6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal fxr modulators

Abstract

The invention relates to compounds of formula (I), wherein R 1 , R 2 , Y, R 4 and R 5b are as defined herein. The compounds are intermediates in the synthesis of synthetic bile acids.

1 . A compound of general formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is C 1-4  alkyl optionally substituted with one or more substituents selected from halo, OR 6  or NR 6 R 7 ;
 where each of R 6  and R 7  is independently selected from H or C 1-4  alkyl; 
 
 R 2  is H, halo or OH or a protected OH, which is stable under basic conditions; 
 Y 1  is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R 3 ; 
 each R 3  is independently halo, OR 8  or NR 8 R 9 ;
 where each of R 8  and R 9  is independently selected from H or C 1-4  alkyl; and 
 
 R 4  is C(O)OR 10 , OC(O)R 10 , C(O)NR 10 R 11 , OR 10 , OSi(R 13 ) 3 , S(O)R 10 , SO 2 R 10 , OSO 2 R 10 , SO 3 R 10 , or OSO 3 R 10 ; 
 where each R 10  and R 11  is independently: 
 a. hydrogen or 
 b. C 1-20  alkyl, C 2-20  alkenyl, C 2-20  alkynyl, —O—C 1-20  alkyl, —O—C 2-20  alkenyl or —O—C 2-20  alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 , or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; or 
 c. a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; 
 d. a polyethylene glycol residue; 
 each R 19  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with halo, C 1-6  alkyl or C 1-6  haloalkyl; 
 each R 13  is independently 
 a. C 1-20  alkyl, C 2-20  alkenyl or C 2-20  alkynyl optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 , a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; or 
 b. a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; 
 each R 19  is independently selected from H, C 1-6  alkyl or C 1-6  haloalkyl; 
 R 5b  is H or OH or a protected OH; 
 or a salt or an isotopic variant thereof. 
 
     
     
         2 . A compound according to  claim 1  wherein R 1  is ethyl. 
     
     
         3 . A compound according to  claim 1  wherein Y 1  is an alkylene linker group having from 1 to 8 carbon atoms and optionally substituted with one or more groups R 3 , wherein R 3  is as defined in  claim 1 . 
     
     
         4 . A compound according to  claim 1  wherein, independently or in any combination:
 Y 1  is a bond or an alkylene group having 1 to 3 carbon atoms and is optionally substituted with one or two R 3  groups; 
 R 4  is C(O)OR 10 , SO 3 R 10 , or OSO 3 R 10 , where R 10  is as defined above but is more suitably H, C 1-6  alkyl or benzyl; 
 R 5b  is H or OH. 
 
     
     
         5 . A compound according to  claim 4  wherein, independently or in any combination:
 R 1  is ethyl; and/or 
 R 2  is H; and/or 
 Y 1  is a bond, —CH 2 — or —CH 2 CH 2 —; and/or 
 R 4  is C(O)OR 10 , where R 10  H, C 1-6  alkyl or benzyl; and/or 
 R 5b  is H. 
 
     
     
         6 . A compound according to  claim 1  which is selected from (6β,5β)-3,7-dioxo-6-ethyl-cholan-24-oic acid
 and C 1-6  alkyl and benzyl esters thereof and salts thereof, especially the methyl and ethyl esters. 
 
     
     
         7 . A process for the preparation of a compound according to general formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1-4  alkyl optionally substituted with one or more substituents selected from halo, OR 6  or NR 6 R 7 ;
 where each of R 6  and R 7  is independently selected from H or C 1-4  alkyl; 
 
 R 2  is H, halo or OH or a protected OH, which is stable under basic conditions; 
 Y 1  is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R 3 ; 
 each R 3  is independently halo, OR 8  or NR 8 R 9 ;
 where each of R 8  and R 9  is independently selected from H or C 1-4  alkyl; and 
 
