Broad spectrum antiviral and antiparasitic agents

Abstract

The invention provides compounds represented by the formulae: (I) and (II) where the compounds are useful in treating, for example, viral and/or parasitic infections. Also provided are pharmaceutical compositions comprising the compounds and methods of treatment using the compounds.

1 . A compound according to formula Ia or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C 3 -C 6  aryl, C 3 -C 6  heteroaryl, C 3 -C 6  cycloalkyl, or C 3 -C 6  heterocycloalkyl, each optionally substituted with halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; 
       
       halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ;
 R 2  represents one or more substituents independently selected from —OR 3 , —SR 3 , and —NR 4 R 5 ; 
 R 3 , R 4 , and R 5  are independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; and 
 X is O, N, S, NH, or NR 3 . 
 
     
     
         2 . A compound according to formula IIa or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, each optionally substituted with halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; 
         R 2  represents exactly one —OR 3 , —SR 3 , or —NR 4 R 5 ; 
         R 3 , R 4 , and R 5  are independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkoxy, halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; 
         X is O, N, S, NH, or NR 3 ; and 
         Z is O, N, NH, or NR 3 . 
       
     
     
         3 . The compound of  claim 1 , wherein R 3 , R 4 , and R 5  are independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is C 1 -C 6  alkyl. 
     
     
         5 . A method of treating or preventing a disease or condition caused by infection with an enveloped virus, the method comprising administering to a subject a therapeutically effective amount of the compound of  claim 1 . 
     
     
         6 . A method of treating or preventing a disease or condition caused by infection with an enveloped virus, the method comprising administering to a subject a therapeutically effective amount of a compound according to formula IIa or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, each optionally substituted with halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; 
         R 2  represents one or more substituents independently selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , and —SO 2 NR 4 R 5 ; 
         R 3 , R 4 , and R 5  are independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; 
         X is O, N, S, NH, or NR 3 ; and 
         Z is O, N, NH, or NR 3 . 
       
     
     
         7 . The method of  claim 5 , wherein the virus is hepatitis C virus (HCV), human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), Ebola virus, Influenza virus, Nipah virus, Yellow Fever Virus, Dengue virus, Rift Valley Fever Virus, West Nile Virus. 
     
     
         8 . The method of  claim 5 , wherein the compound is administered as a liposomal formulation. 
     
     
         9 . A pharmaceutical composition comprising the compound of  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the composition is suitable as a topical formulation. 
     
     
         11 . The pharmaceutical composition of  claim 10 , which is in the form of a patch, an ointment, a cream, a lotion, a drop, a spray, or an aerosol. 
     
     
         12 . The pharmaceutical composition of  claim 10 , which is in the form of a liposomal formulation. 
     
     
         13 . A method of treating or preventing a disease or condition caused by infection with a parasite, the method comprising administering to a subject a therapeutically effective amount of the compound of  claim 1 . 
     
     
         14 . A method of treating or preventing a disease or condition caused by infection with a parasite, the method comprising administering to a subject a therapeutically effective amount of a compound according to formula II or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein R 1  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C 3 -C 6  aryl, C 3 -C 6  heteroaryl, C 3 -C 6  cycloalkyl, or C 3 -C 6  heterocycloalkyl, each optionally substituted with halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; 
         R 2  represents one or more substituents independently selected from —OR 3 , —SR 3 , and —NR 4 R 5 ; 
         R 3 , R 4 , and R 5  are independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, halo, —NO 2 , —CF 3 , —CN, —OR 3 , —SR 3 , —C(O)R 3 , —NHC(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 R 5 , —C(O)NR 4 R 5 , —NHR 3 C(O)NR 4 R 5 , or —SO 2 NR 4 R 5 ; 
         X is O, N, S, NH, or NR 3 ; and
 Z is O, N, NH, or NR 3 .