AU2006319383A1 - Prodrug ERbeta-selective substances, methods for the production thereof and pharmaceutical compositions containing said compounds - Google Patents

Description

VERIFICATION OF TRANSLATION I, Melissa Stanford, a translator with Chillson Translating Service, 3530 Chas Drive, Hampstead, Maryland, 21074, hereby declare as follows: That I am familiar with the German and English languages; That I am capable of translating from German to English; That the translation attached hereto is a true and accurate translation of German language Iniernational Application No. PCT/EP2006/011729 titled, "Prodrugs of ERp-Selective Substances, Process for their Production, and Pharmaceutical Compositions that Contain These Compounds;" That all statements made herein of my own knowledge are true and that all statements made on information and belief are believed to be true; And further that these statements were made with the knowledge that willful false statements and the like so made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States Code and that such willful false statements may jeopardize the validity of the application or any registration resulting therefrom. By Executed this Q 9 day of 2 0<e Witness 53181ADE_Applicationtext 28.11.2005 Prodrugs of ERP-selective substances, processes for their preparation and pharmaceutical compositions comprising these compounds 5 The invention relates to prodrugs of ERD-selective substances of the general formula (I), R 3 3 ~ R 2

H

2 n

STEROID-O

4 X, R 0 Group Z 10 (I) a process for their preparation, pharmaceutical compositions comprising these compounds and their use for the production of medicaments. 15 Oestrogens play an important role in the body in both sexes. In the maturing body, oestrogens are involved in the imprinting of sex characteristics. In both sexes, oestrogens control the changes in the body during 20 pubescence, such as the sudden increase in growth and subsequently the ending of bone growth. In all phases of life, oestrogens play a central role in bone metabolism in both sexes (1, 4). Their loss leads to the breakdown of osseous tissue and involves the risk 25 of increased brittleness of the bone. In women, the oestrogens secreted by the ovary dominate in the body. In pregnancy, the placenta forms large amounts of oestrogen. In men, oestrogens are mainly 30 formed "peripherally" by the aromatization of testosterone or of the adrenal androgens in various end - 2 - 53181ADEApplicationtext 28.11.2005 organs, such as the CNS, the bone or the intestinal epithelium. This adjustment permits the physiological effects of oestrogen in men at very. low oestradiol levels in the blood. In men and women with a genetic 5 defect of aromatase or of the oestrogen receptor, the bone is massively perturbed with respect to growth and maintenance (2). Whereas for natural oestrogens oral administration (10) 10 is problematical due to their low oral bioavailability, conventional chemically modified oestrogens having improved bioavailability (for example ethynyl oestradiol) often have the disadvantage of causing a markedly increased oestrogen effect in the liver (3, 9, 15 10). This hepatic oestrogenicity concerns a number of functions, such as transport proteins, lipid metabolism, blood pressure regulation and clotting factors (5, 7, 11, 12, 14). The secretion of IGF-I (8), particularly important for the maintenance of 20 musculature and bone, is also adversely affected by hepatic effects of oestrogen (12, 13, 6). In WO 01/77139, novel 8p-substituted oestratrienes are described, where the 8P substituent can be a straight 25 or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical having up to 5 carbon atoms, an ethynyl or propyn-1-yl radical, which as pharmaceutical active compounds show a higher in vitro affinity to oestrogen receptor preparations of 30 rat prostate than to oestrogen receptor preparations of rat uterus and in vivo exhibit a preferential action on bone in comparison to the uterus and/or marked action with respect to stimulation of the expression of 5HT2a receptor and transporter. These compounds can 35 preferably be used for the treatment of diseases which are caused by an oestrogen deficit.

- 3 - 53181ADEApplicationtext 28.11.2005 WO 03/104253 describes novel 9a-substituted oestra trienes having a straight- or branched-chain, optionally partially or completely halogenated alkenyl radical having up to 6 carbon atoms, an ethynyl or 5 propyn-1-yl radical in position 9a, which likewise show a higher in vitro affinity to oestrogen receptor preparations of rat prostate than to oestrogen receptor preparations of rat uterus and in vivo preferably exhibit a preferential action on the ovary in 10 comparison to the uterus. These compounds can preferably be used for the treatment of diseases which are caused by an oestrogen deficit. From WO 01/91797, steroidal compounds are known which 15 are bonded to erythrocytes via a group -SO 2

NR'R

2 and accumulate there. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000:1, preferentially 30-1000:1, such that we can speak of depot formation in the erythrocytes. Owing to the 20 strong bonding of the compounds to the erythrocytes, metabolization during the liver passage is avoided. Disadvantageously, despite reduced metabolization using the dosages indicated, therapy-relevant active compound levels are not afforded. 25 It is therefore the object of the present invention to make available prodrugs of ERP-selective compounds, which make the ERP-selective compounds orally bioavailable. 30 This object is achieved by sulphamoyl compounds of 9a substituted oestratrienes of the general formula (I), in which the group Z is bonded to the steroid to be released 35 - 4 - 53181ADEApplicationtext 28.11.2005 R 3 -' R2 STEROID- A*O 4 % X R O Group Z (I) in which n is a number 0-4, 5 R 1 is a radical -SO 2

NH

2 or -NHSO 2

NH

2 , where R 2 , R 3 and X, X1 independently of one another are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C 1

.

5 -alkyl group, a CpF 2 p+ 1 group with p = 1-3, a group 10 OC(O)-R 20 , COOR 20 , OR20 , C(O) NHR 20 or OC (O) NH R, where R 2 0 and R 2 1 are a C 1

.

5 -alkyl group, a

C

3

.

8 -cycloalkyl group, an aryl group, a C 1

-

4 alkylenearyl group, a C 1

.

4 -alkylene-C 3

.

8 -cyclo 15 alkyl group or C 3

.

8 -cycloalkylene-C 1

.

4 -alkyl group, and R20 can moreover be a hydrogen, or R2 is a radical -SO 2

NH

2 or -NHSO 2

NH

2 , where R1, R 3 and X, X 1 independently of one 20 another are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C 1

-

5 -alkyl group, a CpF 2 p+ 1 group with p = 1-3, a group 012 20 20

OC(O)-R

2 0 , COOR 2 , OR C(O)NHR or OC(O) NH R, 25 where R 20 and R 2 1 are a C 1 -s-alkyl group, a

C

3 ..- cycloalkyl group, an aryl group, a C 1

.

