Novel tricyclic nucleosides or nucleotides as therapeutic agents

Abstract

Nucleosides and nucleotides containing a tricyclic base portion thereof are useful for treating infectious diseases and proliferative disorders, such as viral infections or cancer respectively.

1 . A compound of the formula (I) which may be a D- or L-nucleotide or nucleoside: 
       
         
           
           
               
               
           
         
         wherein
 A is O, S, CH 2 , NH, CHF, CF 2  or protected N; 
 R 1 , R 2 , R 2 ′, R 3 , R 3 ′, and R 4  are independently H, F, Cl, Br, I, OH, SH, NH 2 , NHOH, NHNH 2 , N 3 , COOH, CN, CONH 2 , C(S)NH 2 , COOR, R, OR, SR, SSR, NHR, or NR 2 , wherein R 2  and R 2 ′ are not both hydrogen; 
 L is O, S, NH, NR, CY 2 O, CY 2 S, CY 2 NH, CY 2 , CY 2 CY 2 , CY 2 OCY 2 , CY 2 SCY 2 , or CY 2 NHCY 2 , wherein Y is H, F, Cl, Br, alkyl, alkenyl, or alkynyl, and wherein alkyl, alkenyl, and alkynyl may each optionally contain one or more heteroatoms; 
 R 5  is OH, monophosphate, diphosphate, or triphosphate, or a phosphonate, phosphoamidate, or phosphoester thereof; 
 B is a base selected from formula (II): 
 
       
       
         
           
           
               
               
           
         
         wherein
 dashed lines (---) indicate an optional π bond; 
 X is N, NH, or NR; 
 Z is C-G, O, >C═O, >C═S, or CH-G, wherein if Z is a participant in a π bond then Z is C-G, and when Z is not a participant in a π bond then Z is O, >C═O, >C═S, or CH-G; 
 Z 1  is C-G or CH-G, wherein if Z′ is a participant in a π bond then Z′ is C-G, and when Z 1  is not a participant in a π bond then Z′ is CH-G; 
 Z 2  is C-G or CH-G, wherein if Z 2  is a participant in a π bond then Z 2  is C-G, and when Z 2  is not a participant in a π bond then Z 2  is CH-G; 
 Z 3  is CH or N; 
 Z 4  is C-G, >C═O, >C═S, >C═NH or >C═NR, wherein if Z 4  is a participant in a π bond then Z 4  is C-G, and if Z 4  is not a participant in a π bond then Z 4  is >C═O, >C═S, >C═NH or >C═NR; 
 each G is independently H, F, Cl, Br, I, OH, SH, NH 2 , NHOH, N 3 , COOH, CN, CONH 2 , C(S)NH 2 , C(═NH)NH 2 , R, OR, SR, NHR, or NR 2 ; and 
 each R is independently alkyl, alkenyl, alkynyl, aryl, acyl, or aralkyl, optionally containing one or more heteroatoms; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         2 . The compound of  claim 1  wherein Z 4  is a participant in a π bond, and base B is: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2  wherein G is H, F, Cl, Br, I, R, OR, SR, NH 2 , NHR or NR 2 , and R is alkyl. 
     
     
         4 . The compound of  claim 2  wherein X is NH or NR, and base B is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 2  wherein X is N and base B is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1  wherein Z 4  is not a participant in a π bond, and base B is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6  wherein X is NH or NR, and base B is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7  wherein X is NH, and base B is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 6  wherein X is NH or NR, and base B is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 6  wherein X is N, and base B is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1  wherein the base B is selected from one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claims 1  wherein the nucleotide or nucleoside has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12  wherein R 1 , R 3  and R 4  are hydrogen. 
     
     
         14 . The compound of  claim 13  wherein R 2 , R 2 ′ and R 3 ′ are independently H, F, Cl, Br, I, OH, N 3 , CN, R or OR, and R is alkyl. 
     
     
         15 . The compound of  claim 13  wherein R 2 ′ and R 3 ′ are OH. 
     
     
         16 . The compound of  claim 15  wherein R 2  is H or methyl. 
     
     
         17 . The compound of  claim 1  wherein R 5  is OH, monophosphate, or a monophosphonate thereof. 
     
     
         18 . A method for treating a viral infection comprising administering a therapeutically effective amount of a compound of  claim 1  to a mammal in need thereof. 
     
     
         19 . The method of  claim 18 , wherein the compound is administered in combination with one or more active anti-viral agents.