8Beta-Hydrocarbyl-Substituted Estratrienes As Selectively Active Estrogens

Abstract

This invention describes the new 8β-substituted estratrienes of general formula I in which R 2 , R 3 , R 6 , R 6′ , R 7 , R 7′ , R 9 , R 11 , R 11′ , R 12 , R 14 , R 15 , R 15′ , R 16 , R 16′ , R 17 , R 17′ have the meanings that are indicated in the description, and R 8 means a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl- or prop-1-inyl radical, as pharmaceutical active ingredients that have in vitro a higher affinity to estrogen receptor preparations of rat prostates than to estrogen receptor preparations of rat uteri and in vivo preferably a preferential action on bone rather than the uterus and/or a pronounced action with respect to stimulation of the expression of 5HT2a-receptors and 5HT2a-transporters, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. The invention also describes the use of these compounds for treatment of estrogen-deficiency-induced diseases and conditions as well as the use of an 8β-substituted estratriene structural part in the total structures of compounds that have a dissociation in favor of their estrogenic action on bones rather than the uterus.

1 - 25 . (canceled) 
     
     
         26 . A method for
 treatment of an estrogen-deficiency-induced disease or condition, which is a perimenospausal or postmenopausal symptom, which is hot flashes, sleep disturbances, irritability, mood swings, incontinence, or vaginal atrophy;   therapy of ulcers or hemorrhagic diatheses in the gastrointestinal tract;   therapy of neoplasias of the gastrointestinal tract;   in-vitro treatment of male infertility;   in-vivo treatment of male infertility;   in-vitro treatment of female infertility;   in-vivo treatment of female infertility;   hormone replacement therapy in a patient in need of replacement of estrogen;   therapy of an estrogen-deficiency induced bone mass loss;   therapy of osteoporosis;   treatment of arteriosclerosis;   treatment of neointimal hyperplasias;   treatment of Alzheimer's disease or an estrogen-deficiency induced impairment of memory and learning capacity;   treatment of benign prostate hyperplasia;   inhibiting the proliferation of arterial smooth muscle cells;   treatment of primary pulmonary high blood pressure; or   treatment of rheumatoid arthritis;   comprising administering to a subject in need thereof an effective amount of an 8β-substituted estra-1,3,5(10)-triene compound of formula I′   
       
         
           
           
               
               
           
         
       
       in which
 R 2  means a hydrogen atom, a halogen atom;
 a radical R 18 — or R 18 —O—, in which R 18  means a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms or, a trifluoromethyl group; 
 a group R 19 SO 2 —O—, in which R 19  is an R 20 R 21 N, in which R 20  and R 21 , independently of one another, mean a hydrogen atom, a C 1 -C 5 -alkyl radical, a group C(O)R 22 , in which R 22  represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, an optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C 3 -C 7 -cycloalkyl radical, an optionally substituted C 4 -C 15 -cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or R 20 R 21 N means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical; 
 
 R 3  means a group R 18′ —O—R 19 SO 2 —O— or —O—C(O)R 22 , in which R 18′  is a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, or an aryl heteroaryl or aralkyl radical; 
 R 6  and R 7  each mean a hydrogen atom or together an additional bond; 
 R 6′  and R 7′ , are each independently a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ; 
 R 8  means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms, or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical; 
 R 9  means a hydrogen atom, a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 5 carbon atoms, or together with R 11  means an additional bond; 
 R 11  means a hydrogen atom or together with R 9  or together with R 12  means an additional bond; 
 R 11′  means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or a group —X—R 18″ , in which X is an oxygen or sulfur atom, and R 18″  is an alkyl radical with 1 to 3 carbon atoms; 
 R 12  means a hydrogen atom or together with R 11  means an additional bond; 
 R 14  means a hydrogen atom or together with R 15  means an additional bond; 
 R 15  means a hydrogen atom or together with R 14  or together with R 16  means an additional bond; 
 R 16  means a hydrogen atom or together with R 15  means an additional bond; 
 R 15′  and R 16′ , independently of one another, mean a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ; 
 R 17  and R 17′  each mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R 19 SO 2 —O—; a group R 18  and a group —C(O)R 22  or —O—C(O)R 22 ; a group R 18 —O- and a group R 18 —; a group R 18 —O— and a group —O—C(O)R 22 ; or 
 R 17  and R 17′  together mean a group ═CR 23 R 24 , in which R 23  and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom, 
 
       wherein said administration of the compound of formula I′ achieves a selective effect on estrogen receptor beta. 
     
