Process for preparing inhibitors of nucleoside phosphorylases and nucleosidases

Abstract

The present invention relates to a new process for the preparation of compounds of general formula (I) which are inhibitors of purine nucleoside phosphorylases (PNP), purine phosphoribosyltransferases (PPRT), 5′-methylthioadenosine phosphorylases (MTAP), 5′-methylthioadenosine nucleosidases (MTAN) and/or nucleoside hydrolases (NH). The present invention relates to a new process for the preparation of compounds of general formula (I) which are inhibitors of purine nucleoside phosphorylases (PNP), purine phosphoribosyltransferases (PPRT), 5′-methylthioadenosine phosphorylases (MTAP), 5′-methylthioadenosine nucleosidases (MTAN) and/or nucleoside hydrolases (NH).

1 . A process for preparing a compound of the formula (I) 
     
       
         
         
             
             
         
       
     
     wherein:
 V is selected from CH 2  and NH, and W is NR 1 ; or 
 V is NR 1 , and W is selected from CH 2  and NH; 
 X is selected from CH 2  and CHOH in the R or S-configuration, except where W is selected from NH and NR 1 , then X is CH 2 ; 
 Y is selected from hydrogen, halogen and hydroxy, except where V is selected from NH and NR 1 , then Y is hydrogen; 
 Z is selected from hydrogen, halogen, hydroxy, a sulfonate leaving group, SQ, OQ and Q, where Q is an optionally substituted alkyl, aralkyl or aryl group; and 
 R 1  is a radical of the formula (II) 
 
     
       
         
         
             
             
         
       
     
     wherein:
 A is selected from N, CH and CR 2 , where R 2  is selected from halogen, optionally substituted alkyl, aralkyl or aryl, OH, NH 2 , NHR 3 , NR 3 R 4  and SR 5 , where R 3 , R 4  and R 5  are each optionally substituted alkyl, aralkyl or aryl groups; 
 B is selected from OH, NH 2 , NHR 6 , SH, hydrogen and halogen, where R 6  is an optionally substituted alkyl, aralkyl or aryl group; 
 D is selected from OH, NH 2 , NHR 7 , hydrogen, halogen and SCH 3 , where R 7  is an optionally substituted alkyl, aralkyl or aryl group; and 
 E is selected from N and CH; 
 including reacting a compound of the formula (III) 
 
     
       
         
         
             
             
         
       
     
     wherein:
 V is selected from CH 2  and NH, and W is NH; or 
 V is NH, and W is selected from CH 2  and NH; 
 X is selected from CH 2  and CHOH in the R or S-configuration, except where W is NH, then X is CH 2 ; 
 Y is selected from hydrogen, halogen and hydroxy, except where V is selected from NH, then Y is hydrogen; and 
 Z is selected from hydrogen, halogen, hydroxy, a sulfonate leaving group, SQ, OQ and Q, where Q is an optionally substituted alkyl, aralkyl or aryl group; 
 with a compound of the formula (IV) 
 
     
       
         
         
             
             
         
       
       wherein A, B, D, and E are as defined above; 
       and with formaldehyde or a formaldehyde equivalent. 
     
   
   
       2 . The process of  claim 1 , wherein Z is hydrogen, halogen, hydroxy, SQ or OQ, where Q is an optionally substituted alkyl, aralkyl or aryl group. 
   
   
       3 . The process of  claim 1 , wherein A is CH. 
   
   
       4 . The process of  claim 1 , wherein Y is H. 
   
   
       5 . The process of  claim 1 , wherein W is NR 1 , V is CH 2  and X is CH 2 . 
   
   
       6 . The process of  claim 5 , wherein R 1  is a radical of formula (II), where A is CH and E is N. 
   
   
       7 . The process of  claim 1 , wherein D is H or NH 2 . 
   
   
       8 . The process of  claim 1 , wherein B is NH 2 , OH or Cl. 
   
   
       9 . The process of  claim 1 , wherein Z is methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate. 
   
   
       10 . The process of  claim 9 , wherein Z is methanesulfonate. 
   
   
       11 . The process of  claim 1 , wherein the compounds of formula (III) and (IV) are reacted with formaldehyde. 
   
   
       12 . The process of  claim 1 , wherein the compounds of formula (III) and (IV) are reacted with a formaldehyde equivalent which is paraformaldehyde. 
   
   
       13 . (canceled) 
   
   
       14 . A compound of formula (I) prepared by the a process according to  claim 1 . 
   
   
       15 . A process for preparing a compound of formula (I) as defined in  claim 1  comprising:
 (i) reacting a compound of formula (III) as defined in  claim 1  with a compound of formula (IV) as defined in  claim 1  and with formaldehyde or a formaldehyde equivalent, where any one or more of V, W, X, Y and Z of the compound of formula (III) is protected with a suitable protecting group; and   (ii) removing the one or more protecting groups to give the compound of formula (I).   
   
   
       16 . A process for preparing a compound of formula (I) as defined in  claim 1  comprising:
 (i) reacting a compound of formula (III) as defined in  claim 1  with a compound of formula (IV) as defined in  claim 1  and with formaldehyde or a formaldehyde equivalent, where any one or more of A, B, D and E of the compound of formula (IV) is protected with a suitable protecting group; and   (ii) removing the one or more protecting groups to give the compound of formula (I).   
   
   
       17 . A process of preparing a compound of formula (1) as defined in  claim 1  comprising:
 (i) reacting a compound of formula (III) as defined in  claim 1  with a compound of formula (IV) as defined in  claim 1  and with formaldehyde or a formaldehyde equivalent, where any one or more of V, W, X, Y and Z of the compound of formula (III) is protected with a suitable protecting group and where any one or more of A, B, D and E of the compound of formula (IV) is protected with a suitable protecting group; and   (ii) removing the one or more protecting groups to give the compound of formula (I).