WO2007062876A1

WO2007062876A1 - Prodrugs of er-beta-selective substances method for production thereof and pharmaceutical compositions comprising the same

Info

Publication number: WO2007062876A1
Application number: PCT/EP2006/011728
Authority: WO
Inventors: Olaf Peters; Gudrun Reddersen; Ralf Wyrwa; Alexander Hillisch; Walter Elger; Katja Prelle; Peter Droescher
Original assignee: Bayer Schering Pharma Aktiengesellschaft
Priority date: 2005-11-29
Filing date: 2006-11-27
Publication date: 2007-06-07
Also published as: CN101316856A; CA2630438A1; NO20082918L; AU2006319382A1; JP2009517426A; KR20080072087A; EA200801272A1; EP1957514A1; ZA200805658B; DE102005057225A1; BRPI0619237A2; CR9997A; ECSP088482A

Abstract

The invention relates to prodrugs of 8-ß-substituted estratrienes of general formula (I) in which the Z group is bonded to the steroid, method for production thereof, pharmaceutical compositions comprising said compounds and use thereof. Said compounds of general formula (I) do not bind to a- and/or ß- estrogen receptors, but to carboanhydrases and inhibit said enzymes.

Description

Prodrugs of ERβ-selective substances, processes for their preparation and pharmaceutical compositions containing them

The invention relates to prodrugs of ERβ-selective substances of the general formula (I),

Group Z (I)

a process for their preparation, pharmaceutical compositions containing them and their use for the manufacture of medicaments.

Estrogens play an important role in the organism in both sexes. Estrogens are involved in the maturation of sex characteristics in the maturing organism. Estrogens in both sexes control the organism's transitions during puberty, such as the growth spurt and then the cessation of bone growth. In all stages of life, estrogens play a central role in bone metabolism in both sexes (1, 4). Their loss leads to the breakdown of bone substance and carries the risk of increased brittleness of the bone.

In the woman, the ovaries secreted by the ovary dominate in the organism. During pregnancy, the placenta produces large amounts of estrogen. In man, estrogens are predominantly "peripheral" through the aromatization of testosterone or adrenal androgens in various organs of success, such as the CNS, bone, or intestinal epithelium, allowing for physiological estrogen effects in men at very low levels of estradiol in the blood with a genetic defect of the aromatase or the estrogen receptor, the bone is severely disrupted in growth and maintenance (2).

While oral administration (10) is problematic for natural estrogens due to their low oral bioavailability, conventional chemically modified estrogens with improved bioavailability (eg ethinyl estradiol) often have the disadvantage of being significantly less Increased estrogen effect in the liver (3, 9, 10). This hepatic estrogenicity affects a number of functions, such as transport proteins, lipid metabolism, blood pressure regulation and coagulation factors (5, 7, 11, 12, 14). The secretion of IGF-I (8), which is particularly important for the maintenance of muscle and bone, is also negatively affected by hepatic estrogenic effects (12, 13, 6).

WO 01/77139 describes novel 8β-substituted estratrienes wherein the 8β-substituent is a straight- or branched-chain, optionally partially or fully halogenated alkyl or alkenyl radical having up to 5 carbon atoms, an ethynyl or prop-1-ynyl radical may show, as pharmaceutical active ingredients, a higher in vitro affinity for estrogen receptor preparations of rat prostate than rat uterine estrogen receptor preparations and in vivo a preferential effect on bone compared to uterus and / or pronounced effect on stimulation of expression of 5HT2a receptor and Transporter exhibit. These compounds may preferably be used for the treatment of diseases caused by estrogen deficiency.

Disadvantages of these 8β-substituted estratrienes are their lack of oral bioavailability and metabolic instability.

WO 01/91797 discloses steroidal compounds which are bound to erythrocytes via a group - SO ₂ NR ¹ R ² and accumulate there. The concentration ratio of the compounds between erythrocytes and plasma is 10- 1000: 1, preferably 30-1000: 1, so that one can speak of a deposit formation in the erythrocytes. Strong binding of the compounds to the erythrocytes avoids metabolism during liver passage. Disadvantageously, despite a reduced metabolization with the indicated dosages no therapeutically relevant drug levels are given.

It is therefore an object of the present invention to provide prodrugs of ERβ-selective compounds which render the Erβ-selective compounds orally bioavailable. This object is achieved by sulfamoyl compounds of 8β-substituted estratrenes of the general formula (I) in which the Z group is bound to the steroid to be released

Group Z

(■) where n is a number 0 - 4,

R ^{1 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ^{1 are} independently a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a d_ ₅ alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , wherein R ²⁰ and R ^{21 is} a C _1-5 alkyl group, a C ₃ . ₈ -cycloalkyl group, an aryl group, a

or R ^{20 can} furthermore denote a hydrogen, or R ² denotes a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ¹ , R ³ and X, X ¹ independently represent a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a ds-alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , wherein R ²⁰ and R ^{21 is} a ds-alkyl group, a C ₃ . ₈ -cycloalkyl group, one

Aryl group, one

or R ^{20 can} furthermore denote a hydrogen or R ³ denotes a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ¹ , R ² and X, X ¹ independently of one another for a hydrogen atom, a

Halogen atom, a nitrile group, a nitro group, a Ci. _5- alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ stands, wherein R ²⁰ and R ^{21 is} a ds-alkyl group, a C ₃ . ₈ -cycloalkyl group, an aryl group, a d- ₄ -Alkylenarylgruppe, a

are group or Ca-β-cycloalkylene-d ^ alkyl group and R ^{20 can} also be a hydrogen, and

STEROID for a steroidal ABCD ring system of the formula (A) is:

where the radicals R ³ , R ⁸ , R ¹⁶ and R ^{17 have the} following meaning:

R ³ Z and

R ^{17 is} an OH group, a tri (C 1 -C ₄ -alkyl) silyloxy group or a group OC (O) -R ²⁰ or

R ³ OH, OMe, a TrKd-d-alkoxy-silyloxy group, a group OC (O) -R ²⁰ and R ¹⁷ Z

such as

R ^{8 is} a branched or straight-chain, optionally partially or completely halogenated alkyl, alkenyl or alkynyl radical having up to 3 carbon atoms, R ^{16 is} a hydrogen, a halogen atom or a methyl group,

where the substituents R ¹⁶ and R ^{17 can} each be in both the α and β positions,

and their pharmaceutically acceptable salts.

