Oligomeric compounds comprising bicyclic nucleosides and having reduced toxicity

Abstract

In certain embodiments, the present invention provides oligomeric compounds having favorable toxicity profiles and therapeutic indexes. Compounds of the present invention comprise bicyclic nucleosides. Certain such bicyclic nucleosides are pyrimidines that do not include a methyl group at the 5-carbon. Oligomeric compounds comprising such nucleosides are less toxic than compounds comprising bicyclic nucleosides that do include a methyl group at the 5-carbon. In certain embodiments, the present invention provides methods of preparing and using such compounds.

1 .- 257 . (canceled) 
     
     
         257 . An oligonucleotide consisting of 8-26 linked nucleosides wherein at least one nucleoside is a bicyclic nucleoside comprising a bicyclic sugar moiety and a nucleobase, wherein the nucleobase is selected from among Formula I and Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         258 . The oligonucleotide of  claim 257 , wherein the at least one bicyclic nucleoside is a 4′-2′ bridged bicyclic nucleoside. 
     
     
         259 . The oligonucleotide of  claim 258 , wherein the at least one bicyclic nucleoside has a bicyclic sugar moiety having Formula III: 
       
         
           
           
               
               
           
         
       
       wherein independently for each of the at least one bicyclic nucleoside of formula III:
 X is selected from among: 4′-(CR 1 R 2 ) n —Y-2′; 
 wherein each R 1  and each R 2  is independently selected from among: hydrogen, a halogen, an optionally substituted C 1 -C 6  alkyl, an optionally substituted C 2 -C 6  alkenyl, an optionally substituted C 2 -C 6  alkynyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkenyl, and an optionally substituted heteroalkynyl; 
 Y is selected from among CR 1 R 2 , O, N(J), and S; 
 T 1  and T 2  are each, independently, an internucleoside linking group linking the bicyclic nucleoside to the oligonucleotide or one of T 1  and T 2  is an internucleoside linking group linking the bicyclic nucleoside to the oligonucleotide and the other of T 1  and T 2  is hydroxyl, a protected hydroxyl, a linked conjugate group or a 5′ or 3′-terminal group; 
 n is from 1 to 3; 
 J is hydrogen, a halogen, an optionally substituted C 1 -C 5  alkyl, an optionally substituted C 1 -C 5  alkenyl, an optionally substituted C 1 -C 5  alkynyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkenyl, or an optionally substituted heteroalkynyl; and 
 Bx is the heterocyclic base moiety of Formula I or Formula II. 
 
     
     
         260 . The oligonucleotide of  claim 259 , wherein X is selected from among: 4′-CH 2 O-2′, 4′-CH(CH 3 )O-2′, and 4′-CH 2 CH 2 O-2′. 
     
     
         261 . The oligonucleotide of  claim 260 , wherein X is 4′-CH 2 O-2′ or 4′-CH 2 CH 2 O-2′. 
     
     
         262 . The oligonucleotide of  claim 261 , wherein X is 4′-CH 2 O-2′. 
     
     
         263 . The oligonucleotide of  claim 259 , wherein the bicyclic nucleoside has the configuration: 
       
         
           
           
               
               
           
         
       
     
     
         264 . The oligonucleotide of  claim 259 , wherein the bicyclic nucleoside has the configuration: 
       
         
           
           
               
               
           
         
       
     
     
         265 . The oligonucleotide of  claim 257 , wherein the oligonucleotide does not comprise any 5-methyl pyrimidine bicyclic nucleosides. 
     
     
         266 . The oligonucleotide of  claim 257 , wherein each nucleoside is a bicyclic nucleoside. 
     
     
         267 . The oligonucleotide of  claim 266 , wherein each nucleoside comprises the same bicyclic sugar moiety. 
     
     
         268 . The oligonucleotide of  claim 266 , wherein at least two nucleosides comprise bicyclic sugar moieties that are different from one another. 
     
     
         269 . The oligonucleotide of  claim 257 , comprising at least one non-bicyclic nucleoside. 
     
     
         270 . The oligonucleotide of  claim 269 , comprising at least one modified non-bicyclic nucleoside. 
     
     
         271 . The oligonucleotide of  claim 270 , comprising at least one modified non-bicyclic nucleoside selected from among: 2′-O—(CH 2 ) 2 —OCH 3 , 2′-OCH 3 , and 2′-F. 
     
     
         272 . The oligonucleotide of any of  claim 257 , comprising at least one unmodified nucleoside. 
     
     
         273 . The oligonucleotide of  claim 257 , comprising at least one unmodified ribonucleoside. 
     
     
         274 . The oligonucleotide of  claim 257 , comprising at least one unmodified deoxyribonucleoside. 
     
     
         275 . The oligonucleotide of  claim 257 , consisting of 16-18 linked nucleosides. 
     
     
         276 . The oligonucleotide of  claim 257 , consisting of 18-20 linked nucleosides.