Inhibitors of long and very long chain fatty acid metabolism as broad spectrum anti-virals

Abstract

The present invention provides methods and compounds for treating viral infections using modulators of host cell enzymes relating to long chain fatty acid and lipid droplet metabolism. It includes a method of treating viral infections using triacsin C and its relatives, analogues and derivatives as well as other inhibitors of long chain fatty acid metabolism and lipid droplet metabolism.

We claim: 
     
         1 - 103 . (canceled) 
     
     
         104 . A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug; and a pharmaceutically acceptable carrier, wherein the compound is a compound of
 i) Formula VI:   
       
         
           
           
               
               
           
         
         wherein L is selected from carbamate, urea, or amide including, for example 
       
       
         
           
           
               
               
           
         
         and wherein R is selected from halo; CF 3 ; cyclopropyl; optionally substituted C 1-5  alkyl, wherein the C 1-5  alkyl is substituted with halo, oxo, —OH, —CN, —NH 2 , CO 2 H, and C 1-3  alkoxy; 
         wherein R 1  is selected from substituted phenyl where the substituents are selected from F, CF 3 , Me, OMe, or isopropyl; 
         wherein R 2  is Cl, Ph, 1-(2-pyridone), 4-isoxazol, 3-pyrazol, 4-pyrazol, 1-pyrazol, 5-(1,2,4-triazol), 1-(1,2,4-triazol), 2-imidazolo, 1-(2-pyrrolidone), 3-(1,3-oxazolidin-2-one); and 
         wherein the chiral center at C4 is racemic, (S), (R), or any ratio of enantiomers; 
         ii) Formula VIIa or VIIb: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is selected from OMe, OiPr, OCF 3 , OPh, CH 2 Ph, F, CH 3 , CF 3 , and benzyl; and 
         wherein R 2  is selected from C 1-4  alkyl; phenyl; substituted phenyl where substitutents are selected from OMe, CF 3 , F, tBu, iPr and thio; 2-pyridine; 3-pyridine; and N-methy imidazole; 
         iii) Formula VIII 
       
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H, unsubtitued phenyl; substituted phenyl where substitutents are selected from F, Me, Et, Cl, OMe, OCF 3 , and CF 3 ; C 1-6  alkyl; and C 3-6  cycloalkyl; 
         wherein R 3  and R 4  are independently selected from H; C 1-3  alkyl; and phenyl; or R 3  and R 4  taken together form a cycloalkyl of formula —(CH2) n — where n=2, 3, 4 and 5; 
         wherein R 5  is selected from methyl; CF 3 ; cyclopropyl; unsubtitued phenyl; mono- and disubstituted phenyl where substitutents are selected from F, Me, Et, CN, iPr, Cl, OMe, OPh, OCF 3 , and CF 3 ; unsubstituted heteroaromatic groups; and imidazole; and 
         iv) Formula IX: 
       
       
         
           
           
               
               
           
         
         wherein L is selected from urea, amide, 
       
       
         
           
           
               
               
           
         
         wherein R 1  is selected form 2-, 3-, and 4-pyridine; pyrimidine; unsubstituted heteroaryls such as isoxazol, pyrazol, triazol, imidazole; and unsubstituted phenyl; ortho, meta or para-substituted phenyl where substitutents are F, Me, Et, Cl, OMe, OCF 3 , and CF 3 , Cl, iPr and phenyl; and 
         wherein R 2  is selected from Cl; iPr; phenyl; ortho, meta or para-substituted phenyl where substitutents are F, Me, Et, Cl, OMe, OCF 3 , and CF 3 ; and heteroaryls such as 2-, 3-, and 4-pyridine, pyrimidine, and isoxazol, pyrazol, triazol, and imidazo. 
       
     
     
         105 . The pharmaceutical composition of  claim 104 , wherein the compound of Formula VI is 
       
         
           
           
               
               
           
         
       
     
     
         106 . The pharmaceutical composition of  claim 104 , wherein the compound of Formula VIIa and VIIb is 
       
         
           
           
               
               
           
         
       
     
     
         107 . The pharmaceutical composition of  claim 104 , wherein R 5  in the compound of Formula VIII is 
       
         
           
           
               
               
           
         
       
     
     
         108 . The pharmaceutical composition of  claim 104 , wherein the compound of Formula VIII is 
       
         
           
           
               
               
           
         
       
     
     
         109 . The pharmaceutical composition of  claim 104 , wherein the compound of Formula IX is