Steroids having increased water solubility and resistance against metabolism and methods for their production

Abstract

Steroid compounds having increased resistance against metabolism and increased water solubility are disclosed, together with methods for their production. These substances are suitable for the manufacture of pharmaceuticals for the treatment of steroid related or steroid induced CNS disorders and for use in methods of prevention, alleviation or treatment of such disorders.

1 . A compound as represented by formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
 R 1  is an ethynyl, ethenyl, ethyl, or other saturated or unsaturated alkyl group; hydroxyl, in its free form or combined with carboxylic acid residues, sugars, heterocycles, saturated or unsaturated alkyl groups to form esters or ether or glycosylated compounds; fluorine or other halogens; a proton; 
 R 2  is an ethynyl, ethenyl, ethyl, or other saturated or unsaturated alkyl group; hydroxyl, in its free form or combined with carboxylic acid residues, sugars, alkyl groups to form esters or ether or glycosylated compounds; fluorine or other halogens; a proton; 
 R 3  is 5α- or 5β-H; 
 R 4  is a nitro, hydroxyl, free or bonded with an ester, ether, sugar and R 5  a proton, or 
 
         wherein R 4 , R 5  is O or N as oxime ═NOH, or a homo- or heterocycle;
 R 6  is a methyl, an alkyl group or —CH 2 OR where R is H, a carboxylic acid residue, an alkyl group or a sugar; —CH 2 X where X is fluorine or another halogen; 
 R 7 =an OH, CH 3  or H at the seven position; and 
 R 8 , R 9 =two Me- groups, or Me- and H, respectively, or two —H. 
 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R 7 =an OH or CH 3  at the seven position. 
     
     
         3 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is an ethynyl group; hydroxyl, in its free form or combined with carboxylic acid residues; fluorine; or a proton;   R 2  is an ethynyl group; hydroxyl, in its free form or combined with carboxylic acid residues; fluorine; or a proton;   R 3  is 5α- or 5β-H   R 4  is hydroxyl and R 5  a proton, or   
       R 4 , R 5  together is O or N as oxime ═NOH;
 R 6  is a methyl group; 
 R 7  is H; and 
 R 8 =R 9 =methyl or H. 
 
     
     
         4 . A compound according to  claim 3 , chosen among
 3α-ethynyl, 3β-hydroxyl, 5β-pregnan-20-one,   3α-ethynyl, 5β-pregnan-3β,20(R)-diol,   3β-ethenyl, 5α-pregnan-3α, 20(R)-diol,   3β-fluor, 5β-pregnan-20-one,   3β-fluor, 5β-pregnan-20-(R)-ol,   3β-fluor, 5β-pregnan-20-(S)-ol,   3β-fluor, 5α-pregnan-20-one,   3α-fluor, 5α-pregnan-20-(R)-ol,   3α-ethynyl, 5α-pregnan-3β,20(R)-diol,   3β-ethynyl, 3α-acetyl, 5α-pregnan-20-one,   3β-ethynyl, 3α-hydroxyl, 5α-pregnan-20-one oxime,   3α-fluor, 5α-pregnan-20-one oxime, and   3β-fluor, 5α-pregnan-20-one oxime.   
     
     
         5 . A compound as represented by formula I 
       
         
           
           
               
               
           
         
         having an unsaturation between C4-C5 or C5-C6 or in another position in the molecule, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
 R 1  is an ethynyl, ethenyl, ethyl, or other saturated or unsaturated alkyl group; hydroxyl, in its free form or combined with carboxylic acid residues, sugars, alkyl groups to form esters or ether or glycosylated compounds; fluorine or other halogens; a proton; 
 R 2  is an ethynyl, ethenyl, ethyl, or other saturated or unsaturated alkyl group; hydroxyl, in its free form or combined with carboxylic acid residues, sugars, alkyl groups to form esters or ether or glycosylated compounds; fluorine or other halogens; a proton; 
 R 3  is absent or 5α- or 5β-H when the unsaturation is situated in other positions of the molecule; 
 R 4  is a nitro, hydroxyl, free or bonded with an ester, ether, sugar and R 5  a proton; or 
 
         wherein R 4 , R 5  is O or N as oxime ═NOH, or a homo- or heterocycle;
 R 6  is a methyl, an alkyl group or —CH 2 OR where R is H, a carboxylic acid residue, an alkyl group or a sugar; —CH 2 X where X is fluorine or another halogen; 
 R 7 , =an OH, CH 3  or H at the seven position; and 
 R 8 , R 9  are two Me- groups, or Me- and H, respectively, or two —H, or if said unsaturation is between C4-C5, then one of R 8 , R 9  is Me- or H and the other one absent. 
 
       
     
     
         6 . A compound according to  claim 5 , or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R 7 =an OH or CH 3  at the seven position; and R 8 , R 9  are two Me- groups, or Me- and H, respectively, or two —H. 
     
