Nucleosides with antiviral and anticancer activity

Abstract

The invention provides a compound of formula I: wherein R 1 -R 6 and X have any of the values described herein, as well as pharmaceutical compositions comprising such compounds and therapeutic methods comprising the administration of such compounds.

What is claimed is: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is adenine, guanine, cytosine, thymine, 3-deazaadenine, or uracil, optionally substituted by 1, 2, or 3 U; wherein each U is independently halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, hydroxy(C 1 -C 6 )alkyl, —(CH 2 ) 1-4 P(═O)(OR w ) 2  aryl, aryl(C 1 -C 6 )alkyl, or NR x R y ; 
 R 2  and R 6  are each independently hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae , provided that one of R 2  and R 6  is hydroxy halo, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, trifluoromethyl, cyano, or NR ad R ae ; 
 R 3  is hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae ; 
 R 4  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aryl(C 1 -C 6 )alkyl, or 2-cyanoethyl; 
 R 5  is an amino acid, a peptide, or NR a  R b ; 
 R 7  is hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae ; 
 X is oxy, thio, or methylene; 
 each R a  and R b  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or Het; or R a  and R b  together with the nitrogen to which they are attached form a nitrogen-linked Het; 
 each R w  is independently hydrogen or (C 1 -C 6 )alkyl; 
 R x  and R y  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, phenethyl, or (C 1 -C 6 )alkanoyl; or R x  and R y  together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; 
 R z  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; 
 R aa  and R ab  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; or R aa  and R ab  together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; 
 R ac  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; 
 R ad  is hydrogen (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; 
 R ae  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; 
 wherein any (C 1 -C 6 )alkyl of R 1 -R 7 , R a , R b , R w , R x , R y , R z , R aa , R ab , R ac , R ad , and R ae  is optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, Het, aryl(C 1 -C 6 )alkyl, or Het(C 1 -C 6 )alkyl, or NR aj R ak ; wherein each R aj  and R ak  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; 
 and wherein any aryl or Het may optionally be substituted with one or more substituents selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, and amino; 
 or a pharmaceutically acceptable salt thereof; 
 provided that R 2  and R 3  are each not hydroxy when R 1  is adenine, guanine, cytosine, thymine, or uracil, X is oxy, R 5  is an amino acid or a peptide; R 6  is hydrogen, and R 7  is hydrogen; and; provided R 1  is not 3-deazaadenine, when R 2  is hydroxy; R 3  is hydroxy; R 4  is hydrogen; R 5  a nitrogen linked radical of formula III; 
 
       
       
         
           
           
               
               
           
         
         wherein R h  is benzyl or 3-indolylmethyl; and R j  is methyl; x is oxy, R 6  is hydrogen, and R 7  is hydrogen.