AU2003242683B2

AU2003242683B2 - 9-Alpha-substituted estratrienes as selectively active estrogen

Info

Publication number: AU2003242683B2
Application number: AU2003242683A
Authority: AU
Inventors: Karl-Heinrich Fritzemeier; Alexander Hillisch; Dirk Kosemund; Peter Muhn; Gerd Muller
Original assignee: Bayer Schering Pharma AG
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2002-06-11
Filing date: 2003-06-11
Publication date: 2009-07-02
Anticipated expiration: 2023-06-11
Also published as: NO329563B1; IL165321A; MXPA04012491A; UY27844A1; HK1081203A1; RS50878B; ECSP055530A; PL209910B1; EA200401544A1; JP4615998B2; TW200407331A; CN1659181A; JP2005533053A; EA008442B1; ZA200500217B; CA2486495A1; DE50301116D1; EP1517914A2; HRP20050009B1; CU23414B7

Description

WO 03/104253 PCT/EP03/06172 9-Alpha-Substituted Estratrienes as Selectively Active Estrogens Field of the Invention This invention relates to new compounds as pharmaceutical active ingredients, which iave in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen eceptor preparations from rat uteri and in vivo a preferential action in the ovary in comparison to he uterus, their production, their therapeutic use and pharmaceutical dispensing forms that ontain the new compounds. The chemical compounds are new, steroidal, tissue-selective estrogens. background of the Invention The efficiency of estrogens in the treatment of hormone-deficiency-induced symptoms uch as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful tse of estrogen therapies for prevention of bone mass loss in peri- and postmenopausal women, is well documented and generally accepted (Grady et al. 1992, Ann Intern Med 117: 1016-1037). It is also well documented that estrogen replacement therapy in postmenopausal women or in women with ovarian dysfunction that is caused in some other way reduces the risk of cardiovascular diseases compared to women who are not treated with estrogen (Grady et al., loc. cit.). In conventional estrogen or hormone replacement therapy (= HRT), natural estrogens, such as estradiol, and conjugated estrogens that consist of equine urine are used either by themselves or in combination with a gestagen. Instead of the natural estrogens, derivatives that are obtained by esterification, such as, e.g., 170-estradiol-valerate, can also be used.

2 Because of the stimulating action of the estrogens that are used on the endometrium, vhich results in an increase of the risk of endometrial carcinoma (Harlap, S. 1992, Am J Obstet 3ynecol 166: 1986-1992), estrogen/gestagen combination preparations are preferably used in hormone replacement therapy. The gestagenic component in the estrogen/gestagen combination voids hypertrophy of the endometrium, but the occurrence of undesirable intracyclic menstrual feeding is also linked to the gestagen-containing combination. Selective estrogens represent a more recent alternative to the estrogen/gestagen combination preparations. Up until now, selective estrogens have been defined as those ompounds that have an estrogen-like effect on the brain, bones and vascular system, owing to heir antiuterotropic (i.e., antiestrogenic) partial action, but they do not have a proliferative effect n the endometrium. A class of substances that partially meet the desired profile of a selective estrogen is the o-called "Selective Estrogen Receptor Modulators" (SERM) (R. F. Kauffman, H. U. Bryant 995, DNAP 8 (9): 531-539). In this case, these are partial agonists of estrogen receptor subtype ERa." This substance type is ineffective, however, with respect to the therapy of acute 'ostmenopausal symptoms, such as, e.g., hot flashes. As an example of a SERM, the raloxifene hat was recently introduced for the indication of osteoporosis can be mentioned. DE-A- 19906159 describes new compounds as pharmaceutical active ingredients that have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo a preferential action on bones in comparison to he uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. The compounds are 16x- and 16p-hydroxy-estra-1,3,5(10) estratrienes that carry additional substituents in the steroid skeleton and can exhibit one or more additional double bonds in the B-, C- and/or D-rings. For the treatment of fertility disorders of women, frequently caused by ovarian dysfunction that is caused by surgery, medication, etc., new possible therapies are also opened up 3 y the use of new selective estrogens. The in-vitro fertility treatment is a process that has been stablished for more than 20 years. Numerous methods for treating ovarian-induced infertility iith exogenic gonadotropins are known. By administration of gonadotropins such as FSH (FSH follicle-stimulating hormone), a stimulation of the ovaries, which is to make possible a healthy >llicular maturation, is to be produced. The follicle is the functional unit of the ovary and has two purposes: it accommodates the ocytes and provides for the latter the possibility for growth and for maturation. Folliculogenesis comprises the development of an ovarian follicle from a primordial stage to a continuously creasing antral follicle, which represents the last stage before ovulation. Only an optimally eveloped antral follicle can release a mature ovocyte by ovulation. Patients with ovarian-induced infertility (PCOS = syndrome of polycystic ovaries) suffer -om a disrupted follicular maturation, which is associated both with hormonal and ovulatory isruptions and with inadequately matured ovocytes. The number of primary and secondary >llicles is approximately twice as high here as in the normal ovary (Hughesden et al., Obstet. iynecol. Survey 37, 1982, pp. 59-77). There are indications that the early development stages of folliculogenesis (which relates the development of primordial follicles to antral follicles) are gonadotropin-independent. It is iot clearly explained how great the influence of known paracrine and autocrine factors is on early bolliculogenesis (Elvin et al., Mol. Cell Endocrinol. 13, 1999, pp. 1035-1048; McNatty et al., J. Zeprod. Fertil. Suppl. 54, 1999, pp. 3-16). Gonadotropins such as FSH are mainly involved in the last development stages of olliculogenesis in follicular maturation, i.e., in the development of the early antral follicle to a nature follicle that can undergo ovulation. The in-vivo and in-vitro infertility is preferably treated with gonadotropins (FSH and mtiestrogens) (White et al., J. Clin. Endocrinol. Metab. 81, 1996, pp. 3821-3824). In in-vitro fertilization treatment, oocytes are removed from preovulatory antral follicles to be able to 4 nature in vitro into an ovocyte that can be fertilized. After fertilization and preembryonal evelopment, one to three embryos are implanted in the uterus of the woman. In many respects, the treatment with exogenic gonadotropins is accompanied by numerous risks and side effects. The greatest risk consists in an overstimulation of the ovaries, vhich in severe cases can represent a serious danger to life (OHSS = Ovarian Hyperstimulation .yndrome). Other side effects are the high costs of the in-vitro fertility treatment that must be aid by the couples. Negative side effects such as weight gain, bloatedness, nausea, vomiting nd an as yet unknown long-term risk of developing cancer are attributed to the gonadotropin -eatment. One method to avoid the above-mentioned drawbacks and risks is to ensure the iaturation and stimulation in vivo of follicular growth in the case of ovarian-induced infertility 'ith a suitable active ingredient before treatment with exogenic gonadotropins begins. strogen Receptor Beta (ERO) Several years ago, estrogen receptor 3 (ERO) was discovered as a second subtype of the strogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, 'ijkema (1996) Febs Letters 392: 49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 53-365). The expression pattern of ER3 differs from that of the ERa (Kuiper et al. (1996), .ndocrinology 138: 863-870). ER3 thus predominates over ERa in the rat prostate, while ERa >redominates over ERS3 in the rat uterus. The highest concentrations of ERp and mRNA were found in the ovaries (Couse et al. Endocrinology 138, 1997, pp. 4612-4613). Other organ systems with comparatively higher ER-expression comprise the bones Onoe, Y. et al., 1997, Endocrinology 138: 4509-4512), the vascular system (Register, T. C., kdams, M. R. 1998, J. Steroid Molec Biol 64: 187-191), the urogenital tract (Kuiper, G. J. M. et 1. 1997, Endocrinology 138: 863-870), the gastrointestinal tract (Campbell-Thopson 1997, 3BRC 240: 478-483), as well as the testis (Mosselmann, S. et al. 1996 FEBS Lett. 392, 49-53) 5 including the spermatides (Shugrue et al. 1998, Steroids 63: 498-504). The tissue distribution suggests that estrogens regulate organ functions via ER3. The fact that ER3 is functional in this espect also follows by studies in ERa- (ERKO) or ER-(#ERKO)-knockout mice: ovariectomy >roduces bone mass loss in ERKO-mice, which can be eliminated by estrogen substitution 'Kimbro et al. 1998, Abstract OR7-4, Endocrine Society Meeting, New Orleans). Estradiol in he blood vessels of female ERKO mice also inhibits vascular media and smooth muscle cell >roliferation (lafrati, M. D. et al. 1997, Nature Medicine 3: 545-548). These protective actions )f estradiol are carried out in the ERKO mouse presumably via ER)3. The fact that ERa and ERp have a functionally different action was confirmed after ;uccessful production of aERKO and PERKO mice. ERa consequently plays an important role n the adult uterus, in mammary gland tissue, in the negative regulation of the gonadotropin activity, while ERp is mainly bonded in the processes of ovarian physiology, especially that of olliculogenesis and ovulation (Couse et al., Endocrine Reviews 20, 1999, pp. 358-417). Observations of#3ERKO mice provide an indication on a function of ER3 in the prostate nd bladder: in the case of older male mice, symptoms of prostate and bladder hyperplasia occur Krege, J. H. et al. 1998, Proc Natl Acad Sci 95: 15677-15682). In addition, female ERKO mice Lubahn, D. B. et al. 1993, Proc Natl Acad Sci 90: 11162-11166) and male ERKO mice (Hess, R. A. et al. 1997, Nature 390: 509-512) as well as female #3ERKO mice (Krege, J. H., 1998, Proc Natl Acad Sci 95: 15677-15682) have fertility disorders. Consequently, the important function of estrogens with respect to maintaining testis and ovary functions as well as fertility is confirmed. It was possible to achieve a selective estrogenic action on specific target organs by subtype-specific ligands based on the different tissue or organ distribution of the two subtypes of the ERs. Substances with a preference for ER3 compared to ERa in the in-vitro receptor binding test were described by Kuiper et al. (Kuiper et al. (1996), Endocrinology 138: 863-870). A selective action of subtype-specific ligands of the estrogen receptor on estrogen-sensitive P \WPDOCS\CRPJX\Spc\250(4731 spe 4th SPA doc-I6AM/2009 -6 parameters in vivo was not previously shown. The invention seeks to provide compounds that have in vitro a dissociation with respect to the binding to estrogen receptor preparations from rat prostates and rat uteri. The compounds are to show in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri. The ERp-specific compounds are to produce in vivo a profertility action in the ovary. At the same time, the compounds are to exhibit a dissociation with respect to ovary action in comparison to uterus action. The compounds according to the invention are to have a certain protective action against hormone-deficiency-induced bone mass loss in comparison to uterus-stimulating action. In the broader sense, a structure-action relationship, which allows for access to compounds that have the above-formulated pharmacological profile, is to be made available by this invention. The compounds according to the invention are to produce enhanced fertility in the ovary while at the same time affecting the uterus very little in cases of ovarian-associated infertility. A first aspect of the invention provides a compound of the general formula I R13 R R R 1 R R O " 7. R7 in which radicals R 3 , R 7 , R , R9, R , R as well as R" and R', independently of one another, have the following meaning: R means a hydrogen atom or a group R4, in which P \WPDOCSiCRN\JXJSpee\ 5P473I se 4th SPA do.IMM4OK9 - 6A R8 4 means a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, an aryl, heteroaryl or aralkyl radical, a substituted aryl or heteroaryl radical with a methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(Ci-s-alkyl) or di(Ci.

