DE19954105A1 - Treatment of estrogen deficiency-associated conditions, e.g. menopausal syndrome, osteoporosis, infertility or prostatic hypertrophy, using new or known gonatrienes having tissue-selective estrogenic activity - Google Patents

Abstract

The use of 19-nor-steroids (1,3,5(10)-gonatrienes) (I) is claimed for the treatment of diseases and conditions associated with estrogen deficiency in females or males. The use of 19-nor-steroids of formula (I) is claimed for the treatment of diseases and conditions associated with estrogen deficiency in females or males: R1 = halo, R18, or OR18; R18 = H, optionally unsaturated 1-6C hydrocarbyl or CF3; R2 = R18, OR18 or OSO2R19; R19 = NR20R21, 4-6C polymethyleneimino or morpholino; R20, R21 = H, 1-5C alkyl or COR22; R22 = 1-12C hydrocarbyl (optionally containing 1-3 double and/or triple bonds), 3-7C cycloalkyl, aryl or a combination of these units; R3 = OR'18 OSO2R19 or OCOR22; R'18 = as R18 or aryl, heteroaryl or aralkyl; R6, R7 = H, halo, OR18, OSO2R19, R22, optionally unsaturated partially or completely halogenated 1-10C alkyl or (all optionally substituted) aryl, heteroaryl or aralkyl; R8, R9 = H, optionally unsaturated partially or completely halogenated 1-10C alkyl, XR18, halo, CN or SCN; X = O or S; R11 = H, halo, OR18, OSO2R19, R22, XR18, ONO2, optionally unsaturated partially or completely halogenated 1-10C alkyl or (all optionally substituted) aryl, heteroaryl or aralkyl; and R'11 = H; or R11+ R'11 = CH 2; R14 = H, 1-3C alkyl, 2-3C alkenyl or 2-3C alkynyl; and R15 = H; or R14 + R15 = optionally mono- or dihalogenated =CH2; R'15, R16 = H, halo, OR18, OSO2R19 or R22; R17/R'17 = H/halo; H/OSO2R19; R18/COR22; R18/OCOR22; OR18/R18; or OR18/OCOR22; or R17 + R'17 = CR23R24 or O; and R23, R24 = H or halo. (I) optionally contains one or more double bond(s) in the 6(7), 7(8), 9(11), 11(12), 14(15) and/or 15(16) position(s). Independent claims are included for: (A) the use of a gonatriene partial structure of formula (II) or (II') as a component of the overall structure of compounds showing dissociation between their estrogenic activity on bones and that on the uterus; and (B) as new compounds, with the exception of (I) where: (i) (i) the 13-H has beta -configuration and the following substituents are present (where unspecified substituents are H and double bonds are present only if specifically mentioned): (a) 3-isopropoxycarbonyl and 17-oxo; (b) 3-OAc and 17-oxo, 17 alpha -OH, 17 beta -OH, 17 alpha -OAc or 17 beta -OAc; (c) 3-OH and 17-oxo, 17 alpha -OH, 17 beta -OH, 17 alpha -OVal, 17 beta -OVal, 17 alpha -OAc or 17 beta -OAc; (d) 3-OMe and 17 beta -OH (optionally together with 9 alpha -OH, 9 beta -OH, 9 alpha -OMe or 9 OMICRON Me), 17-oxo (optionally together with a combination of 15-OMe/H plus 9(11) and 15(16) double bonds), 17 beta -Ac (optionally together with 16 alpha -OH, 16 beta -OH or 8(9) and 14(15) double bonds) or 17 alpha -Ac together with 16 alpha -OH or 16 beta -OH; (e) 3-O-n-Bu and 17-oxo, 17 alpha -OH, 17 beta -OH or 17-Ac together with a 16(17) double bond; or (f) 3-Val (Val = valerate) and 17 alpha -Val, 17 beta -Val, 17 alpha -OH or 17 beta -OH; or (ii) the 13-H has alpha -configuration and the following substituents are present: (a) 3-OAc and 17-oxo; (b) 3-OH and 17-oxo; (c) 3-OMe and 17-oxo (optionally together with a 9(11) double bond or with a combination of 15-OMe/H plus 9(11) and 15(16) double bonds), 17 alpha -OH, 17-p-chlorobenzoate, 17 beta -OH, 17 beta -OAc, 17 alpha -OAc or 17 alpha -OH/17 beta -Me together with 16 alpha -OH; or (d) 3-O-n-Bu and 17-oxo, 17- alpha -OH or 17 beta -OH.

Description

Field of the invention

The present invention relates to new compounds as pharmaceutical Active substances that have a higher affinity for estrogen receptor preparations in vitro Rat prostate as on estrogen receptor preparations from rat uterus and in vivo one preferential effect on the bone compared to the uterus and / or pronounced effect with regard to stimulating the expression of 5HT2a receptor and transporter, their manufacture, their therapeutic application and pharmaceutical Dosage forms that contain the new compounds.

The chemical compounds are novel steroidal tissue-selective Estrogens.

Background of the Invention

Established estrogen therapies for the treatment of hormone deficiency-related complaints and the protective effects of estrogens on bones, brain, vessels and others Organ systems.

The Efficiency of Estrogens in the Treatment of Symptoms Related to Hormone Deficiency such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful use of estrogen therapies to prevent Loss of bone mass in peri- and postmenopausal women is well documented and general accepted (Grady et al. 1992, Ann Intern Med 117: 1016-1037). It is also well documented that estrogen replacement therapy in postmenopausal women or in women with other associated ovarian dysfunction, the risk of cardiovascular disease compared to not estrogen-treated women reduced (Grady et al., loc. cit.).

Recent studies have also shown that estrogens have a protective effect neurodegenerative diseases such as B. Alzheimer's disease (Henderson 1997, Neurology 48 (Suppl 7): S27-S35; Birge 1997, Neurology 48 (Suppl 7): S36-S41), a protective effects on brain functions such as memory and learning ability (McEwen et al. 1997, Neurology 48 (Suppl 7): S8-S15; Sherwin 1997, Neurology 48 (Suppl 7): S21-S26), as well as against mood swings caused by hormone deficiency (semi-empire 1997, Neurology 48 (Suppl 7): S16-S20).

Furthermore, estrogen replacement therapy has proven effective in reducing the incidence of colon rectal cancer (Calle EF et al., 1995, J Natl Cancer Inst 87: 517-523).

In conventional estrogen or hormone replacement therapy (Hormone Replacement Therapy = HRT) natural estrogens, such as estradiol and conjugated estrogens from horse urine used alone or in combination with a progestogen. Instead of natural Estrogens can also be derivatives obtained by esterification, such as. B. the 17β-estradiol valerat.

Because of the stimulating effect of the estrogens used on the endometrium, which too increases the risk of endometrial cancer (Harlap S 1992, Am J Obstet Gynecol 166: 1986-1992), estrogen / progestogen Combination preparations used. The progestogen component in the estrogen / progestogen Combination avoids endometrial hypertrophy, but with gestagen containing combination also linked the occurrence of unwanted intermenstrual bleeding.

A newer alternative to the estrogen / progestogen combination preparations are selective Estrogens. So far, selective estrogens are understood to mean those compounds which are estrogen-like on the brain, bones and vascular system, due to their antiuterotrophic antiestrogenic) partial effect, but not proliferative on the endometrium.

A class of substances that partially share the desired profile of a selective estrogen the so-called "Selective Estrogen Receptor Modulators" (SERM) (R.F. Kauffman, H.U. Bryant 1995, DNAP 8 (9): 531-539). It is about Partial agonists of the estrogen receptor subtype "ERα". This type of substance is however ineffective with regard to the treatment of acute postmenopausal complaints, such as e.g. B. Hot flashes. This is an example of a SERM recently for the indication Introduced raloxifene called osteoporosis.

Estrogen receptor beta (ERβ)

Recently, the estrogen receptor-β (ERß) became the second subtype of the estrogen receptor discovered (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53; Tremblay et al. (1997) Molecular Endocrinology 11: 353- 365). The expression pattern of ERβ differs from that of ERα (Kuiper et al. (1996) Endocrinology 138: 863-870). So ERβ outweighs ERα in the Rat prostate, while ERα predominates over ERβ in rat uterus. Were in the brain Areas identified in which only one of the two ER subtypes is expressed (Shugrue et al. (1996), Steroids 61: 678-681; Li et al. (1997), Neuroendocrinology 66: 63-67). ERβ is u. a. expressed in areas of importance for cognitive processes and "mood" is assigned (Shugrue et al. 1997, J Comparative Neurology 388: 507-525).

Molecular targets for ERβ in these brain areas could be the 5HT2a receptor and the Serotonin transporters (G. Fink & B.E.H. Sumner 1996 Nature 383: 306; B.E.H. Sumner et al. 1999 Molecular Brain Research, in press). The neurotransmitter serotonin (5- Hydroxytryptamine) is involved in the regulation of a variety of processes in the Menopause can be affected. Especially the effects of menopause on Mood and cognition are associated with the serotonergic system. Estrogen replacement therapy has been shown to be effective in treating this estrogen deficiency related symptoms, possibly by modulation of serotonin receptor and transporter expression.

Other organ systems with a comparatively high ERβ expression include the bone (Onoe Y et al., 1997, Endocrinology 138: 4509-4512), the vascular system (Register TC, Adams MR 1998, J Steroid Molec Biol 64: 187-191), the urogenital tract (Kuiper GJM et al. 1997, Endocrinology 138: 863-870), the gastrointestinal tract (Campbell-Thompson 1997, BBRC 240: 478-483) and the Testis (Mosselmann S et al. 1996 Febs Lett 392 49-53) including spermatids (Shugrue et al. 1998, Steroids 63: 498-504). The Tissue distribution suggests that estrogens regulate organ functions via ERβ. That ERβ is functional in this regard, also results from studies on ERα- (ERKO) or ERβ- (βERKO) knockout mice: ovariectomy causes loss of bone mass in ERKO mice that can be reversed by estrogen substitution (Kimbro et al. 1998, Abstract OR7-4, Endocrine Society Meeting New Orleans). Likewise inhibits estradiol in Blood vessels of female ERKO mice the vascular media and smooth muscle cell proliferation (Iafrati MD et al. 1997, Nature Medicine 3: 545-548). These protective effects of Estradiol in the ERKO mouse is presumably via ERβ.

Observations on βERKO mice provide an indication of a function of ERβ in Prostate and bladder: in older male mice, symptoms of prostate and Bladder hyperplasia (Krege JH et al. 1998, Proc Natl Acad Sci 95: 15677-15682). In addition, female (Lubahn DB et al. 1993, Proc Natl Acad Sci 90: 11162-11166) and male ERKO mice (Hess RA et al. 1997, Nature 390: 509-512) and female βERKO mice (Krege JH, 1998) on fertility disorders. This will make the important one Function of estrogens in maintaining testis and ovary function as well Fertility proven.

A selective estrogen effect on certain target organs could be due to the different tissue or organ distribution distribution of the two subtypes of the ER can be achieved by subtype-specific ligands. Substances with a preference for ERβ compared to ERα in the in vitro receptor binding test, Kuiper et al. described (Kuiper et al. (1996) Endocrinology 138: 863-870). A selective effect of subtype-specific ligands of the estrogen receptor to estrogen sensitive parameters in vivo has not been shown yet.

The object of the present invention is therefore to provide compounds which are in vitro a dissociation regarding binding to estrogen receptor preparations from rat prostate and rat uterus and the in vivo dissociation for bone compared to Have uterine effects. The compounds are said to have a higher affinity in vitro Estrogen Receptor Preparations from Rat Prostate as on Estrogen Receptor Preparations from Rat uterus and in vivo a higher potency for protection against hormone deficiency loss of bone mass compared to the uterine stimulating effect of the uterus and / or pronounced effect in stimulating the expression of 5HT2a receptor and have transporters.

In a broader sense, the present invention is intended to provide a structure-activity relationship Be provided that allows access to connections that do the above formulated pharmacological profile, better estrogenic effect on the bone than on the uterus, have.