4 alkylenearyl group, a C 1

.

4 -alkylene-C 3

_

8 -cyclo alkyl group or C 3

.

8 -cycloalkylene-C 1

.

4 -alkyl group, and 30 R 20 can moreover be a hydrogen, or

R

3 is a radical -SO 2

NH

2 or -NHSO 2

NH

2

,

- 5 - 53181ADEApplicationtext 28.11.2005 where R1, R 2 and X, X 1 independently of one another are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C 1 -- alkyl group, a CpF 2 p.

1 group with p = 1-3, a group 20 20 20 20 5 OC(O) -R2, COOR , OR , C(O)NHR or OC (0) NH 2012 R, where R20 and R are a C 1

-

5 -alkyl group, a C3- 8 -cycloalkyl group, an aryl group, a C 1

.

4 alkylenearyl group, a C 1

.

4 -alkylene-C 3

.

8 -cyclo 10 alkyl group or C 3

.

8 -cycloalkylene-C 1

.

4 -alkyl group, and R20 can moreover be a hydrogen, and STEROID is a steroidal ABCD ring system of the formula 15 (A): 17 RR where the radicals R', R 9 , R" and R 17 have the following 20 meaning:

R

3 is Z and RM 16is an OH group, a tri(C 1

.

4 -alkyl)silyloxy group or 20 a group OC(O)-R , or R 3 is OH, OMe, a tri(C 1

.

4 -alkyl)silyloxy group, a 25 group OC(O)-R 20 and RM 1 is Z and RT 7 is a hydrogen atom or fluorine atom, a methyl 30 radical or ethyl radical, - 6 - 53181ADE_Applicationtext 28.11.2005 R 9 is a branched or straight-chain, optionally partially or completely halogenated alkyl, alkenyl or alkynyl radical having up to 3 carbon atoms,

R

17 is a hydrogen atom or a halogen atom 5 where the substituents R 7 , R1 6 and R 17 can in each case be both in the a-position and in the P-position, and their pharmaceutically acceptable salts. 10 Furthermore, the present invention comprises the novel compounds as pharmaceutical active compounds, their preparation, their therapeutic application and pharmaceutical administration forms which contain the 15 novel substances. The invention relates to oestrogen derivatives which cannot bind to the oestrogen receptor themselves and from which the parent oestrogen contained is released in the body, to processes for their preparation and to 20 pharmaceutical compositions comprising these compounds. The compounds according to the invention are prodrugs which release an ERP-selective oestrogen (parent oestrogen) after hydrolysis of the ester group Z. 25 As a result of absolutely and relatively strongly attenuated actions on the ER a, undesired estrogen effects of any classical oestrogen therapy on the uterus, the mammary gland and the liver, as are typical of undissociated oestrogens, are avoided. The compounds 30 according to the invention have therapeutically favourable oestrogenic activities, if they are mediated by means of the ER S, in particular in the central nervous system, in the circulatory system and in the bone. 35 The substances. according to the invention are preferably employed for oral therapy. Compared to their - 7 - 53181ADEApplicationtext 28.11.2005 parent oestrogens, the compounds according to the invention have a markedly increased oral bioavailability and an increased systemic oestrogenicity, but as a rule a reduced hepatic 5 oestrogenicity. As a result of this dissociation of desired and undesired hormonal effects, medicaments which at the same time are therapeutically more efficacious and better tolerable in comparison to the prior art are made possible. 10 The substances according to the invention are cleaved enzymatically or hydrolytically in the body, no steroid sulphatases (STS) being needed, such as, for example, for the cleavage of oestradiol 3-sulphamate. Thus the inhibition of the steroid sulphatase typical of 15 oestrogen 3-sulphamates and disadvantageous for the achievement of strong oestrogenic effects, which is typical of oestrogen sulphamates in humans, can also be avoided. In the case of oral therapy with natural oestrogens (oestradiol, oestradiol valerate, oestrone 20 sulfate, conjugated oestrogens), but also in the case of that with oestradiol sulphamate, high levels of oestrone dominate in the blood (10). Other than in the cycle, the concentrations of oestradiol in the blood are lower than those of oestrone. This is therefore 25 disadvantageous, because oestrone is a more weakly active oestrogen than oestradiol. An advantage of the substances according to the invention in comparison to those in the prior art is 30 the preferable release of the respective parent oestrogen, that is instead of the inactive oestrone derivatives, for example 9a-ethyloestra-3,16a-diol, 9a methyloestra-3,16a-diol, 9a-vinyloestra-3,16a-diol and 9a-difluorovinyloestra-3,16a-dio1 and their 17p 35 fluorinated analogues.

- 8 - 53181ADEApplicationtext 28.11.2005 The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts can be employed as an individual component in pharmaceutical preparations or in combination, in 5 particular with anti-oestrogens or gestagens. Combination with ERot-selective anti-oestrogens or with anti-oestrogens which are peripherally selectively active, i.e. which do not cross the blood-brain barrier, is particularly preferred. 10 A therapeutic product comprising an oestrogen and a pure anti-oestrogen for simultaneous, sequential or separate use for selective oestrogen therapy of peri or postmenopausal conditions is already described in 15 EP-A 0 346 014. The substances and the pharmaceuticals comprising them are particularly suitable for the treatment of peri and postmenopausal complaints, in particular hot 20 flushes, sleep disorders, irritability, mood fluctuations, incontinence, vaginal atrophy, hormone deficiency-related emotional disturbances. Likewise, the substances are suitable for hormone substitution and the therapy of hormone deficiency-related 25 complaints in the case of ovarian dysfunction caused surgically, medicinally or in another way. This also includes the prevention of loss of bone mass in postmenopausal women and andropausal men, in hysterectomized women or in women who have been treated 30 with LHRH antagonists or agonists. The prodrugs according to the invention of the ER$ selective agonists can be used on their own or in combination with anti-oestrogens, aromatase inhibitors 35 or selective estrogen receptor modulators (SERM) for the treatment of prostate hyperplasia in order to avoid - 9 - 53181ADEApplicationtext 28.11.2005 estrogen deprivation or in order to reduce its effects. The anti-oestrogen used is preferably 7a-[9-[(4,4,5,5, 5 5-pentafluoropentyl)sulphinyl]nonyl]oestra-1,3,5(10) triene-3,17-diol (fulvestrant). Possible aromatase inhibitors to be used are the following: anastrozole, atamestane, fadrozole, 10 formestane, letrozole. Possible SERM are compounds selected from the following group: raloxifen, tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5 pentafluoropentyl)sulphinyl)pentyl}phenyl)-6-phenyl 15 8, 9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979). The compounds are also suitable for the alleviation of the symptoms of the andropause and menopause, i.e. for male and female hormone replacement therapy (HRT), 20 namely both for prophylaxis and for treatment, furthermore for the treatment of symptoms accompanying dysmenorrhoea and for the treatment of acne. The substances can moreover be employed for prophylaxis 25 of hormone deficiency-related loss of bone mass and osteoporosis, for the prevention of cardiovascular diseases, in particular vascular diseases such as atherosclerosis, for inhibition of the proliferation of arterial smooth muscle cells, and for the treatment of 30 primary pulmonary hypertension. Furthermore, the substances can be employed for the treatment of inflammatory diseases and diseases of the immune system, in particular autoimmune diseases such 35 as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease or endometriosis.