8 -alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, carboxyl, carboxyalkoxy, Ci-C 2 0-acyl or Ci-C 2 o-acyloxy groups as substituents, an acyl radical COR' 9 , in which R 9 is a straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and is partially or completely halogenated, or R means a group R SO 2 , in which 20 21 22 21 22 R is an R R N group, whereby R and R , independently of one another, mean a hydrogen atom, a C,-C -alkyl radical, a group C(O)R , in which R represents a straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and is partially or completely halogenated, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, a C 4 -C 5 -cycloalkylalkyl radical with 3 to 7 carbon atoms in the cycloalkyl portion and with an alkyl portion of up to 8 carbon atoms or an aryl, heteroaryl or aralkyl radical, or a substituted aryl or heteroaryl radical, with a methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), P WPDOCS\CRN\JX1\Spec254731 sp 4th SPA do.23A)4/2(X9 - 6B hydroxy, amino, mono(C,.

8 -alkyl)- or di(CI- 8 -alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, carboxyl, carboxyalkoxy, CI-C 2 0-acyl or Ci-C 2 -- acyloxy groups as substituents, or, together with the N atom, a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical,

R

7 and R', in each case independently of one another, are a hydrogen atom or a halogen atom, R is a straight-chain or branched-chain alkenyl or alkinyl radical with 2 to 6 carbon atoms, which can be partially or completely fluorinated, or an ethinyl- or prop-1-inyl radical, R 1 is a methyl group or an ethyl group, R is a hydroxy group or a group R80-, R 2 0 S0 2 - or OC(0)R 2 1 with R' 8 , R 2 0 23 3 and R 2 in each case in the meaning that is indicated under R , R" and R', in each case independently of one another, are a hydrogen atom or a halogen atom. A second aspect of the invention provides a pharmaceutical composition comprising at least one compound according to the first aspect and a pharmaceutically compatible vehicle. A third aspect of the invention provides a use of a compound according to the first aspect in the manufacture of a medicament for the prevention or treatment of a disease or condition. A fourth aspect of the invention provides a method for the treatment of an estrogen deficiency-related disease and/or condition, the method comprising administering to a subject in need of such treatment a pharmaceutical composition comprising at least one compound according to the first aspect, wherein said estrogen-deficiency related disease and/or condition is selected from the group consisting of: peri- and postmenopausal symptoms, female infertility, ovarian dysfunction, hormone- P \WPDOCSXCRN\JXJ\Spcc\l25u4731 spcm 41h SPA dc-16)4/2(X)9 -6C deficiency-related bone mass loss, osteoporosis, cardiovascular diseases, prostate hyperplasia, diseases of the immune system, autoimmune diseases, rheumatoid arthritis and multiple sclerosis. The invention, provides 9a-substituted estra-1,3,5(10)-triene derivatives of general formula I 13 R17R | RR R O1R R R 0 R(I) P \WPDOCS\CRN\IXASpec\l2504731 spe 41h SPA docI6AM/2009 -7 in which radicals R 3 , R 7 , R , R 9 , RD, R as well as R'' and R' 7 , independently of one another, have the following meaning: 3 1 R means a hydrogen atom or a group R' , in which

R'

8 means a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, an aryl, heteroaryl or aralkyl radical, a substituted aryl, heteroaryl radical with a methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(Ci.g-alkyl)- or di(Ci.s-alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, carboxyl, carboxyalkoxy,

CI-C

2 0-acyl or Ci-C 2 o-acyloxy groups as substituents, an acyl radical COR' 9 , in which R is a straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and partially or completely halogenated, or R'8 means a group R SO 2 , in which 20 21 22 21 22 R is an R R N group, whereby R and R , independently of one another, mean a hydrogen atom, a C,-C 5 -alkyl radical, a 23 23 group C(O)R , in which R represents a straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is 8 saturated or unsaturated in up to three places and is partially or completely halogenated, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, a C 4 -C ,-cycloalkylalkyl radical with 3 to 7 carbon atoms in the cycloalkyl portion and with an alkyl portion of up to 8 carbon atoms or an aryl, heteroaryl or aralkyl radical, or a substituted aryl, or heteroaryl radical, with a methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(CI.8 alkyl)- or di(Ci .-- alkyl) amino, whereby both alkyl groups are identical or different, di (aralkyl)amino, whereby both aralkyl groups are identical or different, carboxyl, carboxyalkoxy, CI -C20 acyl or C 1 -C2o-acyloxy groups as substituents, or, together with the N atom, a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical,

R

7 and R 7 , in each case independently of one another, are a hydrogen atom or a halogen atom, 9 R is a straight-chain or branched-chain alkenyl or alkinyl radical with 2 to 6 carbon atoms, which can be partially or completely fluorinated, or an ethinyl- or prop-I inyl radical, R 1 is a methyl group or an ethyl group, 16 18 20 23 w8 20 23 R is a hydroxy group or a group R 0-, R SO 2 - or OC(O)R with R' , R and R 9 3 in each case in the meaning that is indicated under R , 17 17' R and R , in each case independently of one another, are a hydrogen atom or a halogen atom, R16 can in each case be in cx- or p-position. According to a variant of the invention, gonatriene derivatives are preferred, in which R 7 nd R 7 are a hydrogen atom, R 9 is a vinyl, ethinyl or prop-I -inyl group, R 6 is a hydroxy group, nd R and R in each case are a hydrogen atom. In addition, the following combinations of halogen substitution, preferably fluorine, in C 1717 toms 7 and 17 are preferred: 7-mono or 7-di and R as well as R", in each case a hydrogen, 17 iono or 17-di and R 7 as well as R , in each case a hydrogen as well as 7-mono/17-mono, 7 iono/17-di, 7-di/17-mono, 7-di/17-di. The 7ax-position or the 17p-position is preferred in the ionofluorine compounds. 16 Another variant of the invention in particular calls for compounds in which R stands for 18 20 18 20 group R 0- or R S0 2 -0- with R and R in each case in the meaning that is indicated under 3 Preferred according to this invention are the following compounds: 9a-Vinyl-estra- 1,3,5(1 0)-triene-3,16a-diol 9ca-Allyl-estra- 1,3,5(1 0)-triene-3,16ax-diol 18a-Homo-9ax-vinyl-estra- 1,3,5(1 0)-triene-3,16ax-diol 18a-Homo-9ax-allyl-estra- 1,3,5(1 0)-triene-3,16ca-diol 3-Methoxy-9c-vinyl-estra- 1,3,5(1 0)-trien- 1 6 ca-ol 9aL-Allyl-3-methoxy-estra-1,3,5(1 0)-trien- I 6ax-ol 10 I 8a-Homo-3 -rncthoxy-9cx-vinyI-estra- 1,3,5(1 O)-tnen-1 6ct-ol 1 8a-Homo-9cx-a11y-3-nethoxy-estra- 1,3,5(1 0)-trien- 1 6ct-ol 9(-2,'-Difluorovinyl)-estra- 1,3,5(1 O)-triene-3, 1 6e-dio1 9 cc-( 2 ',2' -Difluorovinyl)-3-methoxy-estra- 1,3,5(1 O)-tnen- 1 6 CC-ol I 6a-Hydroxy-9cc-viny1-estra- 1,3,5(1 O)-trien-3y1-sulfamate 9cx-AI Iyl-lI 6cc-hydroxy-estra- 1 ,3 ,5 (1 )-trien-3y1-sulfamate I 8a-Homo- 1 6ot-hydroxy-9Q-vinyl-estra- 1,3,5(1 O)-trien-3y1-sulfamate I 8a-Homo-9ce-aIlyI- I 6ce-hydroxy-estra- 1,3,5(1 O)-trien-3y1-sulfamate 9a-Vinyl-estra- 1,3,5(1 O)-triene-3,1I6ce-diyl-disulfamate 9c(-Allyl-estra- 1,3,5(1 O)-triene-3,1I6a-diyl-disulfamate 18 a-H omo-9x- vinyl -estra- 1,3,5(1 O)-triene-3, 1 6c-diyl-disulfamate 1 8a-Homo-9cc-al lyl-estra- 1,3,5(1 O)-triene-3,1I6ci-diyl-disulfamate 1 6cx-Hydroxy-9cc-vinyi-estra- 1,3,5(1 O)-trien-3y]-(N-acetyl)-sulfamate 9cc-AllyI- 1 6cc-hydroxy-estra- 1,3,5(1 0)-trien-3y1-(N-acetyl)-sulfamate I 8a-Homo- 1 6cx-hydroxy-9ct-viny1-estra- 1,3,5(1 O)-trien-3y1-(N-acetyl)-sulfamate I 8a-Homo-9cc-aIlyI- 1 6ax-hydroxy-estra- 1,3,5(1 O)-trien-3y1-(N-acetyl)-sulfarnate 9ct-(Prop-(Z)-enyl)-estra- 1,3,5(1 O)-triene-3, I6ca-dioI 9ac-(n-Propyl)-estra- 1,3,5(1 O)-tiene-3, 1 6-dioI 9cc-Ethiny1-estra- 1,3,5(1 O)-triene-3,1I6cc-diol 9a-Vinyi-estra- 1,3,5(1 O)-triene-3, 1 6(-dioI-diacetate 1 8a-Homo-9a-vinyl-estra- 1,3,5(1 O)-tri ene-3,1I6cc-dio I-di acetate 1 6i-Valeroyloxy-9cx-vinyI-estra- 1,3,5(1 O)-trien-3-oI 11 16ax-Acetoxy-9a-vinyl-estra- 1,3,5(1 0)-trien-3-ol 18a-Homo- 1 6a-acetoxy-9a-vinyl-estra- 1,3,5(1 0)-trien-3-ol 7t-Fluoro-9c-vinyl-estra- 1,3,5(1 0)-triene-3,16a-diol 7ca-Fluoro-9ca-allyl-estra- 1,3,5(1 0)-triene-3,16x-diol 17p-Fluoro-9a-vinyl-estra- 1,3,5(1 0)-triene-3,1 6a-diol I 7p-Fluoro-9a-allyl-estra- 1,3,5(1 0)-triene-3,16c-diol 18a-Homo-7ax-fluoro-9ca-vinyl-estra- 1,3,5(1 0)-triene-3,16ax-diol 18a-Homo-7L-fluoro-9a-allyl-estra- 1,3,5(1 0)-triene-3,16c-diol 18a-Homo- 1 7p-fluoro-9c-vinyl-estra- 1,3,5(1 0)-triene-3,1 6a-diol 18a-Homo- 1 7p-fluoro-9ax-allyl-estra- 1,3,5(1 0)-triene-3,16a-diol Other possible configurations of this invention will emerge from the subclaims. 18 Hydrocarbon radical R is, for example, a methyl, ethyl, propyl, isopropyl, butyl, sobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, or hexyl radical. 18 Alkoxy groups OR in the compounds of general formula I in each case can contain 1 to carbon atoms, whereby methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred. Representatives of the C1-C5-alkyl radicals R and R are methyl, ethyl, propyl, sopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl. As representatives of straight-chain or branched-chain hydrocarbon radicals R 23 with 1 to i maximum of 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl can be mentioned; methyl, ethyl, >ropyl and isopropyl are preferred.

