Unsaturated 14, 15-cyclopropanoandrostanes, a method for their production and pharmaceutical compositions containing these compounds

Abstract

The invention relates to new unsaturated 14,15-cyclopropano-androstanes of the general formula (I) to their synthesis and to pharmaceutical compositions, containing these compounds. The compounds of formula (I) have gestagenic and/or androgenic activity.

1. Unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes of the  formula (I): 
                 
 wherein R 1  is  represents a hydrogen atom, a hydroxy group, a C 1-10 -alkyl group, a C 1-10 -alkyloxy group, a C 1-15  acyloxy group, a C 4-15 -aryloxy group, a C 7-15 -aralkyloxy group, or a C 7-15 -alkylaryloxy group;  
 R 2  represents a hydrogen atom, a hydroxy group, a C 1-10  alkyl group, a C 1-10  acyl group, a C 1-10  acyloxy group, a C 6-15  aryl group, a C 7-15  aralkyl group, a C 7-15  alkylaryl group, a —(CH 2 ) n CH 2 Y group in which n=0, 1 or 2 and Y represents a halogen atomor a pseudohalogen , a cyano group, an azido group, a cyanato group, or a thiocyanato group; a —(CH 2   )   m   CH═CH(CH   2   )   p   R   6    group  in which m=0, 1, 2, or 3 and p=0, 1, or 2 and R 6  represents a hydrogen atom, a C 1-10 -alkyl group, a C 6-15  aryl group, a C 7-15  aralkyl group, a C 7-15  alkylaryl group, a hydroxyl group, a C 1-10  alkyloxy group, or a C 1-10  acyloxy group; a —(CH 2   )   o   C≡CR   7    group  in which o=0, 1, or 2 and R 7  represents a hydrogen atom, a halogen atom, a C 1-10  alkyl group, a C 6-15  aryl group, a C 7-15  aralkyl group, a C 7-15  alkylaryl group, or a C 1-10  acyl group; or  
 R 1  and R 2  together represent a keto group, a methylene group, a difluoromethylene group or, with inclusion of C-17, a spirooxirane or a 2,2-dimethyl-1,3-dioxolane;  
 in which optionally a  1 , 2  double bond is present; 
 R 3  represents a hydrogen atom, or  a α-C 1-10  alkyl group, or a β-C 1-10  alkyl group;  
 R 4  represents a halogen atom, a pseudohalogen  cyano group, an azido group, a thiocyanato group, a cyanato group, a hydroxy group, or a perfluoroalkyl group;  
 R 5  represents a C 1-4  alkyl group;  
 in which  an α-cyclopropane group or a β-cyclopropane group is present between C-14 and C-15;  
 in which optionally a  1 , 2 -double bond is present and with the proviso that, if said 1,2-double bond is present, then R 4  can berepresent a hydrogen atom in addition to said halogen atom, said pseudohalogencyano group, said azido group, said thiocyanato group, said hydroxy group, or said perfluoroalkyl group;  
 
       or pharmaceutically tolerated salts thereof. 
     
     
       2. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1 , wherein Y is  denotes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, an azide  azido group, or a rhodanide  thiocyanato group. 
     
     
       3. The unsaturated  14 , 15 -cyclopranoandrostanes  14 , 15 -cyclopropanoandrostanes as defined in  claim 1 , wherein R 7  is  denotes a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. 
     
     
       4. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1 , wherein R 4  is  denotes a fluorine atom, a chlorine atom, a bromine atom, an azide  azido group, or a rhodanide  thiocyanato group. 
     
     
       5. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1 , wherein R 1  is  denotes a hydroxy group or an acyloxy group. 
     
     
       6. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 5 , wherein said acyloxy group is a formyloxy, an acetyloxy, a propionyloxy, a n-butyryloxy, an isobutyryloxy, a heptanyloxy, or an undecanyloxy group. 
     
     
       7. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1 , wherein R 2  is a hydrogen atom or an alkyl group. 
     
     
       8. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 7 , wherein said alkyl group is a methyl group or an ethyl group. 
     
     
       9. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1 , wherein R 3  is a methyl group. 
     