- 10 - 53181ADEApplicationtext 28.11.2005 The compounds can in particular be used for the treatment of arthritic symptoms after therapies which lead to oestrogen deprivation, for example after treatment with aromatase inhibitors or GnRH antagonists 5 or agonists. Moreover, the compounds can be used for the treatment of male fertility disorders and prostatic disorders. The compounds according to the invention are suitable 10 for oestrogen treatment of carcinoma of the prostate. The compounds can also be employed in combination with the natural vitamin D3 or with calcitriol analogues for osteogenesis or as a supportive therapy for therapies 15 which cause loss of bone mass (for example therapy with glucocorticoids, aromatase inhibitors, GnRH agonists or antagonists, chemotherapy). Finally, the compounds of the general formula (I) can 20 be used in combination with progesterone receptor modulators, for example mesoprogestins such as asoprisnil, namely in particular for use in hormone replacement therapy and for the treatment of gynaecological disorders. 25 The compounds according to the invention as set forth in general formula (I) can moreover be used for the treatment of alopecia caused, for example, by chemotherapy. 30

"C

1

-

5 -Alkyl group" is understood in the sense of the present invention as meaning a branched or straight chain alkyl radical having up to 5 carbon atoms, which can be substituted, for example, by halogens such as 35 fluorine, chlorine or bromine, OH or CN. Examples which may be mentioned are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl or n-pentyl.

- 11 - 53181ADE__Applicationtext 28.11.2005 The abovementioned "C 3

-

8 -cycloalkyl group" is, according to the invention, a mono- or bicyclic group which can be substituted, for example by halogens such as 5 fluorine, chlorine or bromine, OH or CN, such as, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a hydroxycyclohexyl group. The term "aryl group" is understood in the sense of the 10 present application 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. 15 The term "Ci_ 4 -alkylenearyl group" is understood in the sense of the present application as meaning a disubstituted alkyl radical which is substituted at least by one aryl radical. Both radicals together have 20 7 to 15 carbon atoms, where the aryl radical can carry further constituents, such as, for example, a halogen atom. Examples are a benzyl group or a halobenzyl group. 25 The term "Ci.-alkylene-C 3

.

8 -cycloalkyl group" is understood in the sense of the present application as meaning a disubstituted alkyl radical which is substituted at least by one C 3

.

8 -cycloalkyl radical. Both radicals together have 4 to 12 carbon atoms, where 30 the cycloalkyl radical can carry further substituents, such as, for example, a halogen atom. Examples are a cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl group. 35 The term "C 3

.

8 -cycloalkylene-C 1

.

4 -alkyl group" in the sense of the present application is understood as meaning a disubstituted C 3

.

8 -cycloalkylene radical which - 12 - 53181ADEApplicationtext 28.11.2005 is at least substituted by one C 1 4 -alkyl radical. Both radicals together have 4 to 12 carbon atoms, where the group can carry further substituents, such as, for example, a halogen atom. Examples are a propyl 5 cyclohexyl or butylcyclohexyl group. A trialkylsilyloxy group is, for example, a trimethyl silyloxy or tert-butyldimethylsilyloxy group. 10 The term "halogen atom" is understood in the context of the present invention as meaning a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine and bromine are preferred. 15 The number "n" is preferably 0, 1 or 2.

R

1 is preferably a group -SO 2

NH

2 , where R 2 , R', X' and X independently of one another are preferably an H, F or Cl atom, an OH group or a methoxy group. 20

R

2 is preferably a group -SO 2

NH

2 , where R 1 , R 3 , X 1 and X independently of one another are preferably an H, F or Cl atom, an OH group or a methoxy group. 25 R 3 is preferably a group -SO 2

NH

2 , where R2, R 2 , X 1 and X independently of one another are preferably an H, F or Cl atom, an OH group or a methoxy group. X1 is preferably an H atom. 30

R

7 is a hydrogen or a fluorine atom or a methyl radical.

R

9 is preferably methyl, ethyl, vinyl, difluorovinyl, 35 ethynyl or prop-1-ynyl.

- 13 - 53181ADEApplicationtext 28.11.2005 Ethyl, vinyl or difluorovinyl are particularly preferred for R 9 .

R

3 is preferably OH, OMe, a trimethylsilyloxy or tert 5 butyldimethylsilyloxy radical, a benzoate, a sulphamoylbenzoate, acetate, propionate, valerate, butcyclate or cyclopentylpropionate radical. R is preferably a hydrogen atom or a fluorine atom. 10 Particularly preferred compounds in the sense of the invention are listed below: 1) 3-hydroxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 3'-sulphamoylbenzoate, 15 2) 3-hydroxy-17 -fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 3) 3-hydroxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 4) 3-hydroxy-7a-fluoro-9a-vinyloestra-1,3,5(10) 20 trien-16a-yl 3'-sulphamoylbenzoate, 5) 3-acetoxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 3'-sulphamoylbenzoate, 6) 3-acetoxy-17 -fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 25 7) 3-acetoxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 8) 3-acetoxy-7a-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 9) 3-hydroxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 30 2'-chloro-5'-sulphamoylbenzoate, 10) 3-hydroxy-17p-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 11) 3-hydroxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 35 12) 3-hydroxy-7a-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, - 14 - 53181ADEApplicationtext 28.11.2005 13) 3-acetoxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 14) 3-acetoxy-173-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 5 15) 3-acetoxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 16) 3-acetoxy-7a-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 17) 3-hydroxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 10 4'-sulphamoylbenzoate, 18) 3-hydroxy-17 -fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate, 19) 3-hydroxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate, 15 20) 3-hydroxy-7a-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate, 21) 3-acetoxy-9a-vinyloestra-1,3,5(10)-trien-16ar-yl 4'-sulphamoylbenzoate, 22) 3-acetoxy-173-fluoro-9a-vinyloestra-1,3,5(10) 20 trien-16a-yl 4'-sulphamoylbenzoate, 23) 3-acetoxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate, 24) 3-acetoxy-7a-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate 25 In vitro experiments a) Blood-plasma concentration ratio - test principle and experimental description: The S0 2

