Substituted tetracycline compounds as antifungal agents

Abstract

Methods and compositions for treating fungal associated disorders in subjects are discussed.

1 . A pharmaceutical composition comprising an effective amount of a substituted tetracycline compound to treat a fungal associated disorder in a subject and a pharmaceutically acceptable carrier.  
     
     
         2 . The pharmaceutical composition of claim  110 , wherein said effective amount is effective to treat  histoplasmosis,  systemic  candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis, dermatophyte infections, tinea pedis, tinea cruris, candidiasis, actinomycosis, mycoses, aspergillosis, candidosis, chromomycosis, entomophthoromycosis, epizootic lymphangitis, geotrichosis, histoplasmosis, mucormycosis, mycetoma,  north american blastomycosis,  oomycosis, paecilimycosis, penicilliosis, rhinosporidiosis,  or  sprotrichiosis.    
     
     
         3 . The pharmaceutical composition of claim  110 , wherein said substituted tetracycline compound is of the formula:  
       
         
           
           
               
               
           
         
         X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O;  
         R 2 , R 2′ , R 4′ , and R 4″  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;  
         R 4  is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;  
         R 3 , R 11  and R 12  are each hydrogen, or a pro-drug moiety;  
         R 10  is hydrogen, a prodrug moiety, or linked to R 9  to form a ring;  
         R 5  is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;  
         R 6  and R 6′  are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;  
         R 7 is hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ;  
         R 9  is hydrogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso(e.g., —N═S), or —(CH 2 ) 0-3 NR 9c C(═Z′)ZR 9a ;  
         Z is CR 9d R 9e , S, NR 9b or O;  
         Z′ is O, S, or NR 9f ;  
         W is CR 7d R 7e , S, NR 7b  or O;  
         W′ is O, NR 7f  S;  
         R 7a ,R 7b ,R 7c ,R 7d ,R 7e ,R 9a ,R 9b ,R 9c ,R 9d , and R 9e  are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;  
         R 8  is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;  
         R 13  is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and  
         Y′ and Y are eah independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts thereof.