12 As a C 3 -C7-cycloalkyl group, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or ycloheptyl group can be mentioned. A C 4 -Cis-cycloalkylalkyl radical has 3 to 7 carbon atoms in the cycloalkyl portion; typical epresentatives are the cycloalkyl groups that are mentioned directly above. The alkyl portion as up to 8 carbon atoms. As examples of a C4-C]5-cycloalkylalkyl radical, the cyclopropylmethyl, yclopropylethyl, cyclopentylmethyl, cyclopentylpropyl groups, etc., can be mentioned. In terms of this invention, an aryl radical is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred. Aryl always also includes a heteroaryl radical. Examples of a heteroaryl radical are the -, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2-or 3-pyrrolyl, the 2-, 4- or 5 nidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical. As substituents that can be present on an aryl or heteroaryl radical, for example, a iethyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, itro-, cyano-, halogen- (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(CI.8 alkyl) )r di(Ci-s alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, carboxyl, carboxyalkoxy, CI-C2o-acyl or i-C2o-acyloxy groups can be mentioned. An aralkyl radical is a radical that contains in the ring up to 14, preferably 6 to 10, C itoms, and in the alkyl chain 1 to 8, preferably 1 to 4, C atoms. Thus, as aralkyl radicals, for xample, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and >yridylpropyl are suitable.

13 The alkyl groups or hydrocarbon radicals can be partially or completely substituted by 1-5 halogen atoms, hydroxy groups or Ci-C 4 -alkoxy groups. A vinyl or allyl radical is primarily defined with a C2-C6-alkenyl radical. A C 2

-C

6 -alkinyl radical is preferably defined as an ethinyl radical or a prop-1-inyl radical. Ci.io-Acyl radicals mean, for example, acetyl, propionyl, butyryl, valeroyl, isovaleroyl, >ivaloyl, hexanoyl, octyl, nonyl, or decanoyl. One or two hydroxyl groups at C atoms 3 and 16 can be esterified with an aliphatic, ;traight-chain or branched-chain, saturated or unsaturated CI-C14-mono- or polycarboxylic acid >r an aromatic carboxylic acid. Suitable as such carboxylic acids for esterification are, for example: Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric icid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propionic Lcid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, and 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, and 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, and isonicotinic acid. Esterification with benzoic acid is preferred. As prodrugs, the esters of the 9ax-substituted estratrienes according to the invention have 14 idvantages compared to the unesterified active ingredients with respect to their method of idministration, their type of action, strength and duration of action. Especially the sulfamates of 9c-substituted estratnienes according to the invention have )harmacokinetic and pharmacodynamic advantages. Related effects were already described in >ther steroid-sulfamates (J. Steroid Biochem. Molec. Biol, 55, 395-403 (1995); Exp. Opinion nvest. Drugs 7, 575-589 (1998)). In this patent application, steroids on which the 9a-substituted estra-1,3,5(l0)-triene keleton is based are described for the treatment of estrogen receptor -mediated disorders and conditions as selective estrogens, which have in-vitro dissociation with respect to their binding to strogen receptor preparations from rat prostates and rat uteri and which have in vivo preferably a issociation with respect to ovary action in comparison to uterus action. In addition, the ompounds have a certain protective action against hormone-deficiency-induced bone mass loss. It was found that the 9a-substituted estra-1,3,5(l0)-trienes according to general formula I re suitable as selective estrogens for the treatment of various conditions and disorders that are haracterized by a higher content of estrogen receptor fl than estrogen receptor a in the -orresponding target tissue or target organ. The invention also relates to pharmaceutical preparations that contain at least one ompound of general formula I (or physiologically compatible addition salts with organic and norganic acids thereof) and the use of the compounds of general formula I for the production of )harmaceutical agents, especially for the indications mentioned below. The new selective estrogens that are described here can be used as individual components n pharmaceutical preparations or in combination especially with gestagens. Especially preferred is the combination of selective estrogens with ERa-selective antiestrogens that are peripherally selectively active, i.e., that do not pass through the blood-brain barriers, as well as with selective ,strogen receptor modulators (SERM). The ERp-selective compounds according to the nvention can be used in particular for the production of pharmaceutical agents for treating Fertility disorders, for prevention and therapy of prostate hyperplasia, for prevention and reatment of hormone-deficiency-induced mood swings in women and men and for use in iormone replacement therapy (HRT) in men and women. A therapeutic product that contains an estrogen and a pure antiestrogen for simultaneous, ;equential or separate use for the selective estrogen therapy of perimenopausal or >ostmenopausal conditions is already described in EP-A 0 346 014. Because of their dissociation of action in the ovary in comparison to the action of the iterus, the substances and the pharmaceutical agents that contain them are especially suitable for he treatment in the case of ovarian dysfunction that is caused by surgery, medication, etc., such s female infertility for stimulation of folliculogenesis for treatment by itself in terms of :nhanced fertility, for supporting in-vitro fertility treatment (IVF) in connection with an in-vivo treatment and for treatment of ovarian-induced disorders in later age ("late fertility") as well as for treatment of hormone-deficiency-induced symptoms. The substances are also suitable for therapy of ovarian diseases such as polycystic ovarian syndrome, POF (premature ovarian failure) syndrome, and ovulation disorders. Finally, the compounds of general formula I can be used in connection with selective estrogen receptor modulators (SERM) or raloxifene, specifically in particular for use in hormone replacement therapy (HRT) and for treatment of gynecological disorders.