Furthermore, the present invention comprises the new compounds as pharmaceutical active ingredients, their preparation, their therapeutic application and pharmaceutical dosage forms containing the new substances. The invention relates to estrogen derivatives which themselves can not bind to the estrogen receptor and from which the parent compound contained in the body is released, processes for their preparation and pharmaceutical compositions containing these compounds. The compounds according to the invention are prodrugs which, after saponification of the ester group Z, release an ERβ-selective estrogen (parent estrogen).

Absolutely and relatively greatly attenuated effects on the ERα avoids the undesirable estrogen effects of any classical estrogen therapy on the uterus, mammary gland, and liver typical of undissociated estrogens. The compounds of the invention have therapeutically favorable estrogenic activities, as far as they are mediated via the ER ß, especially in the central nervous system, in the circulatory system and in the bone.

The substances according to the invention are preferably used for oral therapy. The compounds according to the invention have a markedly increased oral bioavailability compared to their parent estrogens, an increased systemic, but generally reduced hepatic estrogenicity. This dissociation of desired and undesired hormonal effects simultaneously enables therapeutically more effective and more compatible drugs compared to the prior art. The substances according to the invention are cleaved enzymatically or hydrolytically in the body, with no steroid sulphatases (STS) being required, for example for the cleavage of estradiol-3-sulphamate. Thus, the inhibition of the steroid sulfatase which is typical for estrogen-3-sulfamates and which is disadvantageous for the achievement of strong estrogenic effects can be avoided, which is typical for estrogen sulfamates in humans. In oral therapy with natural estrogens (estradiol, estradiol valerate, estrone sulfate, conjugated estrogens), but also in the case of estradiol sulfamate, high levels of estrone are dominant in the blood (10). Unlike in the cycle, blood levels of estradiol are lower than those of estrone. This is disadvantageous because estrone is a less effective estrogen than estradiol. An advantage of the substances according to the invention in comparison with those in the prior art is the preferential release of the respective parent estrogen, thus for example 8β-ethylestradiol, 8β-methylestradiol, 8β-vinylestradiol and 8β-difluorovinylestradiol instead of the inactive estrone derivatives. The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts can be used as a single component in pharmaceutical preparations or in combination, in particular, with antiestrogens or gestagens. Particularly preferred is the combination with ERα-selective antiestrogens or with antiestrogens which are peripherally selectively effective, ie, which do not cross the blood-brain barrier.

The substances and the pharmaceuticals containing them are particularly suitable for the treatment of peri- and post-menopausal symptoms, in particular hot flashes, insomnia, irritability, mood swings, incontinence, vaginal atrophy, hormone-deficiency-related mood disorders. Likewise, the substances for hormone substitution and the therapy of hormone-deficiency-related symptoms in surgical, drug or other conditional ovarian dysfunction are suitable. It also includes prevention of bone loss in postmenopausal women and in andropausal men, in hysterectomized women or in women treated with LHRH antagonists or agonists.

The prodrugs of the ERβ-selective agonists according to the invention can be used alone or in combination with antiestrogens, aromatase inhibitors or Selective Estrogen Receptor Modulators (SERM) for the treatment of prostatic hyperplasia in order to avoid estrogen deprivation or to reduce their effects.

The antiestrogen used is preferably 7alpha- [9 - [(4, 4,5,5, 5-pentafluoropentyl) sulfinyl] nonyl] estra-1,3,5 (10) -thene-3,17β-diol (fulvestrant).

As aromatase inhibitors to be used, the following are contemplated: anastrozole, atamestane, fadrozole, formestan, letrozole.

Suitable SERMs are compounds selected from the following group: raloxifene, tamoxifen, 5- (4- {5 - [(RS) - (4,4,5,5,5-pentafluoropentyl) sulfinyl] pentyl} phenyl) -6 - phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979).

The compounds are also useful for alleviating the symptoms of andropause and menopause, ie male and female hormone replacement therapy (HRT), both Prophylaxis and treatment, continue to treat the symptoms associated with dysmenorrhea and for the treatment of acne suitable.

The substances can also be used for the prophylaxis of hormone-deficiency-induced bone loss and osteoporosis, for the prevention of cardiovascular diseases, in particular vascular diseases such as atherosclerosis, for the inhibition of the proliferation of arterial smooth muscle cells, for the treatment of primary pulmonary hypertension.

Furthermore, the substances for the treatment of inflammatory and immune system disorders, in particular autoimmune diseases such. As rheumatoid arthritis, multiple sclerosis, Crohn's disease and endometriosis can be used.

The compounds can be used in particular for therapies that lead to estrogen deprivation, for example, after treatment with aromatase inhibitors or GnRH antagonists or agonists, for the treatment of arthritic symptoms.

In addition, the compounds may find use in the treatment of male fertility disorders and prostatic diseases. The compounds according to the invention are suitable for estrogen treatment of prostate carcinoma.

The compounds may also be used in combination with the natural vitamin D3 or with calcite analogs for bone formation or as supportive therapy for therapies that cause bone mass loss (for example, therapy with glucocorticoids, aromatase inhibitors, GnRH agonists or antagonists, chemotherapy) ,

Finally, the compounds of general formula (I) may be used in conjunction with progesterone receptor modulators, for example mesoprogestins such as asoprisnil, in particular for use in hormone replacement therapy and for the treatment of gynecological disorders.

The compounds according to the general formula (I) according to the invention can also be used for the treatment of alopecia caused, for example, by chemotherapy. A therapeutic product containing an estrogen and a pure antiestrogen for simultaneous, sequential or separate use for the selective estrogen therapy of peri- or postmenopausal states has already been described in EP-A 0 346 014.

For the purposes of the present invention, "ds-alkyl group" is understood to mean a branched or straight-chain alkyl radical having up to 5 carbon atoms which may be substituted, for example, by halogens, OH, CN, for example methyl, ethyl, n-propyl, Propyl, n-butyl, i-butyl, tert-butyl or n-pentyl called.

The above-mentioned "C ₃ . ₈ -Cycloalkyl "means according to the invention a mono- or bicyclic group which may be substituted for example by halogens such as fluorine, chlorine or bromine, OH, CN, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or hydroxycyclohexyl.

For the purposes of the present application, the term "aryl group" is understood as meaning a substituted or unsubstituted aryl radical having 6 to 15 carbon atoms, for example a phenyl group, a substituted phenyl group, such as a halophenyl group or a nitrophenyl group, or a naphthyl group.