     
         27 . A method according to  claim 26 , wherein in the compound of formula I′
 R 2  means a hydrogen or halogen atom or a hydroxy group;   R 3  means a group R 18′ —O—, R 19 SO 2 —O— or —O—C(O)R 22 ;   R 6  and R 7  each mean a hydrogen atom;   R 6′  means a hydrogen atom, a hydroxy group, or a group R 22 ;   R 7′  means a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ;   R 8  means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms, or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical;   R 9  means a hydrogen atom or together with R 11  an additional bond;   R 11  means a hydrogen atom or together with R 9  an additional bond;   R 11′  means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or a group —X—R 18′ , in which X is a sulfur atom, and R 18′  is an alkyl radical with 1 to 3 carbon atoms;   R 12 , R 14 , R 15  and R 16  in each case mean a hydrogen atom;   R 16′  means a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ;   R 17  and R 17′  in each case mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R 19 SO 2 —O—; a group R 18  and a group —C(O)R 22  or —O—C(O)R 22 ; a group R 18 —O— and a group R 18 —; a group R 18 —O— and a group —O—C(O)R 22 ; and   R 17  and R 17′  together mean a group ═CR 23 R 24 , in which R 23  and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.   
     
     
         28 . A method according to  claim 26 , wherein in the compound of formula I′
 R 2  means a hydrogen atom or a fluorine atom or a hydroxy group,   R 3  means a group R 18′ —O—, R 19 SO 2 —O— or —O—C(O)R 22 ;   R 6  and R 7  in each case mean a hydrogen atom;   R 6′  means a hydrogen atom or a hydroxy group,   R 7′  means a hydrogen atom, a fluorine or chlorine atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ,   R 18  means a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, or a trifluoromethyl group;   R 19  is an R 20 R 21 N group,   R 20  and R 21 , independently of one another, mean a hydrogen atom, a C 1 -C 5 -alkyl radical, a group C(O)R 22 ,   R 22  represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, an optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C 3 -C 7 -cycloalkyl radical, an optionally substituted C 4 -C 15 -cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical,   or R 20 R 21 N means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;   R 8  means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical;   R 9  means a hydrogen atom or together with R 11  an additional bond;   R 11′  means a hydrogen atom, a fluorine or chlorine atom, a saturated, straight-chain or branched-chain C 1 -C 4 -alkyl group, a group —X—R 18″ , in which X is a sulfur atom and R 18″  means a saturated, straight-chain or branched-chain C 1 -C 3 -alkyl group, a chloromethyl or chloroethyl group;   R 12 , R 14 , R 15  and R 16  in each case mean a hydrogen atom;   R 16′  means a hydrogen atom, a fluorine or chlorine atom or a group R 18 —O or —R 22 ;   R 17  and R 17′  in each case mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R 19 SO 2 —O—; a group R 18  and a group —C(O)R 22  or —O—C(O)R 22 ; a group R 18 —O— and a group R 18 —; a group R 18 —O— and a group —O—C(O)R 22 , in all above cases with R 18 , R 19  and R 22  in each case in the meaning that is indicated under R 2 ; or   R 17  and R 17′  together mean a group ═CR 23 R 24 , in which R 23  and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.   
     
     
         29 . A method according to  claim 26 , wherein in the compound of formula I′
 R 6′ , R 7′ , R 9 , R 11 , R 14 , R 15 , R 15′ , and R 16  in each case stand for a hydrogen atom or R 6′ , R 7′ , R 14 , R 15 , R 15′  and R 16  in each case stand for a hydrogen atom and R 9  and R 11  together stand for an additional bond.   
     
     
         30 . A method according to  claim 26 , wherein the compound of formula I′ has a double bond in position 9(11), 14(15) or 15(16) or two double bonds in positions 9(11) and 14(15) or 15(16). 
     
