INHIBITORS OF LONG AND VERY LONG CHAIN FATTY ACID METABOLISM AS BROAD SPECTRUM ANTI-VIRALS
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.
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