NO329563B1 - 9-alpha-substituted ostratrienes as selectively active oestrogens, pharmaceutical compositions containing the compounds, and their use in the preparation of pharmaceutical agents - Google Patents

Abstract

The invention relates to novel 9a-substituted estratrienes of general formula (I) wherein R3, R7, R7 ', R13, R17 and R17' have the designations given in the description, and R9 is a straight-chain or branched, optionally partially or branched halogenated alkenyl radical. comprising between 2 and 6 carbon atoms, or an ethynyl radical or a prop-1-ynyl radical, as pharmaceutically active ingredients which in vitro have a higher affinity for estrogen receptor preparations in the rat prostate than estrogen receptor preparations in the rat uterus, and in vivo preferably a preferred effect on oocytes the uterus. The invention also relates to the preparation of the estratrienes, the therapeutic application thereof and pharmaceutical forms for administration containing the novel compounds. The invention further relates to the use of the compounds for the treatment of diseases and conditions related to estrogen deficiency.

Description

Field of the invention

This invention relates to new compounds as pharmaceutically active ingredients, which in vitro have a higher affinity for estrogen receptor preparations from the rat prostate than for estrogen receptor preparations from the rat uterus, and which in vivo have a preferential effect in the ovaries compared to the uterus, their use for the production of pharmaceutical agents, as well as pharmaceutical preparations containing the new compounds.

The chemical compounds are new, steroidal tissue-selective estrogens.

The background of the invention

The effectiveness of estrogens in the treatment of hormone deficiency-induced symptoms, such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful use of estrogen therapies for the prophylaxis of bone loss in peri- and postmenopausal women, is well documented and generally accepted (Grådy 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 caused in another way reduces the risk of cardiovascular diseases compared to women not treated with estrogen (Grådy et al., loc.cit.)

In normal estrogen or hormone replacement therapy (= HRT), natural oestrogens, such as estradiol, and conjugated oestrogens consisting of horse urine are used, either as such or in combination with a progestogen. Instead of the natural estrogens, derivatives obtained by esterification can also be used, such as e.g. 17P-estradiol valerate.

Because of the stimulating effect on the endometrium of the estrogens used, which results in an increase in the risk of endometrial carcinoma (S. Harlap, 1992, AmJObstet Gynecol 166: 1986-1992), combination preparations of estrogen and progestin are preferably used in hormone replacement therapy . The progestin component in the combination of estrogen and progestin prevents hypertrophy of the endometrium, but the occurrence of unwanted intracyclic menstrual bleeding is also associated with the progestin-containing combination.

Selective estrogens are a newer alternative to the combination preparations of estrogen and progestin. Until now, selective oestrogens have been defined as those compounds which have an oestrogen-like effect on the brain, bones and vascular system, due to their anti-uterotrophic (ie anti-estrogenic) partial action, but they do not have a proliferative effect on the endometrium.

A class of substances that partially meet the desired profile of a selective estrogen are the so-called "selective estrogen receptor modulators" (SERMs) (R. F. Kauffman, H. U. Bryant 1995, DNAP 8 (9): 531:539). In this case, these are partial agonists of the estrogen receptor subtype "ERa". However, this type of drug is ineffective when it comes to the treatment of acute postmenopausal symptoms, such as e.g. hot flashes. As an example of a SERM, we can mention raloxifene which was recently introduced for the osteoporosis indication.

DE-A-19906159 describes new compounds as pharmaceutically active ingredients which in vitro have a high affinity to estrogen receptor preparations from rat prostate than to the estrogen receptor preparations from rat uterus, and which in vivo have a preferential effect on bones compared to the uterus, their preparation, their therapeutic use and pharmaceutical dosage forms containing the new compounds. The compounds are 16a- and 16P-hydroxy-estra-1,3,5(10)-estratrienes which carry additional substituents in the steroid skeleton, and which may exhibit one or more additional double bonds in the B-, C- and/or D-ring.

For the treatment of fertility disorders in women, often caused by uterine dysfunction caused by surgery, medication, etc., new possible therapies have also been opened up by the use of new selective estrogens. Fertility treatment in vitro is a procedure that has been established for more than 20 years. A large number of methods for the treatment of ovarian-induced infertility with exogenous gonadotropins are known. When administering gonadotropins, such as FSH (FSH = follicle-stimulating hormone), a stimulation of the ovaries should be induced to enable healthy egg follicle maturation.

The follicle is the functional unit of the ovary and has two purposes: it accommodates the oocytes and provides the opportunity for their growth and maturation. Folliculogenesis comprises the development of an ovarian follicle from a primordial stage to a continuously growing antral follicle which constitutes the last stage before ovulation. Only an optimally developed antral follicle can release a mature oocyte at ovulation.

Patients with ovarian-induced infertility (PCOS = polycystic ovary syndrome) suffer from an interrupted follicle maturation associated with both hormonal and ovulatory disturbances, and with inadequately matured oocytes. The number of primary and secondary follicles is about twice as great here as in the normal ovary (Hughesden et al., Obstet. Gynecol. Survey 37, 1982, pages 59-77).

There are indications that the early developmental stages of folliculogenesis (relating to the development of primordial follicles into antral follicles) are gonadotropin independent. It is not clearly explained how great the influence of known paracrine and autocrine factors is on early folliculogenesis (Elvin et al., Mol. Cell Endocrinol. 13, 1999, pages 1035-1048; McNatty et al. J. Reprod. Fertil. Suppl. 54, 1999, pages 3-16).

Gonadotropins, such as FSH, are mainly involved in the final developmental stages of folliculogenesis with follicle maturation, i.e. in the development of the early antral follicle into a mature follicle that can undergo ovulation.

Infertility in vivo and in vitro is preferably treated with gonadotropins (FSH and antiestrogens) (White et al., J. Clin. Endocrinol. Metab. 81, 1996, pages 3832-3824). With in vitro fertility treatment, oocytes are removed from preovulatory antral follicles to become able to mature in vitro into oocytes that can be fertilized. After fertilization and pre-embryonic development, one to three embryos are implanted in the woman's uterus.

In many respects, the treatment with exogenous gonadotropins is accompanied by a large number of risks and side effects. The biggest risk consists of overstimulation of the ovaries, which in severe cases can pose a serious threat to life (OHSS = ovarian hyperstimulation syndrome). Other disadvantages are the high costs of the in vitro fertility treatment which must be paid by the couples. Negative side effects, such as weight gain, bloating, nausea, vomiting and a hitherto unknown, long-term risk of developing cancer are attributed to the gonadotropin treatment. One method to avoid the above-mentioned disadvantages and risks is to ensure the maturation and in vivo stimulation of follicle growth in the case of ovarian-induced infertility with a suitable active ingredient before treatment with exogenous gonadotropins begins.

Estrogen receptor beta (ERP)

Several years ago, estrogen receptor β (ERP) was discovered as a second subtype of the estrogen receptor (Kuiper et al. (1996), Proe. Nati. Acad. Sei. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53; Tremblay et al (1997), Molecular Endocrinology 11: 353-365). The expression pattern of ERP differs from that of ERα (Kuiper et al. (1996) Endocrinology 138: 863-870). ERP thus dominates over ERa in the rat prostate, while ERa dominates over ERp in the rat uterus. The highest concentrations of ERP and mRNA were found in the ovaries (Couse et al. Endocrinology 138, 1997, pages 4612-4613).

Other organ systems with comparably higher ERp expression include the bones (Y. Onoe et al., 1997, Endocrinology 138:4509-4512), the vascular system (T. C. Register, M. R. Adams, 1998, J. Steroid Molec Biol 64: 187-191 ), the urinary tract and the genitals (G. J. M Kuiper et al., 1997, Endocrinology 138: 863-870), the gastrointestinal tract (Campbell-Thopson 1997, BBRC 240: 478-483), as well as the testicles (S. Mosselmann et al. , 1996, FEBS Lett. 392, 49-53) including the spermatids (Shugrue et al., 1998, Steroids 63: 498-504). The tissue distribution suggests that estrogens regulate organ functions via ERp. The fact that ERP is functional in this regard also follows from studies in ERα (ERKO) or ERP-(PERKO) "knockout" mice: ovariectomy causes bone loss in ERKO mice, which can be eliminated by estrogen replacement ( Kimbro et al 1998, Abstract OR7- 4, Endocrine Society Meeting, New Orleans). Estradiol in the blood vessels of female ERKO mice also inhibits vascular medium and smooth muscle cell proliferation (M. D. Iafrati et al., 1997, Nature Medicine 3: 545-548). These protective effects of estradiol are carried out in the ERKO mouse probably via ERp.

