Tricyclic nucleosides and oligomeric compounds prepared therefrom

Abstract

The present invention provides fluorine substituted tricyclic nucleosides of formula (I) wherein: the substituents are as defined in the claims. The present invention further provides oligomeric compounds prepared therefrom. Incorporation of one or more of the tricyclic nucleosides into an oligomeric compound enhances one or more properties of the oligomeric compound. Such oligomeric compounds can also be included in double stranded compositions.

1 . A tricyclic nucleoside described by general Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         Bx is a heterocyclic base moiety; 
         one of T 1  and T 2  is hydroxyl (—OH) or a protected hydroxyl and the other of T 1  and T 2  is a phosphate or a reactive phosphorus group; 
         each of q 1 , q 2 , q 3 , q 4 , q 5 , z 1 , and z 2  is, independently, selected from H, F, and Cl; and 
         at least one of q 1 , q 2 , q 3 , q 4 , q, z 1 , and z 2  is F. 
       
     
     
         2 . The tricyclic nucleoside of  claim 1 , wherein Bx is selected from the group consisting of uracil, thymine, cytosine, 5-methylcytosine, adenine, and guanine. 
     
     
         3 . The tricyclic nucleoside of  claim 1 , wherein T 1  is hydroxyl or protected hydroxyl, and wherein T 2  is a reactive phosphorus group selected from an H-phosphonate or a phosphoramidite. 
     
     
         4 . The tricyclic nucleoside of  claim 1 , wherein T 1  is 4,4′ dimethoxytrityl and T 2  is diisopropylcyanoethoxy phosphoramidite. 
     
     
         5 . The tricyclic nucleoside of  claim 1 , wherein one or two of q 3 , q 4 , q 5 , z 1 , and z 2  is F, and the others of q 3 , q 4 , q 5 , z 1 , and z 2  are H. 
     
     
         6 . The A tricyclic nucleoside of  claim 1 , wherein the nucleoside is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and wherein Bx is selected from the group consisting of uracil, thymine, cytosine, 5-methylcytosine, adenine, and guanine. 
     
     
         7 . An oligomeric compound comprising a tricyclic nucleoside described by general Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         Bx is a heterocyclic base moiety; 
         one of T 3  and T 4  is an internucleoside linking group and the other of T 3  and T 4  is hydroxyl, a protected hydroxyl, a 5′ or 3′ terminal group,. or an internucleoside linking group. 
         each of q 1 , q 2 , q 3 , q 4 , q 5 , z 1  and z 2  is, independently, selected from H, F, and Cl; at least one of q 1 , q 2 , q 3 , q 4 , q 5 , z 1 , and z 2  is F; and 
         wherein said oligomeric compound comprises from 8 to 40 monomeric subunits. 
       
     
     
         8 . The oligomeric compound of  claim 7 , wherein Bx is, independently, selected from the group consisting of uracil, thymine, cytosine, 5-methylcytosine, adenine, and guanine. 
     
     
         9 . The oligomeric compound of  claim 7 , wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group. 
     
     
         10 . The oligomeric compound of  claim 7 , wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group. 
     
     
         11 . The oligomeric compound of  claim 7 , comprising a first region having at least two contiguous tricyclic nucleosides described by general Formula II. 
     
     
         12 . The oligomeric compound of  claim 11 , further comprising a second region having at least two contiguous monomeric subunits, wherein each monomeric subunit in the second region is a modified nucleoside different from the tricyclic nucleosides of general Formula II of the first region. 
     
     
         13 . The oligomeric compound of  claim 12 , further comprising a third region located between the first region and the second region, wherein each monomer subunit in the third region is independently, a nucleoside or a modified nucleoside that is different from each tricyclic nucleoside of general Formula II of the first region and each monomer subunit of the second region. 
     
     
         14 . The oligomeric compound of  claim 7 , comprising a gapped oligomeric compound having an internal region of from 6 to 14 contiguous monomer subunits flanked on each side by an external region of from 1 to 5 contiguous monomer subunits, wherein each monomer subunit in each external region is a tricyclic nucleoside of general Formula II and each monomer subunit in the internal region is, independently, a nucleoside or modified nucleoside. 
     
     
         15 . The oligomeric compound of  claim 7 , wherein the tricyclic nucleoside is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A method for solid-phase synthesis of an oligonucleotide, comprising the use of a tricyclic nucleoside according to  claim 1 . 
     
     
         17 . A tricyclic nucleoside described by general Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         Bx is a heterocyclic base moiety; 
         one of T 1  and T 2  is hydroxyl (—OH) or a protected hydroxyl and the other of T 1  and T 2  is a phosphate or a reactive phosphorus group; 
         each of q 1 , q 2 , q 3 , q 4 , and q 5  is, independently, selected from H, F, and Cl; 
         one of z 1  and z 2  is H or F and the other of z 1  and z 2  is selected from H, —OH, Cl, 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 ; and 
         at least one of q 1 , q 2 , q 3 , q 4 , q 5 , z 1 , and z 2  is F. 
       
     
     
         18 . The tricyclic nucleoside of  claim 17 , wherein Bx is selected from the group consisting of uracil, thymine, cytosine, 5-methylcytosine, adenine, and guanine. 
     
     
         19 . The tricyclic nucleoside of  claim 17 , wherein T 1  is hydroxyl or protected hydroxyl, and wherein T 2  is a reactive phosphorus group selected from an H-phosphonate or a phosphoramidite. 
     
     
         20 . The tricyclic nucleoside of  claim 17 , wherein T 1  is 4,4′-dimethoxytrityl and T 2  is diisopropylcyanoethoxy phosphoramidite. 
     
     
         21 . The tricyclic nucleoside of  claim 17 , wherein one or two of q 3 , q 4 , q 5 , z 1 , and z 2  is F, and the others of q 3 , q 4 , q 5 , z 1 , and z 2  are H.