     
         7 . A compound according to  claim 5 , having an unsaturation between C4-C5 or C5-C6, or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is an ethynyl group or hydroxyl;   R 2  is an ethynyl group or hydroxyl;   R 3  is absent;   R 4  is hydroxyl; R 5  a proton; or   R 4  and R 5  is together ═O or N as oxime ═NOH;   R 6  is a methyl group;   R 7  is H;   R 8  is methyl or H; and   R 9  is methyl, H, or, if said unsaturation is between C4-C5, absent.   
     
     
         8 . A compound according to  claim 7 , chosen among
 3β-ethynyl, 3α-hydroxyl, Δ4-pregnen-20-one,   3β-ethynyl, 3α-hydroxyl, Δ4-pregnen-20-one oxime, and   3-dimethyl, Δ5-pregnen-3β,20(R)-diol.   
     
     
         9 . A compound of formula II, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
 R 1  is an ethynyl, ethenyl, ethyl, or other saturated or unsaturated alkyl group; hydroxyl, in its free form or combined with carboxylic acid residues, sugars, alkyl groups to form esters or ether or glycosylated compounds; fluorine or other halogens; a proton; 
 R 2  is an ethynyl, ethenyl, ethyl, or other saturated or unsaturated alkyl group; hydroxyl, in its free form or combined with carboxylic acid residues, sugars, alkyl groups to form esters or ether or glycosylated compounds; fluorine or other halogens; a proton; 
 R 3  is 5α- or 5β-H; 
 R 4  is a nitro, hydroxyl, free or bonded with an ester, ether, sugar and R 5  a proton; or wherein R 4 , R 5  is O or N as oxime ═NOH, or a homo- or heterocycle; 
 R 6  is OH, CH 2  or H at the seven position; and 
 R 7 , R 8  are two Me- groups, or Me- and H, respectively, or two —H. 
 
       
     
     
         10 . A compound according to  claim 9 , or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R 6 =an OH or CH 3  at the seven position. 
     
     
         11 . A compound according to  claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is an ethynyl group or hydroxyl;   R 2  is an ethynyl group or hydroxyl;   R 3  is 5α- or 5β-H;   R 4  and R 5  together is O or N as oxime ═NOH;   R 6  is H; and   R 7 =R 8 =H.   
     
     
         12 . A compound according to  claim 11 , chosen among
 3β-ethynyl, 3α-hydroxyl, androstan-17-one,   3β-ethynyl, 3α-hydroxyl, androstan-17-one oxime, and   3α-ethynyl, 3β-hydroxyl, androstan-17-one oxime   
     
     
         13 . A compound of formula II, 
       
         
           
           
               
               
           
         
         with an unsaturation present between C4-C5 or C5-C6 or other positions in the molecule, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
 R 1  is an ethynyl, ethenyl, ethyl, or other saturated or unsaturated alkyl group; hydroxyl, in its free form or combined with carboxylic acid residues, sugars, alkyl groups to form esters or ether or glycosylated compounds; fluorine or other halogens; a proton; 
 R 2  is an ethynyl, ethenyl, ethyl, or other saturated or unsaturated alkyl group; hydroxyl, in its free form or combined with carboxylic acid residues, sugars, alkyl groups to form esters or ether or glycosylated compounds; fluorine or other halogens; a proton; 
 R 3  is absent or represents a 5α- or 5β-H when the unsaturation is situated in other positions of the molecule; 
 R 4  is a nitro, hydroxyl, free or bonded with an ester, ether, sugar and R 5  a proton; or wherein R 4 , R 5  are O or N as oxime ═NOH, or a homo- or heterocycle; 
 R 6  is an OH or CH 3  at the seven position; and 
 R 7 , R 8  are two Me- groups, or Me- and H, respectively, or two —H, or if said unsaturation is between C4-C5, then one of R 7 , R 8  is Me- or H and the other one absent. 
 
       
     
     
         14 . A compound according to  claim 13 , or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R 7 , R 8  are two Me- groups, or Me- and H, respectively, or two —H. 
     
     
         15 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 5  and a pharmaceutically acceptable carrier. 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 9  and a pharmaceutically acceptable carrier. 
     
     
         18 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 13  and a pharmaceutically acceptable carrier. 
     
     
         19 . A method for the alleviation, prevention or treatment of a CNS disorder, wherein a compound according to  claim 1  is administered to the patient. 
     
     
         20 . A method for the alleviation, prevention or treatment of a CNS disorder, wherein a compound according to  claim 5  is administered to the patient. 
     
     
         21 . A method for the alleviation, prevention or treatment of a CNS disorder, wherein a compound according to  claim 9  is administered to the patient. 
     
     
         22 . A method for the alleviation, prevention or treatment of a CNS disorder, wherein a compound according to  claim 13  is administered to the patient. 
     
     
         23 . A method of producing a 3-etynyl substituted steroid bearing a ketone moiety in position 20 or 17, without destruction of the 17- or 20-keto functionality is performed. 
     
     
         24 . A method of producing a substituted steroid bearing a oxime moiety in position 20, 21 or 17, without destruction of the 17, 21- or 20-keto functionality is performed. 
     
     
         25 . A method of producing a 3-fluoro substituted steroid bearing a ketone moiety in position 20 or 17, without destruction of the 17- or 20-keto functionality is performed.