Antifungal agents used in combination

Abstract

The present invention relates to the use of enfumafungin derivative triterpenoid antifungal compounds in combination with other antifungal agents such azoles, polyenes, lipopeptides, and allylamides to treat fungal diseases. More particularly, the invention relates to antifungal combinations of enfumafungin derivative triterpenoids which are inhibitors of (1,3)-β-D-glucan synthesis, in combination with other antifungal agents such as mold-active agents that have activity against molds, including but not limited to voriconazole, isavuconazole, posaconazole, itraconazole and amphotericin B, for the treatment and/or prevention of infections caused by molds.

What is claimed is: 
     
         1 . A pharmaceutical combination of:
 (a) a first therapeutic agent that is a compound of Formula (I):   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is O or H, H; 
 R e  is C(O)NR f R g  or a 6-membered ring heteroaryl group containing 1 or 2 nitrogen atoms wherein the heteroaryl group is optionally mono-substituted on a ring carbon with fluoro or chloro or on a ring nitrogen with oxygen; 
 R f , R g , R 6  and R 7  are each independently hydrogen or C 1 -C 3  alkyl; 
 R 8  is C 1 -C 4  alkyl, C 3 -C 4  cycloalkyl or C 4 -C 5  cycloalkyl-alkyl; 
 R 9  is methyl or ethyl; and 
 R 8  and R 9  are optionally taken together to form a 6-membered saturated ring containing 1 oxygen atom; and 
 (b) a second therapeutic agent that is an azole, a polyene, a purine or pyrimidine nucleotide inhibitor, an orotomide, a Gwt1 inhibitor, a pneumocandin or echinocandin derivative, a protein elongation factor inhibitor, a chitin inhibitor, a mannan inhibitor, a bactericidal/permeability-inducing (BPI) protein product, or an immunomodulating agent. 
 
     
     
         2 . The pharmaceutical combination according to  claim 1 , wherein the second therapeutic agent is itraconazole, ketoconazole, miconazole, fluconazole, voriconazole, posaconazole, amphotericin B, flucytosine, anidulafungin, micafungin, or caspofungin. 
     
     
         3 . The pharmaceutical combination according to  claim 1 , wherein the first therapeutic agent is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       which is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid,
 or a pharmaceutically acceptable salt thereof; 
 
       and the second therapeutic agent is voriconazole, isavuconazole, posaconazole, itraconazole, or amphotericin B. 
     
     
         4 . The pharmaceutical combination according to  claim 1 , wherein the first therapeutic agent is a compound of Formula (IIa): 
       
         
           
           
               
               
           
         
       
       which is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid,
 or a pharmaceutically acceptable salt thereof; 
 
       and the second therapeutic agent is voriconazole, isavuconazole, posaconazole, itraconazole, or amphotericin B. 
     
     
         5 . The pharmaceutical combination according to  claim 3 , wherein the second therapeutic agent is voriconazole. 
     
     
         6 . The pharmaceutical combination according to  claim 4 , wherein the second therapeutic agent is voriconazole. 
     
     
         7 . The pharmaceutical combination according to  claim 3 , wherein the second therapeutic agent is isavuconazole. 
     
     
         8 . The pharmaceutical combination according to  claim 4 , wherein the second therapeutic agent is isavuconazole. 
     
     
         9 . The pharmaceutical combination according to  claim 3 , wherein the second therapeutic agent is amphotericin B. 
     
     
         10 . The pharmaceutical combination according to  claim 4 , wherein the second therapeutic agent is amphotericin B.