4-Substituted Tetracyclines and Methods of Use Thereof

Abstract

The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds such as blocking tetracycline efflux and modulation of gene expression.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2′  and R 2″  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 3′  is hydroxyl, hydrogen, or a pro-drug moiety; 
 R 4  is O; 
 R 4a  is hydrogen, alkyl, alkenyl, alkynyl, or aryl; 
 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, 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 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 , or a pharmaceutically acceptable salt, ester or enantiomer thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2′ , R 3 , R 10 , R 11 , and R 12  are each hydrogen or a prodrug moiety; X is CR 6 R 6′ ; and R 2″ , R 5 , R 5′ , R 6 , and R 6′  are each hydrogen. 
     
     
         3 . The compound of  claim 1 , wherein R 5  and R 5′  are each hydrogen and X is CR 6 R 6′ , wherein R 6  is methyl and R 6′  is hydroxy. 
     
     
         4 . The compound of  claim 1 , wherein R 5  is hydroxyl; X is CR 6 R 6′ ; R 6  is methyl; and R 5′  and R 6′  are each hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein X is CR 6 R 6′ ; R 5 , R 5′ , R 6  and R 6′  are each hydrogen and R 7  is dimethylamino. 
     
     
         6 . The tetracycline compound of  claim 1 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester or enantiomer thereof. 
     
     
         7 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2′  and R 2″  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 3′  is hydroxyl, hydrogen, or a pro-drug moiety; 
 R 4  is NR 4c R 4d ; 
 R 4c  and R 4d  are each independently hydrogen, sulfonyl, arylcarbonyl, arylaminocarbonyl, aryloxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, acyl, alkyl, alkenyl, alkynyl, or aryl; 
 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, 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 7c ) 0-1 CC(═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 , or a pharmaceutically acceptable salt, ester or enantiomer thereof. 
 
     
     
         8 . The compound of  claim 7 , wherein R 2′ , R 3 , R 10 , R 11 , and R 12  are each hydrogen or a prodrug moiety; X is CR 6 R 6′ ; and R 2″ , R 5 , R 5′ , R 6 , and R 6′  are each hydrogen. 
     
     
         9 . The compound of  claim 7 , wherein R 5  and R 5′  are each hydrogen and X is CR 6 R 6′ , wherein R 6  is methyl and R 6′  is hydroxy. 
     
     
         10 . The compound of  claim 7 , wherein R 5  is hydroxyl; X is CR 6 R 6′ ; R 6  is methyl; and R 5′  and R 6′  are each hydrogen. 
     
     
         11 . The compound of  claim 7 , wherein X is CR 6 R 6′ ; R 5 , R 5′ , R 6  and R 6′  are each hydrogen and R 7  is dimethylamino. 
     
     
         12 . The compound of  claim 7 , wherein R 9  is hydrogen. 
     
     
         13 . The compound of  claim 7 , wherein R 9  is substituted or unsubstituted alkyl. 
     
     
         14 . The compound of  claim 13 , wherein R 9  is aminoalkyl. 
     
     
         15 . The compound of  claim 7 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters and enantiomers thereof. 
     
     
         16 . A method for treating a tetracycline responsive state in a subject, comprising administering to said subject an effective amount of a compound of  claim 1 , such that said subject is treated. 
     
     
         17 . The method of  claim 16 , wherein said tetracycline responsive state is a bacterial infection, a viral infection, or a parasitic infection. 
     
     
         18 . The method of  claim 16 , wherein said subject is a human. 
     
     
         19 . The method of  claim 16 , wherein said compound is administered with a pharmaceutically acceptable carrier. 
     
     
         20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.