Substituted estratrienes as selectively active estrogens

Abstract

This invention describes the new 9α-substituted estratrienes of general formula I in which R 3 , R 7 , R 7′ , R 13 , R 16 as well as R 17 and R 17′ have the meanings that are indicated in the description and R 9 means a straight-chain or branched-chain, optionally partially or completely halogenated alkenyl radical with 2 to 6 carbon atoms, an ethinyl or prop- 1 -inyl radical, as pharmaceutical active ingredients that exhibit in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably a preferential action on the ovary in comparison to the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. The invention also describes the use of these compounds for treating estrogen-deficiency-induced diseases and conditions.

1 - 19 . (canceled) 
     
     
         20 . A method for
 therapy of an estrogen-deficiency-induced bone mass loss   in-vivo treatment of female infertility;   in-vitro treatment of female infertility;   hormone replacement therapy in a patient in need of replacement of estrogen;   therapy of hormone-deficiency-related symptoms in a patient with ovarian dysfunction, wherein said patient is in need of replacement of estrogen;   treatment of polycystic ovary syndrome, or premature ovarian failure syndrome;   treatment of a peri or postmenopausal symptom or condition, which is hot flashes, sleep disorders, irritability, mood fluctuations, incontinence, vaginal atrophy or hormone-deficiency-related emotional disorders;   treatment of rheumatoid arthritis, multiple sclerosis, lupus, or Crohn's disease;   treatment of psoriasis;   treatment of endometriosis;   treatment of asthma;   therapy of hormone-deficiency-related bone mass loss;   therapy of osteoporosis;   treatment of arteriosclerosis;   treatment of high blood pressure;   treatment of Alzheimers disease or an estrogen-deficiency-related impairment of memory and learning; or   therapy of prostate hyperplasia;   
       comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a 9α-Substituted estra-1,3,5(10)-triene compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 3  is hydrogen or R 18 , 
 R 18  is a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, an optionally substituted aryl, heteroaryl or aralkyl radical, an acyl radical COR 19 , or iR SO 2 , 
 R 19  is an optionally substituted, straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and is optionally partially or completely halogenated, 
 R 20  is R 21 R 22 N, 
 R 21  and R 22  are, independently of one another, a hydrogen atom, a C 1 -C 5 -alkyl radical, or C(O)R 23 , 
 R 23  is an optionally substituted, straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and is optionally partially or completely halogenated, 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, together with the N atom, a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical, 
 R 7  and R 7′  are, in each case independently of one another, a hydrogen atom or a halogen atom, 
 R 9  is a straight-chain or branched-chain alkenyl or alkinyl radical with 2 to 6 carbon atoms, which is optionally partially or completely fluorinated, or an ethinyl or prop-1-inyl radical, 
 R 13  is a methyl group or an ethyl group, 
 R 16  is a hydroxy group or R 18 O—, R 20 SO 2 —O— or OC(O)R 23 , and 
 R 17  and R 17′  are, in each case independently of one another, a hydrogen atom or a halogen atom, 
 
       pharmaceutically acceptable salt thereof. 
     
     
         21 . A method according to  claim 20 , wherein in the compound of formula I, R 3  is a hydrogen atom. 
     
     
         22 . A method according to  claim 20 , wherein in the compound of formula I,
 R 7  is a hydrogen atom or an α-position fluorine atom,   R 9  is a vinyl, ethinyl or prop-1-inyl group,   R 16  is a hydroxy group, and   R 17  is a hydrogen atom or an α-position fluorine atom.   
     
     
         23 . A method according to  claim 20 , wherein in the compound of formula I,
 R 16  is R 18 —O— or R 20 SO 2 —O—.   
     
     
         24 . A method according to  claim 20 , wherein the compound of formula I is 
       9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diol 
       9α-Allyl-estra-1,3,5(10)-triene-3,16α-diol 
       18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 
       18a-Homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 
       3-Methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol 
       9α-Allyl-3-methoxy-estra-1,3,5(10)-trien-16α-ol 
       18a-Homo-3-methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol 
       18a-Homo-9α-allyl-3-methoxy-estra-1,3,5(10)-trien-16α-ol 
       9α-(2′,2′-Difluorovinyl)-estra-1,3,5 (10)-triene-3,16α-diol 
       9α-(2′,2′-Difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-16α-ol 
       16α-Hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate 
       9α-Allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate 
       18a-Homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate 
       18a-Homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate 
       9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate 
       9α-Allyl-estra-1,3,5 (10)-triene-3,16α-diyl-disulfamate 
       18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate 
       18a-Homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate 
       16α-Hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate 
       9α-Allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate 
       18a-Homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-N-acetyl)-sulfamate 
       18a-Homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)sulfamate 
       9α-(Prop-(Z)-enyl)-estra-1,3,5(10)-triene-3,16α-diol 
       9α-(n-Propyl)-estra-1,3,5(10)-triene-3,16α-diol 
       9α-Ethinyl-estra-1,3,5(10)-triene-3,16α-diol 
       9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate 
       18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate 
       16α-Valeroyloxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol 
       16α-Acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol 
       18a-Homo-16α-acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol 
       7α-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 
       7α-Fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 
       17β-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 
       17β-Fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 
       18a-Homo-7α-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 
       18a-Homo-7α-fluoro-9αallyl-estra-1,3,5(10)-triene-3,16α-diol 
       18a-Homo-17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol or 
       18a-Homo-17β-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol. 
     
     
         25 . A method according to  claim 20 , which is for hormone replacement therapy in a patient in need of replacement of estrogen, and which further comprises administering a SERM or raloxifene. 
     
     
         26 . A method according to  claim 20 , which is for therapy of an estrogen-deficiency-induced bone mass loss. 
     
     
         27 . A method according to  claim 20 , which is for therapy of osteoporosis. 
     
     
         28 . A method according to  claim 20 , which is for the treatment of endometriosis. 
     
     
         29 . A method according to  claim 24 , which is for the treatment of endometriosis. 
     
     
         30 . A method according to  claim 20 , wherein the compounds administered is 17β-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol. 
     
     
         31 . A method according to  claim 30 , which is for the treatment of endometriosis.