For the purposes of the present application, the term "C 1-4 -alkylene-aryl group" is understood to mean a disubstituted alkyl radical which is substituted by at least one aryl radical. Both radicals together have 7 to 15 carbon atoms, where the aryl radical may carry further substituents, for example a halogen atom Examples are a benzyl group or a halobenzyl group.

The term "C ^ alkylene-Ca-β-cycloalkyl group" is a disubstituted alkyl radical Both residues is in the sense of the present application understood to be cycloalkyl with a C _3. ₈ is substituted. Together have 4 to 12 carbon atoms, whereby the Cycloalkyl may carry further substituents such as, for example, a halogen atom, examples being a cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl group.

For the purposes of the present invention, the term "C 1 -C 4 -cycloalkylene-C 1-4 -alkyl group" is used

Application understood a disubstituted Ca-β-cycloalkylene radical which is substituted with a C _1-4 alkyl radical. Both radicals together have 4 to 12 carbon atoms, wherein the Group can carry further substituents, such as a halogen atom. Examples are a propylcyclohexyl or butylcyclohexyl group.

A trialkylsilyloxy group is, for example, a trimethylsilyloxy. or tert-butyldimethylsilyloxy group.

For the purposes of the present invention, the term "halogen atom" is understood to mean a fluorine, chlorine, bromine or iodine atom, preference being given to fluorine, chlorine and bromine.

The number "n" is preferably 0.1 or 2.

R ¹ is preferably a group -SO ₂ NH ₂ , wherein R ² , R ³ , X ¹ and X are independently of one another preferably an H, F, Cl atom, an OH or a methoxy group.

R ² is preferably a group -SO ₂ NH ₂ , wherein R ¹ , R ³ , X ¹ and X are independently of one another preferably an H, F, Cl atom, an OH or a methoxy group.

R ³ is preferably a group -SO ₂ NH ₂ , wherein R ¹ , R ² , X ¹ and X are independently of one another preferably an H, F, Cl atom, an OH or a methoxy group.

X ¹ is preferably an H atom.

R ⁸ is preferably methyl, ethyl, vinyl, difluorovinyl, ethynyl or prop-1-ynyl.

Particularly preferred for R ^{8 are} methyl, ethyl, vinyl or difluorovinyl.

Y is preferably OH, OMe, a trimethylsilyloxy, tert-butyldimethylsilyloxy, a benzoate, a sulphamoylbenzoate, acetate, propionate, valerate, butcyclate or cyclopentylpropionate radical.

R ¹⁷ is preferably an OH, a trimethylsilyloxy, an acetate, propionate, valerate, a benzoate, an optionally halogenated Sulfamoylbenzoat- radical.

Particularly preferred compounds according to the invention are listed below: 1) (3'-hydroxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 3 sulfamoyl benzoate, 2) (3'-hydroxy-8'-ethyl-estra-1 \ 3 ', 5' (10 ') -trien-17'-β-yl) 3-sulfamoylbenzoate,

3) (3'-hydroxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate,

4) (3'-hydroxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate,

5) (3'-hydroxy-8'-ethyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate, 6) (S'-hydroxy-δ 'ß-vinyl-estra-r.S'.δXIOΗriene-i 7'β-yl) 4-sulfamoylbenzoate,

7) (3'-acetoxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate,

8) (3'-acetoxy-8'-ethyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate,

9) (3'-acetoxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate,

10) (3'-acetoxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate, 11) (S'-acetoxy) δ'β-ethyl-estra-r.S'.δ'OO'Hrien - ^ 'β-yl) 4-sulfamoylbenzoate,

12) (3'-acetoxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate,

13) (3'-benzoyloxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 3-sulfamoylbenzoate,

14) (3'-Benzoyloxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 4-sulfamoylbenzoate,

15) (3'-Benzoyloxy-8'-ethyl-estra-1 ', 3', 5 '(10') - trien-17'-β-yl) 3-sulfamoylbenzoate, 16) (S'-benzoyloxy-δ 'ß-ethyl-estra-r.S'.S'O O'Hrien-i 7'-β-yl) 4-sulfamoylbenzoate,

17) (3'-Benzoyloxy-8'-vinyl-estra-1 ', 3'5' (10 ') -trien-17'-β-yl) 3-sulfamoylbenzoate,

18) (3'-Benzoyloxy-8'-vinyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 4-sulfamoylbenzoate,

19) (3'-hydroxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 2-chloro-5-sulfamoylbenzoate,

20) (3'-hydroxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-yl) 3-sulfamoyl-4-chloro-benzoate, 21) ( 3'-hydroxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 2-chloro-5-sulfamoylbenzoate,

22) (3'-hydroxy-8'-methyl-estra-1 ', 3', 5 '(10') - trien-17'-β-yl) 3-sulfamoyl-4-chloro-benzoate,

23) (3'-hydroxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 2-chloro-5-sulfamoylbenzoate,

24) (3'-hydroxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 3-sulfamoyl-4-chloro-benzoate,

25) (17'β- (n-pentanoyloxy) -8'β-vinyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate, 26) (17 ' β- (n-pentanoyloxy) -8'-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

27) (17'β- (n-pentanoyloxy) -8'-ethyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

28) (17'-Benzoyloxy-8'-vinyl-estra-r, 3 ', 5' (10 ') -trien-3'-yl) 3-sulfamoylbenzoate,

29) (17'-Benzoyloxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

30) (17'-Benzoyloxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate, 31) (17'β- (n Pentanoyloxy) -8'β-vinyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

32) (17'β- (n-pentanoyloxy) -8'-methyl-estra-1 \ 3 ', 5' (10 ') -trien-3'-yl) 4-sulfamoylbenzoate,

33) (17'β- (n-pentanoyloxy) -8'-ethyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

34) (17'-Benzoyloxy-8'-vinyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate, 35) (17'-Benzoyloxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

36) (17'-Benzoyloxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

37) (17'-acetoxy-8'-vinyl-estra-1 ', 3', 5 '(I O') -trien-3'-yl) 3-sulfamoylbenzoate,

38) (17'-acetoxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate, 39) (17'-acetoxy) 8'-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

40) (17'-acetoxy-8'-vinyl-estra-1 ', 3', 5 '(I O') -trien-3'-yl) 4-sulfamoylbenzoate,

