4-Dedimethylamino tetracycline compounds

Abstract

The present invention pertains, at least in part, to novel substituted 4-dedimethylamino 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 IV:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O;  
 R 2  and R 7′  and R ″  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;  
 R 4  and R 4′  are each independently alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy halogen, hydrogen, or when taken together the oxygen of a carbonyl;  
 R 2′ , R 3 , R 10 , R 11  and R 12  are each hydrogen or a pro-drug moiety;  
 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 NR 7′ R 7″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;  
 R 9  is nitro, alkyl, alkenyl, alkynyl, aryl alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, thionitroso, or —(CH 2 ) 0-3 NR 9c C(═Z′)ZR 9a ;  
 Z is CR 9d R 9e , S, NR 9b , or O;  
 Z′ is NR 9f , O, or S;  
 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 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 each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl, and pharmaceutically acceptable salts, esters and prodrugs thereof.  
 
     
     
         2 . The tetracycline compound of  claim 1 , wherein R 4  and R 4′  are each hydrogen or the oxygen of a carbonyl group; X is CR 6 R 6′ ; R 2 , R 2′ , R 5 , R 6 , R 6′ , R 8 , R 9 , R 10 , R 11 , and R 12  are each hydrogen; R 7  is NR 7′ R 7″ ; R 7′  and R 7″  are each lower alkyl; and R 4  and R 4′  are each hydrogen.  
     
     
         3 . The tetracycline compound of  claim 2 , wherein R 9  is substituted or unsubstituted aryl.  
     
     
         4 . The tetracycline compound of  claim 2 , wherein R 9  is substituted or unsubstituted alkynyl.  
     
     
         5 . The tetracycline compound of  claim 2 , wherein R 9  is alkyl.  
     
     
         6 . The tetracycline compound of  claim 2 , wherein R 9  is —(CH 2 ) 0-3  NR 9c C(=Z)ZR 9a .  
     
     
         7 . The tetracycline compound of  claim 2 , wherein R 9  is —N═S.  
     
     
         8 . The tetracycline compound of  claim 2 , wherein R 9  is aminoalkyl.  
     
     
         9 . The tetracycline compound of  claim 8 , wherein said aminoalkyl is alkylaminoalkyl.  
     
     
         10 . The tetracycline compound of  claim 2 , wherein R 9  is substituted or unsubstituted alkyl amino.  
     
     
         11 . 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 subject is treated.  
     
     
         12 . The method of  claim 11 , wherein said subject is a human.  
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of  claim 1 , and a pharmaceutically acceptable carrier.