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 . (canceled) 
     
     
         2 . The method of  claim 11 , wherein R 4  and R 4′  are each hydrogen or taken together to form 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 10 , R 11 , and R 12  are each hydrogen; and R 7  is NR 7′ R 7″ ; R 7′  and R 7″  are each lower alkyl. 
     
     
         3 . The method of  claim 2 , wherein R 9  is substituted or unsubstituted aryl. 
     
     
         4 . The method of  claim 2 , wherein R 9  is substituted or unsubstituted alkynyl. 
     
     
         5 . The method of  claim 2 , wherein R 9  is alkyl. 
     
     
         6 . The method of  claim 2 , wherein R 9  is —(CH 2 ) o-3  NR 9c C(═Z′)ZR 9a . 
     
     
         7 . The method of  claim 2 , wherein R 9  is —N═S. 
     
     
         8 . The method of  claim 2 , wherein R 9  is aminoalkyl. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . A method for treating an inflammatory disorder in a subject in need thereof, the method comprising administering to said subject an effective amount of a tetracycline compound of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O; 
 R 2 , R 7  and R 7″  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 taken together to form the oxygen of a carbonyl; 
 R 2′ , R 3 , R 10 , R 11  and R 12  are each independently hydrogen or a pro-drug moiety; 
 R 5  is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkbxy, 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; 
 Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl. 
 
       
     
     
         12 - 13 . (canceled) 
     
     
         14 . The method of  claim 11 , wherein the compound of formula (IV) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The method of  claim 11 , wherein the inflammatory disorder is an inflammatory disorder of the skin. 
     
     
         16 . A method for treating an inflammatory disorder in a subject in need thereof, the method comprising administering to said subject an effective amount of a pharmaceutical composition comprising a tetracycline compound of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O; 
 R 2 , R 7′  and R 7″  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 taken together to form the oxygen of a carbonyl; 
 R 2 ′, R 3 , R 10 , R 11  and R 12  are each independently hydrogen or a pro-drug moiety; 
 R 5  is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkbxy, 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; 
         Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl. 
       
     
     
         17 . The method of  claim 16 , wherein R 4  and R 4′  are each hydrogen, or taken together to form 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 10 , R 11 , and R 12  are each hydrogen; and R 7  is NR 7′ R 7″ ; R 7′  and R 7″  are each lower alkyl. 
     
     
         18 . The method of  claim 17 , wherein R 9  is substituted or unsubstituted aryl. 
     
     
         19 . The method of  claim 17 , wherein R 9  is substituted or unsubstituted alkynyl. 
     
     
         20 . The method of  claim 17 , wherein R 9  is alkyl. 
     
     
         21 . The method of  claim 17 , wherein R 9  is —(CH 2 ) 0-3 NR 9c C(═Z′)ZR 9a . 
     
     
         22 . The method of  claim 17 , wherein R 9  is —N═S. 
     
     
         23 . The method of  claim 17 , wherein R 9  is aminoalkyl. 
     
     
         24 . The method of  claim 16 , wherein the compound of formula (IV) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The method of  claim 16 , wherein the inflammatory disorder is an inflammatory disorder of the skin.