The fact that ERa and ERP have a functionally different effect was confirmed after the successful production of aERKO and pERKO mice. ERa consistently plays an important role in the fully developed uterus, in mammary gland tissue, by the negative regulation of gonadotropin activity, while ERP is mainly bound in ovarian physiology processes, especially that of folliculogenesis and ovulation (Couse et al., Endocrine Reviews 20, 1999, pages 358-417).

Observations of PERKO mice suggest a function for ERPs in the prostate and bladder: in the case of older male mice, symptoms of prostate and bladder hyperplasia appear (J.H. Krege et al., 1998, Proe Nati Acad Sei 95: 15677-15682 ). In addition, female ERKO mice (D. B. Lubahn et al., 1993, Proe Nati Acad Sei 90: 11162-11166) and male ERKO mice (R. A. Hess et al., 1977, Nature 390: 509-512) as well as female PERKO mice (H.J. Krege, 1998, Proe Nati Acad Sei 95: 15677-15682) fertility disorders. The important function of estrogens in maintaining testicular and ovarian functions as well as fertility is therefore confirmed.

It was possible to achieve a selective estrogenic action on specific target organs by means of subtype-specific ligands based on the different tissue or organ distribution of the two subtypes of the ERs. Substances with a preference for ERβ compared to ERα in the in vitro receptor binding assay were described by Kuiper et al. (Kuiper et al. (1996), Endocrinology 138: 863-870). A selective effect of subtype-specific ligands of the estrogen receptor on estrogen-sensitive parameters in vivo has not been shown previously.

The purpose of this invention is therefore to produce compounds which have a dissociation in vitro when it comes to binding to estrogen receptor preparations from rat prostates and rat uterus. The compounds must show a higher affinity in vitro to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri.

The ERP-specific compounds should in vivo produce a pro-fertility effect in the ovary. At the same time, the compounds must show dissociation when it comes to ovarian action compared to uterine action. The compounds according to the invention must have a specific protective effect against hormone deficiency-induced bone mass loss compared to a uterine stimulating effect.

More generally, a structure-effect relationship is made available that gives access to compounds that have the above-formulated pharmacological profile, with the help of this invention. The compounds according to the invention should provide improved fertility in the ovary, while at the same time affecting the uterus very little in cases of uterus-associated infertility.

According to the invention, the above-mentioned purpose is achieved by means of the provision of 9a-substituted estral-1,3,5(10)-triene derivatives of general formula I

-.17

R13? R17'

R30-^^V>R7

R

(IN)

where the radicals R<3>, R<7>, R7, R9, R<13>, R<16> as well as R<17> and R<17>, independently of each other, have the following meaning:

R<3> means a hydrogen atom or a group R<18>, where

R<18> means a straight-chain or branched, 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-(fluoro-, chloro-, bromo-, iodo-), hydroxy-, amino-, mono(C1_8-alkyl)- or di (Ci-8-alkyl)amino-, in which both alkyl groups are the same or different, di(aralkyl)amino-, in which both aralkyl groups are the same or different, carboxyl-, carboxyalkyl-, C1-C20-acyl- or C1-C20 -acyloxy group as substituents, an acyl radical COR<19>, where R<19> is a straight-chain or branched hydrocarbon radical with up to 10 carbon atoms which is saturated or unsaturated in up to three places, and partially or completely

halogenated, or

R<18> means a group R20SO2, where

R<20> is an R<21>R<22>N group, wherein R<2>1 and R2<2>, independently of each other, mean a hydrogen atom, a C1-C5 alkyl radical, a group C( 0)R , where R is a straight-chain or branched hydrocarbon radical with up to 10 carbon atoms which is saturated or unsaturated in up to three places, and partially or fully halogenated, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, a C4 -C|5 cycloalkylalkyl radical with 3 to 7 carbon atoms in the cycloalkyl part, and with an alkyl part 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 (fluoro-, chloro-, bromo-, iodo-), hydroxy-, amino-, mono(C|.8-alkyl) - or di(C1.8-alkyl)amino-, in which both alkyl groups are the same or different, di(aralkyl)amino-, in which both aralkyl groups are the same or different, carboxyl-, carboxyalkyloxy-,

C1-C20-acyl or C1-C20-acyloxy group as substituents, or together with the N atom, a polymethyleneimino radical with 4 to 6 C atoms or a

morpholino radical,

R<7> and R<7> are, in each case independently of each other, a hydrogen atom or a

halogen atom,

R<9> is a straight-chain or branched alkenyl or alkynyl radical with 2-6

carbon atoms, which may be partially or fully fluorinated, or an ethynyl or prop-1-ynyl radical,

R13 is a methyl group or an ethyl group,

R16 is a hydroxy group or a group R,<8>0-, R<20>SO2- or OC(0)R<23> with

R , R and R in each case have the meanings given under R ,

R17 and R<17> in each case, independently of each other, are a hydrogen atom or a halogen atom.

R<16> can in each case be in the a or [3 position.

According to a variant of the invention, gonatriene derivatives are preferred, where R7 and R7 are a hydrogen atom, R<9> is a vinyl, ethynyl or prop-l-ynyl group, R16 is a hydroxy group and R<17> and R17 are in each case a hydrogen atom.

In addition, the following combinations of halogen substitution, preferably fluorine, in the C atoms 7 and 17 are preferred: 7-mono or 7-di and R<17> as well as R<17>, in each case a hydrogen, 17-mono or 17 -di and R<7> as well as R7 , in each case a hydrogen as well as 7-mono/17-mono, 7-mono/17-di, 7-di/17-mono, 7-di/17-di. The 7a position or the 7B position is preferred in the monofluoro compounds.

Another variant of the invention refers in particular to compounds where R16 stands for a group R<18>0- or R<20>SO2-O- with R<1>8 and R2<0> in each case in the meaning indicated under R<3>.

Preferred according to this invention are the following compounds: 9a-vinyl-estra-1,3,5(10)-trien-3,16a-diol,

9α-allyl-estra-1,3,5(10)-triene-3,16α-diol,

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

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

3-methoxy-9a-vinyl-estra-1,3,5(10)-trien-16a-ol,

9a-allyl-3-methoxy-estra-1,3,5(10)-trien-16a-ol,

18a-homo-3-methoxy-9a-vinyl-estra-1,3,5(10)-trien-16a-ol,

18a-homo-9a-allyl-3-methoxy-estra-1,3,5(10)-trien-16a-ol,

9a-(2<*>,2'-difluorovinyl)-estra-1,3,5(10)-triene-3,16a-diol,

9a-(2',2'-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-16a-ol,

16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate,

9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate,

18α-homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3y 1-sulfamate,

18a-homo-9a-ally 1-16a-hydroxy-estra-1,3,5(10)-trien-3y 1-sulfamate, 9a-vinyl-estra-1,3,5(10)-trien-3, 16a-diylsulfamate,

9a-allyl-estra-1,3,5(10)-triene-3,16a-diylsulfamate,

18α-homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate,

18α-homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate,

16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate, 9α-allyl-16α-hydroxy-estra-1,3,5(10 )-trien-3yl-(N-acetyl)-sulfamate, 18a-homo-16a-hydroxy-9a-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate, 18a -homo-9a-allyl-16a-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate, 9a-(prop-(Z)-enyl)-estra-1, 3,5(10)-triene-3,16a-diol,

9a-(n-propyl)-estra-1,3,5(10)-triene-3,16a-diol,

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

9a-viny 1-estra-1,3,5(10)-triene-3,16a-diol diacetate,

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

16a-valeroyloxy-9a-viny 1-estra-1,3,5(10)-trien-3-ol,

16α-acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol,

18α-homo-16α-acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol,

7a-fluoro-9a-viny 1-estra-1,3,5(10)-triene-3,16a-diol,

7a-Fluoro-9a-ally 1-estra-1,3,5(10)-triene-3,16a-diol,

17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol,

17P-fluoro-9a-ally 1-estra-1,3,5(10)-triene-3,16a-diol,

18α-homo-7α-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol,

18α-homo-7α-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol,

18a-homo-17P-fluoro-9a-vinyl-estra-1,3,5(10)-trien-3,16a-diol and 18a-homol7P-fluoro-9a-allyl-estra-1,3,5(10 )-triene-3,16a-diol.

