Microbiological process for the production of 7-substitued 11-hydroxy steroids, 7,17-substituted 11-halogen steroids, and uses thereof

Abstract

A novel method of synthesis for the manufacture of upstream products for the production of compounds with general formulas 8, 10, and 12 is described. In this synthesis, compounds with general formula 4,B are produced in a microbiological reaction. The meanings of R 7 , R 10 , R 11 , R 13 , R 17 and R 17 ′ as well as of the grouping U—V—W—X—Y-Z are indicated in the claims.

1 . Microbiological process for the production of 7α-substituted 11α-hydroxy steroids with general formula 4,B:  
     
       
         
         
             
             
         
       
     
     in which 
 R 7  is the grouping P-Q, whereby 
 P represents a C 1 - to C 4 -alkylene, and Q represents a C 1 - to C 4 -alkyl- or C 1 - to C 4 -fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton,  
 
 R 10  can be in α- or β-position and stands for H, CH 3  or CF 3 , and  
 R 13  is methyl or ethyl,  
 in which a 7α-substituted steroid with general formula 3,A:  
                     
 in which R 7 , R 10  and R 13  have the same meanings as indicated above,  
 is hydroxylated and oxidized with use of a microorganism that is selected from the group that comprises  Aspergillus  sp.,  Beauveria  sp.,  Glomerella  sp.,  Gnomonia  sp.,  Haplosporella  sp. and  Rhizopus  sp.  
 
   
   
       2 . (canceled)  
   
   
       3 . (canceled)  
   
   
       4 . (canceled)  
   
   
       5 . (canceled)  
   
   
       6 . (canceled)  
   
   
       7 . (canceled)  
   
   
       8 . (canceled)  
   
   
       9 . (canceled)  
   
   
       10 . (canceled)  
   
   
       11 . 7α,17α-Substituted 11β-halogen steroids with general formulas 8,10, and 12:  
     
       
         
         
             
             
         
       
     
     in which 
 U—V—W—X—Y-Z stands for one of ring structures C 1 —C 2 —C 3 —C 4 ═C 5 —C 10 , C 1 —C 2 —C 3 —C 4 —C 5 ═C 10  or C 1 —C 2 —C 3 —C 4 —C 5 —C 10 , whereby in this case, an oxo group (═O) is bonded to W (═C 3 ), or for ring structure C 1 ═C 2 —C 3 ═C 4 —C 5 ═C 6 , whereby in this case radical OR 3  is bonded to W (═C 3 ),  
 R 3  stands for H, C 1 - to C 4 -alkyl, C 1 - to C 4 -alkanoyl or a cyclic C 3 - to C 7 -ether with the O-atom of the OR 3 -radical,  
 R 7  is the grouping P-Q, whereby 
 P represents a C 1 - to C 4 -alkylene and Q represents a C 1 - to C 4 -alkyl- or C 1 - to C 4 -fluoroalkyl, and grouping P-Q is bonded via P to the steroid skeleton,  
 
 R 10  can be in α- or β-position and stands for H, CH 3  or CF 3 , and is present only if X—Y-Z is not C 4 —C 5 ═C 10 ,  
 R 11  is a halogen,  
 R 13  is methyl or ethyl,  
 R 17  stands for H, C 1 - to C 18 -alkyl, alicyclic C 1 - to C 18 -alkyl, C 1 - to C 18 -alkenyl, alicyclic C 1 - to C 18 -alkenyl, C 1 - to C 18 -alkinyl, C 1 - to C 18 -alkylaryl, C 1 - to C 8 -alkylenenitrile or for the grouping P-Q, whereby the grouping P-Q has the above-mentioned meaning,  
 R 17′  stands for H, C 1 - to C 18 -alkyl, alicyclic C 1 - to C 18 -alkyl, C 1 - to C 18 -alkenyl, alicyclic C 1 - to C 18 -alkenyl, C 1 - to C 18 -alkinyl or C 1 - to C 18 -alkylaryl, whereby R 17′  also can be bonded via a keto group to the 17β-oxy group, and whereby R 17′  also in addition can be substituted with one or more groups NR 18 R 19  or one or more groups SO x R 20 , whereby x=0, 1 or 2 and R 18 , R 19  and R 20  in each case independently of one another can have the same meaning as R 17 ,  
 as well as their pharmaceutically compatible addition salts, esters and amides.  
 