-NH

2 group of the substances according to the 30 invention can lead to a concentration in erythrocytes as a result of binding to carboanhydrases. Test principle: Freshly obtained, heparinized blood from a rat is 35 treated with a defined amount of active compound. The active compound concentration in the plasma obtained therefrom is measured against a calibration curve of - 15 - 53181ADEApplicationtext 28.11.2005 spiked (with a known active compound concentration) plasma. The blood-plasma ratio is calculated from the measured concentration and the theoretical concentration. 5 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 from 10-1000:1, but in the range <10:1. The 10 compound 17 -fluoro-3-hydroxy-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate accumulates with a blood/plasma ratio of approximately 3.7 in the rat and in the human erythrocytes at 1.2. 15 b) Carboanhydrase inhibition - test principle and experimental description: Photometric determination of the inhibition of human carboanhydrase I or II by sulphonamides or sulphamates on microtitre plates with the aid of the enzymatic 20 conversion of nitrophenyl acetate with a colour change from colourless to yellow.

- 16 - 53181ADEApplicationtext 28.11.2005 Table 1: IC 50 inhibitory values of human carboanhydrase I and II Inhibitor CAI CAII IC50 (nM) IC50 (nM) IC50 (nm) IC50 (nM) literature literature Oestradiol 3 157 ± 10.6 - 21.6 ± 1.5 sulphamate 17@-Fluoro-3 hydroxy-9a vinyloestra 1,3,5(10)- 3700 - 720 trien-16a-yl 3' -sulphamoyl benzoate 1710-Fluoro-3 hydroxy- 9a vinyloestra >10 000 - >10 000 1,3,5(10) trien-16a -yl benzoate 3 -Hydroxy- 9a vinyloestra 1,3,5(10) 3400 - 490 trien- 16a -yl 3' -sulphamoyl benzoate Acetazolamide (known CA 1200 1900 60 901 inhibitor) 'Literature: C.Landolfi, M. Marchetti, G. Ciocchi, and 5 C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997).

- 17 - 53181ADEApplicationtext 28.11.2005 Despite the low blood-plasma concentration ratio, in all cases binding (inhibition) to the two isoenzymes carboanhydrase CA I and CA II could be shown in the erythrocytes. Of importance for the properties as an 5 oestrogen is the binding to erythrocytes induced by affinity to the carboanhydrases. This binding is essential for a reduced extraction of the orally administered substance in the first liver passage. A high or lower affinity to the erythrocytic 10 carboanhydrases, more rapid or delayed release from this depot and subsequent hydrolysis determine the therapeutic employability of the substances according to the invention. The compounds according to the invention thus open up the possibility on equimolar 15 substance administration of achieving higher short lasting or more uniform low and longer-lasting hormone levels. The potency and duration of action are thus varied and a therapy tailored to the organism is made possible. 20 In vivo experiments i.v./p.o. pharmacokinetics For the investigation of pharmacokinetic properties and parameters, rats were administered i.v. and p.o. and 25 blood samples were obtained for determination at various points in time. Test principle: The various pharmacokinetic parameters can be 30 determined by means of the time profile which the substance shows, and with the aid of appropriate pharmacological software. The concentration of the test substance in the serum or plasma samples was determined by HPLC-UV or by LCMS/MS. 35 By means of the recovery of the substance per point in time the breakdown of the active compound in the organism can be shown. The rate of breakdown serves for - 18 - 53181ADEApplicationtext 28.11.2005 the calculation of the individual pharmacokinetic parameters. Investigations of the i.v./p.o. kinetics on the rat 5 showed that 17 -fluoro-9a-vinyloestra-1,3,5(10)-triene 3,16-a-diol after release form the prodrug 17p-fluoro-3 hydroxy-9a-vinyloestra-1,3,5 (10) -trien-16a-yl 3 sulphamoylbenzoate was bioavailable to 17%. After administration of the "parent oestrogen" 17-fluoro-9a 10 vinyloestra-1,3,5(10)-triene-3,16a-diol it was only possible to detect 6%. These test results open up to the compounds of the general formula (I) according to the invention various 15 possibilities of use for hormone replacement therapy (HRT) and in hormonally related diseases in men and women. The present invention therefore also relates to 20 pharmaceutical compositions which comprise at least one compound of the general formula (I), optionally together with pharmaceutically tolerable excipients and vehicles. 25 Compared to their parent oestrogens, the substances according to the invention have pharmacodynamically and pharmacokinetically improved properties, which are based on reduced hepatic extraction and more uniform and longer-lasting blood levels of the released 30 oestrogen. Dosage For use according to the invention, the ERB-selective compounds of the general formula (I) are administered 35 orally.