41) (17'-acetoxy-8'-ethyl-estra-1 \ 3 ', 5' (10 ') -trien-3'-yl) 4-sulfamoylbenzoate,

42) (17'-acetoxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

43) (3'-methoxy-8'-vinyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 3-sulfamoylbenzoate, 44) (3'-methoxy-8 'β-ethyl-estra-1', 3 ', 5' (10 ') - trien-17'-β-yl) 3-sulfamoylbenzoate,

45) (3'-methoxy-8'-methyl-estra-1 ', 3', 5 '(I O') - triene-17'-β-yl) 3-sulfamoylbenzoate,

46) (3'-methoxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate,

47) (3'-methoxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 4-sulfamoylbenzoate,

48) (3'-methoxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate,

/ n-V / Vo experiments Test principle and test description:

Adult Wistar rats were ovariectomized 14 days after this operation used for the study of the substances according to the invention. One treatment lasted for 3 days (day 1-3) and on day 4 the animals were killed. Subsequently, the plasma was obtained for hormone-analytical and clinical-chemical determinations and the determination of uterine weights. In satellite experiments, killing and blood sampling were carried out on conditioned animals after single treatment and at other times (see Figures 1 and 2). -

Figure 1 Pharmacokinetics of 8-vinyl-E2 vs (3'-hydroxy-8β'-vinyl-estrone)

1 ', 3', 5 '(10') - trien-17'β-yl) 3-sulphamoylbenzoate (single p.o. administration of 1000 μg)

■ vehicle / po -A <(3'-hydroxy-8'b-vinyl-estra-1 ', 3', 5 '(10') -triene-17'b-yl) 3-sulfamoylbenzoate / po ^■ 8- vinyl E2 / po

Raising of 8β-vinylestra-1, 3,5 (10) -triene-3,17β-diol (8-vinyl-E2) in plasma of rats after single oral administration of 1 mg / animal. Significant increase in 8-vinyl E2 levels after administration of 1 mg / animal (3'-hydroxy-8β'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β yl) 3-sulfamoylbenzoate than after oral administration of 8-vinyl-E2.

_y -

Figure 2 Kinetics of 8-vinyl-E2 vs (3'-hydroxy-8'-vinylestra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate according to p.o. Application of 1 mg of 8-vinyl-E2 or equimolar (3'-hydroxy-8'-vinylestra-1 ', 3', 5 '(10') -trien-17'-yl) 4-sulfamoylbenzoate

8 10 12 14 16 18 20 22 24 time after application (h)

'Vehicle po ^• 8-vinyl-E2 / po ^{- am} (3'-hydroxy-8'-b-vinylestra-1', 3 ', 5' (10 ') -lrene-17'b-yl) 4-sulfamoylbenzoate / po

Raising of 8β-vinylestra-1, 3,5 (10) -triene-3,17β-diol (8-vinyl-E2) in plasma of rats after single oral administration of 1 mg / animal. Significant is a greater increase in the 8-vinyl E2 level after administration of 1 mg / animal (3'-hydroxy-8'-vinylestra-1 ', 3', 5 '(10') - triene-17'β -yl) 4-sulfamoylbenzoate as observed after oral administration of 8-vinyl-E2.

In in vivo experiments on rats, it was found that after oral administration of the compounds according to the invention an unexpectedly high increase of the parent estrogen is recorded. This is not the case, for example, with the 17-benzoates and 17-acetates of 8β-vinyl-estradiol.

The substances according to the invention, unlike conventional estrogens, have no effect on the uterus, the ovary and the liver. / n-Vfϊro experiments a) blood plasma concentration ratio - test principle and experimental description:

The SO ₂ -NH ₂ group of the substances according to the invention can lead to an accumulation in erythrocytes by binding to carbonic anhydrases. The displacement of estradiol-3-sulfamate from the erythrocyte binding by test substances is measured. Experimental approach: Human blood is treated with a mixture of ¹⁴ C-labeled and unlabeled estradiol sulfamate. At the selected operating point, the erythrocytes are saturated and the distribution in plasma / erythrocytes is 40:60. A second blood sample is spiked with a mixture of ¹⁴ C-labeled estradiol sulfamate and unlabeled test substance. The relative binding affinity is calculated from the proportion of ¹⁴ C-labeled estradiol sulfamate in the plasma: high proportion = strong displacement of ¹⁴ C-estradiol sulfamate from the erythrocytes by the test substance = high binding affinity.

In contrast to the results published in WO 01/91797, the concentration ratios of the compounds according to the invention between erythrocytes and plasma are not in a range of 10-1000: 1, but in the range <10: 1. In the case of the (S'-hydroxy-δβ'-vinyl-estra-i '.S'.δXIO'J-triene - ^' ß-yl) 3-sulfamoylbenzoates, the ratio is, for example, 1, 4: 1.

b) Carbonic anhydrase inhibition - test principle and experimental description:

Carbonic anhydrases catalyze the CO ₂ hydrogenation.

Experimental approach: A buffer, which was treated with carbonic anhydrase I or carbonic anhydrase II, a constant C0 ₂ -stream is passed. Measurement parameter is the time required to lower the pH within defined limits. This parameter reflects the formation of H ₂ CO ₃ in the medium. IC ₅₀ inhibition values are determined by pipetting test substances to the experimental batch. In the concentration ranges examined, the test substances cause no to complete inhibition of said enzymes. Table 1: IC ₅₀ inhibitory values of human carbonic anhydrase I and II

¹ References: C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997).

Despite the low blood plasma concentration ratio, binding (inhibition) to the two isoenzymes carbonic anhydrase CA I and CA II in the erythrocytes could be demonstrated in all cases. Of importance for the properties as estrogen is the binding to erythrocytes induced by affinity for the carbonic anhydrases. This binding is essential for a reduced extraction of the orally administered substance in the first passage of the liver. High or low affinity for the erythrocytic carbonic anhydrases, faster or delayed release from this depot and subsequent hydrolysis determine the therapeutic substitutability of the substances according to the invention. The compounds according to the invention thus open up the possibility of achieving higher short-lasting or more uniform low and longer-lasting hormone levels in equimolar administration of the substance. As a result, the strength and duration of action are varied and a therapy tailored to the organism is possible.

These test results provide the compounds of the general formula (I) according to the invention with a wide variety of possible uses for hormone replacement therapy (HRT) as well as hormonal disorders in men and women.