Other possible configurations of this invention will appear from the subclaims.

Hydrocarbon radical R<18> is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl radical.

Alkoxy groups OR<18> in the compounds of general formula I can in each case contain 1-6 carbon atoms, with methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups being preferred.

Representatives of the C1-C5 alkyl radicals R<21> and R2<2> are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl.

As representatives of straight-chain or branched hydrocarbon radicals R23 with 1 to a maximum of 10 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl can be mentioned; methyl, ethyl, propyl and isopropyl are preferred.

As a C3-C7 cycloalkyl group, there may be mentioned a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

A C4-C15 cycloalkylalkyl radical has 3-7 carbon atoms in the cycloalkyl part; typical representatives are the cycloalkyl groups mentioned directly above. The alkyl part has up to 8 carbon atoms.

As examples of a C4-C15 cycloalkylalkyl radical, there may be mentioned the cyclopropylmethyl, cyclopropylethyl, cyclopentylpropyl groups, etc.

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

Aryl also always includes a heteroaryl radical. Examples of a heteroaryl radical are 2-, 3- or 4-pyridinyl-, 2- or 3-furyl-, 2- or 3-thienyl-, 2- or 3-pyrrolyl-, 2-, 4- or 5-imidazolyl- , pyrazinyl, 2-, 4-, or 5-pyrimidinyl, or the 3- or 4-pyridazinyl radical.

As substituents which may be present on an aryl or heteroaryl radical, mention may be made, for example, of methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen-, ( fluorine-, chlorine-, bromine-, iodine-), hydroxy-, amino-, mono(C|_8alkyl)- or di(Ci.8alkyl)amino-, both alkyl groups being the same or different, di(aralkyl)amino- , with both aralkyl groups being the same or different, carboxyl, carboxyalkyloxy, C1-C20-acyl or C1-C20-acyloxy groups.

An aralkyl radical is a radical which in the ring contains up to 14, preferably 6-10, C atoms, and in the alkyl chain 1-8, preferably 1-4, C atoms. Suitable aralkyl radicals are, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl and pyridylpropyl.

The alkyl groups or the hydrocarbon radicals may be partially or completely substituted with 1-5 halogen atoms, hydroxy groups or C1-C4 alkoxy groups.

A vinyl or allyl radical is mainly defined by a C2-C6 alkenyl radical.

A C2-C6 alkynyl radical is preferably defined as an ethynyl radical or a prop-1-ynyl radical.

C 1-10 acyl radicals mean, for example, acetyl, propionyl, butyryl, valeroyl, iso-valeroyl, pivaloyl, hexanoyl, octyl, nonyl or decanoyl.

One or two hydroxyl groups at C-atoms 3 and 16 can be esterified with an aliphatic, straight-chain or branched, saturated or unsaturated C1-C14 mono- or polycarboxylic acid, or 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 acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propionic acid, 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 acids, phthalic acid, isophthalic acid, terephthalic acid, naphthenic acid, o-, m- and p-toluene acid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid and iso-nicotinic acid.

Esterification with benzoic acid is preferred.

As prodrugs, the esters of the new 9o>substituted estratrienes according to the invention have advantages compared to the unesterified active ingredients in terms of their methods of administration, their mode of action, strength and duration of action.

In particular, the sulfamates of 9a-substituted estratrienes according to the invention have pharmacokinetic and pharmacodynamic advantages. Related effects were already described for other steroid sulfamates ( J. Steroid Biochem. Molec. Biol, 55, 395-403

(1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998)).

In this patent application, steroids based on the 9α-substituted estra-1,3,5(10)-triene skeleton are described for the treatment of estrogen receptor P-mediated disorders and conditions as selective estrogens having in vzYro dissociation in terms of their binding to estrogen receptor preparations from rat prostates and rat uterus, and which in vivo preferentially have a dissociation in terms of ovarian action compared to uterine action. In addition, the compounds have a specific protective effect against hormone deficiency-induced bone mass loss.

It was found that the 9cc-substituted estra-1,3,5(10)-trienes of the general formula I are suitable as selective estrogens for the treatment of various conditions and disorders characterized by a higher content of estrogen receptor p than estrogen receptor a i the corresponding target tissue or target organ.

The invention also relates to pharmaceutical preparations containing 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 general formula I for the preparation of pharmaceutical agents, especially for the indications mentioned below.

The new selective estrogens described here can be used as individual components in pharmaceutical preparations or in combination, especially with progestogens. Particularly preferred is the combination of selective estrogens with ERα-selective antiestrogens that are peripherally-selectively active, i.e. that it does not pass through the blood-brain barriers, as well as with selective estrogen receptors with modulators (SERMs). The ERp-selective compounds according to the invention can be used in particular for the production of pharmaceuticals for the treatment of fertility disorders, for the prophylaxis and therapy of prostatic hyperplasia, for the prophylaxis and treatment of hormone deficiency-induced mood swings in women and men, and for use in hormone replacement therapy (HRT) in men and women. A therapeutic product containing an estrogen and a pure anti-estrogen for simultaneous, sequential or separate use for the selective estrogen therapy of perimenopausal or postmenopausal conditions is already described in EP-A 0 346 014.

Due to their dissociation of action in the ovary compared to the action in the uterus, the drugs and the pharmaceutical agents containing them are particularly suitable for the treatment in the case of ovarian dysfunction caused by surgery, medication, etc., such as female infertility, for the stimulation of folliculogenesis for treatment alone when it comes to increased fertility, for supporting in vitro fertility treatment (IVF) in connection with an in vitro fertilization treatment, and for the treatment of ovarian-induced disorders at an older age ("late fertility") as well as for the treatment of hormone deficiency-induced symptoms .

The substances are also suitable for the therapy of ovarian diseases, such as polycystic ovary syndrome, POF (premature ovarian failure) syndrome and ovulation disorders.

Finally, the compounds of general formula I can be used in conjunction with selective estrogen receptor modulators (SERMs) or raloxifene, particularly for use in hormone replacement therapy (HRT) and for the treatment of gynecological disorders.

The substances are also suitable as individual components for the treatment of perimenopausal and postmenopausal symptoms, particularly hot flushes, sleep disturbances, irritability, mood swings, incontinence, vaginal atrophy and hormone deficiency-induced mental disturbances. The substances are also suitable for hormone replacement and for the treatment of hormone deficiency-induced symptoms in ovarian dysfunction caused by surgery, medication, etc.

In addition, the substances can also be used to prevent hormone deficiency-induced bone mass loss and osteoporosis, to prevent diseases of the cardiovascular system, especially vascular diseases, such as arteriosclerosis, high blood pressure, and to prevent hormone deficiency-induced neurodegenerative diseases, such as Alzheimer's disease, as well as hormone deficiency-induced disorder of memory and learning capacity.

In addition, the substances can be used as active ingredients in preparations for the treatment of inflammatory diseases and diseases of the immune system, particularly autoimmune diseases, such as, for example, rheumatoid arthritis, multiple sclerosis, lupus, Crohn's disease and other inflammatory bowel diseases, inflammatory diseases of the skin, such as psoriasis, as well as for the treatment of endometriosis.

In addition, the substances are effective against inflammatory diseases of the respiratory system, lungs and bronchi, such as asthma.

The medication is suitable for the therapy and prophylaxis of estrogen deficiency-induced diseases in both women and men.

In men, the compounds are particularly suitable for the therapy of hormone deficiency-induced bone mass loss and osteoporosis, for the prevention of cardiovascular diseases, in particular vascular diseases such as arteriosclerosis, high blood pressure and for the prevention of hormone deficiency-induced neurodegenerative diseases, such as Alzheimer's disease, as well as hormone deficiency-induced disruption of memory and learning capacity, and is suitable for prophylaxis and therapy of prostatic hyperplasia.