According to the invention, the above object is achieved by providing the gona-1,3,5 (10) -triene derivatives of the general formula I '

wherein
R ^{1 is} a halogen atom, a radical R ¹⁸ - or R ¹⁸ -O-, where R ^{18 is} a hydrogen atom or a straight or branched chain, saturated or unsaturated hydrocarbon radical having up to 6 carbon atoms, a trifluoromethyl group,
R ^{2 is} a halogen atom;
a radical R ¹⁸ - or R ¹⁸ -O-, where R ^{18 has} the meaning given under R ¹ ;
a group R ¹⁹ SO ₂ -O-, in which R ^{19 is} an R ²⁰ R ²¹ N group, where R ²⁰ and R ²¹ independently of one another are a hydrogen atom, a C ₁ -C ₅ alkyl radical, a group C (O) R ²² , in which R ^{22 represents} a straight-chain or branched-chain hydrocarbon radical having up to 12 carbon atoms, which can also contain up to three double and / or triple bonds, a C ₃ -C ₇ cycloalkyl radical, an aryl radical or a combination of these structural features, or, together with the N atom, represent a polymethyleneimino radical having 4 to 6 C atoms or a morpholino radical;
R ^{3 is} a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , where for R ^{18 can} additionally be an aryl, heteroaryl or aralkyl radical;
R ⁶ and R ⁷ independently of one another are a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given, a straight or branched chain, saturated or unsaturated, partially or completely halogenated alkyl group with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,
R ⁸ and R ⁹ independently of one another are a hydrogen atom, a straight or branched chain, saturated or unsaturated, optionally partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms, a group -XR ¹⁸ , in which X is an oxygen or sulfur atom and R ¹⁸ is has the meaning given under R ¹ , a halogen atom, a cyano or rhodano group,
R ^{11 is} a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , a group -XR ¹⁸ , in which X is an oxygen or sulfur atom and R ^{18 has} the meaning given under R ¹ , a nitrooxy group, a straight or branched chain, saturated or unsaturated, partially or fully halogenated hydrocarbon radical having up to 10 carbon atoms or a optionally substituted aryl, heteroaryl or aralkyl radical, and
R ^{11 'is} a hydrogen atom or
R ¹¹ and R ^{11 '} together represent a methylene group,
R ^{14 is} an α-hydrogen atom or a straight or branched chain alkyl, alkenyl or alkynyl group with up to 3 carbon atoms and
R ^{15 is} a hydrogen atom or
R ¹⁴ and R ¹⁵ together form a single or double halogenated methylene group;
R ^{15 '} and R ¹⁶ independently of one another are a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given;
R ¹⁷ and R ^{17 'represent} a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R ¹⁹ SO ₂ -O-; a group R ¹⁸ and a group -C (O) R ²² or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ -O- and a group -OC (O) R ²² , in all the above cases with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; or
R ¹⁷ and R ^{17 '} together are a group = CR ²³ R ²⁴ , wherein R ²³ and R ²⁴ independently represent a hydrogen atom and a halogen atom, or an oxygen atom;
mean and
in positions 6, 7; 7, 8; 9, 11; 11, 12; 14, 15 and 15, 16 one or more double bonds can be present
for the treatment of diseases and conditions caused by estrogen deficiency.

The possible substituents on the carbon atoms 6, 7, 11, 15, 16 and 17 and that The hydrogen atom on the carbon atom 13 can each be in the α or β position.

According to a variant of the invention, preference is given to using compounds of the general formula I 'in which
R ^{1 is} a hydrogen atom or a group R ¹⁸ -O-, where R ^{18 is} a hydrogen atom or a straight or branched chain, saturated or unsaturated hydrocarbon radical having up to 6 carbon atoms,
R ^{2 represents} a hydrogen or halogen atom or a hydroxy group,
R ^{3 is} a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , where for R ^{18 can} additionally be an aryl or aralkyl radical;
R ^{6 is} a hydrogen atom, a hydroxyl group, a group R ²² in the meaning given under R ² is an optionally substituted aryl, heteroaryl or aralkyl radical,
R ^{7 is} a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , a straight or branched chain, saturated or unsaturated, partially or completely halogenated alkyl group having up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,
R ⁸ and R ⁹ independently of one another are a hydrogen atom, a straight or branched chain, saturated or unsaturated, optionally partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms, a group -XR ¹⁸ , in which X is an oxygen or sulfur atom and R ¹⁸ is has the meaning given under R ¹ , a halogen atom, a cyano or rhodano group,
R ^{11 is} a hydrogen atom, a halogen atom, a group -R ²² with R ²² in the meaning given under R ² , a group -XR ¹⁸ , in which X is a sulfur atom and R ^{18 has} the meaning given under R ¹ , a straight or branched chain, saturated or unsaturated, partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms or an optionally substituted aryl or heteroaryl radical,
R ^{14 is} an α-hydrogen atom or a straight or branched chain alkynyl group with up to 3 carbon atoms and
R ^{15 is} a hydrogen atom or
R ¹⁴ and R ¹⁵ together are a methylene group;
R ^{15 '} and R ¹⁶ independently of one another are a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given;
R ¹⁷ and R ^{17 'represent} a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R ¹⁹ SO ₂ -O-; a group R ¹⁸ and a group -C (O) R ²² or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ -O- and a group -OC (O) R ²² , in all the above cases with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; such as
R ¹⁷ and R ^{17 '} together are a group = CR ²³ R ²⁴ , wherein R ²³ and R ²⁴ independently represent a hydrogen atom and a halogen atom, or an oxygen atom;
mean.

Another preferred variant of the present invention provides for the use of such compounds of the general formula I 'in which
R ^{1 is} a hydrogen atom, a hydroxyl or straight or branched chain C ₁ -C ₆ alkyl group,
R ^{2 represents} a hydrogen or fluorine atom or a hydroxy group,
R ^{3 is} a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , where for R ^{18 can} additionally be an aryl or aralkyl radical;
R ^{6 represents} a hydrogen atom or a hydroxy group,
R ^{7 is} a hydrogen atom, a fluorine or chlorine atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case under R ¹ or R ² indicated meaning, a straight or branched chain, saturated or unsaturated, partially or completely halogenated alkyl group with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,
R ⁸ and R ⁹ independently of one another are a hydrogen atom, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms, a group -XR ¹⁸ , in which X is an oxygen atom and R ^{18 is} the same as R ¹ has the meaning given, a fluorine or chlorine atom or a cyano group,
R ^{11 is} a hydrogen atom, a fluorine or chlorine atom, a saturated, straight or branched chain C ₁ -C ₆ alkyl group, a group -XR ¹⁸ , in which X is a sulfur atom and R ^{18 is} a saturated, straight or branched chain C ₁ - C ₆ - alkyl group, a chloromethyl or chloroethyl group or an optionally substituted aryl or heteroaryl radical,
R ^{14 is} an α-hydrogen atom and
R ^{15 is} a hydrogen atom or
R ¹⁴ and R ¹⁵ together are a methylene group;
R ^{15 '} and R ¹⁶ independently of one another are a hydrogen atom, a fluorine or chlorine atom or a group R ¹⁸ -O or -R ²² , with R ¹⁸ and R ²² each in the meaning given under R ¹ and R ² ;
R ¹⁷ and R ^{17 'represent} a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R ¹⁹ SO ₂ -O-; a group R ¹⁸ and a group -C (O) R ²² or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ -O- and a group -OC (O) R ²² , in all the above cases with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; such as
R ¹⁷ and R ^{17 '} together are a group = CR ²³ R ²⁴ , wherein R ²³ and R ²⁴ independently represent a hydrogen atom and a halogen atom, or an oxygen atom;
mean.

According to a further variant, gona-1,3,5 (10) -triene derivatives of the general formula I 'are used in which
R ⁶ , R ⁸ , R ⁹ , R ¹⁴ , R ¹⁵ , R ^{15 '} and R ¹⁶ each represent a hydrogen atom and all other substituents have the meanings given in claim 1.

If the gonatriene derivatives of the general formula I 'contain further double bonds in the B-, C- and / or D-ring, then is preferably in position 7, 8 or in position 11, 12 are a double bond or are two double bonds in positions 6, 7 and 8, 9 available.

Another variant of the invention are gonatriene derivatives of the general formula I ',
wherein
R ¹⁷ and R ^{17 'are} a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ - and a group -OC (O) R ²² , with R ¹⁸ and R ²² each in the meaning given under R ¹ and R ² ;
is.

Of the latter, those gonatriene derivatives are preferred in which
R ¹⁷ and R ^{17 'is} a hydroxy group and a hydrogen atom, a C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl group
and particularly preferably those in which
R ¹⁷ and R ^{17 'are} a hydroxyl group and a hydrogen atom, a methyl, ethynyl or prop-1-ynyl group
is.

Further design options of the present invention result from the Subclaims 2 to 15.

In addition to the above use of the compounds of the general formula I ', the invention also relates to the compounds of the general formula I themselves. These are the compounds of the general formula I' with the exception of the compounds which are at the carbon atoms 13, 3, 17, 9, 15 and 16 have the following combinations of substituents and double bonds between the specified carbon atoms:

This group of the compounds mentioned in the table is already known; a selective one estrogenic effect and the use of the known compounds in the sense of the present However, the invention has not yet been described.

The already known gonatrienes are mostly as intermediates, as estrogens in the described conventional sense or for use in analytical methods.

In the compounds of general formulas I and I 'and in the following Substructures II and II 'described can always be a fluorine, chlorine, Bromine or iodine atom; a fluorine atom is preferred in each case. For the 11β position is in particular to name a chlorine atom as a substituent.

In particular, the hydrocarbon residues are partially or completely can be halogenated to fluorinated residues.

The alkoxy groups in the compounds of general formulas I and I 'and in the Substructures II and II 'described below can each have 1 to 6 carbon atoms contain, with methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups preferred are.

Representatives of the alkylthio groups include methylthio, ethylthio and Trifluoromethylthio group called.

In the context of the present invention, an aryl radical is a phenyl, 1- or 2-naphthyl; the phenyl radical is preferred.

If not expressly mentioned, aryl always includes a heteroaryl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.

Examples of substituents for an aryl or heteroaryl radical are a methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine) , Hydroxy, amino, mono (C _1-8 alkyl) - or di (C _1-8 alkyl) amino, where both alkyl groups are identical or different, di (aralkyl) amino, where both aralkyl groups are identical or different , mentioned.

As a representative for straight or branched chain hydrocarbon residues with 1 to max. 12 Carbon atoms are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl, undecyl and dodecyl call; Methyl, ethyl, propyl and isopropyl are preferred.

A C ₃ -C ₇ cycloalkyl group is a cyclopropyl, butyl, pentyl, hexyl or heptyl group.

An aralkyl radical is a radical which contains up to 14, preferably 6 to 10, C atoms in the ring and 1 to 8, preferably 1 to 4, C atoms in the alkyl chain. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl and pyridylpropyl. The rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ alkyl, -NO ₂ , -N ₃ , -CN, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ Acyl, C ₁ -C ₂₀ acyloxy groups.

The alkyl groups can be partially or completely fluorinated or substituted by 1-5 halogen atoms, hydroxyl groups or C ₁ -C ₄ alkoxy groups.

A C ₂ -C ₃ alkenyl or C ₂ -C ₃ alkynyl radical means a vinyl, or allyl or an ethynyl, 1- or 2-propynyl radical.

Examples of perfluorinated alkyl groups are trifluoromethyl, pentafluoroethyl and Called nonafluorobutyl. Representatives of the partially fluorinated alkyl groups are, for example 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 6,6,6,5,5,4,4,3,3-nonafluorohexyl etc.

For the halogen-substituted 14,15-methylene group, monochloromethylene, Monofluoromethylene or difluoromethylene are available.

Further variants of the invention see one or more, optionally conjugated, Double bonds in rings B, C and D of the estratria framework, one or several double bonds in positions 6, 7; 7, 8; 9, 11; 11, 12; 14, 15 and 15, 16.