The present invention therefore also relates to pharmaceutical compositions containing at least one compound of general formula (I), optionally together with pharmaceutically acceptable excipients and carriers. The substances according to the invention have pharmacodynamically and pharmacokinetically improved properties relative to their parent estrogens, which are based on a reduced hepatic extraction and more uniform and longer-lasting blood levels of the released estrogen.

dosage

For use according to the invention, the Erβ-selective compounds of general formula (I) are administered orally.

Suitable dosages of the compounds according to the invention in humans for the treatment of peri- and postmenopausal symptoms, hormone-deficiency-related disorders, gynecological disorders such as ovarian dysfunction and endometriosis, male and female fertility disorders, hormone-related tumor diseases as well as for use in male and female hormone replacement therapy ever according to indication 5 μg to 2000 mg per day, depending on the age and constitution of the patient, where the necessary daily dose can be administered by single or multiple delivery.

For gynecological disorders such as ovarian dysfunction and endometriosis dosages between 0.5 and 100 mg come for the treatment of male and female fertility disorders 5 micrograms to 50 mg for hormone-related tumors 5 to 500 mg and male or female hormone replacement therapy 5 micrograms 100 mg into consideration.

The pharmaceutical compositions contain, in addition to customary carriers and / or diluents, at least one compound of the general formula I. The substances according to the invention can also be used therapeutically in combination with a gestagen, antigestagen or mesoprogestin. The substances according to the invention are preferably used individually as active ingredient in pharmaceutical preparations.

The pharmaceutical compositions of the invention are mixed with the usual solid or liquid excipients or diluents and the commonly used pharmaceutical excipients according to the desired mode of administration with a suitable dosage produced in a known manner. The preferred formulations consist of a dosage form which is suitable for oral administration. Such dosage forms are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms.

Corresponding tablets, for example, by mixing the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve Depot effect such as carboxyl polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, are obtained. The tablets can also consist of several layers.

Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.

Solutions or suspensions with the compounds of general formula I according to the invention may additionally taste-improving agents such as saccharin, cyclamate or sugar and z. B. flavorings such as vanillin or orange extract. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

The capsules containing the compounds of the general formula I can be prepared, for example, by mixing the compound (s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatine capsules.

Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.

The following examples illustrate the present invention without limiting it. Example 1 (3'-hydroxy-8-vinylestra-1 S3S5 '(10-trien-17'-β-yl) -3-sulfamoylbenzoate

3,17β-Bis (tert-butyldimethylsilyloxy) -8-vinyl-estra-1,3,5 (10) -triene

1.0 g of 8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol were placed in 18 ml of DMF and admixed with 2.8 g of imidazole and 3.6 g of tert-butyldimethylchlorosilane. The solution was stirred for 2 h at room temperature and then extracted with n-hexane. The organic phase was washed with saturated aqueous brine and water, dried with sodium sulfate and concentrated in vacuo. In this way, 2.0 g of crude 3,17β-bis (tert-butyldimethylsilyloxy) -8-vinyl-estra-1,3,5 (10) -triene was obtained.

¹ H-NMR (CDCl ₃ ): 0.01, 0.03 (s, 3H, SiMezt-Bu), 0.17 (s, 6H, SiM ^ t -Bu), 0.73 (s, 3H, H-18), 0.88 (s, 9H, SiMe ₂ J ₁ Bu), 0.96 (s, 9H, SiMe ₂ I ₁ Bu), 3.54 (t, 1 H, H-17), 6.49 (d, 1 H, H-4), 6.58 (dd, 1H, H-2), 7.08 (d, 1H, H-1).

3- (tert-butyldimethylsilyloxy) -8-vinylestra-1, 3,5 (10) -triene-17β-ol variant 1

3.79 g of crude 3,17β-bis (tert-butyldimethylsilyloxy) -8-vinyl-estra-1,3,5 (10) -triene from the last step were dissolved at room temperature in 245 ml of THF and 145 ml of acetonitrile , Subsequently, a solution of 240 ml of acetonitrile, 0.4 ml of water and 1, 2 ml of chlorotrimethylsilane was prepared and added dropwise 140 ml of this solution to the steroid solution. After 21 h, methylene chloride was added, washed with water, dried over sodium sulfate and concentrated in vacuo. The resulting 2.84 g of crude product were purified by column chromatography on silica gel (cyclohexane / ethyl acetate 8: 2). Thus, 640 mg (22%) of 3- (tert-butyldimethylsilyloxy) -8-vinylestra-1, 3,5 (10) -thene-17β-ol was obtained.

¹ H-NMR (CDCl ₃ ): 0.17 (s, 6H, SiMe 1 -t Bu), 0.78 (s, 3H, H-18), 0.96 (s, 9H, SiMe ₂ I ₁ Bu), 3.63 (t, 1H, H-17), 6.49 (d, 1H, H-4), 6.58 (dd, 1H, H-2), 7.08 (d, 1H, H-1).

Variant 2

100 mg of 3,17β-bis (tert-butyldimethylsilyloxy) -8-vinyl-estra-1,3,5 (10) -triene were dissolved in 30 ml of acetone, treated with 3.5 ml of 5% hydrochloric acid and 2 h stirred at room temperature. Thereafter, water and ethyl acetate were added, the organic phase separated, washed with water, dried over sodium sulfate and concentrated on a rotary evaporator. After chromatographic purification of the crude product on silica gel (cyclohexane / Ethyl acetate 9: 1), 31 mg (40%) of colorless 3- (tert-butyldimethylsilyloxy) -8-vinylestra-1, 3,5 (10) -triene-17β-ol were obtained.

(3 '- (tert-Butyldimethylsilyloxy) -8'-vinylestra-1', 3 ', 5' (10 ') -triene-17'P-yl) -3-chlorosulfonylbenzoate

300 mg of 3- (tert-butyldimethylsilyloxy) -8-vinylestra-1,3,5 (10) -triene-17β-ol were dissolved in 15 ml of tetrahydrofuran (THF) and admixed with 150 mg of sodium hydride. Subsequently, a solution of 0.3 ml of 3- (chlorosulfonyl) benzoyl chloride in 3 ml of THF was added dropwise and heated at reflux for 4 h. The cooled reaction solution was poured into ice-water, extracted with methylene chloride, the organic phase dried over sodium sulfate and concentrated on a rotary evaporator. After purification by column chromatography on silica gel (cyclohexane), 198 mg (44%) of (3 '- (tert-butyldimethylsilyloxy) -8'-vinylestra-1', 3 ', 5' (10 ') -triene-17 were obtained in this manner 'ß-yl) -3-chlorosulfonylbenzoat won.