The substances can be used for prophylaxis and therapy of age-related dysfunctions or diseases in men. In particular, they can be used for prophylaxis and treatment of an age-related drop in androgens, such as testosterone and DHEA, as well as growth hormone.

In addition, the medication can be used for the treatment of inflammatory diseases and diseases of the immune system, particularly autoimmune diseases in men, such as rheumatoid arthritis, MS (multiple sclerosis) and Crohn's disease, and other inflammatory bowel diseases, as well as inflammatory diseases of the respiratory system, lungs and bronchi . The amount of a compound of general formula I to be administered varies within a wide range and may cover any effective amount. Based on the condition to be treated and the type of administration, the amount of compound administered may be 0.01 ug/kg - 100 mg/kg body weight, preferably 0.04 ug/kg - 1 mg/kg body weight, per day.

In humans, this corresponds to a dose of 0.8 µg to 8 g, preferably 3.2 µg to

80 mg daily.

According to the invention, a dosage unit contains 1.6 ug to 2000 mg of one or more compounds of general formula I.

The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredients one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacological or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known manner, whereby the known or commonly used pharmaceutical adjuvants as well as other commonly used carriers and diluents can be used.

Suitable as such carriers and adjuvants are, for example, those recommended or indicated in the following bibliographic references as adjuvants for pharmaceuticals, cosmetics and related areas: Ullman's Encyklopådie der technischen Chemie, volume 4

(1953), pp. 1-39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq., published by Czetsch-Lidenwald; Hilfstoffe fur Pharmazie und adjacent Gebiete; Pharm Ind., 2nd ed., 1961, page 72 et seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG, Aulendorf in Wurttemberg 1971.

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

For oral administration, capsules, pills, tablets, coated tablets, etc. are suitable. In addition to the active ingredient, the dosage units may contain a pharmaceutically compatible carrier, such as. such as starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.

For parenteral administration, the active ingredients may be dissolved or suspended in a physiologically compatible diluent. Oils are very often used as diluents with or without the addition of a solubilizing agent, a surface-active agent, a suspending agent or an emulsifying agent. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

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 the active ingredient is made possible.

As inert materials, implants can for example contain biodegradable polymers or synthetic silicones such as silicone rubber. In addition, the active ingredients can be added, for example, to a patch for percutaneous administration. For the manufacture of intravaginal systems (e.g. vaginal rings) or intrauterine systems (e.g. pessaries, coils, IUDs, "Mirena") made 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.

In order to achieve better bioavailability for the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with α-, (3- or γ-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.

Methods

Estrogen receptor binding studies:

The binding affinity of the new selective estrogens was tested in competitive experiments using H-estradiol as a ligand to estrogen receptor preparations from rat prostates and rat uterus. The preparation of prostate cytosol and the estrogen receptor assay with prostate cytosol were performed as described by Testas et al., (1981) (J. Testas et al., 1981, Endocrinology 109: 1287-1289).

The preparation of rat uterine cytosol as well as the receptor test with the ER-containing cytosol was 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) (U. Fuhrmann 1995, Contraception 51: 45-52).

The substances described here have a higher binding affinity to the estrogen receptor in rat prostates than to estrogen receptors in the rat uterus. In this case, it is assumed that ERP in the rat prostate dominates over ERa and that ERa in the rat uterus dominates over ERp. Table 1 shows that the relationship between the binding to prostate and uterine receptors qualitatively agrees with the quotient for relative binding affinity (RBA) to human ERp and ERa from rats (according to Kuiper et al. (1996), Endocrinology 138: 863-870) (table 1).

Table 2 shows the results for 4 of the 9a-vinyl-estra-1,3,5(10)-triene-3,16a-diol derivatives (compounds 1,2,4 and 5) according to the invention.

The compounds 1, 2, 4 and 5 according to the invention show a higher binding affinity to the estrogen receptor in rat prostates than to the estrogen receptor in rat uteri.

In addition, the predictability of the prostate ER versus uterine ER test system was confirmed in terms of tissue-selective action in in vivo studies. Substances with a preference for the prostate ER are preferentially dissociated in vivo when it comes to ovarian and uterine action as well as pituitary gland action rather than action on the ovary.

Studies for effect dissociation in ovary/uterus and pituitary gland

The studies concerning the effect on uterine growth and ovulation (indirect effect by influencing the expansion of pituitary gland hormones) are carried out on adult female rats (body weight of 220-250 g). The substances are administered subcutaneously four times on four consecutive days. The first administration is carried out in metoestrus. One day after the last administration, an autopsy is performed. The number of oocytes in the tube (effect on ovulation) and the uterine weight are determined.

While estradiol produces a dose-dependent inhibition of ovulation and an increase in uterine weight with an ED50 of 0.004 mg/kg body weight, compound 1 according to the invention up to a dose of 0.4 mg/kg body weight exerts no effect on ovulation and uterine weight.

Ovarian studies:

The compounds were tested in vivo in hyphysectomized young rats. In a modification of this operative method, a GnRH antagonist is administered to the animals. It is being investigated whether the compound stimulates follicle proliferation (maturation) in the ovary. The ovary weight is the parameter for the measurement.

In each case, 5 animals (body weight 40-50 g) are randomly placed in the treatment groups. The animals are fed as much as they want with a standard diet (altromin) in Makrolon cages in air-conditioned rooms with a lighting program (10 hours dark, 14 hours light) and given acidified tap water to drink. For the subcutaneous administration, the test substance and the control substance (estradiol E2) are dissolved in benzyl benzoate/castor oil (1+4 volume/volume).

Young female rats are either hypophysectomized on day 0 and then treated (administration 1 x daily) from day 1 to day 4 with estradiol, compound 1 or 2 according to the invention, or treated subcutaneously (administration 1 x daily) with a carrier (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 killed 24 hours after the last administration and the ovary weight is determined.

0.5 mg/animal/day of compound 1 administered subcutaneously over 4 days produces a comparable increase in ovarian weight in hypophysectomized animals as estradiol at a dose of 0.1 mg/animal/day. The carrier has no effect.

Compound 1 according to the invention thus exhibits a clear dissociation of action in the ovary compared to the uterine action and the pituitary gland action, and is excellently suitable for the preferred indication, the treatment of female infertility, due to its follicle-stimulating action.

In the GnRH antagonist-treated animals, concentrations of 0.1 and 0.3 mg/animal/day of compound 2 in the ovaries already show the same effect as the dose of 1 mg/animal/day of estradiol used (Fig. 1). Even lower dosages (0.01, 0.03 mg/animal/day) show an ovarian effect and can eliminate the antagonistic effect of cetrorelix (Fig. 2).

Fig. 1: Change in ovarian weight under the influence of a GnRH antagonist in the treatment with estradiol (compound 3) or different dosages of compound 2.

Fig. 2: Positive effect of compound 2 at low dosage on ovarian weight during a combination treatment with the GnRH antagonist cetrorelix.

Compound 2 according to the invention thus also exhibits a clearly positive effect on the ovary by stimulating follicle maturation, and is therefore also suitable for the treatment of female sub- or infertility.

Preparation of the compounds according to the invention

For the preparation of the compounds of general formula I according to the invention, two synthesis strategies are primarily used which can be used in general.

On the one hand, particularly 3,16-protected derivatives of estra-1,3,5(10)-triene-3,16%-diols, but also possibly the free diols, can be used for modifications of individual positions in the steroid skeleton.

On the other hand, it includes similarly modified estrone analogues which can be obtained in large quantities by known means [for a typical synthetic procedure, see J. Chem. Soc. Perk. 1, 1973, 2095 for C(9); Steroids 54, 1988, 71 for C(7)], a flexible access to the compounds according to the invention by relocation of oxygen functionality (Z. Chem. 1970, 221) from C(17) to C(16).

For the case of the 3-methyl ether, the formation of the C(16)-C(17)-olefin (Z.

Chem. 1970, 10, 221 seq.; Liebig's Ann. Chem. 1981, 1973 hereafter), where hypobromide is stored in a regio-/stereo-controlled manner, after the ketone is converted to a sulfonyl hydrazone, in the simplest case by reaction with phenylsulfonyl hydrazide in a decomposition reaction. Reductive dehalogenation and removal of the protecting group at C(3) gives the 16P-alcohol which can be converted according to known methods to the 16a-epimer.

