7-And 9-Carbamate, Urea, Thiourea, Thiocarbamate, And Heteroaryl-Amino Substituted Tetracycline Compounds

Abstract

Substituted tetracycline compounds, methods of synthesis, and methods of use are discussed. Tetracyclines useful for treating tetracycline related disorders are also discussed. Intermediates useful for synthesizing other tetracycline compounds are also included.

1 . A compound, wherein said compound is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O; 
 R 2  is hydrogen, alkyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 4  and R 4′  are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 2′ , R 3 , R 10 , R 11  and R 12  are each hydrogen or a pro-drug moiety; 
 R 5  is hydrogen, hydroxyl, or a prodrug moiety; 
 R 6 , R 6′ , and R 8  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, or halogen; 
 R 7  is hydrogen, or NR 7c C(═W′)WR 7a ; 
 R 8  is hydrogen; 
 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; 
 R 9  is hydrogen, or NR 9c C(═Z′)ZR 9a ; 
 Z is O; 
 Z′ is O or S; 
 R 9a  is unsubstituted C 3 -C 10  alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylamino, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaromatic, wherein said substituted alkyl is substituted with halogen, amino, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl or heteroaryl; further wherein said substituted alkenyl, substituted alkynyl, substituted alkoxy, substituted alkylthio, substituted alkylsulfinyl, substituted alkylsulfonyl, substituted arylsulfonyl, substituted alkoxycarbonyl, substituted arylcarbonyl, substituted alkylamino, substituted arylalkyl, substituted aryl, substituted heterocyclic, or substituted heteroaromatic is substituted with halogen, amino, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl or heteroaryl; 
 R 9c  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic or heteroaromatic; 
 W is CR 7d R 7e , NR 7b  or O; 
 W′ is O or S; and 
 R 7a , R 7b , R 7c , R 7d  and R 7e  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety, and R 7d  and R 7e  may be linked to form a ring; 
 or a pharmaceutically acceptable salt thereof, provided that R 9  is not hydrogen when R 7  is hydrogen. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2 , R 2′ , R 3 , R 8 , R 10 , R 11 , and R 12  are each hydrogen. 
     
     
         3 . The compound of  claim 2 , wherein R 4  and R 4′  are each alkyl. 
     
     
         4 . The compound of  claim 3 , wherein R 4  and R 4′  are each methyl 
     
     
         5 . The compound of  claim 4 , wherein R 5  is hydrogen. 
     
     
         6 . The compound of  claim 5 , wherein X is CH 2 , and R 7  is hydrogen. 
     
     
         7 . The compound of  claim 5 , wherein X is CH 2 , and R 7  is N(Me) 2 . 
     
     
         8 . The compound of  claim 4 , wherein R 5  is hydroxyl or a prodrug moiety, and X is CHR 6 . 
     
     
         9 . The compound of  claim 4 , wherein R 5  is hydroxyl and R 6  is CH 3 . 
     
     
         10 . The compound of  claim 1 , wherein R 9  is NR 9c C(═Z′)ZR 9a . 
     
     
         11 . The compound of  claim 10 , wherein R 9c  is hydrogen. 
     
     
         12 . The compound of  claim 10 , wherein Z′ is oxygen. 
     
     
         13 . The compound of  claim 10 , wherein Z′ is sulfur. 
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound and a pharmaceutically acceptable carrier, wherein said compound is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O; 
 R 2  is hydrogen, alkyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 4  and R 4′  are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 2′ , R 3 , R 10 , R 11  and R 12  are each hydrogen or a pro-drug moiety; 
 R 5  is hydrogen, hydroxyl, or a prodrug moiety; 
 R 6 , R 6′ , and R 8  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, or halogen; 
 R 7  is hydrogen or NR 7c C(═W′)WR 7a ; 
 R 8  is hydrogen; 
 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; 
 R 9  is hydrogen, or NR 9c C(═Z′)ZR 9a ; 
 Z is O; 
 Z′ is O or S; 
 R 9a  is unsubstituted C 3 -C 10  alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylamino, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaromatic, wherein said substituted alkyl is substituted with halogen, amino, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl or heteroaryl; further wherein said substituted alkenyl, substituted alkynyl, substituted alkoxy, substituted alkylthio, substituted alkylsulfinyl, substituted alkylsulfonyl, substituted arylsulfonyl, substituted alkoxycarbonyl, substituted arylcarbonyl, substituted alkylamino, substituted arylalkyl, substituted aryl, substituted heterocyclic, or substituted heteroaromatic is substituted with halogen, amino, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl or heteroaryl; 
 R 9c  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic or heteroaromatic; 
 W is CR 7d R 7e , NR 7b  or O; 
 W′ is O or S; and 
 R 7a , R 7b , R 7c , R 7d , and R 7e  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic, absent, or a prodrug moiety, and R 7d  and R 7e  may be linked to form a ring; 
 or a pharmaceutically acceptable salt thereof, provided that R 9  is not hydrogen when R 7  is hydrogen. 
 
     
     
         15 . A compound, wherein said compound is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O; 
 R 2  is hydrogen, alkyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 4  and R 4′  are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 2′ , R 3 , R 10 , R 11  and R 12  are each hydrogen or a pro-drug moiety; 
 R 5  is hydrogen, hydroxyl, or a prodrug moiety; 
 R 6 , R 6′ , and R 8  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, or halogen; 
 R 7  dialkylamino; 
 R 8  is hydrogen; 
 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; 
 R 9  is NR 9c C(═Z′)ZR 9a ; 
 Z is O; 
 Z′ is O or S; 
 R 9a  is unsubstituted or substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylamino, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaromatic, wherein said substituted alkyl is substituted with halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl or heteroaryl; further wherein said substituted alkenyl, substituted alkynyl, substituted alkoxy, substituted alkylthio, substituted alkylsulfinyl, substituted alkylsulfonyl, substituted arylsulfonyl, substituted alkoxycarbonyl, substituted arylcarbonyl, substituted alkylamino, substituted arylalkyl, substituted aryl, substituted heterocyclic, or substituted heteroaromatic is substituted with halogen, amino, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, cyano, azido, heterocyclyl, alkylaryl, aryl or heteroaryl; and 
 R 9c  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, alkylamino, arylalkyl, aryl, heterocyclic or heteroaromatic; and pharmaceutically acceptable salts thereof. 
 
     
     
         16 . The compound of  claim 15 , wherein R 2 , R 2′ , R 3 , R 8 , R 10 , R 11 , and R 12  are each hydrogen. 
     
     
         17 . The compound of  claim 15 , wherein R 4  and R 4′  are each methyl 
     
     
         18 . The compound of  claim 15 , wherein R 5  is hydrogen. 
     
     
         19 . The compound of  claim 18 , wherein R 9  is NR 9c C(═Z′)ZR 9a . 
     
     
         20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 15  and a pharmaceutically acceptable carrier.