(3 '- (tert-Butyldimethylsilyloxy) -8'-vinylestra-1', 3 ', 5' (10 ') -trien-17'-β-yl) -3-sulfamoylbenzoate

198 mg of (3 '- (tert-butyldimethylsilyloxy) -8'-vinylestra-r, 3', 5 '(10') -triene-17'-yl) -3-chlorosulfonylbenzoate were mixed with 20 ml of methylene chloride and 20 ml of 25% aqueous ammonia solution and stirred at room temperature. After 2 h, water and methylene chloride were added, the phases were separated and the organic phase was washed neutral with water. After drying over sodium sulfate, the mixture was concentrated on a rotary evaporator. There was thus obtained 144 mg (75%) of (3 '- (tert-butyldimethylsilyloxy) -8'-vinylestra-1', 3 ', 5' (10 ') -triene-17'-β-yl) -3-sulfamoylbenzoate , ¹ H-NMR (CDCI _3): 0.15 (s, 6H, SiMezt-Bu), 0.93 _(? S, 9H, SiMe t-Bu), 0.93 (s, 3H, H-18), 4.83 (t, 1 H , H-17), 6.47 (d, 1H, H-4), 6.56 (dd, 1H, H-2), 7.09 (d, 1H, H-1).

(3'-Hydroxy-8'-vinylestra-1 ', 3', 5 '(10') -trien-17'-β-yl) -3-sulfamoylbenzoate

To 144 mg of (3 '- (tert-butyldimethylsilyloxy) -8'-vinylestra-1', 3 ', 5' (10 ') -triene-17'-yl) -3-sulfamoylbenzoates in 10 ml of tetrahydrofuran became 90 Mg tetrabutylammonium fluoride, stirred for 2 h at room temperature and then treated with water and methylene chloride. The organic phase was washed neutral with water, dried over sodium sulfate and concentrated on a rotary evaporator. The foamy crude product was purified by column chromatography on silica gel (cyclohexane / ethyl acetate 8: 2). There were thus obtained 36 mg (31%) of (3'-hydroxy-8'-vinylestra-1 ', 3', 5 '(10') -triene-17'-β-yl) -3-sulfamoylbenzoate. ¹ H-NMR (CDCl ₃ ): 0.92 (s, 3H, H-18), 4.82 (t, 1H, H-17), 6.39 (d, 1H, H-4), 6.48 (dd, 1H , H-2), 7.00 (d, 1H, H-1).

Example 2 (3'-Hydroxy-8'-vinylestra-1 ', 3', 5 '(10') -triene-17'-β-yl) -4-sulfamoylbenzoate

((3 '- (tert-Butyldimethylsilyloxy) -8'-vinylestra-1', 3 ', 5' (10 ') -trien-17'-β-yl) -4-sulfamoylbenzoate

To 300 mg of 3- (tert-butyldimethylsilyloxy) -8-vinylestra-1,3,5 (10) -triene-17β-ol in 4 ml of pyridine was added 750 mg (2.6 mmol) of 4-sulfamidobenzoyl chloride and 28 mg of 4 -Dimethylaminopyridin and stirred at room temperature for 2 h. The reaction mixture was poured onto ice water, the precipitate was filtered off and the resulting crude product (913 mg) was used without further purification in the next step.

(3'-Hydroxy-8'-vinylestra-1 ', 3', 5 '(10') -triene-17'-β-yl) -4-sulfamoylbenzoate

To 913 mg of crude ((3 '- (tert-butyldimethylsilyloxy) -8'-vinylestra-1', 3 ', 5' (10 ') -trien-17'-β-yl) -4-sulfamoylbenzoate in 30 ml of tetrahydrofuran 278 mg of tetrabutylammonium fluoride were added and stirred at room temperature for 2 hours, then the reaction solution was taken up in methylene chloride and water, the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (cyclohexane / ethyl acetate 1: 1 and recrystallized from methanol to give 147 mg (42%) of (3'-hydroxy-8'-vinylestra-1 ', 3', 5 '(10') -triene-17'-yl). ¹ H-NMR (CDCl ₃ ): 0.96 (s, 3H, H-18), 4.87 (t, 1H, H-17), 6.51 (d, 1H ₁ H-4), 6.60 (dd, 1H, H-2), 7.10 (d, 1H, H-1).

References:

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2. Frank GR (1995), The role of estrogen in pubertal skeletal physiology: epiphyseal maturation and mineralization of the skeleton. Acta Paediatr. 84 (6), 627-30.

3. Goldzieher JW (1990), Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications. At the. J. Obstet. Gynecol. 163, 318-22. 4. Gustafsson JA (2000), Novel aspects of estrogen action. J. Soc. Gynecol. Investig. 7,

S8-S9.

5. Helmer OM and Griffith RS (1952), The effect of the administration of estrogens on the renin substrate (hypertensinogen) content on rat plasma. Endocrinology 51, 421-6.

6. Kelly JJ, Rajkovic IA, O ^' Sullivan AJ, Sernia C and Ho KKY (1993), Effects of different oral estrogen formulations on insulin-like growth factor-l, growth hormone and growth hormone binding protein in post-menopausal women. Clin. Endocrinol. 39, 561-67.

7. Krattenmacher R, Knauthe R, Parczyk K, Walker A, Hilgenfeldt U and Fritzemeier K-H (1994), Estrogens action on hepatic synthesis of angiotensinogen and IGF-I: direct and indirect estrogenic effects. J. steroid. Biochem. Mol. Biol. 48, 207-14. 8. Le Roith and Butler AA (1999), Insulin-like growth factors in pediatric health and disease. J. Clin. Endocrinol. Metab. 84, 4355-61.

9. Almond FP, Geola FL, Lu JKH, Eggena P, Sambhi MP, Hershman JM and Judd HL

(1982), Biology effects of various doses of ethinyl estradiol in postmenopausal women.

Obstet. Gynecol. 59, 673-9. 10. Mashchak CA, Lobo RA ₁ Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF and Mishell DR Jr (1982), Comparison of pharmacodynamic properties of various estrogen formulations. At the. J. Obstet. Gynecol. 144, 511-18.