Another variant for the introduction of the hydroxyl group on C-atom 16 is by the hydroboration of the 16(17) double bond with sterically demanding boranes. This reaction is known to result 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 oxidation with alkaline hydrogen peroxide gives 16a-hydroxy-estratrienes. To a lesser extent, the epimeric 16P-hydroxysteroids are formed in this reaction. After the cleavage of the 3-methoxy group, estra-1,3,5(10)-3,16a-diols are obtained. By inversion of the configuration at C-atom 16, e.g. by means of the Mitsunobu reaction (Synthesis 1980, 7), the 16P-hydroxyestratrienes are obtained.

For further production possibilities for the C(16)-C(17)-olefinic intermediate, see also DE 199 06 159 Al.

The introduction of fluorine substituents is carried out via nucleophilic substitution reactions of hydroxyl groups with fluoramine reagents (Org. React., 1974, 27, 158-173). If the hydroxyl groups are converted to the corresponding tosylates in advance, then the fluorinated compounds are obtained by reaction with tetra-n-butylammonium fluoride (J. Chem. Res. (M) 1979, pages 4728-4755). Fluorine compounds are also available by reacting the corresponding alcohols with diethylaminosulfur trifluoride (DAST) (US 3,976,691). Geminal difluoro compounds are produced, for example, by reacting carbonyl compounds with sulfur tetrafluoride (US 3,413,321) or diethylaminosulfur trifluoride (DAST)

(U.S. 979,691).

For the synthesis of the 9a-substituted 17P-fluoroestra-1,3,5(10)-triene-3,16-diols according to the invention, 17-oxo-estra-1,3,5(10)-trienes are converted to 17, 17-difluoroestra-1,3,5(10)-trienes (US 3,976,691). The thereby available 17,17-difluoroestra-1,3,5(10)-trienes are converted by treatment with aluminum oxide into 17-fluoroestra-1,3,5(10),16-tetraene (US 3,413,321). Another possibility for the production of fluoroolefins is found in the reaction of the corresponding ketones with diethylaminosulfur trifluoride (DAST) in the presence of polar catalysts, such as fuming sulfuric acid (US 4,212,815). The reaction of 17-fluoro-estra-1,3,5(10),16-tetraenes with boranes and subsequent oxidation with alkaline hydrogen peroxide gives 17p-fluoroestra-1,3,5(10)-trien-16a-ols ( Org. React.\ 963, 13, 1-54).

Access to the 9a-alkenyl- or 9a-alkynyl-substituted estra-1,3,5(10)-trien-3,16a-diols according to the invention is first carried out from 3,16-dihydroxy-estra-1,3,5(10) -trienes which are protected in the 3- and 16-position. By reaction with trimethylsilyl cyanide in the presence of lithium perchlorate, the regio- and stereoselective introduction of a new α-cyano group is carried out (Synlett, 1992, 821-2). After the protective groups have been removed, the 9a-cyano compound is converted by reduction first into a 9a-formyl compound, and then by means of a Wittig reaction ( Org. React. Vo\. 14, 270) into the 9a-alkenyl- or 9a-alkynyl- substituted compound.

The estratriene sulfamates according to the invention are available in a manner known in the art, from the corresponding hydroxysteroids by esterification with sulfamoyl chlorides 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 to the invention. For the (N-acyl)-sulfamates, pharmacokinetic benefits were already demonstrated Qf. 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 the hydroxyl groups which are to remain unesterified. Silyl ethers have been shown to be protective groups of selective reactivity suitable for this purpose, as these silyl ethers are stable under the conditions of sulfamate formation, and the sulfamate group remains intact when the silyl ether(s) are cleaved again to generate the (remaining) hydroxyl group(s) still present in the molecule { Steroids 61, 710-717 (1996)).

The production of the sulfamates according to the invention with an additional hydroxyl group in the molecule is also possible if the starting material is suitable hydroxysteroid ketones. Depending on the target, one or more hydroxyl groups present are first subjected to sulfamoylation. The sulfamate groups can then optionally be converted with a desired acyl chloride in the presence of a base to the appropriate (N-acyl)sulfamates. The currently present oxosulfamates or oxo-(N-acyl)sulfamates are converted by reduction to the corresponding hydroxysulfamates or hydroxy-(N-acyl)sulfamates ( Steroids 61, 1\0-1\1 (1996)). Sodium borohydride and the borane-dimethylsulphide complex are considered suitable reducing agents.

The examples below are used for a more detailed explanation of the invention.

Analogous to the decomposition of the 9a-vinyl group, other compounds of general formula I can be obtained using reagents homologous to the reagents described in the examples.

Etherification and/or esterification of free hydroxy groups is carried out according to the methods common to those skilled in the art.

Example 1

9α-vinyl estra-1,3»5(10)-triene-3,16α-diol

Step 1

9a- cvan- 3- methoxy- estra- 1. 3. 5( 10)- trien- l 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 of methylene chloride is added dropwise while stirring to a suspension consisting of 2.13 g (6.49 mmol) of 3-methoxy-estra-1,3,5(10)-trien-16a-yl-acetate. 2.07 ml (16.54 mmol) of trimethylsilyl cyanide and 0.14 g of lithium perchlorate in 100 ml of methylene chloride. The reaction mixture is green in color. After a reaction time of 1 hour at room temperature, the mixture is mixed with sodium bicarbonate solution. The separated organic phase is washed with water and concentrated by evaporation under a vacuum. The product mixture is chromatographed on silica gel (cyclohexane/ethyl acetate, 6/1). 0.44 g (21%) of 9α-cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate is obtained.

Step 2

9a- cyano- 3- hydroxy- estral- l, 3, 5( 10)- trien- 16a- yl- acetate

7.51 (50.1 mmol) of sodium iodide and 8.87 ml (70.14 mmol) of trimethylchlorosilane are added to a solution consisting of 0.59 g (1.67 mmol) of 9a-cyano-3-methoxy-estra- 1,3,5(10)-trien-16a-yl acetate in 30 ml of acetonitrile while stirring under an argon atmosphere. After approx. 3 hours at 60-70 °C, the reaction is complete. The reaction solution is added to sodium hydrogen sulphite solution and it is extracted with ethyl acetate. The organic phase is washed several times with water, dried over MgSO 4 and concentrated by evaporation under a vacuum to dryness.

The crude product is chromatographed on silica gel (cyclohexane/ethyl acetate, 4/1). 0.43 g (76%) product is obtained.

Step 3

3, 16ct- dihydroxy ester- 1, 3, 5( 10)- trien- 9- carbonitrile

At room temperature, 0.43 g (1.27 mmol) of 9ct-cyan-3-hydroxy-estra-1,3,5(10)-trien-16a-yl-acetate is stirred for 2 hours with 1.0 g (7, 24 mmol) of potassium carbonate in 40 ml of methanol (1% water). The methanol is then distilled off under vacuum and the organic residue is dissolved in methylene chloride. The organic phase is washed with water and concentrated by evaporation. 3.5 g (93%) of 9α-cyanostra-1,3,5(10)-triene-3,16α-diol are obtained.

Step 4

3, 16a- dihydroxvöstra- 1. 3. 5( 10)- trien- 9- carbaldehyde

A suspension consisting of 100 mg (0.34 mmol) of 3,16α-dihydroxyestra-1,3,5(10)-triene-9-carbonitrile in 40 ml of toluene is cooled to approx. -20 °C while stirring. After 0.9 ml (1.35 mmol) of diisobutylaluminum hydride has been added, the reaction mixture is mixed after approx. 10 minutes with sodium bicarbonate solution, it is filtered over diatomaceous earth and the filter aid is re-extracted with ethyl acetate. The combined organic phases are washed with water. By concentration by evaporation of the solution under a vacuum, 84.6 mg of a pale yellow foam is obtained. The product contained in the mixture corresponds to a yield of approx. 52% of the theoretical and is used without further chromatographic work-up in the next step.