16 The substances are also suitable as individual components for the treatment of >erimenospausal and postmenopausal symptoms, in particular hot flashes, sleep disturbances, rritability, mood swings, incontinence, vaginal atrophy and hormone-deficiency-induced mental lisorders. The substances are also suitable for hormone substitution and for the therapy of iormone-deficiency-induced symptoms in ovarian dysfunction that is caused by surgery, nedication, etc. In addition, the substances can also be used to prevent hormone-deficiency-induced bone nass loss and osteoporosis, to prevent cardiovascular system diseases, in particular vascular liseases such as arteriosclerosis, high blood pressure and to prevent hormone-deficiency-induced ieurodegenerative diseases, such as Alzheimer's disease, as well as hormone-deficiency-induced impairment of memory and learning capacity. In addition, the substances can be used as active ingredients in preparations for treating nflammatory diseases and diseases of the immune system, in particular autoimmune diseases, uch as, e.g., rheumatoid arthritis, multiple sclerosis, lupus, Crohn's disease and other inflammatory intestinal diseases, inflammatory diseases of the skin, such as psoriasis, as well as for treating endometriosis. In addition, the substances are effective against inflammatory diseases of the respiratory system, the lungs and bronchial tubes, such as, e.g., asthma. The medication is suitable for therapy and prophylaxis of estrogen-deficiency-induced diseases both in women and in men. In men, the compounds are especially suitable for therapy of hormone-deficiency-induced bone mass loss and osteoporosis, for prevention of cardiovascular diseases, in particular vascular 17 diseases such as arteriosclerosis, high blood pressure and for prevention of hormone-deficiency nduced neurodegenerative diseases, such as Alzheimer's disease, as well as hormone-deficiency nduced impairment of memory and learning capacity, and are suitable for prevention and therapy f prostate hyperplasia. The substances can be used for prophylaxis and therapy of age-related dysfunctions or diseases of men. In particular, they can be used for prevention and treatment of an age-related rop of androgens, such as testosterone and DHEA, as well as of the growth hormone. In addition, the medication can be used for treating inflammatory diseases and diseases of ie immune system, in particular autoimmune diseases in men, such as, e.g., rheumatoid arthritis, 4S (multiple sclerosis) and Crohn's disease and other inflammatory intestinal diseases, as well s inflammatory diseases of the respiratory system, the lungs, and the bronchial tubes. The mount of a compound of general formula I that is to be administered fluctuates within a wide nge and can cover any effective amount. On the basis of the condition that is to be treated and ie type of administration, the amount of the compound that is administered can be 0.01 jig/kg 00 mg/kg of body weight, preferably 0.04 yig/kg - 1 mg/kg of body weight, per day. In humans, this corresponds to a dose of 0.8 jig to 8 g, preferably 3.2 sg to 80 mg, daily. According to the invention, a dosage unit contains 1.6 pg to 2000 mg of one or more ompounds of general formula I. The compounds according to the invention and the acid addition salts are suitable for the roduction of pharmaceutical compositions and preparations. The pharmaceutical compositions >r pharmaceutical agents contain as active ingredients one or more of the compounds according o the invention or their acid addition salts, optionally mixed with other pharmacologically or 18 Pharmaceutically active substances. The production of the pharmaceutical agents is carried out .n a known way, whereby the known and commonly used pharmaceutical adjuvants as well as )ther commonly used vehicles and diluents can be used. As such vehicles and adjuvants, for example, those are suitable that are recommended or ndicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and elated fields: Ullmans Encyklopadie der technischen Chemie [Ullman's Encyclopedia of [echnical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., issued by Czetsch-Lindenwald, Hilfsstoffe flir Pharmazie und ingrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 961, p. 72 and ff: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fir Pharmazie, Kosmetik und .ngrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related fields , Cantor KG, Aulendorf in Wurttemberg 1971. The compounds can be administered orally or parenterally, for example intraperitoneally, ntramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the issue. For oral administration, capsules, pills, tablets, coated tablets, etc., are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc. For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, very often oils with or without the addition of a solubilizer, a surfactant, a suspending agent or an emulsifying agent are used. Examples of oils hat are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

P \WPDOCSTCRN\JXJ\SpcX] 2504731 spcc 4th SPA doc. IM4/2109 -19 The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated so that a delayed release of active ingredient is made possible. As inert materials, implants can contain, for example, biodegradable polymers, or synthetic silicones such as, for example, silicone rubber. In addition, for percutaneous administration, the active ingredients can be added to, for example, a patch. For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, coils, IUDs, Mirena(R)) that are loaded with active compounds of general formula I for local administration, various polymers are suitable, such as, for example, silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene. To achieve better bio-availability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with a-, p-, or y-cyclodextrin or derivatives of the latter (PCT/EP95/02656). According to the invention, the compounds of general formula I can also be encapsulated with liposomes. Brief Description of the Drawings The present invention is described, by way of non-limiting example only, with reference to the accompanying drawings. Fig. 1: Change in the ovary weight under the influence of a GnRH antagonist in the treatment with estradiol (Sub3) or various dosages of compound 2. (Ovar = Ovary; Feuchtgewicht (%) = Moist weight (%); 0,1 mg = 0.1 mg; 0,3 mg = 0.3 mg; 1,0 mg = 1.0 mg) Fig. 2: Positive effect of compound 2 in low dosage on the ovary weight during a combination treatment with the GnRH antagonist Cetrorelix. (Ovar = Ovary; Feuchtgewicht (%) = Moist weight (%); 0,003 mg = 0.003 mg; 0,01 mg = 0.01 mg; 0,03 mg =0.03 mg; 0,1 mg = 0.1 mg) P \WPDOCS\MDT\SpcsW2504731 doc- 2109/06 - 19a Methods Estrogen Receptor Binding Studies: The binding affinity of the new selective estrogens was tested in competitive experiments with use of 3 H-estradiol as a ligand to estrogen receptor preparations from rat 5 prostates and rat uteri. The preparation of prostate cytosol and the estrogen receptor test with prostate cytosol was carried out as described by Testas et al. (1981) (Testas, J. et al., 1981, Endocrinology 109: 1287- 20 1289). The preparation of rat uterus cytosol as well as the receptor test with the ER-containing .ytosol were basically performed as described by Stack and Gorski, (1985) (Stack, Gorski 1985, endocrinology 117, 2024-2032) with some modifications as described in Fuhrmann et al. (1995) Fuhrmann, U. et al. 1995, Contraception 51: 45-52). The substances that are described here have higher binding affinity to the estrogen eceptor of rat prostates than to estrogen receptors of rat uteri. In this case, it is assumed that Rj predominates in the rat prostates over ERa, and ERa predominates in rat uteri over ER3. Fable 1 shows that the ratio of the binding to prostate and uterus receptors qualitatively coincides vith the quotient of relative binding affinity (RBA) to human ER#3 and ERa of rats (according to .uiper et al. (1996), Endocrinology 138: 863-870) (Table 1).

21 Fable I Estrogen Structure hERa hERfl ER#/ Rat uterus Rat prost. prost. RBA* RBA* ERa ER(RBA) ER(RBA) ER/uterus ER Estradiol 100 100 1 100 100 1 Estrone 60 37 0.6 3 2 0.8 17a-Estra- 58 11 0.2 2.4 1.3 0.5 diol Estriol 14 21 1.5 4 20 5 5-Andro- 6 17 3 0.1 5 50 stene-diol Genisteine 5 36 7 0.1 10 100 Coumes- 94 185 2 1.3 24 18 trol Cited from: Kuiper et al. (1996), Endocrinology 138: 863-870 Table 2 shows the results for 4 of the 9c-vinyl-estra-1,3,5(10)-triene-3,16a-diol derivatives (compounds 1; 2; 4; 5) according to the invention.

22 fable 2 compound RBA RBA Rat Uterus Rat Prostate a-Vinyl-estra-1,3,5(10)- 1.2 100 ,16c-diol (1) a-Vinyl-estra-1,3,5(10)-17F- 2 200 ,16ct-diol (2) c-Di-F-Vinyl-estra- 0.2 4 ,3,5(10)-3,l6ca-diol (4) ca-Di-F-Vinyl-estra- 0.2 6 ,3,5(10)-13-Methyl-3,16ct jol (5) Compounds 1; 2; 4; 5 according to the invention show a higher binding affinity to the strogen receptor of rat prostates than to the estrogen receptor of rat uteri. In addition, the predictability of the prostate-ER versus the uterus-ER test system was :onfirmed with respect to tissue-selective action by in-vivo studies. Substances with a reference for prostate-ER are dissociated in vivo preferably with respect to ovary and uterus action as well as pituitary gland action in favor of action on the ovary. Studies for Dissociation of Action of the Ovary/Uterus and Pituitary Gland The studies with respect to the action on uterus growth and ovulation (indirect effect by nfluencing the secretion of pituitary gland hormones) are performed on adult female rats (body eight of 220-250 g). The substances are subcutaneously administered four times on four -onsecutive days. The first administration is carried out in the metestrus. One day after the last 23 administration, the autopsy is carried out. The number of ovocytes in the tube (effect on the >vulation) as well as the uterus weight are determined. While estradiol produces a dose-dependent ovulation inhibition and an increase in uterus eight with an EDso of 0.004 mg/kg of body weight, substance I according to the invention up to i dose of 0.4 mg/kg of body weight does not exert any effect on ovulation and uterus weight. vary Studies: The substances were tested in vivo on hypophysectomized juvenile rats. In a nodification of this operative method, a GnRH antagonist is administered to the animals. It is -xamined whether the substance stimulates follicular proliferation (maturation) in the ovary. The >vary weight is the measurement parameter. In each case, five animals (body weight 40-50 g) are assigned randomly to the treatment ;roups. The animals are fed as much as they want with a standard diet (altromin) in Makrolon ages in air-conditioned rooms with a lighting program (10 hours of darkness, 14 hours of light) nd are given acidified tap water to drink. For the s.c administration, the test substance as well as ie control substance (estradiol E2) are dissolved in benzylbenzoate/castor oil (1+4 v/v). Juvenile female rats are either hypophysectomized on day 0 and subcutaneously treated (administration 1 x daily) from day I to day 4 with estradiol, compound 1 or 2 according to the nvention, or subcutaneously treated (administration 1 x daily) with a vehicle (castor oil/benzyl benzoate). In the modified version of the method, 0.5 mg/animal/day of Cetrorelix is administered to the animals simultaneously with compound 2 or the vehicle and the control substance estradiol over four days of treatment. In both cases, the animals are sacrificed 24 hours after the last administration, and the ovary weight is determined. 0.5 mg/animal/day of compound 1 that is administered subcutaneously over 4 days )roduces a comparable increase in ovary weight in hypophysectomized animals like estradiol xith a dose of 0.1 mg/animal/day. The vehicle does not produce any effect.