H . Oelkers WKH (1996), Effects of estrogens and progestagens on the renin aldosterone system and blood pressure. Steroids 61, 166-71. 12. 0 ^' Sullivan AJ and Ho KKY (1995), A comparison of the effects of oral and transdermal estrogen replacement on insulin sensitivity in postmenopausal women. J.

Clin. Endocrinol. Metab. 80, 1783-8.

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Metab. 85, 1121-5. 14. Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A and Stege R (1989), estrogen therapy and liver function - metabolic effects of oral and parenteral administration. Prostate 14, 389-95.

Claims

claims

1. Sulfamoyl Compounds of 8β-Substituted Estratrienes of the General Formula (I)

Group Z

(I) where n is a number 0-4, R ^{1 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ² , R ³ and X, X ¹ are each independently a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , wherein R ²⁰ and R ^{21 is} a C 1-6 alkyl group, a C 1-6 cycloalkyl group, a

Aryl group, a d ^ -Alkylenarylgruppe, a C _1-4 alkylene-C _3-8 -cycloalkyl or C ₃ . ₈ -cycloalkylene-C _1-4 -alkyl group and R ^{20 can} furthermore denote a hydrogen, or R ² denotes a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ¹ , R ³ and X ₁ X ¹ independently of one another for a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 -alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , wherein R ²⁰ and R ^{21 is} a C _1-5 alkyl group, a C ₃ . ₈ cycloalkyl group, an aryl group, a d ^ -Alkylenarylgruppe, a C _1-4 alkylene-C. ₃ ₈ -cycloalkyl group or Cs ^ -cycloalkylene-C ^ -alkyl group and R ^{20 can} also denote a hydrogen, or R ^{3 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , wherein R ¹ , R ² and X , X ¹ independently represent a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5

Alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ stands . wherein R ²⁰ and R ^{21 is} a ds-alkyl group, a C ₃ . ₈ -cycloalkyl group, an aryl group, a C 1-4 -alkylene-aryl group, a C 1-6 -alkylene-C 1-6 -cycloalkyl group or Ca-β-cycloalkylene-C 1-4 -alkyl group, and also R ²⁰ may denote a hydrogen, and

STEROID for a steroidal ABCD ring system of the formula (A) is:

where the radicals R ₁ R, R and R have the following meaning:

R Z and

R 17 is an OH group, a triCCrC ^ alkysoilyloxy group or a group

OC (O) -R ²⁰ or

R ³ OH, OMe, a tri (C _r C ₄ -alkyl) silyloxy group, a group OC (O) -R ²⁰ and

R ¹⁷ Z

and R ^{8 is} a branched or straight-chain, optionally partially or completely halogenated alkyl, alkenyl or alkynyl radical having up to 3 carbon atoms,

R 16 is a hydrogen, a halogen atom or a methyl group,

and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, characterized in that n is O, 1 or 2.

3. Compounds according to claim 1 or 2, characterized in that in each case a radical R ¹ , R ² or R ^{3 represents} a group -SO ₂ NH ₂ .

4. Compounds according to any one of claims 1 or 2, characterized in that R ^{1 represents} a group -SO ₂ NH ₂ or -NHSO ₂ NH ₂ .

5. Compounds according to claim 4, characterized in that R ^{1 represents} a group - SO ₂ NH ₂ .

6. Compounds according to one of claims 1 to 5, characterized in that, if one of the radicals R ¹ , R ² , R ^{3 is} not -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , the other two radicals of R ¹ , R ² , R ³ and X and X ¹ independently of one another

Hydrogen, fluorine, chlorine atom, a hydroxy or a methoxy group.

7. Compounds according to one of claims 1 to 6, characterized in that R ^{8 is} a methyl, ethyl, vinyl or Difluorvinylrest.

8. Compounds according to one of claims 1 to 7,

1) (3'-hydroxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate,

2) (3'-hydroxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 3-sulfamoylbenzoate, 3) (3'-hydroxy-8 'β-vinyl-estra-1', 3 ', 5' (10 ') - trien-17'-β-yl) 3-sulfamoylbenzoate,

4) (3'-hydroxy-8'-methyl-estra-r, 3 ', 5' (10 ') -trien-17'-β-yl) 4-sulfamoylbenzoate,

5) (3'-hydroxy-8'-ethyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate,

6) (3'-hydroxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate,

7) (3'-acetoxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 3-sulfamoylbenzoate, 8) (3'-acetoxy-δ 'β-ethyl-estra-1', 3 ', 5' (10 ') - trien-17'-β-yl) 3-sulfamoylbenzoate,

10) (3'-acetoxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate,

11) (3'-acetoxy-8'-ethyl-estra-1 \ 3 ', 5' (10 ') -trien-17'-β-yl) 4-sulfamoylbenzoate,

12) (3'-acetoxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate, 13) (S'-benzoyloxy-δ 'β-methyl-estra-i' .S'.δXIO'J-triene - ^ 'β-yl) 3-sulphamoylbenzoate,

14) (S'-benzoyloxy-δ'β-methyl-estra-i '.S'.SXIO'-helium -' 'β-y-sulfamoyl benzoate,

15) (3'-Benzoyloxy-8'-ethyl-estra-1 \ 3 ', 5' (10 ') -trien-17'-β-yl) 3-sulfamoylbenzoate,

16) (3'-Benzoyloxy-δ'β-ethyl-estra-1 ', 3', 5 '(I O') - triene-17'-β-yl) 4-sulfamoylbenzoate,

17) (3'-Benzoyloxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate, 18) (3'-Benzoyloxy-8'-vinyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 4-sulfamoylbenzoate,

20) (3'-hydroxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoyl-4-chloro-benzoate,

21) (3'-hydroxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 2-chloro-5-sulfamoylbenzoate, 22) (S ') -Hydroxy-δ'β-methyl-estra-i '.S'.δ'OO'-helium-i 7'-β-yl) 3-sulfamoyl-4-chloro-benzoate,

23) (3'-hydroxy-8'-ethyl-estra-1 ', 3', 5 '(10> trien-17'-β-yl) 2-chloro-5-sulfamoylbenzoate,

24) (3'-hydroxy-8'-ethyl-estra-1 \ 3 ', 5' (10 ') -triene-17'-yl) 3-sulfamoyl-4-chloro-benzoate,

