5' and 2' bis-substituted nucleosides and oligomeric compounds prepared therefrom

Abstract

The present invention provides modified nucleosides and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides having at least one 5′-substituent and a 2′-O-substituent, oligomeric compounds comprising at least one of these modified nucleosides and methods of using the oligomeric compounds. In some embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

What is claimed is: 
     
         1 - 205 . (canceled) 
     
     
         206 . A compound having Formula III: 
       
         
           
           
               
               
           
         
         wherein:
 Bx is a heterocyclic base moiety; 
 T 5  is a phosphorus moiety having 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; 
 T 6  is a diisopropylcyanoethoxy phosphoramidite or H-phosphonate group; 
 Q 1 , Q 2 , Q 3  and Q 4  are each, independently, H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; 
 G 1  is O—[C(R 2 )(R 3 )] n -[(C═O) m —X] j —Z or halogen; 
 each R 2  and R 3  is, independently, H or halogen; 
 X is O, S or N(E 1 ); 
 Z is H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 2 -C 6  alkynyl or N(E 2 )(E 3 ); 
 E 1 , E 2  and E 3  are each, independently, H, C 1 -C 6  alkyl or substituted C 1 -C 6  alkyl; 
 n is from 1 to about 6; 
 m is 0 or 1; 
 j is 0 or 1; 
 each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , N(J 1 )(J 2 ), =NJ 1 , SJ 1 , N 3 , CN, OC(=L)J 1 , OC(=L)N(J 1 )(J 2 ) and C(=L)N(J 1 )(J 2 ); 
 L is O, S or NJ 3 ; 
 each J 1 , J 2  and J 3  is, independently, H or C 1 -C 6  alkyl; and 
 when j is 1 then Z is other than halogen or N(E 2 )(E 3 ). 
 
       
     
     
         207 . The compound of  claim 206  wherein Bx is an optionally protected uracilyl, thyminyl, cytosinyl, 5-methylcytosinyl, adeninyl or guaninyl. 
     
     
         208 . The compound of  claim 206  wherein G 1  is OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH—CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 4 )(R 5 ), O(CH 2 ) 2 —ON(R 4 )(R 5 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 4 )(R 5 ), OCH 2 C(═O)—N(R 4 )(R 5 ), OCH 2 C(═O)—N(R 6 )—(CH 2 ) 2 —N(R 4 )(R 5 ) or O(CH 2 ) 2 —N(R 6 )—C(═NR 7 )[N(R 4 )(R 5 )] wherein R 4 , R 5 , R 6  and R 7  are each, independently, H or C 1 -C 6  alkyl. 
     
     
         209 . The compound of  claim 206  wherein G 1  is OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH—CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2  or OCH 2 —N(H)—C(═NH)NH 2 . 
     
     
         210 . The compound of  claim 206  wherein G 1  is OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3  or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 . 
     
     
         211 . The compound of  claim 206  wherein G 1  is F. 
     
     
         212 . The compound of  claim 206  wherein R a  and R c  are each OCH 3  and R b  is O. 
     
     
         213 . The compound of  claim 206  wherein R a  and R c  are each OCH 2 CH 3  and R b  is O. 
     
     
         214 . The compound of  claim 206  wherein R b  is O. 
     
     
         215 . The compound of  claim 206  wherein R b  is S. 
     
     
         216 . The compound of  claim 206  wherein T 6  is diisopropylcyanoethoxy phosphoramidite. 
     
     
         217 . The compound of  claim 206  wherein T 6  is H-phosphonate. 
     
     
         218 . The compound of  claim 206  wherein one of Q 1 , Q 2 , Q 3  and Q 4  is substituted C 1 -C 6  alkyl. 
     
     
         219 . The compound of  claim 206  wherein one of Q 1 , Q 2 , Q 3  and Q 4  is C 1 -C 6  alkyl. 
     
     
         220 . The compound of  claim 206  wherein one of Q 1  and Q 2  is C 1 -C 6  alkyl and the other three of Q 1 , Q 2 , Q 3  and Q 4  are H. 
     
     
         221 . The compound of  claim 220  wherein said C 1 -C 6  alkyl is methyl. 
     
     
         222 . The compound of  claim 206  wherein at least one of Q 1 , Q 2 , Q 3  and Q 4  is F. 
     
     
         223 . The compound of  claim 222  wherein one of Q 3  and Q 4  is F. 
     
     
         224 . The compound of  claim 222  wherein Q 3  and Q 4  are each F. 
     
     
         225 . The compound of  claim 224  wherein Q 1  and Q 2  are each H. 
     
     
         226 . The compound of  claim 206  having the configuration: