Substituted tetracycline compounds for treatment of bacillus anthracis infections

Abstract

Methods and compositions for the treatment of Bacillus anthracis infections are described.

1 . A method for treating a  bacillus anthracis  infection in a subject, comprising administering to said subject an effective amount of a substituted tetracycline compound, such that said  bacillus anthracis  infection in said subject is treated. 
     
     
         2 . The method of  claim 1 , wherein said substituted tetracycline compound has an MIC less than that of doxycycline for at least one strain of  bacillus anthracis.    
     
     
         3 . The method of  claim 1 , wherein said substituted tetracycline compound has an MIC less than 32 μg/ml for a doxycycline resistant strain of  bacillus anthracis.    
     
     
         4 . The method of  claim 1 , wherein said substituted tetracycline compound has an MIC less than that of ciproflaxin for at least one strain of  bacillus anthracis.    
     
     
         5 . The method of  claim 1 , wherein said substituted tetracycline compound is of the formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, or halogen, optionally linked to R 2  to form a ring; 
 R 2″  is cyano or C(═O)—NR 2 R 2′ ; 
 R 2  is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl, hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino, alkylamino, heterocyclic, or absent, optionally linked to R 1  to form a ring; 
 R 2′ , R 3 , R 4a , and R 4b  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 10 , R 11 , and R 12  are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; 
 R 4  and R 4′  are each independently NR 4a R 4b , alkyl, acyl, alkenyl, alkynyl, hydroxyl, halogen, hydrogen, or taken together ═N—OR 4a ; 
 R 5  and R 5′  are each independently 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, dialkylamino, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, boronic ester, alkylcarbonyl, thionitroso, or —(CH 2 ) 0-3  (NR 7c ) 0-1 C(═W′)WR 7a ; 
 R 8  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3  (NR 8c ) 0-1 C(=E′)ER 8a ; 
 R 9  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3  (NR 9c ) 0-1  C(═Z′)ZR 9a ; 
 R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 9a , R 9b , R 9c , R 9d , R 9e , and R 9f  are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 13  is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an aryl alkyl; 
 E is CR 8d R 8e , S, NR 8b  or O; 
 E′ is O, NR 8f , or S; 
 W is CR 7d R 7e , S, NR 7b  or O; 
 W′ is O, NR 7f , or S; 
 X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6 , or O; 
 Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 Z is CR 9d R 9e , S, NR 9b  or O; 
 Z′ is O, S, or NR 9f , and pharmaceutically acceptable salts, esters and enantiomers thereof. 
 
     
     
         6 . The method of  claim 5 , wherein R 2″  is C(═O)NH 2 ; R 3 , R 10 , R 11 , and R 12  are each hydrogen or a prodrug moiety; R 4  is NR 4a R 4b ; R 4a  and R 4b  are each methyl; R 5  is hydrogen; R 8  is hydrogen; X is CR 6 R 6′ ; R 6  is hydrogen; and R 5′  and R 6′  are hydrogen. 
     
     
         7 . The method of  claim 6 , wherein R 8  and R 9  are hydrogen. 
     
     
         8 . The method of  claim 7 , wherein R 7  is substituted phenyl, a boronic ester, alkylcarbonyl, heterocyclic, aminoalkyl, or arylalkynyl. 
     
     
         9 . The method of  claim 8 , wherein R 7  is phenyl substituted with alkoxy, alkyl-O—N═C—CR 7g R 7h , alkylaminoalkyl, alkenylaminoalkyl, alkoxyalkylaminoalkyl, substituted alkyl, or substituted carbonylamino, wherein R 7g  and R 9h  are each independently hydrogen or alkyl. 
     
     
         10 . The method of  claim 8 , wherein R 7  is substituted or unsubstituted heteroaryl. 
     
     
         11 . The method of  claim 10 , wherein R 7  is substituted or unsubstituted pyrimidinyl, pyridinyl, or furanyl. 
     
     
         12 . The method of  claim 8 , wherein R 7  is substituted or unsubstituted piperdinyl-alkyl. 
     
     
         13 . The method of  claim 8 , wherein R 7  is pyridinyl-alkynyl or substituted or unsubstituted phenyl alkynyl. 
     
     
         14 . The method of  claim 6 , wherein R 7  is hydrogen. 
     
     
         15 . The method of  claim 14 , wherein R 9  is substituted carbonylamino. 
     
     
         16 . The method of  claim 6 , wherein R 8  is hydrogen; R 7  is heterocyclic, alkyl, alkyl-O—N═C—CR 7g R 7h —, or dimethylamino, wherein R 7g  and R 9h  are each independently hydrogen or alkyl. 
     
     
         17 . The method of  claim 16 , wherein R 9  is aminoalkyl. 
     
     
         18 - 36 . (canceled) 
     
     
         37 . A pharmaceutical composition comprising an effective amount of a substituted tetracycline compound for the treatment of a  bacillus anthracis  infection and a pharmaceutically acceptable carrier. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein said substituted tetracycline compound is of formula (I): 
       formula I: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, or halogen, optionally linked to R 2  form a ring;
 R 2″  is cyano or C(═O)—NR 2 R 2′ ; 
 R 2  is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl, hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino, alkylamino, heterocyclic, or absent, optionally linked to R 1  to form a ring; 
 R 2′ , R 3 , R 4a , and R 4b  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 10 , R 11 , and R 12  are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; 
 R 4  and R 4′  are each independently NR 4a R 4b , alkyl, acyl, alkenyl, alkynyl, hydroxyl, halogen, hydrogen, or taken together ═N—OR 4a ; 
 R 5  and R 5′  are each independently 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′  each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 R 7  is hydrogen, dialkylamino, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, boronic ester, alkylcarbonyl, thionitroso, or —(CH 2 ) 0-3  (NR 7c ) 0-1 C(═W′)WR 7a ; 
 R 8  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3  (NR 8c ) 0-1 C(=E′)ER 8a ; 
 R 9  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl heterocyclic, thionitroso, or —(CH 2 ) 0-3  (NR 9c ) 0-1  C(═Z′)ZR 9a ; 
 R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 9a , R 9b , R 9c , R 9d , R 9e , and R 9f  are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 13  is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 E is CR 8d R 8e , S, NR 8b  or O; 
 E′ is O, NR 8f , or S; 
 W is CR 7d R 7e , S, NR 7b  or O; 
 W′ is O, NR 7f , or S; 
 X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6 , or O; 
 Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 Z is CR 9d R 9e , S, NR 9b  or O; 
 Z′ is O, S, or NR 9f , and pharmaceutically acceptable salts, esters and enantiomers thereof. 
 
     
     
         39 - 49 . (canceled)