Step 5

9a-viny loestra- 1, 3, 5( 10)- trien- 3. 16- diol

Under an inert gas atmosphere, 3.1 g (7.9 mmol) of triphenylmethylphosphonium iodide and 0.24 g (8 mmol) of sodium hydride (80% in paraffin oil) in 20 ml of DMSO are brought to reaction in an ultrasonic bath at approx. 55 °C. After 10 minutes, 80 mg (0.16 mmol, approx. 60%) of 3,16α-dihydroxyestra-1,3,5(10)-triene-9-carbaldehyde is added to the solution and the mixture is allowed to react for a further 60 minutes at approx. 55 °C in an ultrasonic bath. After water has been added, it is extracted with ethyl acetate. The collected organic phases are washed with water and the organic phase is concentrated by evaporation under a vacuum.

The crude product is purified using column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1) and subsequent recrystallization from chloroform. Yield: 24 mg (50%), melting point 88-95 °C.

1H-NMR (400 MHz, DMSO-d6, 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=CH2), 5.00 (dd, 10.5/1.9 Hz, -CH=CH2), 4.47 (d, 4.69 Hz, 16a-OH), 4.45 (dd, 17, 2/1.9 Hz, -CH=CH 2 ), 4.24 (m, 16p-H), 2.68 (m, H-6), 0.69 (s, H-18).

Example 2

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

Step 1

3. 16a- bisr( perhvdropvran- 2- v0oxv1- 18a- homo- estra- 1. 3. 5( 10)- trien- 9-carbonitrile

1.03 g (2.26 mmol) 3,16α-bis[(perhydropyran-2-yl)oxy]-18α-homo-estra-1,3,5(10)-triene, 48.2 mg (0, 45 mmol) lithium perchlorate and 0.71 ml (5.66 mmol) trimethylsilyl cyanide are introduced into 10 ml methylene chloride (molecular sieve) and it is cooled under inert gas to approx. -70 °C while stirring. Then 0.77 g (3.39 mmol) of dichloro-5,6-dicyan-1,4-benzoquinone, dissolved in 65 ml of methylene chloride, is added dropwise over the course of 1 hour. After approx. For 1 hour (warming to room temperature), the reaction solution is mixed with sodium bicarbonate solution and the reaction products are extracted with methylene chloride. The crude product obtained by concentration by evaporation of the organic phases is purified by chromatography. After chromatography on silica gel (cyclohexane/ethyl acetate, 4/1), 0.74 g (68% of theory) of product is obtained.

Step 2

3, 16a- dihydroxyv- 18a- homo- estra- 1, 3, 5( 10)- trien- 9- carbaldehyde

1.3 g (2.7 mmol) of 3,16a-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile is dissolved in 40 ml toluene and it is mixed at room temperature

under inert gas with 7.2 mL (10.8 mmol) of diisobutylaluminum hydride solution (1.5 M in toluene). After a reaction time of 30 minutes, a mixture of 30 ml of methanol and 5 ml of diluted hydrochloric acid (1/1) is added to the reaction solution. The reaction solution is concentrated by evaporation under vacuum and the residue is taken up in ethyl acetate. The organic phase obtained is extracted with water and washed with sodium bicarbonate solution. After the solution has been dried and after concentration by evaporation under vacuum, 0.73 g (86% of theory) of yellow crystals are obtained.

Step 3

9a- vinvl- 18a- homo- estral- l, 3, 5( 10)- triene- 3, 16a- diol

Under an inert gas atmosphere, 13.7 g (34.8 mmol) of triphenylmethylphosphonium iodide and 1.0 g (34.8 mmol) of sodium hydride (approx. 80% on paraffin oil) in 80 ml of DMSO are brought to reaction in an ultrasonic bath at approx. 50 °C. After 30 minutes, 0.73 g (2.3 mmol) of 3,16α-dihydroxy-18α-homo-estra-1,3,5(10)-triene-9-carbaldehyde, dissolved in 10 ml of DMSO, is added to the reaction solution and the mixture is allowed to react in an ultrasonic bath for a further 60 minutes. After water has been added, it is extracted with ethyl acetate, the organic phase is washed with water, dried and concentrated by evaporation.

The crude product is purified using column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1) and crystallization from chloroform.

Yield: 0.59 g (81% of theory) after chromatography

Melting point: 214-220 °C.

1H-NMR (400 MHz, DMSO-d6, 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=l 7.2/10.5 Hz,

-CH=CH2), 5.00 (dd, J=10.5/1.9 Hz, -CH=CH2), 4.48 (d, J=4.7 Hz, 16a-OH), 4.43 (dd, J=17.2/l.9 Hz, -CH=CHA 4.18 (m, 16P-H), 2.68 (m, H-6), 0.72 (t, J=6, 8 Hz, H-18a)

Example 3

9a-(2,,2,-difluorovinyl)-estra-1,3,5(10)-triene-3,16a-diol

Step 1

3. 16a- bisr( perhydropyran- 2- vDoksv1- estra- 1. 3. 5( lOVtriene- 9- carbonitrile

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-oestra-1,3,5(10)-triene analogously to Example 1, step 1, gives 3,16a-bis[(perhydropyran-2- yl)oxy]-estra-1,3,5(10)-trien-9-carbonitrile.

Yield: 58% of the theoretical

Step 2

3, 16a- dihydro- estra- 1, 3, 5( 10)- trien- 9- carbaldehyde

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 1, step 2, gives 3,16a-dihydroxy-estra -1,3,5(10)-triene-9-carbaldehyde.

Yield: 83% of the theoretical.

Step 3

9a-( 2. 2- difluorovinvlV estradiol- 1. 3. 5( 10 Vtriene- 3. 16a- diol

1.5 ml of dimethoxyethane (molecular sieve), 0.3 ml of pentane and 0.13 ml (0.77 mmol) of diethyl (difluoromethyl)phosphonate are introduced into a reaction flask which was made inert, and it was cooled to approx. -75 °C. After 0.72 ml of tert-butyllithium (1.5 M in pentane) has been added and after a reaction time of 30 minutes, 0.14 g (0.31 mmol) of 3,16a-dihydroxy-estra-1,3,5(10 )-triene-9-carbaldehyde, dissolved in a mixture of 1.5 ml dimethoxyethane/0.3 ml pentane, to the reaction solution. The reaction solution is boiled under reflux until the reaction is complete. After being added to cooled ammonium chloride solution, it is extracted with ethyl acetate. The organic phase is concentrated by evaporation under vacuum, the residue is taken up in 5 ml of methanol and mixed with 0.5 ml of diluted hydrochloric acid (1/1). Ethyl acetate is added to the reaction solution, the organic phase is washed with sodium bicarbonate solution and concentrated by evaporation under vacuum. The crude product obtained is purified by means of column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1).

Yield: 22 mg (21% of theoretical)

1H-NMR (400 MHz, DMSO-d6, TMS): 9.08 (s, 3-OH), 7.10 (d, J=8.6 Hz, H-1), 6.51 (dd, 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=CF2), 4.51 (d, J=4.69 Hz, 16a-OH), 4.25 (m, 16(3-H), 2.68 (m, H-6), 0.68 (pp, H-l8).

Example 4

9α-(2,2,-difluorovinyl)-18α-homo-estra-1,3,5(10)-triene-3,16α-diol

Step 1

3, 16a- bis[(perhydropvran-2- yl) oxv1- 18a- homo- estra- 1. 3, 5( 10)- trien- 9-carbonitrile

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene analogously to Example 1, step 1, gives 3,16a-bis[( perhydropyran-2-yl)oxy]-18α-homoestra-1,3,5(10)-trien-9-carbonitrile.

Yield: 58% of the theoretical.

Step 2

3, 16a- dihydroxv- 18a- homo- estra- 1. 3. 5( 10)- trien- 9- carbaldehyde

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile analogously to example 1, step 2, gives 3, 16α-dihydroxy-18α-homo-estra-1,3,5(10)-triene-9-carbaldehyde.

Yield: 87% of the theoretical.

Step 3

9a-( 2, 2- diTuorvinyn- 18a- homo- ustral- l, 3, 5( 10)- trien- 3, 16a- diol

Conversion of 3,16α-dihydroxy-18α-homo-estra-1,3,5(10)-triene-9-carbaldehyde; reaction conditions and execution of the reaction as well as molar ratios as in the third step to 9a-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,16-diol.

The crude product is purified using column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1) and crystal in serine from ethyl acetate.

Yield: 12% of the theoretical

Melting point: 225-232 °C.