   
   
       12 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein U—V—W—X—Y-Z stands for ring structure C 1 —C 2 —C 3 —C 4 ═C 5 —C 10  or C 1 —C 2 —C 3 —C 4 —C 5 ═C 10  or C 1 ═C 2 —C 3 ═C 4 —C 5 ═C 10 .  
   
   
       11 . 7α,17α-Substituted 11β-halogen steroids with general formulas 8,10, and 12:  
     
       
         
         
             
             
         
       
     
     in which 
 U—V—W—X—Y-Z stands for one of ring structures C 1 —C 2 —C 3 —C 4 ═C 5 —C 10 , C 1 —C 2 —C 3 —C 4 —C 5 ═C 10  or C 1 —C 2 —C 3 —C 4 —C 5 —C 10 , whereby in this case, an oxo group (═O) is bonded to W (═C 3 ), or for ring structure C 1 ═C 2 —C 3 ═C 4 —C 5 ═C 6 , whereby in this case radical OR 3  is bonded to W (═C 3 ),  
 R 3  stands for H, C 1 - to C 4 -alkyl, C 1 - to C 4 -alkanoyl or a cyclic C 3 - to C 7 -ether with the O-atom of the OR 3 -radical,  
 R 7  is the grouping P-Q, whereby 
 P represents a C 1 - to C 4 -alkylene and Q represents a C 1 - to C 4 -alkyl- or C 1 - to C 4 -fluoroalkyl, and grouping P-Q is bonded via P to the steroid skeleton,  
 
 R 10  can be in α- or β-position and stands for H, CH 3  or CF 3 , and is present only if X—Y-Z is not C 4 -C 5 =C 10 ,  
 R 11  is a halogen,  
 R 13  is methyl or ethyl,  
 R 17  stands for H, C 1 - to C 18 -alkyl, alicyclic C 1 - to C 18 -alkyl, C 1 - to C 18 -alkenyl, alicyclic C 1 - to C 18 -alkenyl, C 1 - to C 18 -alkinyl, C 1 - to C 18 -alkylaryl, C 1 - to C 8 -alkylenenitrile or for the grouping P-Q, whereby the grouping P-Q has the above-mentioned meaning,  
 R 17′  stands for H, C 1 - to C 18 -alkyl, alicyclic C 1 - to C 18 -alkyl, C 1 - to C 18 -alkenyl, alicyclic C 1 - to C 18 -alkenyl, C 1 - to C 18 -alkinyl or C 1 - to C 18 -alkylaryl, whereby R 17′  also can be bonded via a keto group to the 17β-oxy group, and whereby R 17′  also in addition can be substituted with one or more groups NR 18 R 19  or one or more groups SO x R 20 , whereby x=0, 1 or 2 and R 18 , R 19  and R 20  in each case independently of one another can have the same meaning as R 17 ,  
 as well as their pharmaceutically compatible addition salts, esters and amides.  
 
   
   
       12 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein U—V—W—X—Y-Z stands for ring structure C 1 —C 2 —C 3 —C 4 ═C 5 —C 10  or C 1 —C 2 —C 3 —C 4 —C 5 ═C 10  or C 1 ═C 2 —C 3 ═C 4 —C 5 ═C 10 .  
   
   
       13 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein R 1  stands for H.  
   
   
       14 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein R 7  stands for CH 3 .  
   
   
       15 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein R 11  stands for fluorine.  
   
   
       16 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein R 13  stands for CH 3 .  
   
   
       17 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein R 17  stands for H, CH 3 , C 1 - to C 18 -alkinyl, CH 2 CN or CF 3 .  
   
   
       18 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein R 17  is ethinyl.  
   
   
       19 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , wherein R 17′  stands for H.  
   
