Macrocyclic isoquinoline peptide inhibitors of hepatitis C virus

Abstract

Macrocyclic isoquinoline peptides are disclosed having the general formula: A compound of formula I: wherein R 1 to R 9 , Q and W are described in the description. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.

1 . A process for resolving a mixture of alkyl ester enantiomers comprising contacting the mixture with an enzyme effective to preferentially promote the hydrolysis of one of the enantiomers; characterized in that the contacting is conducted in the presence of a buffer.  
     
     
         2 . The process of  claim 1  wherein the alkyl ester has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 25  is an amino protecting group; and  
 R 26  is selected from the group consisting of C 1-10  alkyl, C 6-14  aryl, C 7-16  alkylaryl, C 3-7  cycloalkyl or C 3-10  alkyl cycloalkyl.  
 
     
     
         3 . The process of  claim 1  wherein the buffer is selected from the group consisting of phosphates, borates and carbonates.  
     
     
         4 . The process of  claim 1  wherein the enzyme is a protease.  
     
     
         5 . The process of  claim 1  wherein the enzyme is selected from the group consisting of  Bacillus globigii, Bacillus licheniformis, Bacillus halodurans, Bacillus clausii, Aspergillus oryzase  and mixtures thereof.  
     
     
         6 . The process of  claim 5  wherein the enzyme is selected from the group consisting of Alcalase® (subtilisin protease), Savinase® (subtilisin protease), Esperase® (subtilisn protease), Flavourzyme™ (fungal protease) and mixtures thereof.  
     
     
         7 . The process of  claim 1  wherein the contacting is conducted at pH of from about 7.0 to 11.  
     
     
         8 . The process of  claim 1  wherein the contacting is conducted at a temperature of from about 30 to 60° C.  
     
     
         9 . The process of  claim 1  wherein the contacting is conducted for a time of less than about seven days.  
     
     
         10 . The process of  claim 9  wherein the contacting is conducted for a time of from about two hours to three days.