Macrocyclic peptides active against the hepatitis C virus

Abstract

Compounds of formula (I): wherein R 1 is (C 1-8 )alkyl, (C 3-7 )cycloalkyl, {(C 1-6 )alkyl-(C 3-7 )cycloalkyl} or Het, which are all optionally substituted from 1 to 3 times with halo, cyano, nitro, O—(C 1-6 )alkyl, amido, amino or phenyl, or R 1 is C 6 or C 10 aryl which is optionally substituted from 1 to 3 times with halo, cyano, nitro, (C 1-6 )alkyl, O—(C 1-6 )alkyl, amido, amino or phenyl; or a pharmaceutically acceptable salt thereof, useful as an inhibitor of the HCV NS3 protease.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein R 1  is (C 1-8 )alkyl, (C 3-7 )cycloalkyl, {(C 1-6 )alkyl-(C 3-7 )cycloalkyl} or Het, which are all optionally substituted from 1 to 3 times with halo, cyano, nitro, O—(C 1-6 )alkyl, amido, amino or phenyl; or R 1  is C 6  or C 10  aryl which is optionally substituted from 1 to 3 times with halo, cyano, nitro, (C 1-6 )alkyl, O—(C 1-6 )alkyl, amido, amino or phenyl; or a pharmaceutically acceptable salt thereof.  
     
     
         2 . A compound according to  claim 1 , wherein said Het is:  
       
         
           
           
               
               
           
         
       
       or a heteroaryl selected from:  
       
         
           
           
               
               
           
         
       
       said heteroaryl being optionally substituted with C 1-6  alkyl.  
     
     
         3 . A compound according to  claim 1 , wherein R 1  is (C 1-8 )alkyl, (C 3-7 )cycloalkyl or {(C 1-6 )alkyl-(C 3-7 )cycloalkyl}, which are all optionally substituted from 1 to 3 times with halo, cyano, nitro, O—(C 1-6 )alkyl, amido, amino or phenyl; or R 1  is C 6  or C 10  aryl which is optionally substituted from 1 to 3 times with halo, cyano, nitro, (C 1-6 )alkyl, O—(C 1-6 )alkyl, amido, amino or phenyl; or a pharmaceutically acceptable salt thereof.  
     
     
         4 . A compound according to  claim 3 , wherein R 1  is (C 1-6 )alkyl, (C 3-6 )cycloalkyl or {(C 1-6 )alkyl-(C 3-6 )cycloalkyl}, which are all optionally substituted from 1 to 3 times with halo, nitro or O—(C 1-6 )alkyl, or phenyl which is optionally substituted from 1 to 3 times with halo, nitro, (C 1-6 )alkyl or O—(C 1-6 )alkyl.  
     
     
         5 . A compound according to  claim 4 , wherein R 1  is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclohexylethyl, CCl 3 , CF 3 , phenyl, 2-fluorophenyl, or 4-methylphenyl.  
     
     
         6 . A compound according to  claim 5  wherein R 1  is methyl, cyclopropyl, CF 3  or phenyl.  
     
     
         7 . A compound according to  claim 6  wherein R 1  is methyl.  
     
     
         8 . A compound according to  claim 6  wherein R 1  is cyclopropyl.  
     
     
         9 . A compound according to  claim 6  wherein R 1  is phenyl.  
     
     
         10 . A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula I according to  claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.  
     
     
         11 . A pharmaceutical composition according to  claim 10 , further comprising a therapeutically effective amount α-interferon  
     
     
         12 . A pharmaceutical composition according to  claim 10 , further comprising a therapeutically effective amount of pegylated α-interferon.  
     
     
         13 . A pharmaceutical composition according to  claim 10 , further comprising a therapeutically effective amount of ribavirin.  
     
     
         14 . A pharmaceutical composition according to  claim 11 , further comprising a therapeutically effective amount of ribavirin.  
     
     
         15 . A pharmaceutical composition according to  claim 12 , further comprising a therapeutically effective amount of ribavirin.  
     
     
         16 . A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of a compound of formula I according to  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         17 . A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of the composition according to  claim 10 .  
     
     
         18 . A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of the composition according to  claim 11 .  
     
     
         19 . A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of the composition according to  claim 12 .  
     
     
         20 . A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of the composition according to  claim 13 .  
     
     
         21 . A method of inhibiting the replication of hepatitis C virus comprising exposing the virus to a hepatitis C viral NS3 protease inhibiting amount of a compound of formula I according to  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         22 . A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of a pharmaceutical composition comprising a compound of formula I according to  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more other anti-HCV agents.  
     
     
         23 . A method according to  claim 22 , wherein said other anti-HCV agent is selected from the group consisting of: α-, β- δ-, γ-, ω-interferon, pegylated α-, β-, δ-, γ-, ω-interferon, ribavirin and amantadine.  
     
     
         24 . A method according to  claim 23 , wherein said other anti-HCV agent is α-interferon.  
     
     
         25 . A method according to  claim 23 , wherein said other anti-HCV agent is pegylated α-interferon.  
     
     
         26 . A method according to  claim 24 , wherein the composition further comprises ribavirin.  
     
     
         27 . A method according to  claim 25 , wherein the composition further comprises ribavirin.  
     
     
         28 . A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of a combination of a compound of formula I according to  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more other anti-HCV agents, wherein said one or more other anti-HCV agents are administered to the mammal prior to, concurrently with, or following the administration of the compound of formula I.