     
         31 . A method according to  claim 26 , wherein in the compound of formula I′
 R 17  and R 17′  are a group R 18 —O— and a group R 18 —; a group R 18 — and a group —O—C(O)R 22 .   
     
     
         32 . A method according to  claim 26 , wherein in the compound of formula I′
 R 17  and R 17′  are a hydroxy group and a hydrogen atom, a C 1 -C 4 -alkyl group or a C 2 -C 4 -alkinyl group.   
     
     
         33 . A method according to  claim 26 , wherein in the compound of formula I′
 R 17  and R 17′  are a hydroxy group and a hydrogen atom, a methyl, ethinyl or prop-1-inyl group.   
     
     
         34 . A method according to  claim 26 , wherein in the compound of formula I′
 R 16′  stands for a group R 18 —O— or R 19 SO 2 —O—.   
     
     
         35 . A method according to  claim 26 , wherein the compound of formula I′ is 
       8β-vinyl-estra-1,3,5(10),9(11)-tetraene-3, 17β-diol 
       3-methoxy-8β-vinyl-estra-1,3,5(10),9(11)-tetraen-17β-ol 
       8β-(2′,2′-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3, 17β-diol 
       8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol 
       8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol 
       3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol 
       8β-(2′,2′-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol 
       8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β-ol 
       8β-vinyl-estradiol-3-sulfamate 
       8β-vinyl-estradiol-3,17-disulfamate 
       8β-vinyl-estradiol-3-(N-acetyl)-sulfamate 
       8β-vinyl-estrone-3-sulfamate 
       8β-vinyl-estron-3-acetate 
       8β-vinyl-estriol 
       8β-vinyl-estriol-3-sulfamate 
       8β-(prop-(Z)-enyl)-estradiol 
       8β-ethinyl-estradiol 
       17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol 
       17α-methyl-8β-vinyl-estra-1,3,5,(10)-triene-3,17β-diol 
       8β-vinyl-estra-1,3,5(10)-triene-3, 17α-diol 
       8β-vinyl-estradiol-diacetate 
       8β-vinyl-estradiol-17-valerianate or 
       17β-acetoxy-8β-vinyl-estra-1,3,5(10)-trien-3-ol. 
     
     
         36 . A method for treatment of an estrogen-deficiency-induced disease or condition, which is a perimenospausal or postmenopausal symptom, which is hot flashes, sleep disturbances, irritability, mood swings, incontinence, or vaginal atrophy;
 therapy of ulcers or hemorrhagic diatheses in the gastrointestinal tract;   therapy of neoplasias of the gastrointestinal tract;   in-vitro treatment of male infertility;   in-vivo treatment of male infertility;   in-vitro treatment of female infertility;   in-vivo treatment of female infertility;   hormone replacement therapy in a patient in need of replacement of estrogen;   therapy of an estrogen-deficiency induced bone mass loss;   therapy of osteoporosis;   treatment of arteriosclerosis;   treatment of neointimal hyperplasias;   treatment of Alzheimer's disease or an estrogen-deficiency induced impairment of memory and learning capacity;   treatment of benign prostate hyperplasia;   inhibiting the proliferation of arterial smooth muscle cells;   treatment of primary pulmonary high blood pressure; or   treatment of rheumatoid arthritis;   comprising administering to a subject in need thereof an effective amount of an 8β-substituted estra-1,3,5(10)-triene compound of formula I   
       
         
           
           
               
               
           
         
       
       in which
 R 2  means a hydrogen atom, a halogen atom;
 a radical R 18 — or R 18 —O—, in which R 18  means a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, or a trifluoromethyl group; 
 a group R 19 SO 2 —O—, in which R 19  is an R 20 R 21 N group, in which R 20  and R 21 , independently of one another, mean a hydrogen atom, a C 1 -C 5 -alkyl radical, a group C(O)R 22 , in which R 22  represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, an optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C 3 -C 7 -cycloalkyl radical, an optionally substituted C 4 -C 15 -cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or R 20 R 21 N means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical; 
 
