Anti-fungals targeting the synthesis of fungal shingolipids

Abstract

The present invention provides a compound having the structure:

1 - 16 . (canceled) 
     
     
         17 . A method of inhibiting the growth of a fungus 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, 
 
         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, 
         or a pharmaceutically acceptable salt or ester thereof, so as to thereby inhibit the growth of the fungus. 
       
     
     
         18 . A method of inhibiting fungal shingolipid synthesis in a fungus 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, 
 
         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 1 , 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, 
         or a pharmaceutically acceptable salt or ester thereof, so as to thereby inhibit shingolipid synthesis in the fungus. 
       
     
     
         19 . A method of inhibiting fungal shingolipid synthesis in a fungus in a mammal without substantially inhibiting mammalian shingolipid synthesis comprising administering to the mammal 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 2 , 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, 
 
         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, 
         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. 
       
     
     
         20 . The method of  claim 17 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 3 , R 4 , R 5 , and 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 ,
 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. 
       
     
     
         21 . The method of  claim 17 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method of claim  1 , 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 Neoformans, 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 18 , wherein the fungal shingolipid is glucosylceramide (GlcCer). 
     
     
         26 - 36 . (canceled) 
     
     
         37 . The method of  claim 18 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 3 , R 4 , R 5 , and 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 ,
 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. 
       
     
     
         38 . The method of  claim 18 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         39 . The method of  claim 18 , further comprising contacting the fungus with an amount of an anti-fungal agent. 
     
     
         40 . The method of  claim 38 , wherein the anti-fungal agent is fluconazole, amphotericin B, caspofungin, tunicamycin or aureobasidin A. 
     
     
         41 . The method of  claim 18 , wherein the fungus is  Cryptococcus Neoformans, 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. 
     
     
         42 . The method of  claim 19 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 3 , R 4 , R 5 , and 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 ,
 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. 
       
     
     
         43 . The method of  claim 19 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         44 . The method of  claim 19 , further comprising contacting the fungus with an amount of an anti-fungal agent. 
     
     
         45 . The method of  claim 43 , wherein the anti-fungal agent is fluconazole, amphotericin B, caspofungin, tunicamycin or aureobasidin A. 
     
     
         46 . The method of  claim 19 , wherein the fungus is  Cryptococcus Neoformans, 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. 
     
     
         47 . The method of  claim 19 , wherein the fungal shingolipid is glucosylceramide (GlcCer).