Amino-lna, thio-lna and alpha-l-oxy-ln

Abstract

A novel class of pharmaceuticals which comprises a Locked Nucleic Acid (LNA) which can be used in antisense therapy. These novel oligonucleotides have improved antisense properties. The novel oligonucleotides are composed of at least one LNA selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides.

1 - 43 . (canceled) 
     
     
         43 . A LNA nucleoside having the formula: 
       
         
           
           
               
               
           
         
       
       wherein X is O; R′ and R″ are independently either H or a terminal group; and (CH 2 )n is a methylene substituted with methyl, or a pharmaceutically acceptable salt thereof. 
     
     
         44 . A gapmer oligomer having 10-15 nucleotide units, comprising central region of at least 4, 5, 6, 7 or 8 DNA nucleotides which is flanked both 5′ and 3′ by locked nucleotides having the formula: 
       
         
           
           
               
               
           
         
       
       wherein X is O; (CH 2 )n is a methylene substituted with a C 1-6  alkyl. 
     
     
         45 . The gapmer oligomer of  claim 44  wherein at least one of the locked nucleotides has the formula: 
       
         
           
           
               
               
           
         
       
       wherein X is O; (CH 2 )n is a methylene substituted with a methyl group. 
     
     
         46 . The gapmer oligomer of  claim 45  wherein all of the locked nucleotides have the formula: 
       
         
           
           
               
               
           
         
       
       wherein X is O; (CH 2 )n is a methylene substituted with a methyl group. 
     
     
         47 . The gapmer oligomer of  claim 44 , wherein the at least one or all the internucleoside linkages are phosphorothioate. 
     
     
         48 . The gapmer oligomer of  claim 45 , wherein the at least one or all the internucleoside linkages are phosphorothioate. 
     
     
         49 . The gapmer oligomer of  claim 46 , wherein the at least one or all the internucleoside linkages are phosphorothioate. 
     
     
         50 . The gapmer oligomer of  claim 47 , wherein the central region is 8-10 nucleotides 
     
     
         51 . The gapmer oligomer of  claim 48 , wherein the central region is 8-10 nucleotides 
     
     
         52 . The gapmer oligomer of  claim 49 , wherein the central region is 8-10 nucleotides 
     
     
         53 . The gapmer oligomer of  claim 50 , wherein the flanks have 1-4 of the locked nucleotides. 
     
     
         54 . The gapmer oligomer of  claim 51 , wherein the flanks have 1-4 of the locked nucleotides. 
     
     
         55 . The gapmer oligomer of  claim 52 , wherein the flanks have 1-4 of the locked nucleotides. 
     
     
         56 . The gapmer oligomer of  claim 50 , wherein the flanks have 2-3 of the locked nucleotides. 
     
     
         57 . The gapmer oligomer of  claim 51 , wherein the flanks have 2-3 of the locked nucleotides. 
     
     
         58 . The gapmer oligomer of  claim 52 , wherein the flanks have 2-3 of the locked nucleotides. 
     
     
         59 . The gapmer oligomer according to  claim 56 , wherein the oligomer has 12-14 nucleotide units. 
     
     
         60 . The gapmer oligomer according to  claim 57 , wherein the oligomer has 12-14 nucleotide units. 
     
     
         61 . The gapmer oligomer according to  claim 58 , wherein the oligomer has 12-14 nucleotide units. 
     
     
         62 . A gapmer oligomer having 12-14 nucleotide units having a central region of at least 8 DNA nucleotides which is flanked both 5′ and 3′ by 1-3 locked nucleotides having the formula: 
       
         
           
           
               
               
           
         
       
       wherein X is O; (CH 2 )n is a methylene substituted with methyl group; wherein all the internucleoside linkages are phosphorothioate linkages. 
     
     
         63 . The gapmer oligomer according to  claim 62 , wherein the central region is of 8 DNA nucleotides. 
     
     
         64 . The gapmer oligomer according to  claim 62 , wherein the central region is of 9 DNA nucleotides. 
     
     
         65 . The gapmer oligomer according to  claim 62 , wherein the central region is of 10 DNA nucleotides. 
     
     
         66 . The gapmer oligomer according to  claim 62 , wherein the 5′ and 3′ flank consists of 1, 2 or 3 of the locked nucleotides. 
     
     
         67 . The gapmer oligomer according to  claim 66 , wherein the 5′ and 3′ flanks each consist of 2 of the locked nucleotides. 
     
     
         68 . The gapmer according to  claim 62 , wherein all of the nucleotides other than the central region of at least 8 DNA nucleotides are locked nucleotides having the formula: 
       
         
           
           
               
               
           
         
       
       wherein X is O; (CH 2 )n is a methylene substituted with a C 1-6  alkyl. 
     
     
         69 . The gapmer according to  claim 62  wherein all of the nucleotides other than the central region of at least 8 DNA nucleotides are locked nucleotides having the formula: 
       
         
           
           
               
               
           
         
       
       wherein X is O; (CH 2 )n is a methylene substituted with methyl group.