2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-1,3-propanediol derivative

Abstract

The L-monovaline ester derived from 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol and its pharmaceutically acceptable salts are of value as antiviral agents with improved absorption.

What is claimed is:  
     
         1 . The compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt thereof, in the form of its (R)- or (S)-diastereomers, or in the form of mixtures of the two diastereomers.  
     
     
         2 . The compound according to  claim 1  comprising said mixture containing equal amounts of its (R)- and (S)-diastereomers.  
     
     
         3 . The compound according to  claim 1  wherein the pharmaceutically acceptable salt is the hydrochloride.  
     
     
         4 . A compound according to  claim 1  in crystalline form.  
     
     
         5 . The compound of  claim 1  which is (R)-2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate and its pharmaceutically acceptable salts.  
     
     
         6 . The compound of  claim 1  which is (S)-2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate and its pharmaceutically acceptable salts.  
     
     
         7 . A compound according to  claim 5  wherein said salt is the hydrochloride.  
     
     
         8 . A compound according to  claim 6  wherein said salt is the hydrochloride.  
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 1 .  
     
     
         10 . A pharmaceutical composition according to  claim 9  which includes a pharmaceutically acceptable excipient or carrier.  
     
     
         11 . The composition according to  claim 10  for intravenous administration.  
     
     
         12 . The composition according to  claim 10  for oral administration.  
     
     
         13 . The composition according to  claim 10  for topical administration.  
     
     
         14 . The composition according to  claim 10  in the form of an intravitreal implant.  
     
     
         15 . A method of treating an animal afflicted with, or at risk for, a viral or related disease which method comprises administering a therapeutically acceptable amount of a compound of  claim 1  to said animal.  
     
     
         16 . The method of  claim 15  wherein the compound is administered orally.  
     
     
         17 . The method of  claim 15  wherein the compound is administered topically.  
     
     
         18 . The method of  claim 15  wherein the compound is administered as an intravitreal implant.  
     
     
         19 . The method of  claim 15  wherein the compound is administered as the form of an injection.  
     
     
         20 . A process for preparing the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt or diastereomers thereof which process comprises: 
 (a) removal of an amino- and/or hydroxy-protecting group from a compound with the formula                          wherein: 
 P 1  is a hydroxy-protecting group or hydrogen, P 2  is an amino-protecting group, and P 3  is hydrogen or P 2 ;  
    to afford the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt thereof;    (b) conversion of the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate into a pharmaceutically acceptable salt thereof;    (c) esterification of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol (ganciclovir) or a salt thereof, with an activated derivative of L-valine;    (d) condensation of an optionally substituted guanine of the formula                          (IV)     optionally in persilylated form,     wherein: 
 P 3  is hydrogen or an amino-protecting group, with an 2-substituted glycerol of the formula  
                     
    wherein: 
 Y 1  and Y 2  independently are halo, lower acyloxy, lower alkyloxy, or aryl(lower)alkyloxy groups, and Z is a leaving group selected from lower acyloxy, methoxy, isopropyloxy, benzyloxy, halo, mesyloxy or tosyloxy; optionally in the presence of a Lewis acid catalyst, to provide the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate; or  
   (e) partial hydrolysis of the bis ester 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediyl bis(L-valinate) or a salt thereof to afford the monoester 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt thereof; or    (f) diastereomeric separation of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate into its (R) and (S) diastereomers.    
     
     
         21 . The process of  claim 20 , wherein the removal of amino- and hydroxy-protecting groups is carried out under acidic conditions.  
     
     
         22 . A compound of the formula OH  
       
         
           
           
               
               
           
         
       
       wherein 
 P 1  is hydrogen or a hydroxy-protecting group and P 2  is an amino-protecting group.