- 19 - 53181ADEApplicationtext 28.11.2005 Suitable dosages of the compounds according to the invention to humans for the treatment of peri- and postmenopausal symptoms, of hormone deficiency-related symptoms, of gynaecological disorders such as ovarian 5 dysfunction and endometriosis, of male and female fertility disorders, of hormone-related oncoses and for use in male and female hormone replacement therapy are, depending on indication, 5 pg to 2000 mg per day, depending on age and constitution of the patient, where 10 the necessary daily dose can be administered by single or repeated delivery. For gynaecological disorders such as ovarian dysfunction and endometriosis, dosages between 0.5 and 15 100 mg, for the treatment of male and female fertility disorders 5 pg to 50 mg, for hormone-related oncoses 5 to 500 mg and for male or female hormone replacement therapy 5 pg to 100 mg are possible. 20 In addition to customary vehicles and/or diluents, the pharmaceutical compositions comprise at least one compound of the general formula I. The substances according to the invention can also be employed therapeutically in combination with a gestagen, 25 antigestagen or mesoprogestin. Preferably, the substances according to the invention are administered individually as an active compound in pharmaceutical preparations. 30 The medicaments of the invention are prepared in a known manner with a suitable dosage using the customary solid or liquid vehicles or diluents and the customarily used pharmaceutical excipients according to the desired type of administration. The preferred 35 preparations consist in an administration form which is suitable for oral administration. Such administration forms are, for example, tablets, film-coated tablets, - 20 - 53181ADEApplicationtext 28.11.2005 coated tablets, capsules, pills, powders, solutions or suspensions or alternatively depot forms. Appropriate tablets can be obtained, for example, by 5 mixing the active compound with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as maize starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium 10 stearate or talc and/or agents for achieving a depot effect such as carboxypolyethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of a number of layers. 15 Correspondingly, coated tablets can be prepared by coating of cores produced analogously to the tablets with agents customarily used in coated tablet coatings, for example polyvinylpyrrolidone or shellac, gum 20 arabic, talc, titanium oxide or sugar. Here, the coated tablet shells can also consist of a number of layers, where the excipients mentioned above in the case of the tablets can be used. 25 Solutions or suspensions using the compounds of the general formula I according to the invention can additionally comprise taste-enhancing agents such as saccharin, cyclamate or sugar and also, for example, flavourings such as vanillin or orange extract. They 30 can moreover comprise suspending excipients such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates. The capsules comprising compounds of the general 35 formula I can be prepared, for example, by mixing the compound(s) of the general formula I with an inert - 21 - 53181ADEApplicationtext 28.11.2005 carrier such as lactose or sorbitol and encapsulating them in gelatine capsules. The following examples illustrate the present invention 5 without restricting it. Example 1 3-Hydroxy-9-vinyloestra-1,3,5(10) -trien-16a-yl 3' - sulphamoylbenzoate 10 Stage 1 3, 16a -Bis (tert-butyldimethylsilyloxy) -9a-vinyloestra 1,3,5(10) -triene. 15 1.0 g (3.35 mmol) of 9a-vinyloestra-1,3,5(10)-triene 3,16a-diol and 2.1 g (13.4 mmol) of tert-butyldimethyl chlorosilane are initially introduced in 25 ml of dimethylformamide and treated in portions with 1.8 g (26.8 mmol) of imidazole with stirring at room 20 temperature. After about 30 minutes, a white suspension is obtained. The reaction solution is poured into ice water with vigorous stirring. The precipitated product is filtered off with suction, washed with water and dried. 1.62 g (92% of theory) of 3,16a-bis(tert-butyl 25 dimethylsilyloxy)-9a-vinyloestra-1,3,5(10)-triene are obtained. Stage 2 3- (tert-Butyldimethylsilyloxy) -9a-vinyloestra- 30 1,3,5(10)-trien-16ax-ol 0.8 g (1.52 mmol) of 3,16a-bis(tert-butyldimethyl silyloxy)-9a-vinyloestra-1,3,5(10)-triene is initially introduced in 40 ml of absolute ethanol and treated at 35 room temperature with 1.0 ml (8.0 mmol) of boron trifluoride etherate with stirring and exclusion of moisture. After about 60 minutes, the reaction is ended - 22 - 53181ADEApplicationtext 28.11.2005 by addition of sodium hydrogencarbonate solution. Ethanol is distilled off from the reaction mixture and the reaction products are extracted with ethyl acetate. The 3-(tert-butyldimethylsilyloxy)-9a-vinyloestra 5 1,3,5(10)-trien-16a-ol is purified by column chromatography on silica gel 60 and isolated. 0.59 g (94% of theory) is obtained. Stage 3 10 3-(tert-Butyldimethylsilyloxy)-9a-vinyloestra 1,3,5(10)-trien-16a-yl 3'-sulphamoylbenzoate 0.3 g (0.73 mmol) of 3-(tert-butyldimethylsilyloxy)-9a vinyloestra-1,3,5(l0)-trien-17 -ol is dissolved in 2 ml 15 of pyridine and 2 ml of methylene chloride. 0.3 ml (2 mmol) of 3-chlorosulphonylbenzoyl chloride is added to the reaction mixture at -20 0 C with stirring. Subsequently, the mixture is warmed to room temperature and stirred for 15 min. 25ml of conc. ammonia solution 20 are added to the reaction solution and it is stirred intensively for 15 min. The pH is adjusted to 5 using 10% strength hydrochloric acid. The organic solvents are distilled off to the greatest possible extent. The precipitated substance is filtered off with suction and 25 washed with water. 420 mg of 3-(tert-butyldimethyl silyloxy)-9a-vinyloestra-1,3,5(l0)-trien-16a-yl 3' sulphamoylbenzoate are obtained as a crude product. Stage 4 30 3-Hydroxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 3' sulphamoylbenzoate 420 mg of crude product from Stage 3 are dissolved in 10 ml of tetrahydrofuran. 420 mg (1.3 mmol) of tetra-n 35 butylammonium fluoride trihydrate are added at room temperature with stirring. After 1 hour, 40 ml of water are stirred in, tetrahydrofuran is distilled off and - 23 - 53181ADE_Applicationtext 28.11.2005 the reaction product is extracted with ethyl acetate. After isolation of the reaction product by distilling off the ethyl acetate, the crude product is purified by chromatography on silica gel 60. 295 mg of 3-hydroxy 5 9a-vinyloestra-1,3,5(10)-trien-16a-yl 3'-sulphamoyl benzoate (84% of theory based on 3-(tert-butyldimethyl silyloxy)-9a-vinyloestra-1,3,5(l0)-trien-17p-ol) are obtained. 10 1 H-NMR (400MHz, DMSO-dG, TMS) 9.00 (s, 3-OH); 8.39 (s, 1H); 8.16 (m, 1H); 8.08 (m, 1H); 7.73 (m, 1H); 7.55 (s, 2H, NH 2 ); 7.00 (d, J = 8.6 Hz, H-1); 6.53 (dd, J = 8.6/2.7 Hz, H-2); 6.43 (d, J = 2.7 Hz, H-4); 6.28 (dd, J = 17.2/10.5 Hz, -CH=CH 2 ) ; 15 5.44 (m, 1H, H-16); 5.02 (dd, J = 10.5/1.9 Hz,