1H-NMR (400 MHz, DMSO-d6, TMS): 9.06 (s, 3-OH), 7.08 (d, J=8.6 Hz, H-1), 6.50 (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=CF2), 4.47 (d, J=4.50 Hz, 16a-OH), 4.18 (m, 16(3-H), 2.68 (m, H-6), 0.72 (t , J=6.8 Hz, H-18a).

Example 5

17P-fluoro-9a-vinyl-estra-1,3,5(10)-triene-3,16a-diol

Step 1

3. 16a- bisr( perhvdropvran- 2- vnoksv1- 17B- fluoro- estra- 1. 3. 5( 10)- trien- 9- carbonitrile

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-17p-fluoro-estra-1,3,5(10)-triene analogously to Example 2, step 1, gives 3,16a-bis[( perhydropyran-2-yl)oxy]-17β-fluoro-estra-1,3,5(10)-trien-9-carbonitrile

Yield: 45% of the theoretical.

Step 2

3. 16a- dihvdroksv- 17 B- fluoro- estra- 1. 3. 5( 10)- trien- 9- carbaldehvd

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-17p-fluoro-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 2, step 2, gives 3,16a -dihydroxy-17β-fluoro-estra-1,3,5(10)-triene-9-carbaldehyde.

Yield: 83% of the theoretical.

Step 3

17B- fluoro- 9a- vinvl- estradiol- 1. 3. 5( 10Vtriene- 3. 16ct- diol

Reaction of 3,16α-dihydroxy-17β-fluoro-estra-1,3,5(10)-triene-9-carbaldehyde analogously to Example 2, step 3, gives 17β-fluoro-9α-vinyl-oestra-1,3 ,5(10)-triene-3,16a-diol.

The crude product is purified by means of column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1) and crystallization from chloroform.

Yield: 51% of the theoretical.

Melting point: 94-98 °C.

1H-NMR (400 MHz, DMSO-d6, 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=CH2), 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=CH2), 4.35 (dd, J=55.1/4.7 Hz, H-17a), 4.11 (m, 16(3 -H), 2.68 (m, H-6), 0.79 (d, J=1.9Hz, H-18).

Example 6

17,17-difluoro-9a-vinyl-estra-1,3,5(10)-triene-3,16a-diol

Step 1

3. 16a- bisr( perhydropvran- 2- vDoxy]- 17. 17- difluoro- estra- 1. 3. 5( 10)- trien- 9-carbonitrile

Reaction of 3,16o>bis[(perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene analogous to Example 2, step 1, gives 3,16a-bis[ (perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-trien-9-carbonitrile.

Yield: 46% of the theoretical

Step 2

3. 16a- dihvdroksv- 17. 17- difluoro- estra- 1. 3. 5( 10)- trien- 9- carbaldehvd

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene-9-carbonitrile analogously to example 2, step 2, gives 3 ,16α-dihydroxy-17,17-difluoro-estra-1,3,5(10)-triene-9-carbaldehyde.

Yield: 88% of the theoretical.

Step 3

17. 17- difluoro- 9a- vinvl- estradiol- 1. 3. 5( 10Vtriene- 3. 16a- diol

Reaction of 3,16a-dihydroxy-17,17-difluoro-estra-1,3,5(10)-triene-9-carbaldehyde analogously to Example 2, step 3, gives 17,17-difluoro-9oc-vinyl-estra -1,3,5(10)-triene-3,16a-diol.

The crude product is purified by means of column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1) and crystallization from chloroform.

Yield: 75% of the theoretical.

1H NMR (400 MHz, CDCl 3 , 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=CH2), 5.08 (dd, J=10 .5/1.9 Hz, -CH=CH2), 4.48 (dd, J=17.2/1.9 Hz, -CH=CH2), 4.44 (m, 16P-H), 2, 79 (m, H-6), 0.95 (d, J=1.9 Hz, H-18).

Example 7

9a-(hex-1'-enyl)-estra-1,3,5(10)-triene-3,16a-diol

Step 1

3. 16a- bisr( perhvdropvran- 2- vnoxvl- estra- 1. 3. 5( 10Vtriene- 9- carbonitrile

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-oestra-1,3,5(10)-triene analogously to Example 2, step 1, gives 3,16a-bis[(perhydropyran-2- yl)oxy]-estra-1,3,5(10)-trien-9-carbonitrile.

Yield: 61% of the theoretical.

Step 2

3. 16a- dihydroxy- ustral, 3. 5( 10)- trien- 9- carbaldehvd

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 2, step 2, gives 3,16a-dihydroxy-estra -1,3,5(10)-triene-9-carbaldehyde.

Yield: 87% of the theoretical.

Step 3

9a -( hex- 1 - envlVostra- 1. 3. 50 OVtriene- 3. 16a- diol

8.68 g (20 mmol) pentyltriphenyl-phosphonium bromide + sodium amide (1 g contains 2.3 mmol pentyltriphenyl-phosphonium bromide), 0.2 g (0.67 mmol) 3,16a-dihydroxy-estra-1,3,5( 10)-triene-9-carbaldehyde and 30 ml of DMSO are introduced into a reaction flask which has been rendered inert. The reaction mixture is treated for approx. 2 hours in an ultrasonic bath at 60 °C. After the reaction is complete, water is added to the reaction solution. The crude product is isolated by extraction with ethyl acetate, washing the organic phase with water and concentration by evaporation until a dry state is reached.

The crude product obtained is purified by means of 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.

1H-NMR(400 MHz, DMSO-d6, TMS): 8.97 (s, 3-OH), 7.08 (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), 5.73 (d, J=12.5 Hz, -CH=CH- CH2-), 5.20 (dt, J=12.5/7.4 Hz, -CH=CH-CH2), 4.48 (d, J-4.7 Hz, 16a-OH), 4.24 (m, 16p<->H), 2.66 (m, H-6), 0.68 (t, J=7.0 Hz, CH3-CH2-), 0.66 (s, H-18) .

Example 8

9α-(but-1'-enyl)-estra-1,3,5(10)-triene-3,16-diol

Step 1

3, 16a- bis[(perhydropyran-2- yl) oxvl- estra- 1. 3, 5( 10)- trien- 9- carbonitrile

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-oestra-1,3,5(10)-triene analogously to Example 2, step 1, gives 3,16a-bis[(perhydropyran-2- yl)oxy]-estra-1,3,5(10)-trien-9-carbonitrile.

Yield: 52% of the theoretical.

Step 2

3, 16a- dihydro- estra- 1. 3. 5( 10)- trien- 9- carbaldehvd

Reaction of 3,16a-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 2, step 2, gives 3,16a-dihydroxy-estra -1,3,5(10)-triene-9-carbaldehyde.

Yield: 87% of the theoretical.

Step 3

9a-( but- 1 - env P- estradiol- 1. 3. 5( 1 OVtriene- 3. 16a- diol

8.68 g (20 mmol) propyltriphenyl-phosphonium bromide + sodium amide (lg contains 2.3 mmol propyltriphenyl-phosphonium bromide), 0.2 g (0.67 mmol) 3,16a-dihydroxy-estra-1,3,5(10 )-triene-9-carbaldehyde and 30 ml of DMSO are introduced into a reaction flask which has been rendered inert. The reaction mixture is treated for approx. 2 hours in an ultrasonic bath at 60 °C. After the reaction is complete, water is added to the reaction solution. The crude product is isolated by extraction with ethyl acetate, washing the organic phase with water and concentration by evaporation until a dry state is reached.

The crude product obtained is purified by means of column chromatography on silica gel (cyclohexane/ethyl acetate, 1/1).

Yield: 0.16 g (73% of theory) after chromatography.

Melting point: 140-148 °C.

1H-NMR (400 MHz, DMSO-d6, 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- CH2-), 5.19 (dt, J=12.5/7.4 Hz, -CH=CH-CH2-), 4.47 (d, J=4.7 Hz, 16a-OH), 4, 24 (m, 16(3-H), 2.66 (m, H-6), 0.66 (s, H-18), 0.57 (t, J=7.2 Hz, CHrCH2-).