     
       10. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1 , wherein R 4  is  denotes a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, or a trifluoromethyl group. 
     
     
       11. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1 , wherein R 5  is  denotes a methyl group or an ethyl group. 
     
     
       12. The unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes selected from the group consisting of 
       4-chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4-chloro-17α-hydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4-chloro-17β-hydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4-chloro-17α-hydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4-bromo-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4-bromo-17α-hydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4-bromo-17β-hydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4-bromo-17α-hydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4-fluoro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4-fluoro-17α-hydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4-fluoro-17β-hydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4-fluoro-17α-hydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4,17β-dihydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4,17α-dihydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4,17β-dihydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4,17α-dihydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4-trifluoromethyl-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4-trifluoromethyl-17α-hydroxy-14α,15α-methylene-androst-4-ene-3-one,  
       4-trifluoromethyl-17β-hydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       4-trifluoromethyl-17α-hydroxy-14β,15β-methylene-androst-4-ene-3-one,  
       17β-hydroxy-14α,15α-methylene-androsta-1,4-diene-3-one,  
       17α-hydroxy-14α,15α-methylene-androsta-1,4-diene-3-one,  
       17β-hydroxy-14β,15β-methylene-androsta-1,4-diene-3-one,  
       17α-hydroxy-14β,15β-methylene-androsta-1,4-diene-3-one,  
       4-chloro-17α-hydroxy-14α,15α-methylene-androsta-1,4-diene-3-one,  
       4-chloro-17β-hydroxy-14α,15α-methylene-androsta-1,4-diene-3-one,  
       4-chloro-17β-hydroxy-14β,15β-methylene-androsta-1,4-diene-3-one, and  
       4-chloro-17α-hydroxy-14β,15β-methylene-androsta-1,4-diene-3-one.  
     
     
       13. A method for the  of synthesis of the  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes defined in  claim 1 , wherein, in compounds of formula (II): 
                 
 in which R 1 , R 2 , R 3 , R 5  are as defined in  claim 1 ,  4 , 5  double  and in which a  4 , 5 -double bond is present, the  4 , 5 -double bond is epoxidized with hydrogen peroxide under alkaline conditions and the resulting epoxide mixture is treated in a solvent with acids of the  formula HR 8 , R 8  being a halogen atom, a cyano group, an azido group, a cyanato, or a pseudohalogen atom,  thiocyanato group, or reacted with catalytic amounts of a mineral acid,  to obtain 4-bromo -compounds and, optionally, the obtained 4-bromo compounds of the formula (I), as defined in  claim 1 , are reacted with methyl 2,2-difluoro-2-(fluorosulfonyl) acetate in dimethylformamide in the presence of CuI.  
 
     
     
       14. The method as defined in  claim 13 , wherein said halogen atom is  denotes a fluorine, chlorine, or bromine atom. 
     
     
       15. The method as defined in  claim 13 , wherein said pseudohalogen is an azide or a rhodanide  R 8    represents said azido or said thiocyanato  group. 
     
     
       16. A pharmaceutical composition containing at least one of the unsaturated  14 , 15 -cyclo-pranoandrostanes   14 , 15 -cyclopropanoandrostanes defined in  claim 1  and at least one additional ingredient selected from the group consisting of pharmaceutically tolerated inactive materials and vehicles. 
     
     
       17. A method of hormone replacement therapy in a man or woman in need of said therapy, said method comprising administering to said man or said woman an effective amount of at least one of the unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1  for said hormone replacement therapy. 
     
     
       18. A method of controlling fertility of a human being, said method comprising administering to said human being an effective amount of at least one of the unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1  for controlling said fertility. 
     
     
       19. A method of treating a hormone-induced disease suffered by a man or a woman, said method comprising administering to said man or said woman an effective amount of at least one of the unsaturated  14 , 15 -cyclopranoandrostanes   14 , 15 -cyclopropanoandrostanes as defined in  claim 1  for treating said hormone-induced disease. 
     
     
       20. The method as defined in  claim 19 , wherein said hormone-induced disease is endometriosis, breast cancer, or hypogonadism.