17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives, method of production thereof and use thereof for the treatment of diseases

Abstract

The invention relates to 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives of Formula I with progesterone antagonizing action and method of production thereof, use thereof for the treatment and/or prophylaxis of diseases and use thereof for the production of medicinal products for the treatment and/or prophylaxis of diseases, in particular of fibroids of the uterus (myomas, uterine leiomyoma), endometriosis, heavy menstrual bleeds, meningiomas, hormone-dependent breast cancers and complaints associated with the menopause or for fertility control and emergency contraception.

1 . Compound of formula I 
       
         
           
           
               
               
           
         
       
       in which
 R 1  stands either for a residue Y or for a phenyl ring substituted once or twice with a residue Y, 
 Y is selected from the group comprising SR 2 , S(O)R 3 , S(O) 2 R 3 , S(O)(NH)R 3 , S(O)(NR 4 )R 3 , S(O) 2 NR 9 R 10 , 
 R 2  stands for hydrogen, C 1 -C 6 -alkyl, C 7 -C 10 -aralkyl or aryl, 
 R 3  stands for C 1 -C 6 -alkyl or aryl, 
 R 4  stands for a group S(O) 2 R 6 , 
 R 6  stands for phenyl or 4-methylphenyl 
 X denotes an oxygen atom, NOR 7  or NNHSO 2 R 7 , 
 R 7  is selected from the group comprising hydrogen, C 1 -C 10 -alkyl, aryl 
 R 9 , R 10  independently of one another are selected from the group comprising hydrogen, C 1 -C 10 -alkyl or aryl or alternatively represent, together with the nitrogen atom, a 3- to 8-membered, saturated or unsaturated heterocyclic ring 
 and their separate stereoisomers, their salts, solvates or solvates of the salts, including all crystal modifications. 
 
     
     
         2 . Compound according to  claim 1 , in which
 R 1  stands either for a residue Y or for a phenyl ring substituted once with a residue Y,   Y is selected from the group comprising SR 2 , S(O)R 3 , S(O) 2 R 3 , S(O)(NH)R 3 , S(O)(NR 4 )R 3 , S(O) 2 NR 9 R 10  and   R 2  stands for hydrogen, C 1 -C 6 -alkyl or S—CH 2 -phenyl,   R 3  stands for C 1 -C 6 -alkyl and   X represents an oxygen atom,   R 6  represents phenyl or 4-methylphenyl and   R 9 , R 10  independently of one another represent hydrogen or C 1 -C 6 -alkyl or phenyl and their separate stereoisomers, their salts, solvates or solvates of the salts.   
     
     
         3 . Compound according to  claim 1 , in which R 1  represents S(O) 2 R 3  and X represents O. 
     
     
         4 . Compound according to  claim 3 , in which R 3  represents C 1 -C 6 -alkyl. 
     
     
         5 . Compound according to  claim 4 , in which R 3  represents methyl. 
     
     
         6 . Compound according to  claim 1 , in which R 1  represents S(O)(NH)R 3  and X represents O and the separate stereoisomers thereof. 
     
     
         7 . Compound according to  claim 6 , in which R 3  represents C 1 -C 6 -alkyl and the separate stereoisomers thereof. 
     
     
         8 . Compound according to  claim 7 , in which R 3  represents methyl and the separate stereoisomers thereof. 
     
     
         9 . Compound according to  claim 1 , in which R 1  represents SOR 3  and X represents O and the separate stereoisomers thereof. 
     
     
         10 . Compound according to  claim 9 , in which R 3  represents C 1 -C 6 -alkyl and the separate stereoisomers thereof. 
     
     
         11 . Compound according to  claim 10 , in which R 3  represents methyl and the separate stereoisomers thereof. 
     
     
         12 . Compound according to  claim 1 , in which R 1  represents SR 2  and X represents O. 
     
     
         13 . Compound according to  claim 12 , in which R 2  represents hydrogen. 
     
     
         14 . Compound according to  claim 12 , in which R 2  represents C 1 -C 6 -alkyl. 
     
     
         15 . Compound according to  claim 14 , in which R 2  represents methyl. 
     
     
         16 . Compound according to  claim 12 , in which R 2  represents aryl. 
     
     
         17 . Compound according to  claim 16 , in which R 2  represents phenyl. 
     
     
         18 . Compound according to  claim 12 , in which R 2  represents C 7 -C 10 -aralkyl. 
     