-CH=CH

2 ); 4.48 (dd, J = 17.2/1.9 Hz, -CH=CH 2 ); 0.82 (s, 3H, H-18). Example 2 20 3-Hydroxy-17p-fluoro-9-vinyloestra-1,3,5(10) -trien-17p yl 3' -sulphamoylbenzoate Stage 1 3,16a-Bis(tert-butyldimethylsilyloxy)-17@-fluoro-9a 25 vinyloestra-1,3,5(10)-triene 1.0 g (3.16 mmol) of 9a-vinyloestra-1,3,5(10)-triene 3,16a-diol and 2.1 g (13.4 mmol) of tert-butyldimethyl chlorosilane are initially introduced in 25 ml of 30 dimethylformamide and treated in portions with 1.8 g (26.8 mmol) of imidazole with stirring at room temperature. After about 30 minutes, a white suspension is obtained. The reaction solution is poured into ice water with vigorous stirring. The precipitated product 35 is filtered off with suction, washed with water and dried. 1.53 g (87% of theory) of 3,16ax-bis(tert-butyl- - 24 - 53181ADEApplicationtext 28.11.2005 dimethylsilyloxy)-17p-fluoro-9a-vinyloestra-1,3,5(10) triene are obtained. Stage 2 5 3-(tert-Butyldimethylsilyloxy)-17p-fluoro-9a-vinyl oestra-1,3,5(10)-trien-16a-ol 1.53 g (2.81 mmol) of 3,16at-bis(tert-butyldimethyl silyloxy)-17p-fluoro-9a-vinyloestra-1,3,5(10)-triene 10 are initially introduced in 40 ml of absolute ethanol and treated at room temperature with 1.8 ml (14.8 mmol) of boron trifluoride etherate with stirring and exclusion of moisture. After about 60 minutes, the reaction is ended by addition of sodium hydrogen 15 carbonate solution. Ethanol is distilled off from the reaction mixture and the reaction products are extracted with ethyl acetate. The 3-(tert-butyl dimethylsilyloxy)-17p-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-ol is purified by column chromatography on 20 silica gel 60 and isolated by distilling off the eluent. 1.21 g (91% of theory) are obtained. Stage 3 3-(tert-Butyldimethylsilyloxy)-170-fluoro-9a-vinyl 25 oestra-1,3,5(10)-trien-16at-yl 3'-sulphamoylbenzoate 1.21 g (2.81 mmol) of 3-(tert-butyldimethylsilyloxy) 17p-fluoro-9a-vinyloestra-1,3,5(10)-trien-17@-ol are dissolved in 8 ml of pyridine and 8 ml of methylene 30 chloride. 1.2 ml (8.0 mmol) of 3-chlorosulphonylbenzoyl chloride are added to the reaction mixture at -200C with stirring. Subsequently, the mixture is warmed to room temperature and stirred for 15 min. 25 ml of conc. ammonia solution are added to the reaction solution and 35 it is stirred intensively for 15 min. The pH is adjusted to 5 using 10% strength hydrochloric acid. The organic solvents are distilled off to the greatest - 25 - 53181ADEApplicationtext 28.11.2005 possible extent. After separating off, the precipitated substance is washed with water. 1.62 g of 3-(tert butyldimethylsilyloxy)-17 -fluoro-9a-vinyloestra 1,3,5(10)-trien-16a-yl 3'-sulphamoylbenzoate are 5 obtained as an oily crude product. Stage 4 3-Hydroxy-170-fluoro-9a-vinyloestra-1,3,5(10)-trien 16a-yl 3'-sulphamoylbenzoate 10 1.62 g of crude product from Stage 3 are dissolved in 30 ml of tetrahydrofuran. 1.62 g (5.0 mmol) of tetra-n butylammonium fluoride trihydrate are added at room temperature with stirring. After 1 hour, 40 ml of water 15 are stirred in, tetrahydrofuran is distilled off and the reaction product is extracted with ethyl acetate. After isolation of the reaction product by distilling off the ethyl acetate, the crude product is purified by chromatography on silica gel 60. 1.14 g of 3-hydroxy 20 17 -fluoro-9a-vinyloestra-1,3,5(10)-trien-17a-yl 3' sulphamoylbenzoate (81% of theory based on 3-(tert butyldimethylsilyloxy)-175-fluoro-9a-vinyloestra 1,3,5(10)-trien-17p-ol) are obtained. 25 'H-NMR (400MHz, DMSO-d 6 , TMS): 9.07 (s, 3-OH); 8.42 (s, 1H); 8.22 (d, J = 7.8 Hz, 1H); 8.09 (d, J = 7.8 Hz, 1H) ; 7.76 (t, J = 7.8 Hz, 1H) ; 7.56 (s, 2H, NH 2 ); 7.00 (d, J = 8.6 Hz, H-1); 6.52 (dd, J = 8.6/2.7 Hz, H-2); 6.42 (d, J = 2.4 Hz, H-4); 6.29 30 (dd, J = 17.2/10.7 Hz, -CH=CH 2 ); 5.39 (m, 1H, H-16B); 5.03 (dd, J = 10.7/1.9 Hz, -CH=CH 2 ); 4.95 (dd, J = 54.3/5.1 Hz, H-17a); 4.45 (dd, J = 17.2/1.9 Hz,

-CH=CH

2 ); 0.92 (d, J = 1.0 Hz, 3H, H-18).

- 26 - 53181ADEApplicationtext 28.11.2005 References: 1. Cummings SR, Browner WS, Bauer D, Stone K, 5 Ensrud K, Jamal S and Ettinger B (1998), Endogenous hormones and the risk of hip and vertebral fractures among older women. N. Engl. J. Med. 339, 733-38. 2. Frank GR (1995), The role of estrogen in 10 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 15 estrogens and their clinical implications. Am. 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 20 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 25 oestrogen formulations on insulin-like growth factor-I, growth hormone and growth hormone binding protein in post-menopausal women. Clin. Endocrinol. 39, 561-67. 7. Krattenmacher R, Knauthe R, Parczyk K, Walker 30 A, Hilgenfeldt U and Fritzemeier K-H (1994), Estrogen action on hepatic synthesis of angiotensinogen and IGF-I: direct and indirect estrogen effects. J. Steroid. Biochem. Mol. Biol. 48, 207-14. 35 8. Le Roith and Butler AA (1999), Insulin-like growth factors in pediatric health and disease. J. Clin. Endocrinol. Metab. 84, 4355-61.

