3, 10, AND 12a SUBSTITUTED TETRACYCLINE COMPOUNDS

Abstract

The present invention pertains to novel 3, 10, and/or 12a-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 minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.

1 . A tetracycline compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CHC(R 13 Y′Y) or CR 6′ R 6 ; 
 R 2″  is —C(═O)NR 2 R 2′  or —CN; 
 R 2 , R 2′ , 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 3 , R 11  and R 12″  are each independently hydrogen, alkyl, alkenyl, aryl, alkynyl, aryallkyl, acetyl, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl; 
 R 10  is hydrogen, alkenyl, aryl, alkynyl, arylalkyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl; 
 R 12  is hydrogen, alkyl, alkenyl, aryl, alkynyl, arylalkyl, alkenylcarbonyl, alkynylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl, provided that at least one of R 3 , R 10 , R 11  or R 12  is not hydrogen when R 12′  is OR 12 ; 
 R 4  and R 4′  are each independently NR 4a R 4b , alkyl, alkenyl, alkynyl, hydroxyl, halogen or hydrogen; 
 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 arylalkyl; 
 R 7  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso or —(CH 2 ) 1-3 NR 7c 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 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 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 12′  is OR 12  or NR 12 R 12″ ; 
 R 13  is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino or 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; 
 Z is CR 9d R 9e , S, NR 9b  or O; 
 Z′ is O, S or NR 9f ; and 
 Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 
 
       or pharmaceutically acceptable salts, esters or enantiomers thereof. 
     
     
         2 . The tetracycline compound of  claim 1 , wherein X is CR 6 R 6′ ; R 2 , R 2′ , R 6 , R 6′ , R 8  and R 11  are each hydrogen; and R 5  is hydroxyl or hydrogen. 
     
     
         3 . The tetracycline compound of  claim 2 , wherein R 4  is dialkylamino, and R 4′  and R 5  are each hydrogen. 
     
     
         4 . The tetracycline compound of  claim 1 , wherein R 3  is hydrogen, alkyl, alkenyl, aryl, acetyl, arylalkyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl. 
     
     
         5 . The tetracycline compound of  claim 4 , wherein R 3  is benzyl. 
     
     
         6 . The tetracycline compound of  claim 4 , wherein R 3  is alkyl. 
     
     
         7 . The tetracycline compound of  claim 4 , wherein R 3  is acetyl. 
     
     
         8 . The tetracycline compound of  claim 4 , wherein R 3  is alkenyl. 
     
     
         9 . The tetracycline compound of  claim 4 , wherein R 3  is hydrogen. 
     
     
         10 . The tetracycline compound of  claim 1 , wherein R 10  hydrogen, alkenyl, aryl, arylalkyl, alkynyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl. 
     
     
         11 . The tetracycline compound of  claim 10 , wherein R 10  is benzyl. 
     
     
         12 . The tetracycline compound of  claim 10 , wherein R 10  is alkenyl. 
     
     
         13 . The tetracycline compound of  claim 10 , wherein R 10  is hydrogen. 
     
     
         14 . The tetracycline compound of  claim 1 , wherein R 12  is hydrogen, alkyl, alkenyl, aryl, arylalkyl, alkynyl, alkenylcarbonyl, alkynylcarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl, or arylthiothiocarbonyl. 
     
     
         15 . The tetracycline compound of  claim 14 , wherein R 12  is benzyl. 
     
     
         16 . The tetracycline compound of  claim 14 , wherein R 12  is hydrogen. 
     
     
         17 . A tetracycline compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A method for treating a tetracycline responsive state in a subject, comprising administering to said subject a tetracycline compound of  claim 1 , such that said tetracycline responsive state is treated. 
     
     
         19 . The method of  claim 18 , wherein said tetracycline compound is non-antibacterial. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of  claim 1 , and a pharmaceutically acceptable carrier.