Benzimidazoles that enhance the activity of oligonucleotides

Abstract

This disclosure is directed to methods, compounds and compositions for delivering nucleic acids to a cell of interest. In particular, it provides salts that are particularly effective in delivering nucleic acids to cells in the lung for disorders such as cystic fibrosis (CF).

1 . A compound having the Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —NR 6 R 7 , an N-containing heterocycle or an N-containing heterocycloalkyl with the proviso that R 1  is not a pyrrolidine group; 
         R 2  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 3  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 4  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 5  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 6  is C 1-8  alkyl or H; 
         R 7  is C 1-8  alkyl or H; or 
         R 6  and R 7  together make a 4-8-member ring which may be substituted with one or more nitrogens; 
         each n is an integer between 1 and 8; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein n is 2-4 and the N-containing heterocycle or N-containing heterocycloalkyl is an imidazole, a morpholine, a piperidine, a piperidone, or a piperazine, group. 
     
     
         3 . The compound of  claim 1 , wherein n is 2-4 and R 2 -R 5  are each independently C 1-4  alkyl, C 1-4  alkoxy, H or halogen. 
     
     
         4 . The compound of  claim 3 , wherein the halogen is bromine or chorine. 
     
     
         5 .- 6 . (canceled) 
     
     
         7 . A composition comprising an oligonucleotide and a compound having the Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —NR 6 R 7 , an N-containing heterocycle or an N-containing heterocycloalkyl with the proviso that R 1  is not a pyrrolidine group; 
         R 2 -R 5 is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 3  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 4  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 5  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 6  is C 1-8  alkyl or H; 
         R 7  is C 1-8  alkyl or H; or 
         R 6  and R 7  together make a 4-8-member ring which may be substituted with one or more nitrogens; 
         each n is an integer between 1 and 8; and 
         a pharmaceutically acceptable carrier. 
       
     
     
         8 .- 9 . (canceled) 
     
     
         10 . The composition of  claim 1 , wherein the oligonucleotide is a phosphorodiamidate morpholino oligomer (PMO) or a peptide conjugated to a PMO (PPMO). 
     
     
         11 . A method of administering an oligonucleotide of interest to a cell which comprises administering to the cell the oligonucleotide and a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —NR 6 R 7 , an N-containing heterocycle or an N-containing heterocycloalkyl with the proviso that R 1  is not a pyrrolidine group; 
         R 2 is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 3  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 4  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 5  is C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 3-8  alkynyl, C 3-8  cycloalkyl, H or halogen; 
         R 6  is C 1-8  alkyl or H; 
         R 7  is C 1-8  alkyl or H; or 
         R 6  and R 7  together make a 4-8-member ring which may be substituted with one or more nitrogens; 
         each n is an integer between 1 and 8; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11 , wherein the oligonucleotide is a phosphorodiamidate morpholino oligomer (PMO) or a peptide conjugated to a PMO (PPMO). 
     
     
         14 . The method of  claim 11 , wherein the cell is a mammalian cell. 
     
     
         15 . The method of  claim 11 , wherein the method is carried out in vitro or in vivo in a human or an animal. 
     
     
         16 . The method of  claim 11 , wherein the method is carried out by administering the oligonucleotide to the cell, and concurrently administering the compound having formula I to the cell. 
     
     
         17 . The method of  claim 11 , wherein the compound having formula I is administered after the oligonucleotide is administered to the cell. 
     
     
         18 . The method of  claim 11 , wherein the oligonucleotide is single stranded or double stranded. 
     
     
         19 . The method of  claim 11 , wherein the oligonucleotide is from 2, 4, 6 or 8 to 100 or 200 nucleotides in length. 
     
     
         20 . The method of  claim 11 , wherein the oligonucleotide is an antisense oligonucleotide. 
     
     
         20 . The method of  claim 11 , wherein the oligonucleotide is a splice switching oligonucleotide. 
     
     
         21 . The method of  claim 11 , wherein the oligonucleotide is an siRNA. 
     
     
         22 . The method of  claim 11 , wherein the cell is a lung cell or an airway cell. 
     
     
         23 . The method of  claim 23 , wherein the lung cell is a bronchial epithelial cell, a nasal epithelial cell, a tracheal epithelial cell, a alveolar type I or type II cell, a lung submucosal gland cell, a lung leucocyte, a liver cell, a muscle cell, an intestinal cell, or a lung inflammatory cell. 
     
     
         24 .- 39 . (canceled) 
     
     
         40 . The method of  claim 14 , wherein the mammalian cell is a human cell.