A double bond in position 7, 8 or in position 11, 12 or is preferred two double bonds in positions 6, 7 and 8, 9 (i.e. together with the aromatic A-ring is formed the naphthalene system).

One or both of the hydroxyl groups on the C atoms 3 and 17 can be esterified with an aliphatic, straight or branched chain, saturated or unsaturated C ₁ -C ₁₄ mono- or polycarboxylic acid or an aromatic carboxylic acid or with an α- or β-amino acid .

Examples of suitable carboxylic acids for esterification are:
Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, elaidic acid. Esterification with acetic acid, valeric acid or pivalic acid is preferred.
Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic 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-toluic acid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, isonicotinic acid.
Esterification with benzoic acid is preferred.
Suitable amino acids are those representatives of this class of substances which are well known to the person skilled in the art, for example alanine, β-alanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline etc.
Esterification with β-alanine is preferred.

According to the present invention, the following compounds are preferred:
11β-fluoro-gona-1,3,5 (10) -triene-3,17-diol
11β-chloro-gona-1,3,5 (10) -triene-3,17-diol
11β-methyl-gona-1,3,5 (10) -triene-3,17-diol
11β-ethyl-gona-1,3,5 (10) -triene-3,17-diol
11β-phenyl-gona-1,3,5 (10) -triene-3,17-diol
7α-fluoro-gona-1,3,5 (10) -triene-3,17-diol
7α-methyl-gona-1,3,5 (10) -triene-3,17β-diol
7α-phenyl-gona-1,3,5 (10) -triene-3,17β-diol
7α-methyl-gona-1,3,5 (10) -triene-3,17-diol
7β-fluoro-gona-1,3,5 (10) -triene-3,17-diol
7β-methyl-gona-1,3,5 (10) -triene-3,17β-diol
7β-phenyl-gona-1,3,5 (10) -triene-3,17β-diol
7β-methyl-gona-1,3,5 (10) -triene-3,17-diol
2-fluoro-gona-1,3,5 (10) -triene-3,17β-diol
17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11-methylene-17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11β-methyl-17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11β, 17α-dimethyl-gona-1,3,5 (10) -triene-3,17β-diol
11β, 17β-dimethyl-gona-1,3,5 (10) -triene-3,17α-diol
18-Nor-estriol
11β-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
11β-chloro-gona-1,3,5 (10) -triene-1,3,17-triol
11β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β-ethyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
7α-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
7β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
2-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
17α- (1-propynyl) gona-1,3,5 (10) -triene-1,3,17-triol
11-methylene-17α- (1-propynyl) gona-1,3,5 (10) -triene-1,3,17-triol
11β-methyl-17α- (1-propynyl) gona-1,3,5 (10) -triene-1,3,17-triol
11β, 17α-dimethyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β, 17β-dimethyl-gona-1,3,5 (10) -triene-1,3,17-triol.

Within the scope of the use aspect of the invention, in addition to the above enumerated new compounds also the use of the already known Compound 18-nor-17β-estradiol preferred.

Another aspect of the present invention relates to the use of the structural part of the formula II (Gona-1,3,5 (10) structural part)

as part of the overall structure of compounds that dissociate in favor of theirs have estrogenic effects on the bone compared to the uterus.

In addition to the aromatic A ring, the B, C and / or D ring in positions 6, 7; 7, 8; 9, 11; 11, 12; 14, 15 and 15, 16 one or more, optionally conjugated, Double bonds are present.

The possible substituents on the carbon atoms 6, 7, 11, 15, 16 and 17 and that The hydrogen atom on the carbon atom 13 can each be in the α or β position.

The present invention preferably relates to structural parts of the general formula II '

wherein the radicals R ¹ to R ^{17 have} the meanings given in the general formula I.

Likewise, these structural parts can have one or more in addition to the aromatic A ring several, optionally conjugated, double bonds in the B, C and / or D ring exhibit.

The possible substituents on the carbon atoms 6, 7, 11, 15, 16 and 17 can again in the α or β position and the hydrogen atom on the carbon atom 13 are preferably in the β position.

The esters of 18-nor steroids according to the invention have advantages as prodrugs the unesterified active ingredients with regard to their mode of application, their mode of action, Effectiveness and duration of action.

Pharmacokinetic and pharmacodynamic advantages also have the advantages according to the invention 18-nor steroid sulfamates. Effects in this regard have already been observed with sulfamates described, which are derived from estrogens with a 13-methyl group (J. Steroid Biochem. Molec. Biol, 55: 395-403 (1995); Exp. Opinion invest. Drugs 7, 575-589 (1998)).

In the present patent application, steroids to which the gonatria - (= 18-nor estratrien-) framework is based, for the treatment of estrogen receptor β-mediated Diseases and conditions described as selective estrogens that dissociate in vitro regarding binding to estrogen receptor preparations of rat prostate and rat uterus and in vivo dissociation for bone versus uterine effects have: over a wide dose range, the substances have a bone protective effect without the Stimulate uterus. Their liver effects are low in the same dose range.

The substances also have an estrogen-like effect on the vascular system and Brain functions. Substances with higher binding to the rat prostate compared to the rat uterus estrogen receptor are more potent in increasing the expression of Serotonin receptor and transporter, compared to their positive effect on LH Distribution. Therefore, processes that regulate the neurotransmitter serotonin is involved, favorably influenced and the compounds of the invention exercise in particular have a positive influence on mood and cognition.

They can be used as estrogens in the sense described in WO 97/45125 for Manufacture of drugs to influence the levels of serotonin and Serotonin mRNA can be used in humans.

It has been found that the nor steroids according to the invention are used as selective estrogens Treatment of various conditions and diseases caused by a higher content Estrogen receptor β as estrogen receptor α in the corresponding target tissue or organ are marked, are suitable.

The invention also relates to pharmaceutical preparations which contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids thereof) and the use of the compounds of the general formula I 'for the manufacture of medicaments, in particular for the following Indications.

The compounds can be used for the following, both after oral and parenteral administration Indications are used.

The novel selective estrogens described in the present patent can be used as Single component in pharmaceutical preparations or in combination in particular with Antiestrogens or progestogens can be used. The combination is particularly preferred of selective estrogens with ERα-selective antiestrogens, or with antiestrogens that are peripherally selective, d. H. that don't cross the blood brain barrier.

The substances and the pharmaceuticals containing them are particularly suitable for Treatment of peri- and postmenopausal complaints, especially hot flashes, Sleep disorders, irritability, mood swings, incontinence, vaginal atrophy, Mental disorders due to hormone deficiency. Likewise, the substances for that Hormone replacement and the therapy of hormone deficiency-related complaints suitable for surgical, medicinal or other ovarian dysfunction. For this prevention of bone mass loss in postmenopausal women in hysterectomized women or in women with LHRH agonists or antagonists were treated.

The compounds are also used to relieve symptoms of andropause and menopause, d. H. for male and female hormone replacement therapy (HRT), both for Prevention as well as treatment, continue to treat those with dysmenorrhea associated complaints as well as for the treatment of acne.

The substances are also used for prophylaxis against hormone deficiency Loss of bone mass and osteoporosis, to prevent cardiovascular diseases, especially vascular diseases such as atherosclerosis, to inhibit the proliferation of the arterial smooth muscle cells, for the treatment of primary pulmonary hypertension and for the prevention of hormone deficiency-related neurodegenerative diseases, such as Alzheimer's disease and hormone deficiency-related impairment of memory and learning ability, applicable.

Furthermore, the substances for the treatment of inflammatory and diseases of the Immune system, especially autoimmune diseases, such as B. rheumatoid arthritis, applicable.

The compounds can also be used to treat male fertility disorders and prostate diseases find use.

The compounds can also be used in combination with the natural vitamin D3 or with Calcitriol analogues for bone building or as supportive therapy for therapies, which cause loss of bone mass (e.g. therapy with Glucocorticoids, chemotherapy) can be used.

Finally, the compounds of general formula I 'in connection with Progesterone receptor antagonists are used, especially for Use in hormone replacement therapy and for the treatment of gynecological disorders.

A therapeutic product containing an estrogen and a pure anti-estrogen for simultaneous, sequential or separate use for selective estrogen therapy Perimenopausal or postmenopausal conditions are already in EP-A 0 346 014 described.

The amount to be administered of a compound of general formula I 'varies within a wide range and can cover any effective amount. Dependent on of the condition to be treated and the mode of administration, the amount of administered compound 0.01 µg / kg-10 mg / kg body weight, preferably 0.04 µg / kg- 1 mg / kg body weight, per day.

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

According to the invention, a dose unit contains 1.6 μg to 200 mg of one or more Compounds of the general formula I.

The compounds according to the invention and the acid addition salts are for the preparation pharmaceutical compositions and preparations suitable. The pharmaceutical Compositions or drugs contain one or as the active ingredient several of the compounds according to the invention or their acid addition salts, optionally in a mixture with other pharmacologically or pharmaceutically effective substances. The pharmaceuticals are produced in a known manner, the known and customary pharmaceutical auxiliaries and other usual carriers and Diluents can be used.

Examples of suitable carriers and auxiliaries are those described in the following Literature recommended as auxiliary substances for pharmacy, cosmetics and related areas or are given: Ullman's Encyclopedia of Industrial Chemistry, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., H. v. Czetsch-Lindenwald, auxiliaries for pharmacy and neighboring areas; Pharm. Ind., Issue 2, 1961, page 72 u. ff .: Dr. H. P. Fiedler, Lexicon of excipients for pharmacy, Cosmetics and related areas, Cantor KG, Aulendorf in Württemberg 1971.

The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, administered subcutaneously or percutaneously. The connections can also be made in the tissue be implanted.

Capsules, pills, tablets, coated tablets, etc. can be used for oral administration. The In addition to the active ingredient, dosage units can include a pharmaceutically acceptable carrier, such as starch, sugar, sorbitol, gelatin, lubricant, silica, talc, etc., contain.

For parenteral administration, the active ingredients can be administered in a physiologically acceptable manner Diluent must be dissolved or suspended. Thinners are very common Oils with or without the addition of a solubilizer, a surfactant, one Suspending or emulsifying agent used. Examples of oils used are olive oil, Peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

The compounds can also be in the form of a depot injection or Use implant preparations that can be formulated so that a delayed active ingredient Release is enabled.

Implants can be used as inert materials, for example biodegradable polymers contain or synthetic silicones such as silicone rubber. The active ingredients can also be incorporated into a plaster for percutaneous application, for example will.

For the preparation of those loaded with active compounds of the general formula I ' Intravaginal (e.g. vaginal rings) or intrauterine systems (e.g. pessaries, spirals, IUSs, Various polymers such as, for example, are suitable for local administration Silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.

In order to achieve a better bioavailability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds with α-, β- or γ-cyclodextrin or derivatives thereof implemented (PCT / EP95 / 02656).

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

Methods Estrogen receptor binding studies

The binding affinity of the new selective estrogens was determined in competition experiments using 3H estradiol as a ligand on estrogen receptor preparations from Rat prostate and rat uterus tested. The preparation of the prostatacytosol and the Estrogen receptor test with the prostatacytosol was carried out as described by Testas et al. (1981), (Testas J. et al., 1981, Endocrinology 109: 1287-1289).

The preparation of rat uterine cytosol and the receptor test with the ER-containing one In principle, cytosols were carried out as described by Stack and Gorski, 1985 (Stack, Gorski 1985, Endocrinology 117, 2024-2032) with some modifications as with Führmann et al. (1995) (Führmann U. et al. 1995, Contraception 51: 45-52).

The substances described in the present patent have a higher binding affinity Estrogen receptor from rat prostate than to estrogen receptor from rat uterus. Doing so assumed that ERβ compared to ERα in the rat prostate, in rat uterus ERα outweighs ERβ. Table 1 shows that the ratio of binding to prostate and Uterine receptor qualitatively with the quotient of the relative binding affinity (RBA) human ERβ and ERα from rats (according to Kuiper et al. (1996), Endocrinology 138: 863-870) agrees (Table 1).