     
         19 . Compound according to  claim 18 , in which R 2  represents benzyl. 
     
     
         20 . Compounds according to  claim 2 , in which R 2  represents methyl, ethyl or hydrogen. 
     
     
         21 . Compounds according to  claim 1 , in which R 3  represents C 1 -C 6 -alkyl. 
     
     
         22 . Compounds according to  claim 4 , in which R 3  represents methyl or ethyl. 
     
     
         23 . Compounds according to  claim 1 , in which R 5  represents phenyl. 
     
     
         24 . Compounds according to  claim 6 , in which n=1. 
     
     
         25 . Compounds according to  claim 1 , in which X is an oxygen atom. 
     
     
         26 . Compounds according to  claim 1 , in which Y stands for SR 2  or S(O) 2 R 3  or S(O)(NH)R 3  with R 2  equal to hydrogen, methyl or ethyl and R 3  equal to methyl or ethyl. 
     
     
         27 . Compounds according to  claim 1 , in which Y stands for S(O) 2 R 3 . 
     
     
         28 . Compounds according to  claim 1   (11β,17β)-17-hydroxy-11-[4-(methylsulphanyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one;   (11β,17β)-11-[4-(ethylsulphanyl)phenyl]-17-hydroxy-17-(pentafluoroethyflestra-4,9-dien-3-one;   (11β,17β)-17-hydroxy-11-{4-[(RS)-methylsulphinyl]phenyl}-17-(pentafluoroethyl)estra-4,9-dien-3-one;   (11β,17β)-17-hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one;   (11β,17β)-11-[4-(ethylsulphonyl)phenyl]-17-hydroxy-17-(pentafluoroethyl)estra-4,9-dien-3-one;   (11β,17β)-11-[4-(benzylsulphanyl)phenyl]-17-hydroxy-17-(pentafluoroethyl)estra-4,9-dien-3-one;   N-[{4-[(11β,17β)-17-hydroxy-3-oxo-17-(pentafluoroethyl)estra-4,9-dien-11-yl]phenyl}(RS)(methyl)oxidoa-λ 6 -sulphanylidene]-4-methylbenzene sulphonamide;   (11β,17β)-17-hydroxy-11-[4-(RS-methylsulphonimidoyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one;   (11β,17β)-17-hydroxy-11-[4′-(methylsulphanyl)biphenyl-4-yl]-17-(pentafluoroethyl)estra-4,9-dien-3-one;   (11β,17β)-17-hydroxy-11-[4′-(methylsulphonyl)biphenyl-4-yl]-17-(pentafluoroethyl)estra-4,9-dien-3-one;   N-[{4′-[(11β,17β)-17-hydroxy-3-oxo-17-(pentafluoroethyflestra-4,9-dien-11-yl]biphenyl-4-yl}(RS)(methyl) oxido-λ 6 -sulphanylidene]-4-methylbenzene sulphonamide;   (11β,17β)-17-hydroxy-11-[4′-(RS-methylsulphonimidoyl)biphenyl-4-yl]-17-(pentafluoroethyl)estra-4,9-dien-3-one;   (11β,17β)-17-hydroxy-17-(pentafluoroethyl)-11-(4′-sulphanylbiphenyl-4-yl)estra-4,9-dien-3-one;   4′-[(11β,17β)-17-hydroxy-3-oxo-17-(pentafluoroethyl)estra-4,9-dien-11-yl]-N,N-dimethylbiphenyl-4-sulphonamide;   4-[(11β,17β)-17-hydroxy-3-oxo-17-(pentafluoroethyl)estra-4,9-dien-11-yl]-N,N-dimethylbenzene sulphonamide   
     
     
         29 . Compound according to  claim 1 , for the treatment and prophylaxis of diseases. 
     
     
         30 . A method for the treatment and prophylaxis of fibroids of the uterus, endometriosis, heavy menstrual bleeds, meningiomas, hormone-dependent breast cancers and complaints associated with the menopause or for fertility control and emergency contraception, comprising administering to a subject in need thereof an effect amount of a compound of  claim 1 . 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . A pharmaceutical composition containing a compound as defined in  claim 1 , in combination with another active substance. 
     
     
         34 . A pharmaceutical composition containing a compound as defined in  claim 1 , in combination with an inert, non-toxic, pharmaceutically suitable excipient. 
     
     
         35 . (canceled)