 R 3  means a group R 18′ —O—R 19 SO 2 —O— or —O—C(O)R 22 , in which R 18″  is a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, or an aryl, heteroaryl or aralkyl radical; 
 R 6  and R 7  each mean a hydrogen atom or together an additional bond; 
 R 6′  and R 7′ , are each independently a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ; 
 R 8  means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms, or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical; 
 R 9  means a hydrogen atom, a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 5 carbon atoms, or together with R 11  means an additional bond; 
 R 11  means a hydrogen atom or together with R 9  or together with R 12  means an additional bond; 
 R 11′  means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or a group —X—R 18″ , in which X is an oxygen or sulfur atom, and R 18″  is an alkyl radical with 1 to 3 carbon atoms; 
 R 12  means a hydrogen atom or together with R 11  means an additional bond; 
 R 14  means a hydrogen atom or together with R 15  means an additional bond; 
 R 15  means a hydrogen atom or together with R 14  or together with R 16  means an additional bond; 
 R 16  means a hydrogen atom or together with R 15  means an additional bond; 
 R 15′  and R 16′ , independently of one another, mean a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ; 
 R 17  and R 17′  each mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R 19 SO 2 —O—; a group R 18  and a group —C(O)R 22  or —O—C(O)R 22 ; a group R 18 —O— and a group R 18 —; a group R 18 —O— and a group —O—C(O)R 22 ; or 
 R 17  and R 17′  together mean a group ═CR 23 R 24 , in which R 23  and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom; 
 
       excluding the compounds of formula I, in which
 R 3  is a hydroxy, methoxy or acetyloxy group, and simultaneously 
 R 2  represents a hydrogen atom, 
 R 6 , R 6′ , R 7  and R 7′  in each case represent a hydrogen atom; 
 R 9  represents a hydrogen atom or 
 R 9  and R 11  together represent an additional bond, 
 R 11′  and R 12  in each case represent a hydrogen atom, 
 R 14 , R 15 , R 15′ , R 16  and R 16′  in each case represent a hydrogen atom, and 
 R 17  and R 17′  form a β-hydroxy group and a hydrogen atom; form a β-(2-bromoacetyl)oxy group and a hydrogen atom; or form a β-acetyl group and a hydrogen atom; or 
 R 17  and R 17′  together represent an oxygen atom. 
 
     
     
         37 . A method according to  claim 36 , wherein in the compound of formula I
 R 2  means a hydrogen or halogen atom or a hydroxy group;   R 3  means a group R 18′ —O—, R 19 SO 2 —O— or —O—C(O)R 22 ,   R 6  and R 7  each mean a hydrogen atom;   R 6′  means a hydrogen atom, or a hydroxy group, a group R 22 ;   R 7′  means a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ;   R 8  means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms, or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical;   R 9  means a hydrogen atom or together with R 11  an additional bond;   R 11  means a hydrogen atom or together with R 9  an additional bond;   R 11′  means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or a group —X—R 18′ , in which X is a sulfur atom, and R 18′  is an alkyl radical with 1 to 3 carbon atoms;   R 12 , R 14 , R 15  and R 16  in each case mean a hydrogen atom;   R 16′  means a hydrogen atom, a halogen atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ;   R 17  and R 17′  in each case mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R 19 SO 2 —O—; a group R 18  and a group —C(O)R 22  or —O—C(O)R 22 ; a group R 18 —O— and a group R 18 —;   a group R 18 —O— and a group —O—C(O)R 22 ; and   R 17  and R 17′  together mean a group ═CR 23 R 24 , in which R 23  and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.   
     