Table 2 shows the results for the compound to be used in the present invention
18-nor-17β-estradiol (compound A)
as well as for the compounds according to the invention
11β, 17α-dimethyl-gona-1,3,5 (10) -triene-3,17β-diol (compound B),
11-methylene-17α- (1-propynyl) -gona-1,3,5 (10) -triene-3,17β-diol (compound C),
17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol (compound D) as well
11β-methyl-17α- (1-propynyl) -gona-1,3,5 (10) -triene-3,17β-diol (compound E).

The compounds A, B, C, D and E show a higher binding affinity on Estrogen receptor from rat prostate as at estrogen receptor from rat uterus.

Furthermore, the predictivity of the "prostate ER versus uterine ER test system" with regard to tissue-selective effect confirmed by in vivo studies. Substances with preference for prostate ER are in vivo regarding bone and uterine effects dissociated in favor of the effect on the bone.

Bone examinations

3-month-old female rats are ovariectomized and immediately after surgery 28 Treated with the test compound once a day for days. The application takes place subcutaneously in Arachis oil / ethanol. The animals are sacrificed the day after the last application and tibia as well as the uterus. The uteri are weighed, fixed and for histological Investigations processed. The bone density is determined ex vivo prepared long bones using pQCT (quantitative computed tomography). The Measurements are taken at a distance of 4-6 mm from the condyle of the proximal tibia carried out.

The ovariectomy reduces the density of the trabecular bone in the measured range from approx. 400 mg Ca ²⁺ / cm ³ to approx. 300 mg Ca ²⁺ / cm ³ . The treatment with a compound of the general formula I according to the present invention prevents or inhibits the degradation of the bone density. The bone density on the proximal tibia was measured.

In vivo, the higher binding affinity to estrogen receptor from rat prostate is reflected to estrogen receptor from rat uterus in significantly lower amounts of the invention Compounds that cause a 50% bone protection compared to the Amounts that cause 50% uterine stimulation, based on the Loss of bone mass of 28 days in ovariectomized, untreated female rats after ovariectomy, in contrast to sham-exposed, intact animals.

The vascular effect of the estrogens according to the invention is shown in the ApoE knockout model. Mouse, as described by R. Elhage et al., 1997, determined (Elhage R. et al. 1997, Arteriosclerosis, Thrombosis, and Vascular Biology 17: 2679-2684).

To demonstrate the effect of estrogens on brain function, the oxytozine receptor mRNA expression is used as a surrogate parameter (Hrabovszky E et al. 1998, Endocrinology 1339: 2600-2604). Ovariectomized rats are treated with the test substance or vehicle for 7 days (application: subcutaneously or orally, 6 times a day). On day 7 after the first application, the animals are decapitated, the uterine weight is determined and the oxytocin receptor mRNA level is examined by means of in situ hybridization on suitable brain sections. The ED ₅₀ values with regard to stimulation of uterine growth and induction of the oxytocin receptor mRNA are determined.

Another possibility, the dissociated estrogen effect of the invention Detecting substances in vivo consists of adding the substances after a single application Rat effects on the expression of 5HT2a receptor and serotonin transporter protein and mRNA levels in ERβ-rich brain areas. Comparative to the effect on Serotonin receptor and transporter expression will have an effect on LH secretion measured. Substances with higher binding to the rat prostate compared to that Rat uterine estrogen receptors are more potent in increasing expression of Serotonin receptor and transporter, compared to their positive effect on LH Distribution. The density of the serotonin receptor and transporter is measured on brain sections using radioactive ligands, the corresponding mRNA using in situ hybridization certainly. The method is described in the literature: G. Fink & B. E. H. Sumner 1996 Nature 383: 306; B. E. H. Sumner et al. 1999 Molecular Brain Research, in press.

Consistent with their stronger attachment to the rat prostate compared to Rat uterus estrogen receptor carry substances A, B, C, D and E according to the invention to an increased expression of the serotonin receptor and transporter.

Preparation of the compounds according to the invention

There are two synthetic routes known from the literature for the production of gonatrienes (= 18-nor-estratrienes):

• 1. Synthesis according to Coombs and Pinhey: M. M. Coombs, C. W. Vose, J. C. S. Chem. Comm. 1974, 602; J.C. Chapman, J.T. Pinhey, Austr. J. Chem. 1974, 2421; and A. Kuhl, H. Karels, W. Kreiser, Helv. Chem. Acta 1999, 30;
• 2. Zeelen synthesis: M. J. von den Heuvel, C. W. von Bokhoven, H. P. de Jongh, F. J. Zeelen, Recl.Trav.Chim.Pays-Bas 107, 1988, 331.

Synthesis according to Zeelen

This synthetic route is suitable for the construction of 11β-substituted 18-nor steroids.

According to this method and subsequent further functionalizations at numerous positions on the steroid structure, gestagenic 18-nor-3-keto-Δ ⁴ derivatives with a diverse substitution pattern on the steroid can be obtained according to DE 195 35 851 Al.

Subsequent aromatization of the 18-nor-3-keto-Δ ⁴ derivatives enables compounds of the general formula I according to the invention to be prepared.

This synthesis route is particularly suitable for the production of such compounds, in which the 11-position is substituted. Via the 11-hydroxy or by oxidation therefrom accessible 11-keto group can be functionalized, e.g. B. by a Wittig Reaction, numerous other substituents by methods known to those skilled in the art build up.

This process is illustrated by Examples 10 and 11.

According to these examples, the aromatization is carried out with selenium dioxide.

Aromatization can also be carried out just as well with microbiological agents known to the skilled worker Procedures are accomplished.

A stem screening showed that the following microorganisms can carry out the reaction:
Bacillus lentus ATCC 13805
Corynebacterium simplex ATCC 6946
Nocardia corallina ATCC 14350
Nocardia globerula ATCC 9356.

The best results can be achieved with the Bacillus lentus ATCC 13805 strain. This Stamm was therefore used for the preparative implementation.

Examples 12 to 14 serve for illustration.

The order of the reaction steps for the introduction of functional groups on Steroid structure, for example the introduction of a side chain at carbon atom 17 nucleophilic addition, and the aromatization can also be interchanged.

Synthesis according to Coombs and Pinhey

This synthetic route is shown below using the example of the preparation of the unsubstituted 18-nor-17β-estradiol.

The opening of the D-ring due to anomalous Beckmann reaction can be approx. 40% Carry out yield, the total yield of the two subsequent stages is about 17% each. This synthetic route for the preparation of the compounds of the general Formula I is illustrated in Examples 1-9.

Possible substituents according to the general formula I can already be found in the final Form or in the form of a precursor already in the starting product, one already that desired end product correspondingly substituted estrone.

Thus, substituents on the carbon atom 7 are known to the person skilled in the art, for example in the field of antiestrogenic active substances, by copper-catalyzed 1,6 addition of the substituent, or a reactive precursor thereof, to a 3-keto-Δ ^4.6 - Connection, introduced and optionally further developed (EP 0 138 504 B, WO 98/07740, WO 99/33855).

The introduction of a substituent or reactive precursor on carbon atom 7 is also possible by nucleophilic addition of the substituent or precursor to a 6-vinyl sulfone (DE 42 18 743 A1).

In the latter two cases, different proportions, depending on the Reaction partners and the chosen reaction conditions, 7α- and 7β-substituted Obtain compounds that separate, for example, by chromatographic methods to let.

17-substituents are, likewise by known methods, by nucleophilic addition the desired substituent or a reactive precursor thereof, and if necessary, further built up.

However, substituents according to the general formula I can also be used at the 18-nor- Steroids are introduced. This can be particularly the case with multiple substitution of the desired end connection may be useful or necessary.

For example, an 11β-hydroxy group according to the Vorbrüggen et al. described Process converted into an 11β-fluorine atom.

Functionalizations on carbon atom 2 are, for example, by electrophilic Substitution after prior deprotonation of position 2 of the corresponding 3- (2- Tetrahydropyranyl) - or 3-methyl ether with a lithium base (e.g. methyl lithium, Butyllithium) possible. For example, a fluorine atom can be converted by reacting the C-H activated substrate with a fluorination reagent such as N-fluoromethanesulfonimide (WO 94/24098).

The introduction of variable substituents in the rings B, C and D of the gonatrial framework can be done according to the same chemical teaching with which the corresponding Estratriene derivatives are produced (see among others: Steroids, L.F. Fieser, M. Fieser, Verlag Chemie, Weinheim / Bergstr., 1961; Organic Reactions in Steroid Chemistry, J. Fried, J.A. Edwards, Van Nostrand Reinhold Company, New York, Cincinnati, Toronto, London, Melbourne, 1972; Medicinal Chemistry of Steroids, F.J. Zeelen, Elsevier, Amsterdam, Oxford, New York, Tokyo, 1990). This applies, for example, to the introduction of Substituents such as hydroxyl or alkyloxy groups, alkyl, alkenyl or alkynyl groups or halogen, especially fluorine.

The 18-nor steroid carboxylic acid esters according to the invention are analogous to the esters manufactured, which are derived from natural steroid active ingredients (see e.g. Pharmaceutical Active ingredients, syntheses, patents, applications; A. Kleemann, J. Engel, Georg Thieme Verlag Stuttgart 1978. Medicines, progress from 1972 to 1985; A. Kleemann, E. Lindner, J. Engel (Ed.), VCH 1987, pp. 773-814).

The 18-nor steroid sulfamates according to the invention are known from the corresponding hydroxy steroids by esterification with sulfamoyl chlorides in the presence a base (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)). Subsequent acylation of the sulfamide group leads to the 18-nor according to the invention steroidal (N-acyl) sulfamates, for which already in the 13-methyl series pharmacokinetic Advantages have been demonstrated (cf. DE 195 40 233 A1).

The regioselective esterification of polyhydroxylated steroids with N-substituted and N- Unsubstituted sulfamoyl chlorides take place after partial protection of those Hydroxyl groups that should remain unesterified. As protective groups with suitable for this selective reactivity have proven to be silyl ethers, since these are under the conditions of Sulfamate formation are stable and the sulfamate group remains intact when the silyl ether is used Regeneration of the remaining hydroxyl group still contained in the molecule can be split off (Steroids 61, 710-717 (1996)).

The preparation of the sulfamates according to the invention with one or more additional ones Hydroxyl groups in the molecule are also possible by using suitable hydroxy Steroid ketones runs out. First, depending on the objective, one or more existing ones Hydroxyl groups subjected to sulfamoylation. Then the sulfamate groups optionally with a desired acyl chloride in the presence of a base relevant (N-acyl) sulfamates are transferred. The oxosulfamates now present or oxo (N-acyl) sulfamates are reduced by reduction into the corresponding Hydroxysulfamate or hydroxy- (N-acyl) sulfamate converted (Steroids 61, 710-717 (1996)).

Suitable reducing agents are sodium borohydride and the borane dimethyl sulfide Complex in question.

The compounds of general formula I according to the invention are as in the Examples described produced. Using an analogous procedure homologous reagents to the reagents described in the examples can be receive further compounds of general formula I.

Etherification and / or esterification of free hydroxyl groups takes place according to the person skilled in the art common methods.

The compounds of the invention can on the carbon atoms 6, 7, 11, 13, 15, 16 and 17 exist as α, β stereoisomers. When making the connections according to described processes the compounds fall mostly as mixtures of the corresponding α, β isomers. The mixtures can be, for example, by chromatographic Separate procedures.

The following examples serve to explain the invention in more detail.

