Bicyclic cyclohexose nucleic acid analogs

Abstract

The present invention provides bicyclic cyclohexose nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.

What is claimed is: 
     
         1 . A bicyclic nucleoside analog of Formula I e : 
       
         
           
           
               
               
           
         
       
       wherein:
 Bx is a heterocyclic base moiety; 
 Q is a bridge group comprising one C(R 3 )═C(R 4 ), N(R 5 )—O or N(R 5 )—S biradical group and one C(R 3 )(R 4 ) biradical group or one O, S or N(R 5 ) biradical group and two C(R 3 )(R 4 ) biradical groups; 
 each R 3  and R 4  is, independently, H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy or halogen; 
 R 5  is H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy or substituted C 1 -C 6  alkoxy; 
 L 1  and L 2  are each H or one of L 1  and L 2  is H and the other of L 1  and L 2  is CH 3  or OCH 3 ; 
 one of E 1 , E 2 , E 3  and E 4  is O-T 2 , two of E 1 , E 2 , E 3  and E 4  are H and the remaining one of E 1 , E 2 , E 3  and E 4  is H, halogen, C 1 -C 6  alkyl or substituted C 1 -C 6  alkyl; 
 one of T 1  and T 2  is H, a hydroxyl protecting group or a phosphorus moiety and the other of T 1  and T 2  is H, a hydroxyl protecting group or a reactive phosphorus group. 
 each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 5 , N(J 5 )(J 6 ), =NJ 5 , SJ 5 , N 3 , CN, OC(=L)J 5 , OC(=L)N(J 5 )(J 6 ) and C(=L)N(J 5 )(J 6 ); 
 L is O, S or NJ 7 ; and 
 each J 5 , J 6  and J 7  is, independently, H, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 5 -C 20  aryl or C 1 -C 12  aminoalkyl. 
 
     
     
         2 . The bicyclic nucleoside analog of  claim 1  wherein Bx is an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 
     
     
         3 . The bicyclic nucleoside analog of  claim 1  wherein three of E 1 , E 2 , E 3  and E 4  are H. 
     
     
         4 . The bicyclic nucleoside analog of  claim 1  wherein L 1  and L 2  are each H. 
     
     
         5 . The bicyclic nucleoside analog of  claim 1  wherein one of L 1  and L 2  is H and the other of L 1  and L 2  is CH 3 . 
     
     
         6 . The bicyclic nucleoside analog of  claim 1  wherein T 1  is 4,4′-dimethoxytrityl and T 2  is diisopropylcyanoethoxy phosphoramidite. 
     
     
         7 . The bicyclic nucleoside analog of  claim 1  wherein Q comprises two C(R 3 )(R 4 ) biradical groups. 
     
     
         8 . The bicyclic nucleoside analog of  claim 7  wherein each R 3  and R 4  is H. 
     
     
         9 . The bicyclic nucleoside analog of  claim 1  wherein Q comprises one O biradical group; 
     
     
         10 . The bicyclic nucleoside analog of  claim 1  wherein said phosphorus moiety has the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  and R c  are each, independently, OH, SH, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, amino or substituted amino; and 
 R b  is O or S. 
 
     
     
         11 . The bicyclic nucleoside analog of  claim 1  having the configuration of one of formulas I f , I g , I h  and I i : 
       
         
           
           
               
               
           
         
       
     
     
         12 . An oligomeric compound consisting of from 8 to 40 monomers comprising at least one bicyclic nucleoside analog of Formula II e : 
       
         
           
           
               
               
           
         
       
       wherein independently for each bicyclic nucleoside analog having Formula II e :
 Bx is a heterocyclic base moiety; 
 Q is a bridge group comprising one C(R 3 )═C(R 4 ), N(R 5 )—O or N(R 5 )—S biradical group and one C(R 3 )(R 4 ) biradical group or one O, S or N(R 5 ) biradical group and two C(R 3 )(R 4 ) biradical groups; 
 each R 3  and R 4  is, independently, H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy or halogen; 
 R 5  is H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy or substituted C 1 -C 6  alkoxy; 
 L 1  and L 2  are each H or one of L 1  and L 2  is H and the other of L 1  and L 2  is CH 3  or OCH 3 ; 
 one of E 5 , E 6 , E 7  and E 8  is O-T 4 , two of E 5 , E 6 , E 7  and E 8  are H and the remaining one of E 5 , E 6 , E 7  and E 8  is H, halogen, C 1 -C 6  alkyl or substituted C 1 -C 6  alkyl; 
 one of T 3  and T 4  is an internucleoside linking group linking the bicyclic nucleoside analog to the remainder of the oligomeric compound and the other of T 3  and T 4  is H, a protecting group, a phosphorus moiety, a 5′ or 3′-terminal group or an internucleoside linking group linking the bicyclic nucleoside analog to the remainder of the oligomeric compound; 
 each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 5 , N(J 5 )(J 6 ), =NJ 5 , SJ 5 , N 3 , CN, OC(=L)J 5 , OC(=L)N(J 5 )(J 6 ) and C(=L)N(J 5 )(J 6 ); 
 L is O, S or NJ 7 ; and 
 each J 5 , J 6  and J 7  is, independently, H, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 5 -C 20  aryl or C 1 -C 12  aminoalkyl. 
 
     
     
         13 . The oligomeric compound of  claim 12  wherein independently for each bicyclic nucleoside analog of Formula II e , Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 
     
     
         14 . The oligomeric compound of  claim 12  wherein independently for each bicyclic nucleoside analog of Formula II e , three of E 5 , E 6 , E 7  and E 8  are H. 
     
     
         15 . The oligomeric compound of  claim 12  wherein independently for each bicyclic nucleoside analog of Formula II e , L 1  and L 2  are each H. 
     
     
         16 . The oligomeric compound of  claim 12  wherein independently for each bicyclic nucleoside analog of Formula II e , one of L 1  and L 2  is H and the other of L 1  and L 2  is CH 3 . 
     
     
         17 . The oligomeric compound of  claim 12  wherein each Q comprises two C(R 3 )(R 4 ) biradical groups. 
     
     
         18 . The oligomeric compound of  claim 17  wherein each R 3  and R 4  is H. 
     
     
         19 . The oligomeric compound of  claim 12  wherein each Q comprises one O biradical group; 
     
     
         20 . The oligomeric compound of  claim 12  wherein said phosphorus moiety has the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  and R c  are each, independently, OH, SH, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, amino or substituted amino; and 
 R b  is O or S. 
 
     
     
         21 . The oligomeric compound of  claim 12  wherein each bicyclic nucleoside of Formula II e  has the configuration of one of formulas II f , II g , II h  and II i : 
       
         
           
           
               
               
           
         
       
     
     
         22 . The oligomeric compound of  claim 21  comprising a gapped oligomeric compound having two external regions independently comprising from 2 to 5 contiguous bicyclic nucleoside analogs wherein each bicyclic nucleoside analog has Formula II f , II g , II h  or II i , wherein the two external regions are separated by an internal region comprising from about 8 to about 14 monomer subunits independently selected from nucleosides and modified nucleosides that are different from the bicyclic nucleoside analogs. 
     
     
         23 . The oligomeric compound of  claim 22  wherein said internal region comprises from about 8 to about 14 contiguous β-D-2′-deoxyribofuranosyl nucleosides. 
     
     
         24 . The oligomeric compound of  claim 12  wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate internucleoside linking group. 
     
     
         25 . The oligomeric compound of  claim 12  wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group. 
     
     
         26 . A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of  claim 21 .