- 27 - 53181ADEApplicationtext 28.11.2005 9. Mandel FP, Geola FL, Lu JKH, Eggena P, Sambhi MP, Hershman JM and Judd HL (1982), Biologic effects of various doses of ethinyl estradiol in postmenopausal women. Obstet. Gynecol. 59, 673-9. 5 10.Mashchak CA, Lobo RA, Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF and Mishell DR Jr (1982), Comparison of pharmacodynamic properties of various estrogen formulations. Am. J. Obstet. Gynecol. 144, 511-18. 10 11.Oelkers WKH (1996), Effects of estrogens and progestagens on the renin-aldosterone system and blood pressure. Steroids 61, 166-71. 12. O'Sullivan AJ and Ho KKY (1995), A comparison of the effects of oral and transdermal estrogen 15 replacement on insulin sensitivity in postmenopausal women. J. Clin. Endocrinol. Metab. 80, 1783-8. 13. Span JPT, Pieters GFFM, Sweep CGJ, Hermus ARMM and Smals AGH (2000), Gender difference in 20 insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: role of sex hormone replacement. J. Clin. Endocrinol. Metab. 85, 1121-5. 14.von Schoultz B, Carlstr6m K, Collste L, 25 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 (8)

1. 28.11.2005 Patent claims 1. Sulphamoyl compounds of 9a-substituted oestra 5 trienes of the general formula (I) R 3 x RR X (H2C n A STEROID-MO 4 X R Group Z (I) 10 in which n is a number 0-4, R' is a radical -SO 2 NH 2 or -NHSO 2 NH 2 , where R 2 , R 3 and X, X 1 independently of one another are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C 1 . 5 -alkyl 15 group, a CpF 2 p+i group with p = 1-3, a group OC(O)-R 20 , COOR 20 , OR20, C(O)NHR20 or OC (0) NH R, where R 20 and R 2 1 are a Ci- 5 -alkyl group, a C 3 . 8 -cycloalkyl group, an aryl group, a C 1 . 4 20 alkylenearyl group, a C 1 - 4 -alkylene-C 3 . 8 -cyclo alkyl group or C 3 - 8 -cycloalkylene-Ci- 4 -alkyl group, and R 20 can moreover be a hydrogen, or R2 is a radical -SO 2 NH 2 or -NHSO 2 NH 2 , 25 where R 1 , R 3 and X, X 1 independently of one another are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C 1 . 5 -alkyl group, a CpF 2 p. 1 group with p = 1-3, a group OC(O)-R 20 , COOR 20 , OR2, C(O)NHR 20 or OC () NH 30 R - 29 - 53181ADEApplicationtext 28.11.2005 where R 2 0 and R 21 are a C 1 -- alkyl group, a C 3 .- cycloalkyl group, an aryl group, a C 1 . 4 alkylenearyl group, a C 1 .. 4 -alkylene-C 3 . 8 -cyclo alkyl group or C 3 .. 8 -cycloalkylene-Ci_ 4 -alkyl 5 group, and R20 can moreover be a hydrogen, or R 3 is a radical -SO 2 NH 2 or -NHSO 2 NH 2 , where R 1 , R 2 and X, X 1 independently of one another are a hydrogen atom, a halogen atom, 10 a nitrile group, a nitro group, a C 1 . 5 -alkyl group, a CpF 2 pa group with p = 1-3, a group 2020 20 R r)H OC(O)-R 20 , COOR , OR , C(O)NHR'o or OC(O)NH R, where R 20 and R 21 are a C 1 - 5 -alkyl group, a 15 C 3 - 8 -cycloalkyl group, an aryl group, a C 1 . 4 alkylenearyl group, a C 1 . 4 -alkylene-C 3 . 8 -cyc1o alkyl group or C 3 . 8 -cycloalkylene-C. 4 -alkyl group, and R20 can moreover be a hydrogen, and 20 STEROID is a steroidal ABCD ring system of the formula (A): 17 R+, R 16 RR 25 where the radicals R 7 , R 9 , R 1 and R 17 have the following meaning: R 3 is Z and R 16 is an OH group, a tri(C 1 . 4 -alkyl)silyloxy group 20 30 or a group OC (O) -R , or - 30 - 53181ADEApplicationtext 28.11.2005 R 3 is OH, OMe, a tri(Ci 4 -alkyl)silyloxy group, a group OC(O)-R 20 and R3 is Z 5 and R 7 is a hydrogen atom or fluorine atom, a methyl radical or ethyl radical, R 9 is a branched or straight-chain, optionally partially or completely halogenated alkyl, 10 alkenyl or alkynyl radical having up to 3 carbon atoms, R1 7 is a hydrogen atom or a halogen atom where the substituents R 7 , R" and R 17 can in each 15 case be both in the a-position and in the position, and their pharmaceutically acceptable salts. 20 2. Compounds according to Claim 1, characterized in that n is 0, 1 or 2. 3. Compounds according to Claim 1 or 2, characterized in that in each case one radical R 1 , R 2 or R 3 is a 25 group -SO 2 NH 2 . 4. Compounds according to one of Claims 1 or 2, characterized in that R1 is a group -S0 2 NH 2 or -NHSO 2 NH 2 30 5. Compounds according to Claim 4, characterized in that R 1 is a group -SO 2 NH 2 . 6. Compounds according to one of Claims 1 to 5, 35 characterized in that if one of the radicals R 1 , R 2, R3 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 X1 in each case - 31 - 53181ADEApplicationtext 28.11.2005 independently of one another are a hydrogen, fluorine or chlorine atom, or a hydroxyl or a methoxy group. 5 7. Compounds according to one of Claims 1 to 6, characterized in that R 6 is a methyl, ethyl, vinyl or difluorovinyl radical. 8. Compounds according to one of Claims 1 to 7, 10 1) 3-hydroxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 3'-sulphamoylbenzoate, 2) 3-hydroxy-17p-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 3) 3-hydroxy-7a-methyl-9a-vinyloestra-1,3,5(10) 15 trien-16a-yl 3'-sulphamoylbenzoate, 4) 3-hydroxy-7a-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 5) 3-acetoxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 3'-sulphamoylbenzoate, 20 6) 3-acetoxy-17 -fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 7) 3-acetoxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 3'-sulphamoylbenzoate, 8) 3-acetoxy-7a-fluoro-9a-vinyloestra-1,3,5(10) 25 trien-16a-yl 3'-sulphamoylbenzoate, 9) 3-hydroxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 10)3-hydroxy-17 -fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 30 11)3-hydroxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-i6a-yl 