Examples example 1 11β-fluoro-gona-1,3,5 (10) -triene-3,17-diol 1.1 11β-fluoro-1,3,5 (10) -estratrien-3-ol-17-one

43.55 g of 11β-fluoro-4-estren-17-ol-3-one (150 mmol, Tetrahedron Letters 1995, 2611), adds 50 g of copper (II) bromide and stirs Room temperature. After 16 hours, another copper II is added within 6 hours bromide in three portions (25 g, 12 g, 6 g) and stir in for a further 6 hours Room temperature. The reaction mixture is cooled in an ice bath with 500 ml of water added and extracted with ethyl acetate. Little is added to the organic phase Methanol, wash them out with saturated bicarbonate and saline and dry with sodium sulfate. After concentration, the substance crystallizes out, yield 30.8 g (71% of theory Th.), Mp 233-234 ° C.

1.2 11β-fluoro-3-mesyloxy-estra-1,3,5 (10) -trien-17-one

28.84 g of 11β-fluoro-1,3,5 (10) -estratrien-3-ol-17-one (100 mmol) are dissolved in 200 ml of pyridine, cooled in an ice bath, 20 ml of methanesulfonic acid chloride are added dropwise and the mixture is stirred 2 Hours at room temperature. Then it is stirred into 2.5 liters of ice water and, after stirring for 2 hours, filtered off. The solid residue is dissolved in dichloromethane, the solution is shaken with 1N hydrochloric acid, water and saturated sodium chloride solution and dried with Na ₂ SO ₄ . The residue after stripping off the solvent is 37 g, after crystallization from methanol, 33.6 g of 11β-fluoro-3-mesyloxy-estra-1,3,5 (10) -trien-17-one (91% of theory) are obtained. Th.), Fp.

1.3 11β-fluoro-3-mesyloxy-17-oximinoestra-1,3,5 (10) -triene

This substance is suspended in 500 ml of ethanol, with 20 g of hydroxylamine hydrochloride and 40 g of anhydrous sodium acetate are added and the mixture is heated under reflux for 2.5 hours. To cooling is diluted with ethyl acetate, with water, saturated bicarbonate solution and Washed saline and dried the organic phase with sodium sulfate and evaporated. The residue crystallized from ethanol, yield 31.8 g (91% of theory), mp.

1.4 11β-fluoro-3-mesyloxy-13,17-seco-estra-1,3,5 (10), 13 (18) -tetraen-17-nitrile

2.3 g of 11β-fluoro-3-mesyloxy-17-oximidoestra-1,3,5 (10) -triene (6.3 mmol) are dissolved in 10 ml Dimethyl sulfoxide and 10 ml of carbon tetrachloride, gives 3.9 g of dicyclohexylcarbodiimide and cools down in the ice bath. Then 0.33 ml of trifluoroacetic acid are added dropwise and for 3 hours stirred, the temperature rising to + 9 ° C. Now the reaction mixture is in Given ice water, shaken three times with dichloromethane, the organic phase with Washed water, saturated bicarbonate solution and brine with sodium sulfate dried and evaporated. The residue of 4.4 g is on silica gel with a hexane Chromatographed ethyl acetate mixture, yield 0.79 g (36% of theory) as a colorless oil.

1.5 13 (18) -epoxy-11β-fluoro-3-mesyloxy-13,17-seco-estra-1,3,5 (10) -triene-17-nitrile

256 mg of seconitrile (0.7 mmol) are dissolved in 10 ml of dichloromethane, 500 mg of m- Chloroperbenzoic acid (70%) in two portions and stir for 20 hours Room temperature. The mixture is made with 10% potassium iodide solution, 1 molar Sodium dithionite, saturated bicarbonate solution and saline, washed with Dried sodium sulfate and evaporated. The residue (280 mg) is on silica gel Chromatographed hexane and ethyl acetate, yield 131 mg (49% of theory) as a colorless oil (Mixture of isomers).

1.6 11β-fluoro-3-mesyloxy-gona-1,3,5 (10) -trien-17-one

571 mg of the above epoxide (1.5 mmol) are dissolved in 200 ml of toluene, 1.3 ml are added Boron trifluoride etherate and heated at 110 ° C for 16 hours. After cooling, the mixture diluted with ethyl acetate, washed with saturated bicarbonate and saline, with Dried sodium sulfate and evaporated. The residue of 577 mg is on silica gel Chromatographed hexane and acetone, yield 90 mg (17% of theory) as a solid foam.

1.7 11β-fluoro-gona-1,3,5 (10) -triene-3,17-diol

To dissolve 90 mg 11β-fluoro-3-mesyloxy-gona-1,3,5 (10) -trien-17-one in 10 ml water Free THF is given 200 mg of lithium aluminum hydride and stirred in for 2 hours Ice cooling, 16 hours at room temperature and 1 hour under reflux. After cooling mixed with saturated saline, extracted with ethyl acetate, the organic is dried Phase with sodium sulfate and evaporate the solvent. The residue is on silica gel Chromatographed with hexane and ethyl acetate, 42 mg of 11β-fluoro-gonadiol (59% of theory. Th.) As a solid foam.

Example 2 11β-methyl-gona-1,3,5 (10) -triene-3,17-diol 2.1 11-β-methyl-3-mesyloxy-estra-1,3,5 (10) -17-one

28.4 g 11β-methyl-estra-1,3,5 (10) -3-ol-17-one (100 mmol, Gantchev, J. Med. Chem 1994, 4164) are converted into the mesylate as described in Example 1.2, yield 33.5 g (92% d. Th.) As a solid foam.

2.2 11β-methyl-3-mesyloxy-17-oximinoestra-1,3,5 (10) -triene

The oxime is prepared as described in Example 1.3 in 89% yield (34.0 g), Mp

2.3 11β-methyl-3-mesyloxy-13,17-seco-estra-1,3,5 (10), 13 (18) -tetraen-17- nitrile

The oxime is converted into the seco compound as described in Example 1.4, it falls as a solid foam in a yield of 9.1 g (28% of theory).

2.4 13 (18) -Epoxy-11β-methyl-3-mesyloxy-13,17-seco-estra-1,3,5 (10) -triene-17-nitrile

The epoxidation is carried out as described in Example 1.5, particularly 18820 00070 552 001000280000000200012000285911870900040 0002019954105 00004 18701 and provides 6.7 g of epoxy (71% of theory) as a colorless oil.

2.5 11β-methyl-3-mesyloxy-gona-1,3,5 (10) -trien-17-one

Cyclization with boron trifluoride etherate gives this as described in Example 1.6 Gonadiol derivative in a yield of 14% of theory Th. (780 mg).

2.6 11β-methyl-gona-1,3,5 (10) -triene-3,17-diol

The reduction of the carbonyl group and elimination of the protective group with lithium alanate to The end product (as in Example 1.7) succeeds in 48% yield (290 mg).

Example 3 11β-ethyl-gona-1,3,5 (10) -triene-3,17-diol

As described in Example 1, the 11β-ethyl-18-nor-estradiol is made from 11β-ethyl-estra- 1,3,5 (10) -trien-3-ol-17-one (Pomper, J. Med. Chem. 1990, 3143) in a total yield of 1.3% produced, mp.

Example 4 11β-phenyl-gona-1,3,5 (10) -triene-3,17-diol

In the same way, 11β-phenyl-estra-1,3,5 (10) -trien-3-ol-17-one (Tedesco, J. Org.Chem. 1995, 5316) produced the corresponding 18-nor compound, overall yield 0.7%, mp.

Example 5 7α-fluoro-gona-1,3,5 (10) -triene-3,17-diol 5.1 3-Benzyloxy-7β-hydroxy-estra-1,3,5 (10) -trien-17-one

To a suspension of 20 g (67.74 mmol) 3.7β-dihydroxy-estra-1,3,5 (10) -trien-17-one, 3.55 g (148.23 mmol) lithium hydroxide in 700 ml dry dimethylformamide are added 12.83 g (75 mmol) benzyl bromide and stirred under an argon atmosphere for 30 minutes at 100 ° C. To Working up, the reaction solution is poured into tartaric ice water and the precipitated solution is sucked out Product and dries in the air. The crude product is taken up in dichloromethane, the organic phase washed with water and dried over sodium sulfate. To Stripping off the solvent in vacuo is chromatographed on silica gel (Dichloromethane-ethyl acetate, gradient up to 3: 2), yield 22.81 g (87%).

5.2 3-Benzyloxy-7α-fluoro-estra-1,3,5 (10) -trien-17-one

1.50 g (4 mmol) of 7β-alcohol are placed with 1.52 g (10 mmol) of DBU in 30 ml of dry toluene before, cools to 0 ° C with stirring and exclusion of moisture (argon atmosphere) and 1.51 g (5 mmol) of perfluorobutanesulfonic acid fluoride in 10 ml of toluene are added dropwise. The ice bath is then removed and the mixture is stirred for 5 hours at room temperature. For working up, dilute with ethyl acetate (150 ml) and wash the organic phase first with dilute hydrochloric acid, then with sodium hydroxide solution and finally with water / brine. It is allowed to dry over sodium sulfate, concentrated in vacuo and the residue is also shown Ethyl acetate. After concentration again, the residue is chromatographed on silica gel (Toluene-ethyl acetate, gradient up to 95: 5), yield 0.35 g (23%).

5.3 3-Benzyloxy-7α-fluoro-gona-1,3,5-trien-17-one

37.8 g of 3-benzyloxy-7α-fluoro-estra-1,3,5-trien-17-one are obtained as in Example 1.2 to 1.6 described 3-benzyloxy-7α-fluoro-gona-1,3,5 (10) -trien-17-one in a yield of 1.03 g (2.8% of theory) as a solid foam.

5.4 7α-fluoro-18-nor-1,3,5 (10) -trien-3-ol-17-one

0.30 g (0.79 mmol) of benzylated 7α-fluoro-18-nor-estrone is mixed with a mixture 3 ml of thioanisole and 2 ml of trifluoroacetic acid and omitted overnight at room temperature Shielding gas and moisture exclusion. For working up, stir in ice / potassium hydroxide solution , extracted with ethyl acetate, washed the organic phase until neutral and dried over Sodium sulfate. The crude product is chromatographed on silica gel (toluene-ethyl acetate, Gradient up to 4: 1), yield 0.200 g (87%).

5.5 7α-fluoro-8-nor-estra-1,3,5 (10) -triene-3,17β-diol

0.22 g (0.76 mmol) 7α-fluoro-18-nor-estrone in a mixture of 3 ml Dissolved dichloromethane and 9 ml of methanol and under a protective gas atmosphere at 0 ° C with 0.35 g Sodium borohydride added in portions. Then stir for another 30 minutes Room temperature, diluted with dichloromethane (150 ml) and worked up tartaric. The After washing with water, the organic phase is dried over sodium sulfate. The After the solvent has been stripped off, the crude product is chromatographed on silica gel (toluene Ethyl acetate, gradient up to 1: 1), yield 0.22 g (quant.) As a solid foam.

Example 6 7α-methyl-gona-1,3,5 (10) -triene-3,17β-diol

As described in Example 1, 7α-methyl-estra-1,3,5 (10) -trien-3-ol-17-one (Ali et. Al., J. Med. Chem. 1993, 264) converted into the final product in a yield of 1.8%. Mp

Example 7 7α-phenyl-gona-1,3,5 (10) -triene-3,17β-diol 7.1. 7α-phenyl-estr-4-en-3,17-dione

5.76 g of magnesium shavings (237 mmol) are suspended in 60 ml of anhydrous THF and added until the reaction starts slowly, then more quickly a total of 36.1 g bromobenzene (230 mmol) dissolved in 100 ml of anhydrous THF and heated to 80 ° C. for 1 hour. The mixture of 24 g copper iodide (120 mmol) and 43 g lithium bromide (480 mmol) in 115 ml anhydrous THL heats up to about 50 ° C, then 40 ml of DMPU are added and 30 are stirred Minutes. The solution of phenyl magnesium iodide is cooled to -60 ° C and slowly with the solution of the copper salt. Then hold at -30 ° C for 15 minutes, again cooled to -65 ° C and with a solution of 12.4 g of Estra-4,6-diene-3,17-dione (46 mmol) in 115 ml of anhydrous THF are added. After the last addition, the mixture is left inside heat from 45 minutes to -5 ° C, cool again to -40 ° C and add 15 ml Trimethylchlorosilane (115 mmol) too. Over the next 45 minutes, it increases Internal temperature to -18 ° C, 15 ml of glacial acetic acid are added, the cooling bath and stir another hour. Then it is diluted with ethyl acetate, washed with semi-saturated ammonium chloride solution, saturated bicarbonate solution and saline from, the organic phase dries with sodium sulfate and evaporates the solvent. The The residue is chromatographed on silica gel with hexane, methylene chloride and ethyl acetate. The yield of 7α-phenyl-estr-4-en-3,17-dione is 8.6 g (54% of theory).