25) (17'β- (n-pentanoyloxy) -8'β-vinyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

26) (17'β- (n-pentanoyloxy) -8'β-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate, 27) (17 ' β- (n-pentanoyloxy) -8'-ethyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

28) (17'-Benzoyloxy-8'-vinyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

30) (17'-Benzoyloxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

31) (17'β- (n-pentanoyloxy) -8'β-vinyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate, 32) (17 ' β- (n-pentanoyloxy) -8'-methyl-estra-r, 3 ', 5' (10 ') -trien-3'-yl) 4-sulfamoylbenzoate,

34) (17'-Benzoyloxy-8'-vinyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

35) (17'-Benzoyloxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

36) (17'-Benzoyloxy-8'-ethyl-estra-1 ', 3', 5 '(I O') -trien-3'-yl) 4-sulfamoylbenzoate, 37) (17'-Acetoxy -8'β-vinyl-estra-r, 3 ', 5' (10 ') -trien-3'-yl) 3-sulfamoylbenzoate,

38) (17'-acetoxy-8'-ethyl-estra-1 ', 3 ", 5' (10 ') -trien-3'-yl) 3-sulfamoylbenzoate,

39) (17'-acetoxy-8'-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 3-sulfamoylbenzoate,

40) (17'-acetoxy-8'-vinyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

41) (17'-acetoxy-8'-ethyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate, 42) (17'-acetoxybenzoate). 8'-methyl-estra-1 ', 3', 5 '(10') -trien-3'-yl) 4-sulfamoylbenzoate,

43) (3'-methoxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate,

44) (3'-methoxy-8'-ethyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate,

45) (3'-methoxy-8'-methyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate,

46) (3'-methoxy-8'-vinyl-estra-1 ', 3', 5 '(10') -trien-17'-β-yl) 4-sulfamoylbenzoate, 47) (3'-methoxy-8 'β-ethyl-estra-1', 3 ', 5' (10 ') - trien-17'-β-yl) 4-sulfamoylbenzoate,

9. Pharmaceutical compositions containing at least one compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. Pharmaceutical composition according to claim 9, characterized in that at least one further steroidal compound is contained.

11. Pharmaceutical composition according to claim 10, characterized in that the further steroidal compound is a gestagen, antigestagen or mesoprogestin.

12. A pharmaceutical composition according to claim 11, wherein the progestin is drospirenone, dienogest, norethisterone or levonorgestrel, the antiprogestin onapristone or mifepristone or the mesoprogestin asoprisnil.

13. Use of the compounds according to the invention according to claim 1-8 for the preparation of a medicament.

14. Use according to claim 13 for the treatment of diseases and conditions in women and men, which are caused by estrogen deficiency.

15. Use according to claim 13 for the treatment of peri- and postandropausal complaints.

16. Use according to claim 13 for the in vitro treatment of male infertility.

17. Use according to claim 13 for the in vivo treatment of male infertility.

18. Use according to claim 13 for the in vitro treatment of female infertility.

19. Use according to claim 13 for the in vivo treatment of female infertility.

20. Use according to claim 13 for the treatment of hormone-deficiency-related symptoms in surgical, drug or other conditional ovarian dysfunction.

21. Use according to claim 13 for hormone replacement therapy (HRT).

22. Use according to claim 20 in combination with a Selective Estrogen Receptor Modulator (SERM), for example raloxifene.

23. Use according to claim 13 for the prophylaxis and therapy of hormone deficiency-related bone mass loss.

24. Use according to claim 13 for the prophylaxis and therapy of osteoporosis.

25. Use according to claim 23 in combination with the natural vitamin D3 or with calcitriol analogues for bone formation or as supportive therapy for therapies which cause bone mass loss (for example a therapy with glucocorticoids, aromatase inhibitors, GnRH agonists or antagonists, chemotherapy) ,

26. Use according to claim 13 for the prevention and therapy of cardiovascular diseases.

27. Use according to claim 13 for the treatment of inflammatory diseases and diseases of the immune system.

28. Use according to claim 27 for the treatment of rheumatoid arthritis.

29. Use according to claim 27 for the treatment of multiple sclerosis, Crohn's disease or endometriosis.

30. Use according to claim 13 for the prevention and treatment of benign prostatic hyperplasia (BPH).

31. Use according to claim 30 in combination with antiestrogens and selective estrogen receptor modulators for the prevention and treatment of benign prostatic hyperplasia (BPH).

32. Use according to claim 31, wherein as an antiestrogen 7alpha- [9 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl] estra-1, 3,5 (10) -triene-3,17ß- diol (fulvestrant) or as SERM raloxifene, tamoxifen, 5- (4- {5 - [(RS) - (4, 4,5,5, 5-pentafluoropentyl) sulfinyl] - pentyl} phenyl) -6-phenyl- 8,9-dihydro-7H-benzocyclohepten-2-ol are used.

33. Use according to claim 13 for the treatment of arthritic symptoms, in particular after therapies that lead to estrogen deprivation, for example, after treatment with aromatase inhibitors or GnRH antagonists or agonists.

34. Use of compounds according to any one of claims 1 to 8 for the preparation of medicaments for the treatment of diseases which can be positively influenced by the inhibition of the Carboanhydraseaktivität.

35. Use of compounds according to any one of claims 1 to 8 for the preparation of medicaments for the treatment of alopecia.

36. Use of 3'-hydroxy-8'-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 3-sulfamoylbenzoate, (3'-hydroxybenzoate) 8'β-vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulfamoylbenzoate, 3'-hydroxy-8'-vinyl-estra-1 ', 3 ', 5' (10 ') - trien-17'-β-yl) 3-sulfamoyl-4-chloro-benzoate, (3 ¹ -methoxy-8'-vinyl-estra-1', 3 ', 5' ( 10 ') - trien-17'β-yl) 3-sulfamoylbenzoate and (3'-methoxy-

8'β-Vinyl-estra-1 ', 3', 5 '(10') -triene-17'-β-yl) 4-sulphamoylbenzoate according to one of the preceding claims 13-35.

37. A process for the preparation of compounds of general formula (I) according to any one of claims 1 to 8

Group Z

by reacting 8ß-substituted Estratrienen according to formula (A) with corresponding sulfamoylphenylcarboxylic acids or their derivatives or by Reaction of corresponding compounds with sulfamide, sulfamoyl chloride or aminosulfonyl isocyanate.