 R 4  is C(O)OR 10 , OC(O)R 10 , C(O)NR 19 R 11 , OR 10 , OSi(R 13 ) 3 , S(O)R 10 , SO 2 R 10 , OSO 2 R 19 , SO 3 R 10 , or OSO 3 R 10 ; 
 where each R 10  and R 11  is independently: 
 a) hydrogen or 
 b) C 1-20  alkyl, C 2-20  alkenyl, C 2-20  alkynyl, —O—C 1-20  alkyl, —O—C 2-20  alkenyl or —O—C 2-20  alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 , or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; or 
 c) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2  CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; 
 d) a polyethylene glycol residue; 
 each R 19  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with halo, C 1-6  alkyl or C 1-6  haloalkyl; 
 each R 13  is independently 
 a) C 1-20  alkyl, C 2-20  alkenyl or C 2-20  alkynyl optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 , a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; or 
 b) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2  CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; 
 each R 19  is independently selected from H, C 1-6  alkyl or C 1-6  haloalkyl; and 
 R 5b  is H or OH or a protected OH; 
 comprising: 
 A) epimerisation of a compound of general formula (II): 
 
       
         
           
           
               
               
           
         
         wherein R 5  is H or OH or a protected OH; 
         by treatment with a base; or 
         B) conversion of a compound of general formula (I) to another compound of general formula (I). 
       
     
     
         8 . A process according to  claim 7  wherein, in the compound of general formula (II), R 4  is C(O)OR 10 , where R 10  is C 1-6  alkyl or benzyl, wherein the base is a strong base such as sodium or potassium hydroxide and where epimerisation is accompanied by hydrolysis to give a compound of general formula (I) in which R 4  is C(O)OH. 
     
     
         9 . A process according to  claim 7  wherein, in the compound of general formula (II), R 2  and/or R 5  is a protected OH which is stable in basic conditions and the process optionally comprises and additional step of removing the protecting group to give a compound of general formula (I) in which R 2  and/or R 5b  is OH. 
     
     
         10 . A process according to  claim 7  for the preparation of a compound of general formula (I) in which R 4  is C(O)OR 10 , wherein R 10  is as defined from a compound of general formula (II) where R 4  is also C(O)OR 10 . 
     
     
         11 . A process for the preparation of a compound of general formula general formula (XXI): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is C 1-4  alkyl optionally substituted with one or more substituents selected from halo, OR 6  or NR 6 R 7 ;
 where each of R 6  and R 7  is independently selected from H or C 1-4  alkyl; 
 
 R 2  is H, halo or OH; and 
 Y 1  is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R 3 ; 
 each R 3  is independently halo, OR 8  or NR 8 R 9 ;
 where each of Wand R 9  is independently selected from H or C 1-4  alkyl; and 
 
 R 4  is C(O)OR 19 , OC(O)R 19 , C(O)NR 19 R 11 , OR 10 , OSi(R 13 ) 3 , S(O)R 10 , SO 2 R 10 , OSO 2 R 19 , SO 3 R 19 , or OSO 3 R 19 ; 
 where each R 19  and R 11 is independently: 
 a) hydrogen or 
 b) C 1-20  alkyl, C 2-20  alkenyl, C 2-20  alkynyl, —O—C 1-20  alkyl, —O—C 2-20  alkenyl or —O—C 2-20  alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO 2  CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 , or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; or 
 c) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; 
 d) a polyethylene glycol residue; 
 each R 19  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with halo, C 1-6  alkyl or C 1-6  haloalkyl; 
 each R 13  is independently 
 a) C 1-20  alkyl, C 2-20  alkenyl or C 2-20  alkynyl optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 , a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; or 
 b) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C 1-6  alkyl, C 1-6  haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19  or N(R 19 ) 2 ; 
 each R 19  is independently selected from H, C 1-6  alkyl or C 1-6  haloalkyl; 
 R 5a  is H or OH; 
 the process comprising: 
 i) reduction of the compound of general formula (I) 
 
       
         
           
           
               
               
           
         
         wherein R 2  is H, halo or OH or a protected OH, which is stable under basic conditions; and R 5b  is H or OH or a protected OH; 
         using a suitable reducing agent and, where R 2  and/or R 5b  is a protected OH, removal of the protecting group(s), to give a compound of general formula (XXI) as defined above, wherein removal of the protecting group can take place before or after the reduction; and optionally 
         ii) conversion of a compound of general formula (XXI) to another compound of general formula (XXI). 
       
     
     
         12 . A process according to  claim 11  wherein the reducing agent is a hydride, such as sodium borohydride. 
     
     
         13 . A process according to  claim 11  for the preparation of a compound of formula (XXI) in which R 1  is ethyl, R 2  and R 5a  are both H, Y 1  is —CH 2 CH 2 —, and R 4  is C(O)OH.