Nucleoside metabolism inhibitors

Abstract

The present invention provides a compound of formula (I), wherein: A is selected from N, CH and CR, where R is selected from halogen, optionally substituted alkyl, aralkyl and aryl, OH, NH 2 , NHR 1 , NR 1 R 2 and SR 3 , where R 1 , R 2 and R 3 are each optionally substituted alkyl, aralkyl or aryl groups; B is selected from OH, NH 2 , NHR 4 , H and halogen, where R 4 is an optionally substituted alkyl, aralkyl or aryl group; D is selected from OH, NH 2 , NHR 5 , H, halogen and SCH 3 , where R 5 is an optionally substituted alkyl, aralkyl or aryl group; X and Y are independently selected from H, OH and halogen, with the proviso that when one of X and Y is hydroxy or halogen, the other is hydrogen; Z is OH, or, when X is hydroxy, Z is selected from hydrogen, halogen, hydroxy, SQ and OQ, where Q is an optionally substituted alkyl, aralkyl or aryl group; and W is OH or H, with the proviso that when W is OH, then A is CR where R is as defined above; or a tautomer thereof; or a pharmaceutically acceptable salt thereof; or an ester thereof; or a prodrug thereof. The invention also provides a pharmaceutical composition comprising a compound of formula (I), as well as methods of treatment using a compound of formula (I). The invention further provides methods of preparing compounds of formula (I).

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 A is selected from N, CH and CR, where R is selected from halogen, optionally substituted alkyl, aralkyl and aryl, OH, NH 2 , NHR 1 , NR 1 R 2  and SR 3 , where R 1 , R 2  and R 3  are each optionally substituted alkyl, aralkyl or aryl groups;  
 B is selected from OH, NH 2 , NHR 4 , H and halogen, where R 4  is an optionally substituted alkyl, aralkyl or aryl group;  
 D is selected from OH, NH 2 , NHR 5 , H, halogen and SCH 3 , where R 5  is an optionally substituted alkyl, aralkyl or aryl group;  
 X and Y are independently selected from H, OH and halogen, with the proviso that when one of X and Y is hydroxy or halogen, the other is hydrogen;  
 Z is OH, or, when X is hydroxy, Z is selected from hydrogen, halogen, hydroxy, SQ and OQ, where Q is an optionally substituted alkyl, aralkyl or aryl group; and  
 W is OH or H, with the proviso that when W is OH, then A is CR where R is as defined above;  
 or a tautomer thereof; or a pharmaceutically acceptable salt thereof; or an ester thereof; or a prodrug thereof.  
 
   
   
       2 . A compound as claimed in  claim 1  wherein B is NHR 4  and/or D is NHR 5 , and R 4  and/or R 5  are C 1 -C 4  alkyl.  
   
   
       3 . A compound as claimed in  claim 1  wherein when one or more halogens are present, they are chosen from chlorine or fluorine.  
   
   
       4 . A compound as claimed in  claim 1  wherein when Z is SQ or OQ, Q is C 1 -C 5  alkyl or phenyl.  
   
   
       5 . A compound as claimed in  claim 1  wherein either D is H, or B is OH, or both.  
   
   
       6 . A compound as claimed in  claim 1  wherein B is OH, D is H, OH or NH 2 , X is OH or H and Y is H.  
   
   
       7 . A compound as claimed in  claim 1  wherein Z is OH, H or methylthio.  
   
   
       8 . A compound as claimed in  claim 1  wherein W is OH, Y is H, X is OH, and A is CR where R is methyl or halogen.  
   
   
       9 . A compound as claimed in  claim 1  wherein W is H, Y is H, X is OH and A is CH.  
   
   
       10 . A compound as claimed in  claim 1  selected from 
 (1S)-1-(9-deaza-8-fluorohypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol;    (1S)-1-(9-deaza-8-methylhypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol; or    (1S)-1-(9-deazahypoxanthin-9-yl)-1,3,4-trideoxy-1,4-imino-D-ribitol; 
 or a tautomer thereof; or a pharmaceutically acceptable salt thereof.  
   
   
   
       11 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula (I) as claimed in  claim 1 , and a pharmaceutically acceptable carrier or diluent.  
   
   
       12 . A method for treatment of a disease or condition in which it is desirable to decrease the level of T lymphocyte activity, the method comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound as claimed in  claim 1 .  
   
   
       13 . A method for treatment and/or prophylaxis of a parasitic infection, the method comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound as claimed in  claim 1 .  
   
   
       14 . A method as claimed in  claim 13  wherein the parasite infection is caused by protozoan parasites.  
   
   
       15 . A method for preparing a compound of the formula (I) as defined in  claim 1 , wherein A is CR and R is as defined in  claim 1 , the method comprising reacting a compound of formula (II)  
     
       
         
         
             
             
         
       
     
     wherein R 9  is an alkoxycarbonyl or aralkyloxycarbonyl group, Z′ is a hydrogen or halogen atom, a group of formula SQ or OQ, or a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group and Q is an optionally substituted alkyl, aralkyl or aryl group, and R 6  is an N-protecting group, B′ and D′ are independently selected from H, OR 7  and N(R 8 ) 2 , and R 7  and R 8  are O- and N-protecting groups respectively; 
 (i) with a strong base capable of deprotonation at C-8 of the 9-deazapurine moiety; then  
 (ii) with an electrophile; and  
 (iii) O- and N-deprotecting the product by acid-, alkali- or fluoride ion-catalyzed hydrolysis or alcoholysis or catalytic hydrogenolysis as required for the O- and N-protecting groups in use.  
 
   
   
       16 . A method as claimed in  claim 15  wherein the strong base comprises butyllithium.  
   
   
       17 . A method for preparing a compound of the formula (I) as defined in  claim 1 , wherein W is H, the method comprising reacting a compound of formula (III)  
     
       
         
         
             
             
         
       
     
     wherein R 9  is an alkoxycarbonyl or aralkyloxycarbonyl group, Z′ is a hydrogen or halogen atom, a group of formula SQ or OQ, or a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group and Q is an optionally substituted alkyl, aralkyl or aryl group, and R 6  is an N-protecting group, B′ and D′ are independently selected from H, OR 7  and N(R 8 ) 2 , R 7  and R 8  are O- and N-protecting groups, respectively, and R 10  is an O-protecting group; 
 (i) with a thiocarbonylating agent; then  
 (ii) with a radical reducing agent; and  
 (iii) O- and N-deprotecting the product by acid-, alkali- or fluoride ion-catalyzed hydrolysis or alcoholysis or catalytic hydrogenolysis as required for the O- and N-protecting groups in use.  
 
   
   
       18 . A method as claimed in  claim 17  wherein the thiocarbonylating agent is thiocarbonyl diimidazole.  
   
   
       19 . A method as claimed in  claim 17  wherein the radical reducing agent comprises tributyltin hydride.