2'-chloro-5'-sulphamoylbenzoate, 12)3-hydroxy-7a-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 13)3-acetoxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 35 2'-chloro-5'-sulphamoylbenzoate, 14)3-acetoxy-17B-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, - 32 - 53181ADEApplicationtext 28.11.2005 15)3-acetoxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 2' -chloro-5' -sulphamoylbenzoate, 16)3-acetoxy-7ax-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 2'-chloro-5'-sulphamoylbenzoate, 5 17)3-hydroxy-9a-vinyloestra-1,3,5(10)-trien-16a-y1 4'-sulphamoylbenzoate, 18)3-hydroxy-17p-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate, 19)3-hydroxy-7a-methyl-9c-vinyloestra-1,3,5(10) 10 trien-16a-yl 4'-sulphamoylbenzoate, 20)3-hydroxy-7a-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate, 21)3-acetoxy-9a-vinyloestra-1,3,5(10)-trien-16a-yl 4'-sulphamoylbenzoate, 15 22)3-acetoxy-173-fluoro-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate, 23)3-acetoxy-7a-methyl-9a-vinyloestra-1,3,5(10) trien-16a-yl 4'-sulphamoylbenzoate, 24)3-acetoxy-7ax-fluoro-9a-vinyloestra-1,3,5(10) 20 trien-16at-yl 4'-sulphamoylbenzoate. 9. Pharmaceutical compositions comprising at least one compound according to one of Claims 1 to 8, and a pharmaceutically tolerable carrier. 25 10. Pharmaceutical composition according to Claim 9, characterized in that at least one further steroidal compound is present. 30 11. Pharmaceutical composition according to Claim 10, characterized in that the further steroidal compound is a gestagen, antigestagen or mesoprogestin. 35 12. Pharmaceutical composition according to Claim 11, where the gestagen is drospirenone, dienogest, norethisterone or levonorgestrel, and the anti- - 33 - 53181ADEApplicationtext 28.11.2005 gestagen is onapristone or mifepristone or the mesoprogestin is asoprisnil. 13. Use of the compounds according to the invention as 5 set forth in Claim 1-8 for the production of a medicament. 14. Use according to Claim 13 for the treatment of diseases and conditions in women and in men which 10 are caused by an oestrogen deficit. 15. Use according to Claim 13 for the treatment of peri- and postandropausal symptoms. 15 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. 20 18. Use according to Claim 13 for the in vitro treatment of female infertility. 19. Use according to Claim 13 for the in vivo 25 treatment of female infertility. 20. Use according to Claim 13 for the therapy of hormone deficiency-related symptoms in ovarian dysfunction caused surgically, medicinally or in 30 another way. 21. Use according to Claim 13 for hormone replacement therapy (HRT). 35 22. Use according to Claim 20 in combination with a selective oestrogen receptor modulator (SERM), for example raloxifen. - 34 - 53181ADE _Applicationtext 28.11.2005 23. Use according to Claim 13 for the prophylaxis and therapy of a hormone deficiency-related loss of bone mass. 5 24. Use according to Claim 13 for the prophylaxis and therapy of osteoporosis. 25. Use according to Claim 23 in combination with the 10 natural vitamin D3 or with calcitriol analogues for osteogenesis or as a supportive therapy for therapies which cause a loss of bone mass (for example a therapy using glucocorticoids, aromatase inhibitors, GnRH agonists or antagonists, 15 chemotherapy). 26. Use according to Claim 13 for the prevention and therapy of cardiovascular diseases. 20 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 25 rheumatoid arthritis.
2. 29. Use according to Claim 27 for the treatment of multiple sclerosis, Crohn's disease or endometriosis. 30
3. 30. Use according to Claim 13 for the prevention and treatment of benign prostate hyperplasia (BPH).
4. 31. Use according to Claim 30 in combination with 35 anti-oestrogens and selective oestrogen receptor modulators for the prevention and treatment of benign prostate hyperplasia (BPH). - 35 - 53181ADEApplicationtext 28.11.2005
5. 32. Use according to Claim 31, where the anti oestrogen used is 7a-[9-[(4,4,5,5,5-pentafluoro pentyl)sulphinyl]nonyl]oestra-1,3,5(10)-triene 5 3,173-diol (fulvestrant) and the SERM used is raloxifen, tamoxifen or 5-(4-{5-[(RS)-(4,4,5,5,5 pentafluoropentyl)sulphinyl)pentyl}phenyl)-6 phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol. 10 33. Use according to Claim 13 for the treatment of arthritic symptoms, in particular after therapies which lead to oestrogen deprivation, for example after treatment with aromatase inhibitors or GnRH antagonists or agonists. 15
6. 34. Use of compounds according to one of Claims 1 to 8 for production of medicaments for the treatment of diseases which can be positively influenced by the inhibition of the carboanhydrase activity. 20
7. 35. Use of compounds according to one of Claims 1 to 8 for production of medicaments for the treatment of alopecia. 25 36. Use of 3-hydroxy-9a-vinyloestra-1,3,5(10)-trien 16p-yl 3'-sulphamoylbenzoate, 3-acetoxy-9a-vinyl oestra-1,3,5(10)-trien-16p-yl 3'-sulphamoyl benzoate as set forth in one of the preceding Claims 13-35. 30
8. 37. Process for the preparation of compounds of the general formula (I) according to one of Claims 1 to 8 - 36 - 53181ADEApplicationtext 28.11.2005 R 3 R 2 H2C n \ STEROID O X R Group Z (I) 5 by reaction of 9a-substituted oestratrienes as set forth in formula (A) with appropriate sulphamoyl phenylcarboxylic acids or their derivatives or by reaction of appropriate compounds with sulphamide, sulphamoyl chloride or aminosulphonyl isocyanate.