Anti-fungals targeting the synthesis of fungal shingolipids

Abstract

The present invention provides a compound having the structure:

1 . A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —H; 
         R 2  is —H; 
         R 3 , R 4 , R 5  and R 6  are each —H and R 7  is —CH 3 , or R 3 , R 4 , R 5  and R 7  are each —H and R 6  is —Br; 
         R 9 , R 10 , and R 11  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , —NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ; and 
         R 8  and R 12  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OAc, —OH, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ,
 wherein each occurrence of R 13  is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 wherein each occurrence of R 14  is independently —H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 wherein each occurrence of R 15  is independently —H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 
         wherein when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 11  and R 12  are each —H, R 9  is —Br, and R 10  is —OH, then R 7  is other than —CH 3 , 
         or a pharmaceutically acceptable salt or ester thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein at least one of R 8 , R 9 , R 10 , R 11 , and R 12  are other than —H. 
     
     
         3 . The compound of  claim 1 , wherein at least two of R 8 , R 9 , R 10 , R 11 , and R 12  are other than —H. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The compound  claim 1 ,
 wherein   R 8 , R 9 , R 10 , R 11 , and R 12  are each independently —H, —Br, alkyl, —OH, —OR 13 , or —NR 14 R 15 ,
 wherein each occurrence of R 13 , R 14 , and R 15  is alkyl, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         7 . The compound of  claim 6 ,
 wherein   R 8 , R 9 , R 10 , R 11 , and R 12  are each independently —H, —Br, —OH, —OR 13 , or —NR 14 R 15 ,
 wherein each occurrence of R 13 , R 14 , and R 15  is alkyl, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 9 , R 10 , and R 11  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ; and 
         R 8  and R 12  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OAc, —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ,
 wherein each occurrence of R 13  is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 wherein each occurrence of R 14  is independently —H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 wherein each occurrence of R 15  is independently —H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The compound of  claim 9 ,
 wherein   R 8  and R 12  are each independently —H, —Br, or —NR 14 R 15 ,   R 9 , R 10 , and R 11  are each independently —H, —Br, —OH, —OR 13 , or —NR 14 R 15 ,
 wherein each occurrence of R 13 , R 14 , and R 15  is alkyl, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         11 . The compound of  claim 1 ,
 wherein   R 8  and R 12  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ,   or a pharmaceutically acceptable salt thereof.   
     
     
         12 - 14 . (canceled) 
     
     
         15 . The compound of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . A method of inhibiting the growth of a fungus or of inhibiting fungal shingolipid synthesis in a fungus or comprising contacting the fungus with an effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H, alkyl, alkenyl, or alkynyl; 
         R 2  is H, alkyl, alkenyl, or alkynyl; 
         R 3 , R 4 , R 5 , R 6 , and R 7  are each independently —H, halogen, CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —NH 2 , —NHR 13 , —NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ; 
         R 8  and R 9  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ; 
         R 10  is —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , —NHCOR 12 , or —CONR 14 R 15 ; and 
         R 11  and R 12  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ,
 wherein each occurrence of R 13  is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 wherein each occurrence of R 14  is independently —H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 wherein each occurrence of R 15  is independently —H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 
         or a pharmaceutically acceptable salt or ester thereof, so as to thereby inhibit the growth of the fungus or inhibit fungal shingolipid synthesis in the fungus, 
         wherein when the fungus is  Cryptococcus neoformans , then when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 11 , R 12  are each —H, R 9  is —Br, and —R 10  is —OH or —OCH 3 , then R 7  is other than —CH 3 ; and 
         when R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 11 , and R 12  are each —H, and —R 10  is OH, then R 6  and R 7  are other than —H and —CH 3 , or —Br, and H, respectively. 
       
     
     
         18 . (canceled) 
     
     
         19 . A method of inhibiting fungal shingolipid synthesis in a fungus in a mammal without substantially inhibiting mammalian shingolipid synthesis or of inhibiting the growth of or killing a fungus in a subject afflicted with a fungal infection comprising administering to the mammal or subject an effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H, alkyl, alkenyl, or alkynyl; 
         R 2  is H, alkyl, alkenyl, or alkynyl; 
         R 3 , R 4 , R 5 , R 6 , and R 7  are each independently —H, halogen, CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —NH 2 , —NHR 13 , —NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ; 
         R 8  and R 9  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ; 
         R 10  is —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , —NHCOR 12 , or —CONR 14 R 15 ; and 
         R 11  and R 12  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OH, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ,
 wherein each occurrence of R 13  is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 wherein each occurrence of R 14  is independently —H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 wherein each occurrence of R 15  is independently —H, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, 
 
         or a pharmaceutically acceptable salt or ester thereof, so as to thereby inhibit fungal shingolipid synthesis in the fungus in the mammal without substantially inhibiting mammalian shingolipid synthesis or inhibit the growth of or kill the fungus in the subject afflicted with the fungal infection, 
         wherein when the fungus is  Cryptococcus neoformans , then when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 11 , R 12  are each —H, R 9  is —Br, and —R 10  is —OH or —OCH 3 , then R 7  is other than —CH 3 ; and 
         when R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 11 , and R 12  are each —H, and —R 10  is OH, then R 6  and R 7  are other than —H and —CH 3  or —Br and H, respectively. 
       
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 17 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method of  claim 17 , further comprising contacting the fungus with an amount of an anti-fungal agent. 
     
     
         23 . The method of  claim 22 , wherein the anti-fungal agent is fluconazole, amphotericin B, caspofungin, tunicamycin or aureobasidin A. 
     
     
         24 . The method of  claim 17 , wherein the fungus is  Cryptococcus gattii, Candida albicans, Candida krusei, Candida glabrata, Candida parapsilosis, Candida guilliermondii, Aspergillus fumigatus, Rhizopus oryzae, Rhizopus  spp.,  Blastomyces dermatitis, Histoplasma capsulatum, Coccidioides  spp.,  Paecilomyces variotii, Pneumocystis murina, Pneumocystis jiroveci, Histoplasma capsulatum, Aspergillus  spp., a dimorphic fungi or a mucorales fungi. 
     
     
         25 . The method of  claim 17 , wherein the fungal shingolipid is glucosylceramide (GlcCer). 
     
     
         26 - 29 . (canceled) 
     
     
         30 . The method of  claim 17 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         31 - 36 . (canceled) 
     
     
         37 . The method of  claim 17 , wherein the fungus is  Cryptococcus Neoformans.    
     
     
         38 . The method of  claim 17 ,
 wherein   R 8  and R 12  are each independently —H, halogen, —CN, —CF 3 , —OCF 3 , —NO 2 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OAc, —OR 13 , —COR 13 , —SH, —SR 13 , —SO 2 R 13 , —SO 2 NR 14 R 15 , —NH 2 , —NHR 13 , NR 14 R 15 , —NHCOR 12 , or —CONR 14 R 15 ,   or a pharmaceutically acceptable salt thereof.