P:\WPDOCS\MDT\Spcs\1250473 1 doc-21/09/06 - 24 Substance 1 according to the invention thus shows a clear dissociation of action in the ovary in comparison to the uterus action and the pituitary gland action and is excellently suited for the preferred indication, the treatment of female infertility, because of its follicle-stimulating action. 5 In the GnRH antagonist-treated animals, concentrations of 0.1 and 0.3 mg/animal/day of compound 2 in the ovary already show the same action as the dose of 1 mg/animal/day of estradiol that is used (Fig. 1). Even lower dosages (0.01, 0.03 mg/animal/day) show an ovary action and can eliminate the antagonistic effect of Cetrorelix (Fig. 2). 10 Substance 2 according to the invention thus also shows a clearly positive action on the ovary by stimulating the follicular maturation and therefore is also suitable for the treatment of female sub- or infertility.

P \WPDOCSWDrSpecs\2504731 doc.21/9/06 - 25 This page has been intentionally left blank P :WPDOCS\MD7Spsi2 504731 doc.21/09/06 - 26 This page has been intentionally left blank P:\WPDOCS\MDT\Spccs\l254731doc-21/09/06 - 27 This page has been intentionally left blank 28 Production of the Compounds According to the Invention For the production of the compounds of general formula I according to the invention, primarily two synthesis strategies that can generally be applied are used. On the one hand, in particular 3,16-protected derivatives of estra-1,3,5(10)-triene-3,16 diols, but also optionally the free diols, can be used for modifications of individual positions of the steroid skeleton. On the other hand, correspondingly modified estrone analogs, which can be obtained in large numbers in known ways [for a typical synthesis process, see J. Chem. Soc. Perk. 1, 1973, 2095 for C(9); Steroids 54, 1989, 71 for C(7)], include a flexible access to the compounds according to the invention by transposition of oxygen functionality (Z. Chem. 1970, 221) from 2(17) to C(16). For the case of the 3-methyl ether, after the ketone is converted into a sulfonyl hydrazone, he formation of the C(16)-C(17) olefin (Z. Chem. 1970, 10, 221 ff; Liebigs Ann. Chem. 1981, 1973 ff), in which hypobromide is stored in a regio-/stereo-controlled way, is carried out in the simplest case by reaction with phenyl sulfonylhydrazide, in a degradation reaction. Reductive dehalogenation and removal of the protective group of C(3) yield the 16p-alcohol, which can be converted according to known methods into the 1 6a-epimer. Another variant for the introduction of the hydroxyl group at C-atom 16 is in the hydroboration of the 16(17)-double bond with sterically exacting boranes. It is known of this reaction that it results in 16-oxidized products (Indian J. Chem. 1971, 9, 287-8). Consequently, the reaction of estra- 1,3,5(10),16-tetraenes with, for example, 9-borabicyclo[3.3.1 ]nonane after 29 )xidation with alkaline hydrogen peroxide yields 16a-hydroxyestratrienes. To a lesser extent, he epimeric 16p-hydroxy steroids are formed in this reaction. After the cleavage of the 3 nethoxy group, estra-1,3,5(10)-triene-3,16a-diols are obtained. By inversion of the .onfiguration at C-atom 16, e.g., by Mitsunobu reaction (synthesis 1980, 1), in turn the 16p iydroxyestratrienes are obtained. For further production possibilities of the C(16)-C(17) olefinic intermediate stage, see Iso DE 199 06 159 A]. The introduction of fluorine substituents is carried out via nucleophilic substitution eactions of hydroxyl groups with fluoroamine reagents (Org. React. 1974, 21, 158-173). If the hydroxyl groups are converted into the corresponding tosylates in advance, then the fluorinated ompounds are obtained by reaction with tetra-n-butylammonium fluoride (J. Chem. Res. (M) 979, pp. 4728-4755). Fluorine compounds are also accessible by reaction of corresponding lcohols with diethylamino sulfur trifluoride (DAST) (US 3 976 691). Geminal di fluorine ompounds are produced, for example, by reaction of carbonyl compounds with sulfur strafluoride (US 3 413 321) or diethylamino sulfur trifluoride (DAST) (US 3 979 691). For synthesis of the 9a-substituted 17p-fluoroestra- 1,3,5(1 0)-triene-3,l6-diols according o the invention, 17-oxo-estral,3,5(10)-trienes are converted into the 17,17-difluoroestra 1,3,5(10)-trienes (US 3 976 691). The thus accessible 17,17-difluoroestra-1,3,5(10)-trienes are :onverted by treatment with aluminum oxide into 17-fluoroestra-1,3,5(10),16-tetraene (US 3 413 321). Another possibility for the production of fluoro-olefins exists in the reaction of the .orresponding ketones with diethylamino sulfur trifluoride (DAST) in the presence of polar :atalysts, such as fuming sulfuric acid (US 4 212 815). The reaction of 17-fluoroestra- 30 1,3,5(10),16-tetraenes with boranes and subsequent oxidation with alkaline hydrogen peroxide yields the 17p-fluoroestra-1,3,5(10)-trien-16ca-ols (Org. React. 1963, 13, 1-54). Access to the 9a-alkenyl- or 9c-alkinyl-substituted estra- 1,3,5(1 0)-triene-3,1 6a-diols iccording to the invention is carried out first from the 3,16-dihydroxy-estra-1,3,5(10)-trienes that ire protected in 3- and 16-position. By reaction with trimethyl silyl cyanide in the presence of ithium perchlorate, the regio- and stereoselective introduction of a 9a-cyano grouping (Synlett, .992, 821-2) is carried out. After the protective groups are cleaved, the 9a-cyano compound is :onverted by reduction first into a 9a-formyl compound and then by a Wittig reaction (Org. eact. Vol. 14, 270) into the 9a-alkenyl- or 9a-alkinyl-substituted compound. The estratriene sulfamates according to the invention are accessible in a way that is known in the art from the corresponding hydroxy steroids by esterification with sulfamoyl hlorides in the presence of a base [Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)]. Subsequent acylation of the sulfamate group results in the (N-acyl)sulfamates according o the invention. For the (N-acyl)sulfamates, pharmacokinetic advantages were already detected cf. DE 195 40 233 Al). The regioselective esterification of polyhydroxylated steroids with N-substituted and N unsubstituted sulfamoyl chlorides is carried out after partial protection of those hydroxyl groups that are to remain unesterified. Silyl ethers have turned out to be protective groups with selective reactivity that is suitable for this purpose since these silyl ethers are stable under the conditions of sulfamate formation, and the sulfamate group remains intact when the silyl ether(s) is (are) again cleaved for regeneration of the (residual) hydroxyl group(s) still contained in the molecule (Steroids 61, 710-717 (1996)).

31 The production of the sulfamates according to the invention with an additional hydroxyl ;roup in the molecule is also possible in that the starting material is suitable hydroxy-steroid :etones. First, depending on the goal, one or more hydroxyl groups that are present are subjected o sulfamoylation. Then, the sulfamate groups optionally can be converted with a desired acyl hloride in the presence of a base into the (N-acyl)sulfamates in question. The now present xosulfamates or oxo-(N-acyl)sulfamates are converted by reduction into the corresponding ydroxysulfamates or hydroxy-(N-acyl)sulfamates (Steroids 61, 710-717 (1996)). Sodium orohydride and the borane-dimethyl sulfide complex are considered as suitable reducing agents. The examples below are used for a more detailed explanation of the invention. Analogously to the degradation of the 9c-vinyl grouping, other compounds of general >rmula I can be obtained with use of reagents that are homologous to the reagents that are escribed in the examples. Etherification and/or esterification of free hydroxy groups is carried out according to the methods that are common to one skilled in the art.

