7a-methyl-estr-l, 3,5 (10) -triene-3, Ιδβ-diol, 7a-methyl-estr-l, 3,5 (10) -triene-3,16x-diol, 18a-hcmo-estra-1,3,5 (10) -triene-3,16a-diol 7-Phenyl-l, 3,5 (10) -triene-3, Ιββ-diol, 7? ~ Phenyl-l, 3,5 (10) -triene-3,16-diol, 7β-phenylestra-1,3,5 (10) -triene-3,16a-diol, 7-ethylestra-l, 3,5 (10) -triene-3, Ιββ-diol, 7p-ethylestra-l, 3,5 (10) -triene-3,16x-diol, 7p-ethylestra-l, 3,5 (10) -triene-3, Ιββ-diol. 26. Use of 3,16-dihydroxyestra-1,3,5 (10) -triene derivatives of the general formula I ' • ·· • ·· • · · • · · ·· · · • · • · • · · • · · • · • ··· · • · · · • · • · • · · • · ·· ·· ··· ·· · · • · wherein the substituents R ¹ to R ¹⁷ independently of one another have the following meanings: R ¹ is a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a hydrogen atom; R ² is halogen, hydroxy, straight or branched, saturated or unsaturated alkoxy group with up to 6 carbon atoms, or hydrogen; R ⁴ is a halogen atom, a straight or branched, saturated or unsaturated alkyl group having up to 10 carbon atoms, a trifluoromethyl group, a pentafluoroethyl group, a straight or branched, saturated or unsaturated alkoxy group having up to 6 carbon atoms, or a hydrogen atom; R ⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the a or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy group having up to 6 atoms a carbon atom, an optionally substituted aryl or heteroaryl radical, or a hydrogen atom; R ⁸ is a hydrogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, or a q in the α or β position; · · · · · · · · · · · · · · · · · · · · · · · · · R ⁹ is a hydrogen atom in the α or β position, the methyl group in the α or β position, the ethyl group in the α or β position, the trifluoromethyl group in the α or β position, or the pentafluoroethyl group in the α or β position; R ^1- is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, optionally a partially or fully fluorinated alkyl group of up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy- or alkylthio group of up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical, or a hydrogen atom; R ¹³ is a methyl group at the a or β position, an ethyl group at the a or β position, a trifluoromethyl group at the a or β position, or a pentafluoroethyl group at the a or β position; and either R ¹⁴ is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, or a hydrogen atom in the α or β position; and R * 'is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, one or more sulfoxide or sulfone groups or imino groups = NR ' ^: (R ¹⁵ is hydrogen, methyl, ethyl, propyl, isopropyl), e · · · · e T or a hydrogen atom; or R ¹⁴ and R ^{15 taken} together form a 14α, 15α-methylene or 14β, 15β-methylene group, which is optionally substituted with one or two halogen atoms; _t R ¹⁶ is straight or branched, saturated or unsaturated, optionally partially or completely fluorinated alkyl group in the a- or β up to 10 carbon atoms, a trifluoromethyl group or a pentafluoroethyl group, a cyanomethyl or a hydrogen atom in a- or β; R ¹⁷ is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, a hydrogen atom or a hydroxyl group; wherein the dotted lines (----) in circles B, C, and D indicate an optional one or more double bonds and the wavy lines () indicate that the substituent may be in the α or β position; for the preparation of a medicament for the treatment of diseases and conditions caused by estrogen deficiency in both men and women. Use according to claim 26 for the treatment of perimenopausal and postmenopausal disorders. Use according to claim 26 for the treatment of periandropausal and postandropausal disorders. Use according to claim 27 for the prophylaxis and therapy of hot flushes, sleep disorders, irritability, mood swings, incontinence, vaginal atrophy and mental disorders caused by hormonal deficiency. · · 100 ·· 30. Use genitourinary by tract claim 29 on the prophylaxis and therapy diseases 31. Use by claim 26 on the prophylaxis and therapy žalúdoč- intestinal and intestinal diseases. 32. Use by claim 31 on the prophylaxis and therapy ulcers and hemorrhagic diatheses in the digestive tract. 33rd Use according to claim 32 for the prophylaxis and therapy of neoplasia. Use according to claim 26 for in vitro therapy of male infertility. Use according to claim 26 for in vivo therapy of male infertility. Use according to claim 26 for in vitro therapy of female infertility. The use of claim 26 for in vivo therapy of female infertility. 