17-Side chain alkynyl-and 20-oxopregna-derivatives of vitamin D, methods for their production and pharmaceutical compositions thereof

Abstract

1-Hydroxy pregnacalciferol derivatives of formula (I) and their corresponding 5,6-trans isomers wherein R 1 is hydroxyl or lower alkoxy and R 2 is optionally hydroxylated or lower alkoxylated lower alkynyl and R 1 is C(R A ) (R B )CH 3 where R A is optionally hydroxylated or lower alkoxylated lower alkynyl and R B is hydroxyl or lower alkoxy or R A and R B together represent oxo and R 2 is hydrogen, hydroxyl or lower alkoxy, and R 3 and R 4 represent hydrogen atoms, exhibit anti-progesterone activity and may be useful as antineoplastic, antifertility, antiproliferative, immunosuppressive and/or antiinflammatory agents.

1 . Compounds of general formula (I)  
       
         
           
           
               
               
           
         
       
       and the corresponding 5,6-trans isomers thereof, wherein: 
 R 1  denotes a hydroxyl, protected hydroxyl or C 1-6  alkoxy group and R 2  denotes a C 1-6  alkynyl group optionally substituted by a hydroxyl, protected hydroxyl or C 1-6  alkoxy group;  
 or R 1  denotes a group —C(R A ) (R B )CH 3  where R A  is a C 1-6  alkynyl group optionally substituted by a hydroxyl, protected hydroxyl or C 1-6  alkoxy group and R B  is a hydroxyl, protected hydroxyl or C 1-6  alkoxy group, or R A  and R B  together represent an oxo group, and R 2  denotes a hydrogen atom or a hydroxyl, protected hydroxyl or C 1-6  alkoxy group;  
 and R 3  and R 4  are each selected from hydrogen atoms and O-protecting groups;  
 with the proviso that when R 1  denotes a group —C(R A ) (R B ) CH 3  in which R A  and R B  together represent an oxo group and the group —OR 4  is in the a-configuration then R 2  is other than hydrogen.  
 
     
     
         2 . Compounds as claimed in  claim 1  wherein: 
 R 1  denotes a hydroxyl, tri(C 1-6  alkyl)silyloxy or methoxy group and R 2  denotes a C 1-6  alkynyl group optionally substituted by a hydroxyl, tri(C 1-6  alkyl)silyloxy or methoxy group;  
 or R 1  denotes a group —C(R A ) (R 8 )CH 3  where R A  is a C 1-6  alkynyl group optionally substituted by a hydroxyl, tri(C 1-6  alkyl)silyloxy or methoxy group and R B  is a hydroxyl, tri(C 1-6  alkyl)silyloxy or methoxy group, or R A  and R B  together represent an oxo group, and R 2  denotes a hydrogen atom or a hydroxyl, tri(C 1-6  alkyl)silyloxy or methoxy group.  
 
     
     
         3 . Compounds as claimed in  claim 1  or  claim 2  wherein R 2  or R A  represents a C 1-6  alk-1-yn-1-yl group and the group —OR 4  is in the α-configuration.  
     
     
         4 . The compounds: 
 1α,3β,17α-trihydroxy-20-oxo-9,10-secopregna-5(E),7,10(19)-triene;    1α,3β,17α-trihydroxy-20-oxo-9,10-secopregna-5(Z),7,10(19)-triene;    1α,3β,17β-trihydroxy-17α-ethynyl-9,10-secoandrosta-5(Z),7,10(19)-triene;    1α,3β-dihydroxy-17α-ethynyl-17β-methoxy-9,10-secoandrosta-5(Z),7,10(19)-triene;    20-ethynyl-1α,3β,20-trihydroxy-9,10-secopregna-5(Z),7,10(19)-triene;    1α,3β-dihydroxy-20-ethynyl-20-methoxy-9,10-secopregna-5(Z),7,10(19)-triene; and    1α,3β,20-trihydroxy-20-propynyl-9,10-secopregna-5(Z),7,10(19)-triene.    
     