32 examplee 1 a-Vinylestra-1,3,5(1 0)-triene-3,16cc-diol stage 1 a-Cyano-3-methoxy-estra-1,3,5(10)-trien-1 6a-yl-acetate A solution of 2.21 g (9.73 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 80 ml f methylene chloride is added drop by drop while being stirred to a suspension that consists of .13 g (6.49 mmol) of 3-methoxy-estra-1,3,5(10)-trien-16a-y-acetate, 2.07 ml (16.54 mmol) of imethylsilyl cyanide and 0.14 g of lithium perchlorate in 100 ml of methylene chloride. The action mixture is green in color. After 1 hour of reaction time at room temperature, the mixture mixed with sodium bicarbonate solution. The separated organic phase is washed with water id concentrated by evaporation in a vacuum. The product mixture is chromatographed on silica 1I (cyclohexane/ethyl acetate, 6/1). 0.44 g (21%) of 9ax-cyano-3-methoxy-estra-1,3,5(1 0)-trien Sca-yl-acetate is obtained. 'tage 2 a-Cyano-3-hydroxy-estra-1,3,5(1 0)-trien-1 6a-yl-acetate 7.51 g (50.1 mmol) of sodium iodide and 8.87 ml (70.14 mmol) of trimethylchlorosilane re added to a solution that consists of 0.59 g (1.67 mmol) of 9a-cyano-3-methoxy-estra ,3,5(l0)-trien-16a-yl-acetate in 30 ml of acetonitrile while being stirred in an argon atmosphere. kfter about 3 hours at 60-70'C, the reaction is completed. The reaction solution is added to 33 sodium hydrogen sulfite solution and extracted with ethyl acetate. The organic phase is washed several times with water, dried on MgSO4 and concentrated by evaporation in a vacuum to the fry state. The crude product is chromatographed on silica gel (cyclohexane/ethyl acetate, 4/1). 0.43 (76%) of product is obtained. itage 3 16a-Dihydroxyestra-1,3,5(1 0)-triene-9 carbonitrile At room temperature, 0.43 g (1.27 mmol) of 9c-cyano-3-hydroxy-estra-1,3,5(10)-trien 6a-yl-acetate is stirred for 2 hours with 1.0 g (7.24 mmol) of potassium carbonate in 40 ml of riethanol (1% water). Then, the methanol is distilled off in a vacuum, and the organic residue is dissolved in methylene chloride. The organic phase is washed with water and concentrated by vaporation. 3.5 g (93%) of 9x-cyano-estra- 1,3,5(1 0)-triene-3,16a-diol is obtained. stage 4 3,16a-Dihydroxyestra-1,3,5(10)-triene-9 carbaldehyde A suspension that consists of 100 mg (0.34 mmol) of 3,16a-dihydroxyestra-1,3,5(10) triene-9 carbonitrile in 40 ml of toluene is cooled to about -20'C while being stirred. After 0.9 il (1.35 mmol) of diisobutylaluminium hydride is added, the reaction is mixed after about 10 rninutes with sodium bicarbonate solution, filtered over Celite, and the filtering adjuvant is -xtracted again with ethyl acetate. The combined organic phases are washed with water. By ,oncentration by evaporation of the solution in a vacuum, 84.6 mg of a light yellow foam is 34 )btained. The product that is contained in the mixture corresponds to a yield of about 52% of heory and is used without further chromatographic working-up in the next stage. 'tage 5 )a- Vinylestra-1,3,5(10)-triene-3,16a-diol Under inert-gas atmosphere, 3.1 g (7.9 mmol) of triphenylmethyl phosphonium iodide nd 0.24 g (8 mmol) of sodium hydride (80% in paraffin oil) in 20 ml of DMSO in an ultrasound ath are brought to reaction at about 55*C. After 10 minutes, 80 mg (0.16 mmol, about 60%) of ,16a-dihydroxyestra-1,3,5(10)-triene-9 carbaldehyde is added to the solution, and the mixture is Ilowed to react for 60 more minutes at about 55*C in an ultrasound bath. After water is added, it s extracted with ethyl acetate. The collected organic phases are washed with water, and the rganic phase is concentrated by evaporation in a vacuum. The crude product is purified by column chromatography on silica gel (cyclohexane/ethyl cetate, 2/1) and subsequent recrystallization from chloroform. Yield: 24 mg (50%), melting oint 88-95'C. H-NMR (400 MHz, DMSO-d 6 , TMS): 9.00 (s, 3-OH); 6.98 (d, J = 8.6 Hz, H-1); 6.49 [dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 6.25 (dd, J = 17.2/10.5 Hz, -CH=CH 2 ); 5.00 dd, 10.5/1.9 Hz, -CH=CH 2 ); 4.47 (d, 4.69 Hz, 16ax-OH); 4.45 (dd, 17.2/1.9 Hz, -CH=_LH2); 4.24 m, 16p-H); 2.68 (m, H-6); 0.69 (s, H-18) 35 Example 2 ac-Vinyl-18a-homo-estra-1,3,5(10)-triene-3,1 6a-dioI 'tage 1 16a-Bis[(perhydropyran-2-yl)oxy]-I8a-homo-estra-1,3,5(10)-triene-9-carbonitrile 1.03 g (2.26 mmol) of 3,16c-bis[(perhydropyran-2-yl)oxy]-I 8a-homo-estra-1,3,5(10) riene, 48.2 mg (0.45 mmol) of lithium perchlorate and 0.71 ml (5.66 mmol) of trimethylsilyl yanide are introduced into 10 ml of methylene chloride (molecular sieve) and cooled under inert as to about -70'C while being stirred. Then, 0.77 g (3.39 mmol) of 2,3-dichloro-5,6-dicyano ,4-benzoquinone, dissolved in 65 ml of methylene chloride, is added in drops within 1 hour. Lfter about 1 hour (heating to room temperature), the reaction solution is mixed with sodium icarbonate solution, and the reaction products are extracted with methylene chloride. The crude roduct that is obtained by concentration by evaporation of the organic phases is purified by bromatography. After chromatography on silica gel (cyclohexane/ethyl acetate, 4/1), 0.74 g 58% of theory) of product is obtained. stagee 2 16a-Dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde 1.3 g (2.7 mmol) of 3,16a-bis[(perhydropyran-2-yl)oxy]- 1 8a-homo-estra- 1,3,5(1 0)-triene )-carbonitrile is dissolved in 40 ml of toluene and mixed at room temperature under inert gas vith 7.2 ml (10.8 mmol) of diisobutylaluminum hydride solution (1.5 M in toluene). After a action time of 30 minutes, a mixture of 30 ml of methanol and 5 ml of dilute hydrochloric acid 36 1/1) is added to the reaction solution. The reaction solution is concentrated by evaporation inder vacuum, and the residue is taken up in ethyl acetate. The organic phase that is obtained is xtracted with water and washed with sodium bicarbonate solution. After the solution is dried, nd after concentration by evaporation under vacuum, 0.73 g (86% of theory) of yellow crystals s obtained. 'tage 3 'a- Vinyl-I 8a-homo-estra- 1, 3,5(1 0)-triene-3,16a-diol Under inert gas atmosphere, 13.7 g (34.8 mmol) of triphenylmethyl-phosphonium iodide nd 1.0 g (34.8 mmol) of sodium hydride (about 80% on paraffin oil) in 80 ml of DMSO is rought to reaction in an ultrasound bath at about 50'C. After 30 minutes, 0.73 g (2.3 mmol) of I 6a-dihydroxy- I 8a-homo-estra- 1,3,5(1 0)-triene-9-carbaldehyde, dissolved in 10 ml of DMSO, added to the reaction solution, and the mixture is allowed to react in an ultrasound bath for other 60 minutes. After water is added, it is extracted with ethyl acetate, the organic phase is 'ashed with water, dried and concentrated by evaporation. The crude product is purified by column chromatography on silica gel (cyclohexane/ethyl cetate, 2/1) and crystallization from chloroform. Yield: 0.59 g (81% of theory) after chromatography Melting point: 214 - 220'C H-NMR (400 MHz, DMSO-d 6 , TMS): 9.00 (s, 3-OH); 6.96 (d, J = 8.6 Hz, H-1); 6.49 dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 6.29 (dd, J = 17.2/10.5 Hz, -CH=CH 2 ); 5.00 dd, J = 10.5/1.9 Hz, -CH=_CH); 4.48 (d, J = 4.7 Hz, 16at-OH); 4.43 (dd, J = 17.2/1.9 Hz, 37 CH=CHq); 4.18 (m, 16p-H); 2.68 (m, H-6); 0.72 (t, J = 6.8 Hz, H-18a) xample 3 a~-(2',2'-Difluorovinyl)-estra-1,3,5(10)-triene-3,16ax-dioI tage 1 ,16a-Bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-estra- 1,3,5(1 0)-triene analogously to xample 1, stage I yields 3,16c-bis[(perhydropyran-2-yl)oxy]-estra- 1,3,5(1 0)-triene-9 arbonitrile. Yield: 58% of theory age 2 16a-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde Reaction of 3,1 6a-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile nalogously to Example 1, stage 2 yields 3,16c-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde. Yield: 83% of theory tage 3 a-( 2 ,2-Difluorovinyl)-estra-1,3,5(10)-triene-3,16a-diol 1.5 ml of dimethoxyethane (molecular sieve), 0.3 ml of pentane and 0.13 ml (0.77 mmol) 38 >f diethyl(difluoromethyl)-phosphonate are introduced into a reaction flask that was rendered nert, and cooled to about -75*C. After 0.72 ml (1.07 mmol) of tert-butyllithium (1.5 M in entane) is added and after 30 minutes of reaction time, 0.14 g (0.31 mmol) of 3,16-dihydroxy stra-1,3,5(10)-triene-9-carbaldehyde, dissolved in a mixture of 1.5 ml of dimethoxyethane/0.3 11 of pentane, is added to the reaction solution. The reaction solution is refluxed until the action is completed. After being added into cooled ammonium chloride solution, it is extracted tith ethyl acetate. The organic phase is concentrated by evaporation under vacuum, the residue taken up in 5 ml of methanol and mixed with 0.5 ml of dilute hydrochloric acid (1/1). Ethyl cetate is added to the reaction solution, the organic phase is washed with sodium bicarbonate solution and concentrated by evaporation under vacuum. The crude product that is obtained is urified by column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1). Yield: 22 mg (21% of theory) IH-NMR (400 MHz, DMSO-d 6 , TMS): 9.08 (s, 3-OH); 7.10 (d, J = 8.6 Hz, H-1); 6.51 Id, J = 8.6/2.3 Hz, H-2); 6.41 (d, J = 2.3 Hz, H-4); 4.76 (dd, J = 25.4/10.9 Hz, -CH=CF 2 ); 4.51 1, J = 4.69 Hz, 16ax-OH); 4.25 (m, 16p-H); 2.68 (m, H-6); 0.68 (s, H-18) Example 4 )a-( 2 ',2'-Difluorovinyl)-18a-homo-estra-1,3,5(10)-triene-3,16a-diol 'tage I 3,16a-Bis[(perhydropyran-2-yl)oxy]-I8a-hono-estra-1,3,5(10)-triene-9-carbonitrile 39 Reaction of 3,16ct-bis[(perhydropyran-2-yl)oxy]- I 8a-homo-estra- 1,3,5(1 0)-tnene analogously to Example 1, stage I yields 3,16a-bis[(perhydropyran-2-yl)oxy]- I 8a-homoestra ,3,5(1 0)-tnene-9-carbonitrile. Yield: 58% of theory. tage 2 16a-Dihydroxy--18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]- I 8a-homo-estra- 1,3,5(1 0)-triene-9 arbonitrile analogously to Example 1, stage 2 yields 3,16ca-dihydroxy-18a-homo-estra ,3,5(1 0)-triene-9-carbaldehyde. Yield: 87% of theory 'tage 3 a-( 2 ,2-Difluorovinyl)-18a-homo-estra-1,3,5(10)-triene-3,I6a-diol Reaction of 3,1 6a-dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde; rd Reaction conditions and execution of the reaction as well as molar ratios as in the 3 stage of 9 aC 2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,16ax-diol. The crude product is purified by column chromatography on silica gel (cyclohexane/ethyl icetate, 2/1) and crystallization from ethyl acetate. Yield: 12% of theory Melting point: 225 - 232*C 1 H-NMR (400 MHz, DMSO-d 6 , TMS): 9.06 (s, 3-OH); 7.08 (d, J = 8.6 Hz, H-1); 6.50 40 (dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 4.78 (dd, J = 21.5/14.8 Hz, -CH=CF 2 ); 4.47 (d, J = 4.50 Hz, 16a-OH); 4.18 (m, 16p-H); 2.68 (m, H-6); 0.72 (t, J = 6.8 Hz, H-18a) Example 5 17p-Fluoro-9a-vinyI-estra-1,3,5(10)-triene-3,1 6a-diol Stage I 3,16a-Bis[(perhydropyran-2-yl)oxy]-17p-fluoro-estra-1,3,5(10)-triene-9-carbonitrile Reaction of 3,1 6a-bis[(perhydropyran-2-yl)oxy]- 1 7p-fluoro-estra- 1,3,5(1 0)-triene inalogously to Example 2, stage 1 yields 3,16x-bis[(perhydropyran-2-yl)oxy]- I 7p-fluoro-estra 1,3,5(1 0)-triene-9-carbonitrile. Yield: 45% of theory stage 2 3,16a-Dihydroxy-I 7-fluoro-estra-1,3,5(1 0)-triene-9-carbaldehyde Reaction of 3,1 6a-bis[(perhydropyran-2-yl)oxy]-17p-fluoro-estra-1,3,5(10)-triene-9 carbonitrile analogously to Example 2, stage 2 yields 3,16a-dihydroxy-17p-fluoro-estra 1,3,5(1 0)-triene-9-carbaldehyde. Yield: 83% of theory 41 Stage 3 17p-Fluoro-9a-vinyl-estra-1,3,5(1 0)-triene-3,16a-diol Reaction of 3,16c-dihydroxy- I 7p-fluoro-estra- 1,3,5(1 0)-triene-9-carbaldehyde analogously to Example 2, stage 3 yields 17p-fluoro-9c-vinyl-estra-1,3,5(10)-triene-3,16ax-diol. The crude product is purified by column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1) and crystallization from chloroform. Yield: 51%oftheory Melting point: 94 - 98'C H-NMR (400 MHz, DMSO-d 6 , TMS): 9.02 (s, 3-OH); 6.97 (d, J = 8.2 Hz, H-1); 6.51 dd, J = 8.2/2.7 Hz, H-2); 6.42 (d, J = 2.7 Hz, H-4); 6.22 (dd, J = 17.2/10.5 Hz, -CH=CH 2 ); 5.09 'd, J = 5.5 Hz, 16a-OH); 5.01 (dd, J = 10.5/1.9 Hz, -CH=CH2); 4.45 (dd, J = 17.2/1.9 Hz,