7.2. 7α-phenyl-gona-1,3,5 (10) -triene-3,17β-diol

The synthesis sequence is carried out as described in Examples 1.1 to 1.7. The yield across all levels is 2.3%.

Example 8 7α-methyl-gona-1,3,5 (10) -triene-1,3,17-triol 8.1 7α-methyl-estra-1,3,5 (10) -triene-1,3-diol-17-one

The solution of 38.4 g of diacetoxy-7α-methyl-1,3,5 (10) estra-1,3,5 (10) trien-17-one (100 mmol; Sauer, Chem. Ber. 1982, 459) is dissolved in 300 ml of anhydrous ethanol, 30 ml of 4N NaOH are added and the mixture is heated to 60 ° C. for 30 minutes. Then the solvent is largely distilled off, the residue is taken up in ethyl acetate and washed neutral with water. The organic phase is dried with sodium sulfate and evaporated. The residue is chromatographed on silica gel with gasoline-ethyl acetate and crystallized from ethyl acetate / diisopropyl ether, yield 24 g (80% of theory), mp 228-229 ° C, [α _D ] = + 209 ° (0.5% in Pyridine).

8.2 7α-methyl-gona-1,3,5 (10) -triene-1,3,17-triol

The synthesis sequence is carried out as described in Examples 1.2 to 1.7. The yield is 4.5% across all levels.

Example 9 2-fluoro-gona-1,3,5 (10) -triene-3,17β-diol 9.1 2-fluoro-3-methoxy-gona-1,3,5 (10) -trien-17β-ol

Starting from 30.2 g of 2-fluoro-3-methoxy-estra-1,3,5 (10) -trien-17-one (100 mmol, diorazio, J.C.S. Perkin I 1992, 421) the synthesis of the 18-nor compound is as in Example 1.3 to 1.7 described, yield 5.3%

9.2 2-fluoro-gona-1,3,5 (10) -triene-3,17-diol

The solution of 0.53 g of 2-fluoro-3-methoxy-gona-1,3,5 (10) -trien-17β-ol in 50 ml of toluene mixed with 5 ml of 20% solution of DIBAH in toluene and heated to 80 ° C for 2 hours. After cooling, water is added dropwise until the reaction has subsided, then divided between water and ethyl acetate, washes the ethyl acetate phase with concentrated Saline and dries with sodium sulfate. After evaporation, a residue remains is chromatographed on silica gel with hexane-ethyl acetate, the yield is 0.32 g (63% d. Th.).

Example 10 11β, 17α-dimethylgona-1,3,5 (10) -triene-3,17β-diol 10.1 5,6α-epoxy-3,3- [1,2-ethanediylbis (oxy)] - 11-methylene-5α-gonan-17-one

1.4 g (4.45 mmol) of 3,3- [1,2-ethanediylbis (oxy)] - 11-methylengon-5-en-17-one (for preparation see DE 195 35 851, Example 2c) are obtained in 20 ml of dichloromethane dissolved. 1.5 ml of saturated aqueous sodium hydrogen carbonate solution are added, the mixture is then cooled to 0 ° C. and 490 mg (18.3 mmol) of 2,2,2-trifluoro-1- (3-nitrophenyl) ethanone and 1.9 are added at this temperature ml of hydrogen peroxide (30% aqueous solution, 18.6 mmol). The mixture is then stirred at 25 ° C for 100 hours. Then 9 ml of saturated sodium thiosulfate solution are added to the reaction mixture with gentle cooling. It is extracted with dichloromethane. The organic phase is washed with 5% sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulfate. Column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate gives 1 g (68%) 10.1.
¹ H NMR (CDCl ₃ ): δ = 4.97 (1H), 4.69 (1H), 3.85-4.08 (1H), 3.02 (1H), 2.66 (1H) ppm .

10.2 3,3- [1,2-ethanediylbis (oxy)] - 11-methylene-5α-gonan-5,17β-diol

A solution of 1 g (3.03 mmol) of the compound described under a) in 10 ml of tetrahydrofuran is added to a suspension of 990 mg (26 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran. The mixture is stirred for one hour at 0 ° C and then carefully added 20 ml of saturated ammonium chloride solution. The precipitate that forms is filtered off. The filtrate is diluted with ethyl acetate. The organic phase is then washed with saturated sodium chloride solution and dried over sodium sulfate. Column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate gives 980 mg (90%) 10.2.
¹ H NMR (CDCl ₃ ): δ = 4.88 (1H), 4.54 (1H), 3.90-4.06 (4H), 3.84 (1H) ppm.

10.3 3,3- [1,2-Ethanediylbis (oxy)] - 11β-methyl-5α-gonan-5,17β-diol

A solution of 980 mg (2.93 mmol) of the compound described under b) in 80 ml of ethanol is mixed with 90 mg of palladium / carbon (10%). The mixture is then hydrogenated under 1 atmosphere of hydrogen (reaction time approx. 20 min). It is then filtered through Celite / silica gel and concentrated in vacuo. The crude product obtained (986 mg (100%) is used in the next step without purification.
¹ H NMR (CDCl ₃ ): δ = 3.89-4.06 (4H), 3.86 (1H), 3.73 (1H), 0.86 (3H) ppm.

10.4 3,3- [1,2-ethanediylbis (oxy)] - 5-hydrox11β-methyl-5α-gonan-17-one

1.76 g (17.6 mmol) of chromium trioxide are added to 5.9 ml of pyridine in 30 ml of dichloromethane at 0 ° C. The mixture is left to stir at 0 ° C. for 15 minutes and then a solution of 986 mg (2.93 mmol) of the compound described under c) in 10 ml of dichloromethane is added. Then allowed to stir for one hour at 0 ° C and then washed twice with 5% aqueous sodium hydroxide solution and once with saturated aqueous sodium chloride solution. It is dried over sodium sulfate and the crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 830 mg (85%) 10.4 are obtained.
¹ H NMR (CDCl ₃ ): δ = 3.92-4.05 (4H), 3.89 (1H), 2.38 (1H), 0.85 (3H) ppm.

10.5 11β, 17α-dimethyl-3,3- [1,2-ethanediylbis (oxy)] - 5α-gonan-5,17β-diol (A) and 11β, 17β-dimethyl-3,3- [1,2-ethanediylbis (oxy)] - 5α-gonan-5,17α-diol (B)

A solution of 260 mg (0.78 mmol) of the compound described under c) in a mixture of 5 ml of tetrahydrofuran and 5 ml of diethyl ether is added at 0 ° C. to 4.7 ml of a 1.6 molar solution of methyl lithium in diethyl ether . The mixture is stirred for one hour at 0 ° C. and then the reaction mixture is poured onto saturated aqueous ammonium chloride solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. The crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 166 mg (61%) of compound A and 60 mg (22%) of compound B are obtained.
¹ H NMR (CDCl ₃ ):
Compound A: δ = 3.90-4.02 (3H), 2.08 (1H), 1.12 (3H), 0.85 (3H) ppm.
Compound B: δ = 3.90-4.03 (3H), 2.12 (1H), 1.28 (3H), 0.85 (3H) ppm.

10.6 11β, 17α-dimethyl-17β-hydroxy-gon-4-en-3-one

0.4 ml of 4 normal hydrochloric acid are added to a solution of 166 mg (0.47 mmol) of compound A described in e) in 10 ml of acetone. The mixture is left to stir at 25 ° C. for one hour and then the reaction mixture is poured onto saturated aqueous sodium bicarbonate solution. The mixture is then extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. The crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 119 mg (87%) 10.6 are obtained.
¹ H NMR (CDCl ₃ ): δ = 5.83 (1H), 1.13 (3H), 0.97 (3H) ppm.

10.7 11β, 17α-dimethylgona-1,3,5 (10) -triene-3,17β-diol

Lithium diisopropylamide (LDA) is prepared from 0.77 ml of a 1.6 molar solution of n-butyllithium in hexane (1.23 mmol) and 0.18 ml (1.28 mmol) of diisopropylamine in 10 ml of tetrahydrofuran at 0 ° C. The mixture is then cooled to -78 ° C. and a solution of 119 mg (0.41 mmol) of the compound described under f) in 8 ml of tetrahydrofuran is added. The mixture is stirred at -78 ° C for one hour. Then 0.16 ml (0.42 mmol) of trimethylchlorosilane are added. The mixture is allowed to come to 0 ° C. and stirred for a further 30 minutes. The reaction mixture is then poured onto saturated aqueous sodium hydrogen carbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude silylenol ether (148 mg) obtained is dissolved in 6 ml of acetonitrile. 102 mg (0.45 mmol) of palladium (II) acetate are added and the mixture is stirred at 25 ° C. for 2.5 hours. The reaction mixture is then filtered through Celite and the filtrate is concentrated in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 61 mg (52%) of the title compound are obtained.
¹ H-NMR (CDCl ₃ ): δ = 7.04 (1H), 6.58 (1H), 6.47 (1H), 2.60-2.75 (3H), 2.40 (1H), 1.14 (3H), 0.72 (3H) ppm.

Example 11 11β, 17β-dimethylgona-1,3,5 (10) -triene-3,17α-diol 11.1 11β, 17β-dimethyl-17α-hydroxy-gon-4-en-3-one

Analogously to Example 10.6, 40 mg (81%) 11.1 are obtained from 60 mg (0.17 mmol) of compound B described in 10.5 by reaction with 4 normal hydrochloric acid in acetone after column chromatography.
¹ H NMR (CDCl ₃ ): δ = 5.83 (1H), 1.29 (3H), 0.98 (3H) ppm.

11.2 11β, 17β-dimethylgona-1,3,5 (10) -triene-3,17α-diol

Analogously to Example 10.7, from 40 mg (0.14 mmol) of the compound described under 11.1, 23 mg (57%) 11.2 are obtained.
¹ H-NMR (CDCl ₃ ): δ = 7.09 (1H), 6.62 (1H), 6.50 (1H), 2.70-2.85 (3H), 2.48 (1H), 1.29 (3H), 0.78 (3H) ppm.

Example 12 11β-methyl-17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol

Amount of substrate: 6.0 mg 17β-hydroxy-11β-methyl-17α- (1-propynyl) -gon-4-en-3-one
The title compound with the strain Bacillus lentus ATCC 13805 is prepared in a 20 ml fermentation flask.
Preculture: 100 ml sterile medium consisting of 0.5% glucose, 0.5% yeast extract, 0.1% peptone and 0.2% coorn steep liquor (pH 7.5) is grown with a slant tube culture from the strain Bacillus lentus ATCC 13805 inoculated and incubated for 24 hours at 28 ° C and 165 rpm on a rotary shaker.
Main culture: For the biotransformation, 3 × 20 ml of the preculture are transferred to a sterile 100 ml shake flask. At the same time, the substrate 17β-hydroxy-11β-methyl-17α- (1-propynyl) -gon-4-en-3-one is dissolved in an organic solvent and added. The concentration in the culture broth is 100 mg / l. Ethanol is preferably used as the solvent, but other water-miscible solvents such as, for. B. dimethylformamide can be used. Incubation is carried out at 28 ° C and 165 rpm on a rotary shaker. The reaction is checked using methods such as thin layer chromatography or, preferably, HPLC. The reaction is complete after 28 hours. The culture broth of the three shaking flasks is extracted 1 × with 1 volume of methyl isobutyl ketone, the organic phases are combined and evaporated to dryness in vacuo.
Isolation: The isolation and purification of the reaction product 11β-methyl-17α- (1-propynyl) - gona-1,3,5 (10) -triene-3,17β-diol was carried out (because of the small amount) via HPLC under the following conditions :
Column: Semi-prep column from Phenomenex (LUNA 5µ, SILICA (2), 250 × 10 mm),
Superplasticizer: hexane / dioxane 75/25
Flow rate: 5 ml / min
Yield: 42% 11β-methyl-17α- (1-propynyl) -gona-1,3,5 (10) -triene-3,17β-diol

Example 13 11-methylene-17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol

Analogously to Example 12, 20 mg of 17β-hydroxy-11-methylene-17α- (1-propynyl) -gon-4-en- 3-one obtained the title compound in 90% yield.