38th The use by claim 26 to hormone replacement therapy WITH • (HRT) • • 39th The use by claim 26 for the treatment of spc Sobenov hormonal deficiency in surgically, medically or otherwise caused by ovarian dysfunction. Use according to claim 26 for the prophylaxis and therapy of hormone deficiency-induced bone loss. 41st Use according to claim 40 for the prophylaxis and therapy of osteoporosis • · · • ·· a a * • · · • · · • ··· · ·· · · • · · • · · • · • · • · · • · • · ·· ·· • · · ··· ·· • · ·· • · zy. Use according to claim 26 for the prophylaxis and therapy of cardiovascular diseases. Use according to claim 26 for the prophylaxis and therapy of vascular diseases. Use according to claim 43 for the prophylaxis and therapy of atherosclerosis. Use according to claim 43 for the prophylaxis and therapy of neointimal hyperplasias. Use according to claim 26 for the prophylaxis and therapy of neurodegenerative diseases caused by hormone deficiency. Use according to claim 26 for the prophylaxis and therapy of Alzheimer's disease and hormone deficiency-related memory and learning disabilities. Use according to claim 26 for the treatment of inflammatory diseases and diseases of the immune system. Use according to claim 26 for the prophylaxis and therapy of benign prostatic hyperplasia (BPE). 50. Use of the partial structure of formula II (II) as part of the overall structure of compounds which are characterized by dissociation in favor of estrogenic action on the bone as compared to the effect on the uterus. Use of a partial structure of formula 11 'according to claim 50 (III') wherein the substituents R ¹ 'to R * ⁷ ' independently of one another have the following meaning: R ¹ 'is halogen, hydroxyl, methyl, trifluoromethyl, methoxy, ethoxy, or hydrogen; R ⁴ 'is a halogen atom, a hydroxyl group, a straight or branched, saturated or unsaturated alkoxy group having up to 6 carbon atoms, or a hydrogen atom; is a halogen atom, a straight or branched, saturated or unsaturated alkyl group containing up to 10 carbon atoms, a trifluoromethyl group, a pentafluoroethyl group, a direct 103 • ·· • · · • · · • ··· · • ·· ·· · · • · · • · · · · • · • · • · « • · • · • · · • · ·· ·· ··· ·· · · · · or a branched, saturated or unsaturated alkoxy group containing up to 6 carbon atoms, or a hydrogen atom; R ¹ 'is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, straight or branched, saturated or unsaturated alkoxy group containing up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical, or a hydrogen atom; R ⁸ 'is a hydrogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, or a cyano group in the α or β position; R ⁹ 'is a hydrogen atom at position a or β, a methyl group at position a or β, an ethyl group at position a or β, a trifluoromethyl group at position a or β, or a pentafluoroethyl group at position a or β; R ¹¹ 'is a nitrooxy group at position a or β, a hydroxyl group at position a or β, a mercapto group at position a or β, a halogen atom at position a or β, a chloromethyl group at position a or β, straight or branched, saturated or unsaturated, an optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy- or alkylthio group of up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical, or a hydrogen atom; R ¹³ 'is a methyl group at position a or β, an ethyl group at position a or β, a trifluoromethyl group at position a or β, or a pentafluoroethyl group at position a or β; 104 · · · · · · · · · · · ··· ·· ··· ·· ·· ··· and either R ¹⁴ 'is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β position containing up to 10 carbon atoms, or a hydrogen atom in the α or β position; and T R ¹⁵ 'is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, which may be interrupted by one or more oxygen or sulfur atoms, one or more sulfoxide or sulfone groups or imino groups = NR * ⁵ (R ¹⁵ is hydrogen, methyl, ethyl, propyl, isopropyl), or hydrogen; or R ¹⁴ 'and R ¹⁵ ' taken together form a 14α, 15α-methylene or 14β, 15β-methylene group, which is optionally substituted with one or two halogen atoms; R ¹⁵ 'is a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the a or β position containing up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group, or a hydrogen atom in the a position or β; R * 'is a halogen atom in the α or β position, straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl in the α or β position containing up to 10 carbon atoms, a hydrogen atom or a hydroxyl group; wherein the dashed lines (----) in circles B, C and D denote at 10 5 • · · • ·· · · • · · ·· · · • • 99 • · · • · · • • • hi · • · · · • · • · • · · • • • · · · ··· ·· • · • · one or more double bonds fall and the wavy lines () indicate that the substituent may be in the α or β position. Pharmaceutical compositions comprising at least one compound according to any one of claims 1 to 25 together with a pharmaceutically acceptable carrier.