CH=CH

2 ); 4.35 (dd, .1 = 55.1/4.7 Hz, H-I7c); 4.11 (m, 16p-H); 2.68 (m, H-6); 0.79 (d, J = 1.9 iz, H-18) Example 6 17,17-Difluoro-9oi-vinyl-estra-1,3,5(10)-triene-3,16c-diol Stage 1 3,16a-Bis[(perhydropyran-2-yl)oxyj'-17,17-difluoro-estra-1,3,5(10)-triene-9-carbonitrile Reaction of 3,16c-bis[(perhydropyran-2-yl)oxy]-17,17-di fluoro-estra-1,3,5(10)-triene analogously to Example 2, stage 1 yields 3,16c-bis[(perhydropyran-2-yl)oxy]- 17,17-difluoro- 42 -stra- 1,3,5 (1 0)-tniene-9-carbonitri le. Yield: 46% of theory stagee 2 ,6a-Dihydroxy-I 7,17-difluoro-estra-1,3,5(10)-triene-9-carbaldehyde Reaction of 3,1 6a-bis[(perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene-9 arbonitrile analogously to Example 2, stage 2 yields 3,16c-dihydroxy-l7,17-difluoro-estra ,3,5(1 0)-triene-9-carbaldehyde. Yield: 88% of theory 'tage 3 7,17-Difluoro-9a-vinyl-estra-1,3,5(10)-triene-3,I6a-dioI Reaction of 3,16a-dihydroxy- 1 7,17-difluoro-estra- 1,3,5(1 0)-triene-9-carbaldehyde nalogously to Example 2, stage 3 yields 17,17-difluoro-9a-vinyl-estra-1,3,5(10)-triene-3,16ax iol. The crude product is purified by column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1) and crystallization from chloroform. Yield: 75% of theory H-NMR (400 MHz, CDCb, TMS): 7.08 (d, J = 8.6 Hz, H-1); 6.63 (dd, J = 8.6/2.7 Hz, H-2); 6.54 (d, J = 2.7 Hz, H-4); 6.23 (dd, J = 17.2/10.5 Hz, -CH=CH 2 ); 5.08 (dd, J = 10.5/1.9 Hz, CH=Ci 2 ); 4.48 (dd, J = 17.2/1.9 Hz, -CH=CH 2 ); 4.44 (m, 160-H); 2.79 (m, H-6); 0.95 (d, J = .9 Hz, H-18) 43 Example 7 9ac-(Hex-1'-enyl)-estra-1,3,5(1 0)-triene-3,16ac-diol Stage I 3,16a-Bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-estra- 1,3,5(1 0)-triene analogously to Example 2, stage I yields 3,1 6a-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9 arbonitrile. Yield: 61% of theory 'tage 2 , 16a-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde Reaction of 3,1 6a-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile nalogously to Example 2, stage 2 yields 3,1 6a-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde. Yield: 87% of theory Stage 3 9a-(Hex-I -enyl)-estra-1,3,5(1 0)-triene-3,16a-diol 8.68 g (20 mmol) of pentyltriphenyl-phosphonium bromide + sodium amide (1 g contains 2.3 mmol of pentyltriphenyl-phosphonium bromide), 0.2 g (0.67 mmol) of 3,16c-dihydroxy -stra-1,3,5(10)-triene-9-carbaldehyde and 30 ml DMSO are introduced into a reaction flask that 44 vas rendered inert. The reaction mixture is treated for about 2 hours in an ultrasound bath at )0 0 C. After the reaction is completed, water is added to the reaction solution. Tbe crude product s isolated by extraction with ethyl acetate, washing of the organic phase with water and :oncentration by evaporation until a dry state is reached. The crude product that is obtained is purified by column chromatography on silica gel cyclohexane/ethyl acetate, 1/1) and crystallization from ethyl acetate. Yield: 0.18 g (75% of theory) according to chromatography Melting point: 166 - 168'C H-NMR (400 MHz, DMSO-d 6 , TMS): 8.97 (s, 3-OH); 7.08 (d, J = 8.6 Hz, H-1); 6.49 id, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 5.73 (d, J = 12.5 Hz, -CH=CH-CH 2 -); 5.20 It, J = 12.5/7.4 Hz, -CH=CH-CH 2 -); 4.48 (d, J = 4.7 Hz, 16a-OH); 4.24 (m, 16p-H); 2.66 (m, [-6); 0.68 (t, J = 7.0 Hz, CH 3

-CH

2 -); 0.66 (s, H-18) xample 8 )a-(But-1 '-enyl)-estra-1,3,5(10)-triene-3,1 6a-diol stage 1 16a-Bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile Reaction of 3,1 6a-bis[(perhydropyran-2-y)oxy]-estra- 1,3,5(1 0)-triene analogously to Example 2, stage I yields 3,16cx-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9- 45 arbonitrile. Yield: 52% of theory stage 2 ,16a-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde Reaction of 3,16ax-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 2, stage 2 yields 3,16ac-dihydroxy-estra- 1,3,5(1 0)-triene-9-carbaldehyde. Yield: 87% of theory stage 3 a-(But-]-enyl)-estra-1,3,5(10)-triene-3,16a-diol 8.68 g (20 mmol) of propyltriphenyl-phosphonium bromide + sodium aide (1 g contains .3 mmol of propyltriphenyl-phosphonium bromide), 0.2 g (0.67 mmol) of 3,16x-dihydroxy stra-1,3,5(l 0)-triene-9-carbaldehyde and 30 ml of DMSO are introduced into a reaction flask .at was rendered inert. The reaction mixture is treated for about 2 hours in an ultrasound bath at 60'C. After the reaction is completed, water is added to the reaction solution. The crude product is isolated by extraction with ethyl acetate, washing of the organic phase with water, and concentration by evaporation until a dry state is reached. The crude product that is obtained is purified by column chromatography on silica gel cyclohexane/ethyl acetate, 1/1). Yield: 0.16 g (73% of theory) after chromatography Melting point: 140 - 148*C P \WPDOCS\CRN\JXJ\Spec\l25471I spec 4th SPA doc-IM1/2009 - 46 'H-NMR (400 MHz, DMSO-d 6 , TMS): 8.98 (s, 3-OH); 7.09 (d, J = 8.6 Hz, H-1); 6.49 (dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 5.70 (d, J = 12.5 Hz,

-CH=CH-CH

2 -); 5.19 (dt, J = 12.5/7.4 Hz, -CH=CH-CH 2 -); 4.47 (d, J = 4.7 Hz, 16C-OH); 4.24 (in, 16p-H); 2.66 (m, H-6); 0.66 (s, H-18); 0.57 (t, J = 7.2 Hz, CH-CH 2 -) The reference to any prior art in this specification is not, and should not be taken as an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or 'comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or steps.