Example 14 17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol

In analogy to Example 12, 6 mg of 17β-hydroxy-17α- (1-propynyl) -gon-4-en-3-one is converted into the Obtained title compound in 40% yield.

Table 1

Table 2

Claims (51)

1. Gona-1,3,5 (10) -triene derivatives of the general formula I
wherein
R ^{1 is} a halogen atom, a radical R ¹⁸ - or R ¹⁸ -O-, where R ^{18 is} a hydrogen atom or a straight or branched chain, saturated or unsaturated hydrocarbon radical having up to 6 carbon atoms, a trifluoromethyl group,
R ^{2 is} a halogen atom;
a radical R ¹⁸ - or R ¹⁸ -O-, where R ^{18 has} the meaning given under R ¹ ; a group R ¹⁹ SO ₂ -O-, in which R ^{19 is} an R ²⁰ R ²¹ N group, where R ²⁰ and R ²¹ independently of one another are a hydrogen atom, a C ₁ -C ₅ alkyl radical, a group C (O) R ²² , in which R ^{22 represents} a straight-chain or branched-chain hydrocarbon radical having up to 12 carbon atoms, which can also contain up to three double and / or triple bonds, a C ₃ -C ₇ cycloalkyl radical, an aryl radical or a combination of these structural features, or, together with the N atom, represent a polymethyleneimino radical having 4 to 6 C atoms or a morpholino radical;
R ^{3 is} a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , where for R ^{18 can} additionally be an aryl, heteroaryl or aralkyl radical;
R ⁶ and R ⁷ independently of one another are a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given, a straight or branched chain, saturated or unsaturated, partially or completely halogenated alkyl group with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,
R ⁸ and R ⁹ independently of one another are a hydrogen atom, a straight or branched chain, saturated or unsaturated, optionally partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms, a group -XR ¹⁸ , in which X is an oxygen or sulfur atom and R ¹⁸ is has the meaning given under R ¹ , a halogen atom, a cyano or rhodano group,
R ^{11 is} a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , a group -XR ¹⁸ , in which X is an oxygen or sulfur atom and R ^{18 has} the meaning given under R ¹ , a nitrooxy group, a straight or branched chain, saturated or unsaturated, partially or fully halogenated hydrocarbon radical having up to 10 carbon atoms or a optionally substituted aryl, heteroaryl or aralkyl radical, and
R ^{11 'is} a hydrogen atom or
R ¹¹ and R ^{11 '} together represent a methylene group,
R ^{14 is} an α-hydrogen atom or a straight or branched chain alkyl, alkenyl or alkynyl group with up to 3 carbon atoms and
R ^{15 is} a hydrogen atom
or
R ¹⁴ and R ¹⁵ together form a single or double halogenated methylene group;
R ^{15 '} and R ¹⁶ independently of one another are a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given;
R ¹⁷ and R ^{17 'represent} a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R ¹⁹ SO ₂ -O-; a group R ¹⁸ and a group -C (O) R ²² or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ -O- and a group -OC (O) R ²² , in all the above cases with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; or
R ¹⁷ and R ^{17 '} together are a group = CR ²³ R ²⁴ , wherein R ²³ and R ²⁴ independently represent a hydrogen atom and a halogen atom, or an oxygen atom;
mean and
in positions 6, 7; 7, 8; 9, 11; 11, 12; 14, 15 and 15, 16 one or more double bonds can be present,
except for the compounds which have the following substituent combinations on the carbon atoms 13, 3, 17, 9, 15 and 16 and double bonds between the indicated carbon atoms
2. Compounds of general formula I according to claim 1, wherein
R ^{1 is} a hydrogen atom or a group R ¹⁸ -O-, where R ^{18 is} a hydrogen atom or a straight or branched chain, saturated or unsaturated hydrocarbon radical having up to 6 carbon atoms,
is
and all other substituents have the meanings given in claim 1. 3. Compounds according to claim 2, wherein
R ^{1 is} a hydrogen atom, a hydroxyl or straight or branched chain C ₁ -C ₆ alkyl group,
is. 4. Compounds of general formula I according to claim 1, wherein
R ^{2 is} a hydrogen or halogen atom or a hydroxy group
and all other substituents have the meanings given in claim 1. 5. Compounds according to claim 4, wherein
R ^{2 is} a hydrogen or fluorine atom or a hydroxy group. 6. Compounds of general formula I 'according to claim 1, wherein
R ^{3 is} a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , where for R ^{18 can} additionally be an aryl or aralkyl radical,
is
and all other substituents have the meanings given in claim 1. 7. Compounds of general formula I according to claim 1, wherein
R ^{6 is} a hydrogen atom, a hydroxyl group, a group R ²² in the meaning given under R ² is an optionally substituted aryl, heteroaryl or aralkyl radical,
and all other substituents have the meanings given in claim 1. 8. Compounds according to claim 7, wherein
R ^{6 is} a hydrogen atom or a hydroxy group. 9. Compounds of general formula I according to claim 1, wherein
R ^{7 is} a hydrogen atom, a fluorine or chlorine atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given, a straight or branched chain, saturated or unsaturated, partially or completely halogenated alkyl group having up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,
is
and the other substituents have the meanings given in claim 1. 10. Compounds of general formula I according to claim 1, wherein
R ⁸ and R ⁹ independently of one another are a hydrogen atom, a straight or branched chain, saturated or unsaturated, optionally partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms, a group -X- R ¹⁸ , in which X is an oxygen atom and R ^{18 is} the under R ¹ has the meaning given, a fluorine or chlorine atom or a cyano group,
is
and all other substituents have the meanings given in claim 1. 11. Compounds of general formula I according to claim 1, wherein
R ^{11 is} a hydrogen atom, a halogen atom, a group -R ²² with R ²² in the meaning given under R ² , a group -XR ¹⁸ , in which X is a sulfur atom and R ^{18 has} the meaning given under R ¹ , a straight or branched chain, saturated or unsaturated, partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms or an optionally substituted aryl or heteroaryl radical, or
R ¹¹ and R ^{11 '} together represent a methylene group
is
and all other substituents have the meanings given in claim 1. 12. Compounds according to claim 10, wherein
R ^{11 is} a hydrogen atom, a fluorine or chlorine atom, a saturated, straight or branched chain C ₁ -C ₆ alkyl group, a group -XR ¹⁸ , in which X is a sulfur atom and R ^{18 is} a saturated, straight or branched chain C ₁ - C ₆ - alkyl group, a chloromethyl or chloroethyl group or an optionally substituted aryl or heteroaryl radical, or
R ¹¹ and R ^{11 '} together is a methylene group. 13. Compounds of general formula I according to claim 1, wherein
R ^{14 is} an α-hydrogen atom or a straight or branched chain alkynyl group with up to 3 carbon atoms and
R ^{15 is} a hydrogen atom
or
R ¹⁴ and R ¹⁵ together are a methylene group;
is
and all other substituents have the meanings given in claim 1. 14. Compounds according to claim 12, wherein
R ^{14 is} an α-hydrogen atom and
R ^{15 is} a hydrogen atom or
R ¹⁴ and R ¹⁵ together are a methylene group;
is. 15. Compounds of general formula I according to claim 1, wherein
R ^{15 '} and R ¹⁶ independently of one another are a hydrogen atom, a fluorine or chlorine atom or a group R ¹⁸ -O or -R ²² , with R ¹⁸ and R ²² each in the meaning given under R ¹ and R ² ;
is
and all other substituents have the meaning given in claim 1. 16. Compounds of general formula I according to claim 1, wherein
R ^{1 is} a hydrogen atom or a group R ¹⁸ -O-, where R ^{18 is} a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon test with up to 6 carbon atoms,
R ^{2 represents} a hydrogen or halogen atom or a hydroxy group,
R ^{3 is} a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , where for R ^{18 can} additionally be an aryl or aralkyl radical;
R ^{6 is} a hydrogen atom, a hydroxyl group, a group R ²² in the meaning given under R ² is an optionally substituted aryl, heteroaryl or aralkyl radical,
R ^{7 is} a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , a straight or branched chain, saturated or unsaturated, partially or completely halogenated alkyl group having up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,
R ⁸ and R ⁹ independently of one another are a hydrogen atom, a straight or branched chain, saturated or unsaturated, optionally partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms, a group -XR ¹⁸ , in which X is an oxygen or sulfur atom and R ¹⁸ is has the meaning given under R ¹ , a halogen atom, a cyano or rhodano group,
R ^{11 is} a hydrogen atom, a halogen atom, a group -R ²² with R ²² in the meaning given under R ² , a group -XR ¹⁸ , in which X is a sulfur atom and R ^{18 has} the meaning given under R ¹ , a straight or branched chain, saturated or unsaturated, partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms or an optionally substituted aryl or heteroaryl radical,
R ^{14 is} an α-hydrogen atom or a straight or branched chain alkynyl group with up to 3 carbon atoms and
R ^{15 is} a hydrogen atom or
R ¹⁴ and R ¹⁵ together are a methylene group;
R ^{15 '} and R ¹⁶ independently of one another are a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given;
R ¹⁷ and R ^{17 'represent} a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R ¹⁹ SO ₂ -O-; a group R ¹⁸ and a group -C (O) R ²² or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ -O- and a group -OC (O) R ²² , in all the above cases with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; such as
R ¹⁷ and R ^{17 '} together are a group = CR ²³ R ²⁴ , wherein R ²³ and R ²⁴ independently represent a hydrogen atom and a halogen atom, or an oxygen atom;
mean. 17. Compounds of general formula I according to claim 16, wherein
R ^{1 is} a hydrogen atom, a hydroxyl or straight or branched chain C ₁ -C ₆ alkyl group,
R ^{2 represents} a hydrogen or fluorine atom or a hydroxy group,
R ^{3 is} a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , where for R ^{18 can} additionally be an aryl or aralkyl radical;
R ^{6 represents} a hydrogen atom or a hydroxy group,
R ^{7 is} a hydrogen atom, a fluorine or chlorine atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case under R ¹ or R ² indicated meaning, a straight or branched chain, saturated or unsaturated, partially or completely halogenated alkyl group with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,
R ⁸ and R ⁹ independently of one another are a hydrogen atom, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms, a group -XR ¹⁸ , in which X is an oxygen atom and R ^{18 is} the same as R ¹ has the meaning given, a fluorine or chlorine atom or a cyano group,
R ^{11 is} a hydrogen atom, a fluorine or chlorine atom, a saturated, straight or branched chain C ₁ -C ₆ alkyl group, a group -XR ¹⁸ , in which X is a sulfur atom and R ^{18 is} a saturated, straight or branched chain C ₁ - C ₆ - alkyl group, a chloromethyl or chloroethyl group or an optionally substituted aryl or heteroaryl radical,
R ^{14 is} an α-hydrogen atom and
R ^{15 is} a hydrogen atom or
R ¹⁴ and R ¹⁵ together are a methylene group;
R ^{15 '} and R ¹⁶ independently of one another are a hydrogen atom, a fluorine or chlorine atom or a group R ¹⁸ -O or -R ²² , with R ¹⁸ and R ²² each in the meaning given under R ¹ and R ² ;