   
       20 . 7α,17α-Substituted 11β-halogen steroids according to  claim 11 , namely 
 17α-Ethinyl-11β-fluoro-17β-hydroxy-7α-methylestr-4-en-3-one    17α-Ethinyl-11β-fluoro-17β-hydroxy-7α-methylestr-5(10)-en-3-one    17α-Ethinyl-11β-fluoro-7α-methylestra-1,3,5(10)-triene-3,17β-diol.    
   
   
       21 . 7α-Substituted 11β-haloestra-1,3,5(10)-trienes with general formula 6:  
     
       
         
         
             
             
         
       
     
     in which 
 R 3  stands for H, C 1 - to C 4 -alkyl, C 1 - to C 4 -alkanoyl or a cyclic C 3 - to C 7 -ether with the O-atom of the OR 3 -radical,  
 R 7  is the grouping P-Q, whereby 
 P represents a C 1 - to C 4 -alkylene and Q represents a C 1 - to C 4 -alkyl- or C 1 - to C 4 -fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton,  
 
 R 11  is a halogen;  
 R 13  is methyl or ethyl,  
 as well as their pharmaceutically compatible addition salts, esters and amides.  
 
   
   
       22 . 7α-Substituted 11β-haloestra-1,3,5(10)-trienes according to  claim 21 , namely 
 11β-Fluoro-3-hydroxy-7α-methylestra-1,3,5(10)-trien-17-one.    
   
   
       23 . Process for the production of 7α,17α-substituted 11β-halogen steroids with general formula 10 according to  claim 11 , in which U—V—W—X—Y-Z stands for the ring structure C 1 —C 2 —C 3 —C 4 ═C 5 —C 10 , with the following process steps: 
 Nucleophilic substitution in a 7α-substituted 11α-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent;    Reaction of the 7α-substituted 11β-halogen steroid that is produced in this case with an alkylating agent in a selective manner on the C 17  atom of the ring skeleton to form the 7α,17α-substituted 11β-halogen steroid with general formula 10.    
   
   
       24 . Process for the production of 7α,17α-substituted 11β-halogen steroids with general formula 12 according to  claim 11 , in which U—V—W—X—Y-Z stands for the ring structure C 1 —C 2 —C 3 —C 4 —C 5 ═C 10 , the following process steps: 
 Nucleophilic substitution in a 7α-substituted 11α-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent,    Reaction of the 7α-substituted 11β-halogen steroid that is produced in this case with an alkylating agent in a selective manner on the C 17  atom of the ring skeleton to form the 7α,17α-substituted 11β-halogen steroid with general formula 10,    Isomerization of the 7α,17α-substituted 11β-halogen steroid with general formula 10 to form the corresponding isomer with general formula 12, in which U—V—W—X—Y-Z stands for the ring structure C 1 —C 2 —C 3 —C 4 —C 5  ═C 10 .    
   
   
       25 . Process for the production of 7α,17α-substituted 11β-halogen steroids with general formula 8 according to  claim 11 , in which U—V—W—X—Y-Z stands for the ring structure C 1 ═C 2 —C 3 ═C 4 —C 5 ═C 6  with the following process steps: 
 Nucleophilic substitution in a 7α-substituted 11α-hydroxy steroid with general formula 4,B in 11-position with a halodehydroxylating reagent,    Oxidizing of the 7α-substituted 11β-halogen steroid that is produced in this case to form 7α-substituted estra-1,3,5(10)-triene with general formula 6 according to one of claims  17  and  18 ;    Reaction of the 7α-substituted estra-1,3,5(10)-triene with general formula 6 with an alkylating agent in a selective manner on the C 17  atom of the ring skeleton to form the 7α,17α-substituted 11β-halogen steroid with general formula 8.    
   
   
       26 . Use of the 7α,17α-substituted 11β-halogen steroids with general formulas 8, 10, and 12 according to  claim 11 , for the production of pharmaceutical agents.  
   
   
       27 . Pharmaceutical preparations that contain at least one 7α,17α-substituted 11β-halogen steroid with general formulas 8, 10, and 12 according to  claim 11  as well as at least one pharmaceutically compatible vehicle.