     
         38 . A method according to  claim 36 , wherein in the compound of formula I
 R 2  means a hydrogen atom or a fluorine atom or a hydroxy group,   R 3  means a group R 18′ —O—, R 19 SO 2 —O— or —O—C(O)R 22      R 6  and R 7  in each case mean a hydrogen atom;   R 6′  means a hydrogen atom or a hydroxy group,   R 7′  means a hydrogen atom, a fluorine or chlorine atom, a group R 18 —O—, R 19 SO 2 —O— or —R 22 ,   R 18  means a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, or a trifluoromethyl group;   R 19  is an R 20 R 21 N group, R 20  and R 21 , independently of one another, mean a hydrogen atom, a C 2 -C 5 -alkyl radical, a group C(O)R 22 ,   R 22  represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, an optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C 3 -C 7 -cycloalkyl radical, an optionally substituted C 4 -C 15 -cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical,   or R 20 R 21 N means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;   R 9  means a hydrogen atom or together with R 11  an additional bond;   R 11′  means a hydrogen atom, a fluorine or chlorine atom, a saturated, straight-chain or branched-chain C 1 -C 4 -alkyl group, a group —X—R 18 ″, in which X is a sulfur atom and R 18 ″ means a saturated, straight-chain or branched-chain C 1 -C 3 -alkyl group, a chloromethyl or chloroethyl group;   R 12 , R 14 , R 15  and R 16  in each case mean a hydrogen atom;   R 16′  means a hydrogen atom, a fluorine or chlorine atom or a group R 18 —O or —R 22 ;   R 17  and R 17′  in each case mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R 19 SO 2 —O—; a group R 18  and a group —C(O)R 22  or —O—C(O)R 22 ; a group R 18 —O— and a group R 18 —; a group R 18 —O— and a group —O—C(O)R 22 ; or   R 17  and R 17′  together mean a group ═CR 23 R 24 , in which R 23  and R 24 , independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.   
     
     
         39 . A method according to  claim 36 , wherein in the compound of formula I
 R 6′ , R 7′ , R 9 , R 11 , R 14 , R 15 , R 15′  and R 16  in each case stand for a hydrogen atom or R 6′ , R 7′ , R 14 , R 15 , R 15′  and R 16  in each case stand for a hydrogen atom and R 9  and R 11  together stand for an additional bond, and all other substituents have the meanings that are indicated in claim  1 .   
     
     
         40 . A method according to  claim 36 , wherein the compound of formula I has a double bond in position 9(11), 14(15) or 15(16) or two double bonds in positions 9(11) and 14(15) or 15(16). 
     
     
         41 . A method according to  claim 36 , wherein in the compound of formula I
 R 17  and R 17′  are a group R 18 —O— and a group R 18 —; a group R 18 — and a group —O—C(O)R 22 .   
     
     
         42 . A method according to  claim 36 , wherein in the compound of formula I
 R 17  and R 17′  are a hydroxy group and a hydrogen atom, a C 1 -C 4 -alkyl group or C 2 -C 4 -alkinyl group.   
     
     
         43 . A method according to  claim 36 , wherein in the compound of formula I
 R 17  and R 17′  are a hydroxy group and a hydrogen atom, a methyl, ethinyl, or prop-1-inyl group.   
     
     
         44 . A method according to  claim 36 , wherein in the compound of formula I
 R 16′  stands for a group R 18 —O- or R 19 SO 2 —O—, and R 17  and R 17′  each stand for a hydrogen atom.   
     
     
         45 . A method according to  claim 36 , wherein the compound of formula I is 
       8β-Vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol 
       3-methoxy-8β-vinyl-estra-1,3,5(10),9(11)-tetraen-17β-ol 
       8β-(2′,2′-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β-diol 
       8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol 
       8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol 
       3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol 
       8β-(2′,2′-difluorovinyl)-estra-1,3,5(10)-triene-3,17-diol 
       8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β-ol 
       8β-vinyl-estradiol-3-sulfamate 
       8β-vinyl-estradiol-3,17-disulfamate 
       8β-vinyl-estradiol-3-(N-acetyl)-sulfamate 
       8β-vinyl-estrone-3-sulfamate 
       8β-vinyl-estron-3-acetate 
       8β-vinyl-estriol 
       8β-vinyl-estriol-3-sulfamate 
       8β-(prop-(Z)-enyl)-estradiol 
       8β-ethinyl-estradiol 
       17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol 
       17α-methyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol 
       8β-vinyl-estra-1,3,5(10)-triene-3,17α-diol 
       8β-vinyl-estradiol-diacetate 
       8β-vinyl-estradiol-17-valerianate or 
       17β-acetoxy-8β-vinyl-estra-1,3,5(10)-trien-3-ol.