Claims

1. A compound of the general formula I R13 R 17R17 R1 R R O

7. R7 (I) 3 7 7' 9 13 16 17 17' in which radicals R , R , R , R , R , R as well as R and R , independently of one another, have the following meaning: 3 18 R means a hydrogen atom or a group R , in which R 18 means a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, an aryl, heteroaryl or aralkyl radical, a substituted aryl or heteroaryl radical with a methyl, ethyl, trifluoromethyl, pentafluoroethyl, tnfluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(Cis-alkyl) or di(Ci-8-alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, carboxyl, carboxyalkoxy, CJ-C20-acyl or CI-C2o-acyloxy groups as substituents, an 9 19 acyl radical COR', in which R is a straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and is partially or completely halogenated, or R means a group R SO 2 , in which 20 21 . 22 21 22 R is an R R N group, whereby R and R , independently of one another, mean a hydrogen atom, a C,-C 5 -alkyl radical, a group 23 23 C(O)R , in which R represents a straight-chain or branched chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and is partially or completely halogenated, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, a C -C -cycloalkylalkyl radical with 3 to 7 carbon atoms in the cycloalkyl portion and with an alkyl portion of up to 8 carbon atoms or an aryl, heteroaryl or aralkyl radical, or a substituted aryl or heteroaryl radical, with a methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(Ci-8 alkyl)- or di(Cvs-alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, carboxyl, carboxyatkoxy, CI-C 20 acyl or C 1 -C2o-acyloxy groups as substituents, or, together with the N atom, a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical, R' and R 7 , in each case independently of one another, are a hydrogen atom or a halogen atom, 9 R is a straight-chain or branched-chain alkenyl or alkinyl radical with 2 to 6 carbon atoms, which can be partially or completely fluorinated, or an ethinyl- or prop-I inyl radical, R is a methyl group or an ethyl group, R 1 is a hydroxy group or a group R 0-, R20SO 2 - or OC(O)R with R', R2 and R2 3 in each case in the meaning that is indicated under R , R 17 and R 7', in each case independently of one another, are a hydrogen atom or a halogen atom. 2. A compound according to claim 1, in which R 3 is a hydrogen atom. 3. A compound according to claim I or 2, in which R 7 is a hydrogen atom or an a-position fluorine atom, R 9 is a vinyl, ethinyl or prop-1-inyl group, R' 6 is a hydroxy group, and R is a hydrogen atom or an c-position fluorine atom. 4. Compounds of general formula I according to claim 1 or 2, in which R'* stands for a 18 19 18 group R -0- or R S0 2 -0- with R1 and R'9 in each case in the meaning that is indicated under R 3 P \WPDOCS\CRNXP\Specl2504731 spe 4th SPA do-22A42009 - 50 5. A compound according to claim 1 or 2, selected from the group consisting of: 9c-Vinyl-estra-1,3,5(1 0)-triene-3,16a-diol; 9a-Allyl-estra-1,3,5(10)-triene-3,1 6a-diol; 18a-Homo-9ca-vinyl-estra-1,3,5(10)-triene-3,I 6a-diol; 18a-Homo-9c-allyl-estra-1,3,5(1 0)-triene-3,16t-diol; 3-Methoxy-9a-vinyl-estra- 1,3,5(1 0)-trien- 1 6a-ol; 9a-Allyl-3-methoxy-estra- 1,3,5(1 0)-trien- 1 6ax-ol; 18a-Homo-3-methoxy-9a-vinyl-estra- 1,3,5(1 0)-trien- 1 6a-ol; 18a-Homo-9a-allyl-3-methoxy-estra- 1,3,5(1 0)-trien- 1 6at-ol; 9a-(2',2'-Difluorovinyl)-estra- 1,3,5(1 0)-triene-3,16c-diol; 9a-(2',2'-Difluorovinyl)-3-methoxy-estra- 1,3,5(1 0)-trien- 1 6ca-ol; 16x-Hydroxy-9a-vinyl-estra-1,3,5(I 0)-trien-3yl-sulfamate; 9ca-Allyl-I 6ca-hydroxy-estra- 1,3,5(1 0)-trien-3yl-sulfamate; 18a-Homo- 1 6c-hydroxy-9c-vinyl-estra-1,3,5(1 0)-trien-3yl-sulfamate; 18a-Homo-9a-allyl- I 6a-hydroxy-estra-1,3,5(1 0)-trien-3yl-sulfamate; 9a-Vinyl-estra- 1,3,5(l 0)-triene-3,16a-diyl-disulfamate; 9a-Allyl-estra- 1,3,5(1 0)-triene-3,1 6a-diyl-disulfamate; 18a-Homo-9a-vinyl-estra- 1,3,5(1 0)-triene-3,16a-diyl-disulfamate; 18a-Homo-9c-allyl-estra- 1,3,5(1 0)-triene-3,I 6a-diyl-disulfamate; 16c-Hydroxy-9ca-vinyl-estra- 1,3,5(1 0)-trien-3yl-(N-acetyl)-sulfamate; 9a-Allyl- 1 6c-hydroxy-estra- 1,3,5(1 0)-trien-3yl-(N-acetyl)-sulfamate; 18a-Homo- 1 6ax-hydroxy-9a-vinyl-estra- 1,3,5(1 0)-trien-3yl-(N-acetyl)-sulfamate; P \WPDOCS\CRN\JXASpcclI254731 spec 4th SPA doc-22AW/2ix9 -51 18a-Homo-9at-allyl- I 6a-hydroxy-estra- 1,3,5(1 0)-trien-3yl-(N-acetyl)-sulfamate; 9a-(Prop-(Z)-enyl)-estra- 1,3,5(1 0)-triene-3,16ax-diol; 9cc-(n-Propyl)-estra- 1,3,5(1 0)-triene-3,16ax-diol; 9c-Ethinyl-estra- 1,3,5(1 0)-triene-3,16ca-diol; 9cc-Vinyl-estra- 1,3,5(1 0)-triene-3,16a-diol-diacetate; 18a-Homo-9a-vinyl-estra- 1,3,5(1 0)-triene-3,1 6ca-diol-diacetate; 1 6a-Valeroyloxy-9a-vinyl-estra- 1,3,5(1 0)-trien-3-ol; 1 6a-Acetoxy-9a-vinyl-estra- 1,3,5(1 0)-trien-3-ol; 18a-Homo- I 6c-acetoxy-9ca-vinyl-estra- 1,3,5(1 0)-trien-3-ol; 7ax-Fluoro-9ca-vinyl-estra- 1,3,5(1 0)-triene-3,16ax-diol; 7c-Fluoro-9a-allyl-estra- 1,3,5(1 0)-triene-3,16a-diol; 17p-Fluoro-9ca-vinyl-estra- 1,3,5(1 0)-triene-3,16x-diol; 17p-Fluoro-9a-allyl-estra- 1,3,5(1 0)-triene-3,1 6a-diol; 18a-Homo-7a-fluoro-9a-vinyl-estra- 1,3,5(1 0)-triene-3,16a-diol; 18a-Homo-7ca-fluoro-9a-allyl-estra- 1,3,5(1 0)-triene-3,1 6a-diol; 18a-Homo-17p-fluoro-9a-vinyl-estra-1,3,5(10)-triene-3,1 6a-diol; and 18a-Homo- 1 7p-fluoro-9a-allyl-estra- 1,3,5(1 0)-triene-3,1 6a-diol. 6. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 5 and a pharmaceutically compatible vehicle. 7. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for the prevention or treatment of a disease or condition.

8. Use according to claim 7, wherein the disease or condition is estrogen deficiency-related.

9. Use according to claim 7, wherein the disease or condition is associated with peri- and postmenopausal symptoms.

10. Use according to claim 7, wherein the disease or condition is female P:\WPDOCS\CRN\JXJ\Spec\I 25I4731 spc 4th SPA d-22AM/2(X9 - 52 infertility and wherein the treatment is in-vitro.

11. Use according to claim 7, wherein the disease or condition is female infertility and wherein the treatment is in-vivo.

12. Use according to claim 7, wherein the medicament is for the therapy of hormone-deficiency-related symptoms associated with surgically, medically or otherwise induced ovarian dysfunction.

13. Use according to claim 7, wherein the medicament is for hormone replacement therapy (HRT).

14. Use according to claim 13, wherein the medicament is used in combination with a selective estrogen receptor modulator (SERM).

15. Use according to claim 7, wherein the disease or condition is a hormone deficiency-related bone mass loss.

16. Use according to claim 7, wherein the disease or condition is osteoporosis.

17. Use according to claim 7, wherein the disease is a cardiovascular disease.

18. Use according to claim 7, wherein the disease or condition is prostate hyperplasia.

19. Use according to claim 18, wherein the medicament is used in combination with an antiestrogen and a selective estrogen receptor modulator (SERM).

20. Use according to claim 7, wherein the disease is a disease of the immune system.

21. Use according to claim 20, wherein the disease of the immune system is autoimmune disease.

22. Use according to claim 21, wherein the autoimmune disease is rheumatoid arthritis.

23. Use according to claim 21, wherein the autoimmune disease is multiple sclerosis.

24. Use according to claim 14, wherein the SERM is raloxifene.

25. A method for the treatment of an estrogen-deficiency-related disease and/or P %WPDOCS\CRNUXJ\Spc\12504731 spe 4th SPAdoc-2204/209 - 53 condition, the method comprising administering to a subject in need of such treatment a pharmaceutical composition comprising at least one compound according to any one of claims I to 5, wherein said estrogen-deficiency related disease and/or condition is selected from the group consisting of: peri- and postmenopausal symptoms, female infertility, ovarian dysfunction, hormone-deficiency-related bone mass loss, osteoporosis, cardiovascular diseases, prostate hyperplasia, diseases of the immune system, autoimmune diseases, rheumatoid arthritis and multiple sclerosis.

26. A compound according to any one of claims I to 5, and the use thereof for the production of pharmaceutical agents, substantially as herein described with reference to the Examples.