     
         5 . The compounds: 
 1α,3β,17β-trihydroxy-17β-(3-hydroxypropyn-1-yl)-9,10-secoandrosta-5(Z),7,10(19)-triene;    1α,3β,20-trihydroxy-20-(3-hydroxypropyn-l-yl)-9,10-secopregna-5(Z),7,10(19)-triene;    1α,3β,20-trihydroxy-20-propargyl-9,10-secopregna-5(Z),7,10(19)-triene;    1α,3β,20-trihydroxy-20-propynyl-9,10-secopregna-5 (Z),7,10(19)-triene; and    20-ethynyl-1β,3β,20-trihydroxy-9,10-secopregna-5(Z),7,10(19)-triene.    
     
     
         6 . Active compounds of general formula (I) and 5,6-trans isomers thereof as defined in any of the preceding claims, including active compounds of general formula (I) not subject to the proviso in  claim 1 , for use as antineoplastic, antifertility, antiproliferative, immunosuppressive and/or antiinflammatory agents.  
     
     
         7 . The use of an active compound of general formula (I) or a 5,6-trans isomer thereof as defined in any of  claims 1  to  5 , including an active compound of general formula (I) not subject to the proviso in  claim 1 , in the manufacture of a medicament for use as an antineoplastic, antifertility, antiproliferative, immunosuppressive and/or antiinflammatory agent.  
     
     
         8 . Pharmaceutical compositions comprising an active compound of general formula (I) or a 5,6-trans isomer thereof as defined in any of  claims 1  to  5 , including an active compound of general formula (I) not subject to the proviso in  claim 1 , in admixture with one or more physiologically acceptable carriers and/or excipients.  
     
     
         9 . A method of treatment of a human or animal subject to promote a therapeutic or prophylactic antineoplastic, antifertility, antiproliferative, immunosuppressive and/or antiinflammatory effect, which comprises administering to said subject an effective amount of an active compound of general formula (I) or a 5,6-trans isomer thereof as defined in any of  claims 1  to  5 , including an active compound of general formula (I) not subject to the proviso in  claim 1 .  
     
     
         10 . A process for the preparation of a compound of general formula (I) as defined in  claim 1  which comprises one or more of the steps: 
 A) isomerising a corresponding 5,6-trans isomer;  
 B) oxidising a compound of general formula (I) or a 5,6-trans isomer thereof or a corresponding 1-desoxy compound in which R 1  denotes a group —C(R A ) (R B )CH 3  where R A  and R B  together represent an oxo group and R 2  denotes a hydrogen atom to yield a compound in which R 2  denotes a hydroxyl group, followed where necessary by hydroxylation at the 1-position;  
 C) reacting a compound of general formula (I) or a 5,6-trans isomer thereof in which R 1  and R 2  together or R A  and R B  together denote an oxo group with a C 1-6  alkynyl anion to yield a compound in which R 1  or R A  is C 1-6  alkynyl and R 2  or R B  is a hydroxyl group; and  
 D) reacting a compound of general formula (I) or a 5,6-trans isomer thereof in which R 1 , R 2  or R B  denotes a hydroxyl group with an alkylating agent to yield a compound in which R 1 , R 2  or R B  denotes a C 1-6  alkyl group; followed if necessary and/or desired by removal of any protecting groups.  
 
     
     
         11 . A process as claimed in  claim 10  wherein in step (B) a compound of general formula (I) or a 5,6-trans isomer thereof or a corresponding 1-desoxy compound in which R 1  denotes a group —C(R A ) (R B )CH 3  where R A  and R B together represent an oxo group and R 2  denotes a hydrogen atom is air-oxidised in the presence of a strong base and a phosphine or phosphite to yield a compound in which R 2  denotes a hydroxyl group.  
     
     
         12 . A process as claimed in  claim 10  wherein step (C) employs a starting material of general formula (I) or a 5,6-trans isomer thereof in which R 1  and R 2  together represent an oxo group, which starting material is prepared by air-oxidising a corresponding 20-oxocholecalciferol or O-protested derivative thereof or a 1-desoxy analogue thereof in the presence of strong base, followed where necessary by hydroxylation at the 1-position.  
     
     
         13 . A process for the preparation of compounds of general formula (I) and 5,6-trans isomers thereof in which R 1  and R 2  together represent an oxo group and R 3  and R 4  are each selected from hydrogen atoms and O-protecting groups which comprises air-oxidising a corresponding 20-oxocholecalciferol or O-protested derivative thereof or a 1-desoxy analogue thereof in the presence of strong base, followed where necessary by hydroxylation at the 1-position.