Claims (23)

1. 9a-substituted estra-1,3,5(10)-triene derivatives, characterized in that they have the general formula 1 where the radicals R3, R7, R7, R9, R13, R<16> as well as R<1>7 and R1<7,> independently of each other, has the following meaning: R means a hydrogen atom or a group R, where R means a straight chain or branched, 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 methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyan -, halogen-(fluoro-, chloro-, bromo-, iodo-), hydroxy-, amino-, mono(C1-8-alkyl)- or di(C1-8-alkyl)amino-, where the two alkyl groups are identical or different, di(aralkyl)amino-, where the two aralkyl groups are identical or different, carboxyl-, carboxyalkyloxy-, C1-C20-acyl- or C1-C20-acyloxy groups as substituents, an acyl radical COR<19>, where R <19> is a straight-chain or branched hydrocarbon radical of up to 10 carbon atoms which is saturated or unsaturated in up to three places, and which is partially or fully halogenated, or R<18> means a group R<20>SO2, where R< 20> is an R<21>R<22>N group, where R<2>1 and R2<2>, independently of each other, mean a hydrogen atom, a Ci-C5 alkyl radical, a group C(0)R , where R is a straight-chain or branched hydrocarbon radical of up to 10 carbon atoms which is saturated or unsaturated in up to three places, and which is partially or fully halogenated, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, a C4-Ci5 cycloalkylalkyl radical with 3-7 carbon atoms in the cycloalkyl part, and with an alkyl part of up to 8 carbon atoms or an aryl, heteroaryl or aralkyl radical, or a substituted aryl or heteroaryl radical, with methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen- (fluorine-, chlorine-, bromine-, iodine-), hydroxy -, amino-, mono(Ci_8-alkyl)- or di(Ci_8-alkyl)amino-, where the two alkyl groups are identical or different, di(aralkyl)amino-, where the two aralkyl groups are identical or different, carboxyl-, carboxyl-, C1-C20-acyl or CrC20-acyloxy groups as substituents, or together with N atom et, a polymethyleneimino radical with 4-6 C atoms or a morpholino radical, R 7 and R 7' are, in each case independently of each other, a hydrogen atom or a halogen atom, R<9> is a straight-chain or branched alkenyl or alkynyl radical with 2-6 carbon atoms, which may be partially or fully fluorinated, or an ethynyl or prop-l-ynyl radical, R 13 is a methyl group or an ethyl group, R 16 is a hydroxy group or a group R<l8>0-, R<20>SO2- or OC(0)R<23> with R<18>, R<20> and R<23> in each case have the meaning given under R<3>, and R 17 and R 17' are in each case independently of each other, a hydrogen atom or a halogen atom. 2. Compounds of general formula I according to claim 1, characterized in that R3 is a hydrogen atom. 3. Compounds of general formula I according to claim 1 or 2, characterized in that R 7 is a hydrogen atom or a fluorine atom in the a position, R 0 is a vinyl, ethynyl or prop-l-ynyl group, R 16 is a hydroxy group and R<17> is a hydrogen atom or a fluorine atom in the a- score. 4. Compounds of general formula I according to claim 1 or 2, characterized in that R16 stands for a group R<18->0- or R<19>S02-0-, with R18 and R in each case having the meaning indicated under R. 5. Estratrienes of general formula I according to claim 1 or 2, characterized in that they are: 9a-viny 1-estra-1,3,5(10)-trien-3,16a-diol, 9a-ally 1-estra-1,3,5(10)-trien-3, 16a-diol, 18a-homo-9a-vinyl-estra-1,3,5(10)-triene-3,16a-diol, 18a-homo-9a-ally 1-estra-1,3,5(10) -trien-3,16a-diol, 3-methoxy-9a-vinyl-estra-1,3,5(10)-trien-16a-ol, 9a-ally 1-3 -methoxy-estra-1,3,5 (10)-trien-16a-ol, 18a-homo-3-inethoxy-9a-vinyl-estra-1,3,5(10)-trien-16a-ol, 18a-homo-9a-allyl-3-methoxy -estra-1,3,5(10)-trien-16a-ol, 9a-(2',2'-difluorovinyl)-estra-1,3,5(10)-trien-3,16a-diol, 9a -(2',2'-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-16a-ol, 16a-hydroxy-9a-viny 1-estra-1,3,5( 10)-trien-3yl-sulfamate, 9a-allyl-16a-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate, 18a-homo-16a-hydroxy-9a-vinyl-estra-1, 3,5(10)-trien-3y 1-sulfamate, 18a-homo-9a-ally 1-16a-hydroxy-estra-1,3,5(10)-trien-3y 1-sulfamate, 9a-vinyl-estra -1,3,5(10)-triene-3,16a-diyl-disulfamate, 9a-allyl-oestra-1,3,5(10)-triene-3,16a-diyl-disulfamate, 18a-homo-9a -vinyl-estra-1,3,5(10)-trien-3,16a-diyl-disulfamate, 18a-homo-9a-al ly 1-estra-1,3,5(10)-trien-3,16a-diy 1-disulfamate, 16a-hydroxy-9a-viny 1-estra-1,3,5(10)-trien-3y l- (N-acetyl)-sulfamate, 9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate, 18α-homo-16α-hydroxy-9α- Viny 1-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate, 18α-homo-9α-allyl-16α-hydroxy-estra-1,3,5(10) -trien-3yl-(N-acetyl l)-sulfamate, 9a-(prop-(Z)-enyl)-estra-1,3,5(10)-trien-3,16a-diol, 9a-(n- propyl)-estra-1,3,5(10)-triene-3,16a-diol, 9ct-ethynyl-estra-1 ,3,5(10)-triene-3,16a-diol, 9a-vinyl-estra -1,3,5(10)-triene-3,16a-diol diacetate, 18a-homo-9a-vinyl-oestra-1,3,5(10)-triene-3,16a-diol diacetate, 16a -valeroyloxy-9a-vinyl-estra-1,3,5(10)-trien-3-ol, 16a-acetoxy-9a-vinyl-estra-1,3,5(10)-trien-3-ol, 18a -homo-16a-acetoxy-9a-vinyl-estra-1,3,5(10)-trien-3-ol, 7a-fluoro-9a-vinyl-estra-1,3,5(10)-trien-3 ,16α-diol, 7α-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol, 17 p-fluoro-9a-vinyl-estra-1,3,5(10)-triene-3,16a-diol, 17P-fluoro-9a-allyl-estra-1,3,5(10)-trien-3 ,16α-diol, 18α-homo-7α-fluoro-9α-vinyl-oestra-1,3,5(10)-triene-3,16α-diol, 18α-homo-7α-fluoro-9α-allyl-oestra- 1,3,5(10)-triene-3,16a-diol, 18a-homo-17p-fluoro-9a-viny 1-estra-1,3,5(10)-triene-3,16a-diol and 18a -homol7β-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol. 6. Pharmaceutical preparations, characterized in that they contain at least one compound according to claims 1-5, as well as a pharmaceutically compatible carrier. 7. Use of the compounds of general formula I according to claims 1-5 above for the production of pharmaceutical agents. 8. Use according to claim 7, for the treatment of estrogen deficiency-induced diseases and conditions in women and in men. 9. Use according to claim 7, for the treatment of peri- and postmenopausal symptoms. 10. Application according to claim 7, for the in v/Yrø treatment of female infertility. 11. Application according to claim 7, for the in v/vo treatment of female infertility. 12. Use according to claim 7, for the therapy of hormone deficiency-induced symptoms in ovarian dysfunction caused by surgery, medication, etc. 13. Use according to claim 7, for hormone replacement therapy (HRT). 14. Use according to claim 13, in combination with selective estrogen receptor modulators (SERMs), for example raloxifene. 15. Use according to claim 7, for prophylaxis and therapy of hormone deficiency-related bone loss. 16. Use according to claim 7, for prophylaxis and therapy of osteoporosis. 17. Use according to claim 7, for prophylaxis and therapy of cardiovascular diseases. 18. Use according to claim 7, for the prevention and treatment of prostatic hyperplasia. 19. Use according to claim 18, in combination with anti-estrogens and estrogen receptor modulators (SERMs), for prophylaxis and therapy of prostatic hyperplasia. 20. Use according to claim 7, for the treatment of diseases of the immune system. 21. Use according to claim 20, for the treatment of autoimmune diseases. 22. Use according to claim 21, for the treatment of rheumatoid arthritis. 23. Use according to claim 21, for the treatment of multiple sclerosis.