7,9-substituted tetracycline compounds

Abstract

The present invention pertains to novel 7,9-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 7,9-substituted tetracycline compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 X is CHC(R 13 Y′Y) or CR 6′ R 6 ; 
 R 2 , R 2′ , R 4′  and R 4″  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic or heteroaromatic; 
 R 4  is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, hydroxyl, halogen or hygrogen; 
 R 3 , R 8 , R 10 , R 11  and R 12  are each 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, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 
 R 7  is carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, alkoxy or amino; 
 R 9  is alkyl or carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, alkoxy or amino; 
 R 13  is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 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 or esters thereof. 
 
   
   
       2 . The tetracycline compound of  claim 1 , wherein X is CR 6 R 6′ ; R 2 , R 2′ , R 6  and R 6′  are each hydrogen; R 4  is NR 4′ R 4″ ; R 4′  and R 4″  are lower alkyl; and R 5  is hydroxyl or hydrogen. 
   
   
       3 . The tetracycline compound of  claim 2 , wherein R 4′  and R 4″  are each methyl and R 5  is hydrogen. 
   
   
       4 . The tetracycline compound of  claim 1 , wherein R 7  is carbonyl substituted with alkyl. 
   
   
       5 . The tetracycline compound of  claim 4 , wherein said alkyl is unsubstituted. 
   
   
       6 . The tetracycline compound of  claim 4 , wherein said alkyl is substituted with one or more groups selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, alkylamino, dialkylamino, arylamino, diarylamino, arylalkylamino, acylamino, alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl, and an aromatic or heteroaromatic moiety. 
   
   
       7 . The tetracycline compound of  claim 6 , wherein said alkyl is substituted with dialkylamino. 
   
   
       8 . The tetracycline compound of  claim 1 , wherein R 9  is unsubstituted alkyl. 
   
   
       9 . The tetracycline compound of  claim 1 , wherein R 9  is alkyl substituted with one or more groups selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, alkylamino, dialkylamino, arylamino, diarylamino, arylalkylamino, acylamino, alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl, and an aromatic or heteroaromatic moiety. 
   
   
       10 . The tetracycline compound of  claim 1 , wherein R 9  is carbonyl substituted with alkyl. 
   
   
       11 . The tetracycline compound of  claim 10 , wherein said alkyl is unsubstituted. 
   
   
       12 . The tetracycline compound of  claim 10 , wherein said alkyl is substituted one or more groups selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino, alkylamino, dialkylamino, arylamino, diarylamino, arylalkylamino, acylamino, alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl, and an aromatic or heteroaromatic moiety. 
   
   
       13 . A 7,9-substituted tetracycline compound selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       14 . A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       15 . A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of  claim 13  and a pharmaceutically acceptable carrier.