R ¹⁷ and R ^{17 'represent} a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R ¹⁹ SO ₂ -O-; a group R ¹⁸ and a group -C (O) R ²² or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ -O- and a group -OC (O) R ²² , in all the above cases with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; such as
R ¹⁷ and R ^{17 '} together are a group = CR ²³ R ²⁴ , wherein R ²³ and R ²⁴ independently represent a hydrogen atom and a halogen atom, or an oxygen atom;
mean. 18. Gona-1,3,5 (10) -triene derivatives of the general formula I according to claim 1, wherein
R ⁶ , R ⁸ , R ⁹ , R ¹⁴ , R ¹⁵ , R ^{15 '} and R ¹⁶ each represent a hydrogen atom and all other substituents have the meanings given in claim 1. 19. Gonatriene derivatives of the general formula I 'according to any one of the preceding claims 1 to 18, wherein in position 7, 8 or in position 11, 12 a double bond or in positions 6, 7 and 8, 9 there are two double bonds. 20. gonatriene derivatives of the general formula I according to any one of the preceding claims 1 to 19, wherein
R ¹⁷ and R ^{17 'are} a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ - and a group -OC (O) R ²² , with R ¹⁸ and R ²² each in the meaning given under R ¹ and R ² ;
is. 21. Gonatriene derivatives according to claim 20, wherein
R ¹⁷ and R ^{17 'is} a hydroxy group and a hydrogen atom, a C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl group. 22. Gonatriene derivatives according to claim 21, wherein
R ¹⁷ and R ^{17 'is} a hydroxy group and a hydrogen atom, a methyl, ethynyl or prop-1-ynyl group. 23. Gonatriene derivatives according to claim 1, namely
11β-fluoro-gona-1,3,5 (10) -triene-3,17-diol
11β-chloro-gona-1,3,5 (10) -triene-3,17-diol
11β-methyl-gona-1,3,5 (10) -triene-3,17-diol
11β-ethyl-gona-1,3,5 (10) -triene-3,17-diol
11β-phenyl-gona-1,3,5 (10) -triene-3,17-diol
7α-fluoro-gona-1,3,5 (10) -triene-3,17-diol
7α-methyl-gona-1,3,5 (10) -triene-3,17β-diol
7α-phenyl-gona-1,3,5 (10) -triene-3,17β-diol
7α-methyl-gona-1,3,5 (10) -triene-3,17-diol
7β-fluoro-gona-1,3,5 (10) -triene-3,17-diol
7β-methyl-gona-1,3,5 (10) -triene-3,17β-diol
7β-phenyl-gona-1,3,5 (10) -triene-3,17β-diol
7β-methyl-gona-1,3,5 (10) -triene-3,17-diol
2-fluoro-gona-1,3,5 (10) -triene-3,17β-diol
17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11-methylene-17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11β-methyl-17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11β, 17α-dimethyl-gona-1,3,5 (10) -triene-3,17β-diol
11β, 17β-dimethyl-gona-1,3,5 (10) -triene-3,17α-diol
18-Nor-estriol
11β-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
11β-chloro-gona-1,3,5 (10) -triene-1,3,17-triol
11β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β-ethyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
7α-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
7β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
2-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
17α- (1-propynyl) gona-1,3,5 (10) -triene-1,3,17-triol
11-methylene-17α- (1-propynyl) -gona-1,3,5 (10) -triene-1,3,17-triol
11β-methyl-17α- (1-propynyl) gona-1,3,5 (10) -triene-1,3,17-triol
11β, 17α-dimethyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β, 17β-dimethyl-gona-1,3,5 (10) -triene-1,3,17-triol. 24. Use of Gona-1,3,5 (10) -triene derivatives of the general formula I '
wherein
R ^{1 is} a halogen atom, a radical R ¹⁸ - or R ¹⁸ -O-, where R ^{18 is} a hydrogen atom or a straight or branched chain, saturated or unsaturated hydrocarbon radical having up to 6 carbon atoms, a trifluoromethyl group,
R ^{2 is} a halogen atom;
a radical R ¹⁸ - or R ¹⁸ -O-, where R ^{18 has} the meaning given under R ¹ ; a group R ¹⁹ SO ₂ -O-, in which R ^{19 is} an R ²⁰ R ²¹ N group, where R ²⁰ and R ²¹ independently of one another are a hydrogen atom, a C ₁ -C ₅ alkyl radical, a group C (O) R ²² , in which R ^{22 represents} a straight-chain or branched-chain hydrocarbon radical having up to 12 carbon atoms, which can also contain up to three double and / or triple bonds, a C ₃ -C ₇ cycloalkyl radical, an aryl radical or a combination of these structural features, or, together with the N atom, represent a polymethyleneimino radical having 4 to 6 C atoms or a morpholino radical;
R ^{3 is} a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , where for R ^{18 can} additionally be an aryl, heteroaryl or aralkyl radical;
R ⁶ and R ⁷ independently of one another are a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given, a straight or branched chain, saturated or unsaturated, partially or completely halogenated alkyl group with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,
R ⁸ and R ⁹ independently of one another are a hydrogen atom, a straight or branched chain, saturated or unsaturated, optionally partially or completely halogenated hydrocarbon radical having up to 10 carbon atoms, a group -X- R ¹⁸ , in which X is an oxygen or sulfur atom and R ^{18 has} the meaning given under R ¹ , a halogen atom, a cyano or rhodano group,
R ^{11 is} a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² , a group -XR ¹⁸ , in which X is an oxygen or sulfur atom and R ^{18 has} the meaning given under R ¹ , a nitrooxy group, a straight or branched chain, saturated or unsaturated, partially or fully halogenated hydrocarbon radical having up to 10 carbon atoms or a optionally substituted aryl, heteroaryl or aralkyl radical, and
R ^{11 'is} a hydrogen atom or
R ¹¹ and R ^{11 '} together represent a methylene group;
R ^{14 is} an α-hydrogen atom or a straight or branched chain alkyl, alkenyl or alkynyl group with up to 3 carbon atoms and
R ^{15 is} a hydrogen atom or
R ¹⁴ and R ¹⁵ together form a single or double halogenated methylene group;
R ^{15 '} and R ¹⁶ independently of one another are a hydrogen atom, a halogen atom, a group R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² , with R ¹⁸ , R ¹⁹ and R ^{22 in} each case in the under R ¹ or R ² meaning given;
R ¹⁷ and R ^{17 'represent} a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R ¹⁹ SO ₂ -O-; a group R ¹⁸ and a group -C (O) R ²² or -OC (O) R ²² , with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; a group R ¹⁸ -O- and a group R ¹⁸ -; a group R ¹⁸ -O- and a group -OC (O) R ²² , in all the above cases with R ¹⁸ , R ¹⁹ and R ²² each in the meaning given under R ¹ and R ² ; or
R ¹⁷ and R ^{17 '} together are a group = CR ²³ R ²⁴ , wherein R ²³ and R ²⁴ independently represent a hydrogen atom and a halogen atom, or an oxygen atom;
mean and
in positions 6, 7; 7, 8; 9, 11; 11, 12; 14, 15 and 15, 16 one or more double bonds can be present
for the treatment of estrogen-related diseases and conditions in women and men. 25. Use of gonatriene derivatives of the general formula I 'according to claim 24, wherein the gonatriene derivative is selected from the group of the following compounds:
11β-fluoro-gona-1,3,5 (10) -triene-3,17-diol
11β-chloro-gona-1,3,5 (10) -triene-3,17-diol
11β-methyl-gona-1,3,5 (10) -triene-3,17-diol
11β-ethyl-gona-1,3,5 (10) -triene-3,17-diol
11β-phenyl-gona-1,3,5 (10) -triene-3,17-diol
7α-fluoro-gona-1,3,5 (10) -triene-3,17-diol
7α-methyl-gona-1,3,5 (10) -triene-3,17β-diol
7α-phenyl-gona-1,3,5 (10) -triene-3,17β-diol
7α-methyl-gona-1,3,5 (10) -triene-3,17-diol
7β-fluoro-gona-1,3,5 (10) -triene-3,17-diol
7β-methyl-gona-1,3,5 (10) -triene-3,17β-diol
7β-phenyl-gona-1,3,5 (10) -triene-3,17β-diol
7β-methyl-gona-1,3,5 (10) -triene-3,17-diol
2-fluoro-gona-1,3,5 (10) -triene-3,17β-diol
17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11-methylene-17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11β-methyl-17α- (1-propynyl) gona-1,3,5 (10) -triene-3,17β-diol
11β, 17α-dimethyl-gona-1,3,5 (10) -triene-3,17β-diol
11β, 17β-dimethyl-gona-1,3,5 (10) -triene-3,17α-diol
18-Nor-estriol
11β-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
11β-chloro-gona-1,3,5 (10) -triene-1,3,17-triol
11β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β-ethyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
7α-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7α-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
7β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-phenyl-gona-1,3,5 (10) -triene-1,3,17-triol
7β-methyl-gona-1,3,5 (10) -triene-1,3,17-triol
2-fluoro-gona-1,3,5 (10) -triene-1,3,17-triol
17α- (1-propynyl) gona-1,3,5 (10) -triene-1,3,17-triol
11-methylene-17α- (1-propynyl) -gona-1,3,5 (10) -triene-1,3,17-triol
11β-methyl-17α- (1-propynyl) gona-1,3,5 (10) -triene-1,3,17-triol
11β, 17α-dimethyl-gona-1,3,5 (10) -triene-1,3,17-triol
11β, 17β-dimethyl-gona-1,3,5 (10) -triene-1,3,17-triol
18-nor-17β-estradiol. 26. Use according to claim 24 for the treatment of peri- and postmenopausal Complaints. 27. Use according to claim 24 for the treatment of peri- and postandropausal Complaints. 28. Use according to claim 26 for the prevention and treatment of Hot flashes, sleep disorders, irritability, mood swings, incontinence, Vaginal atrophy and hormone deficiency-related mood disorders. 29. Use according to claim 28 for the prevention and treatment of diseases in the urogenital tract. 30. Use according to claim 24 for the prevention and therapy of gastric and Intestinal diseases. 31. Use according to claim 30 for the prevention and therapy of ulcers and Hemoragic diathesis in the gastrointestinal tract. 32. Use according to claim 31 for the prevention and therapy of neoplasia. 33. Use according to claim 24 for the in vitro treatment of the male Infertility. 34. Use according to claim 24 for the in vivo treatment of male infertility. 35. Use according to claim 24 for the in vitro treatment of female infertility. 36. Use according to claim 24 for the in vivo treatment of female infertility. 37. Use according to claim 24 for hormone replacement therapy (HRT). 38. Use according to claim 24 for the therapy of hormone deficiency-related Symptoms of surgical, drug or other ovarian dysfunction. 39. Use according to claim 24 for the prophylaxis and therapy of a Bone mass loss due to hormone deficiency. 40. Use according to claim 39 for the prophylaxis and therapy of osteoporosis. 41. Use according to claim 24 for the prevention and therapy of Cardiovascular disease. 42. Use according to claim 24 for the prevention and treatment of Vascular diseases. 43. Use according to claim 42 for the prevention and treatment of Atherosclerosis. 44. Use according to claim 42 for the prevention and treatment of neointimal Hyperplasia. 45. Use according to claim 24 for prevention and treatment hormone deficiency-related neurodegenerative diseases. 46. Use according to claim 24 for the prevention and treatment of Alzheimer's Disease and hormone deficiency-related impairment of memory and Ability to learn. 47. Use according to claim 24 for the treatment of inflammatory diseases and Immune system disorders. 48. Use according to claim 24 for the prevention and treatment of benign Prostatic hyperplasia (BPH). 49. Use of the structural part of the formula II
(Gonatrial structure) as part of the overall structure of compounds that have a dissociation in favor of their estrogenic effect on the bone compared to the uterus. 50. Use of the structural part of the formula II '
wherein the substituents R ¹ to R ^{17 'have} the meanings given in formula I, according to claim 49. 51. Pharmaceutical compositions containing at least one compound according to one of claims 1 to 23 and a pharmaceutically acceptable carrier.