Aromatic a-ring derivatives of tetracycline compounds

Abstract

Aromatized A-ring derivatives of tetracycline compounds are described.

1 . A compound of formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, amino, alkylamino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthiol, arylthiol, alkenyl, heterocyclic, hydroxyl or halogen, or R 1  is optionally linked to R 2  to form a ring; 
 R 2  is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl, hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino, alkylamino, heterocyclic or absent, or R 2  is optionally linked to R 1  to form a ring; 
 R 2′ , R 2″ , R 4a  and R 4b  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 10 , R 11  and R 12  are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl or a pro-drug moiety; 
 R 4  and R 4′  are each independently NR 4a R 4b , alkyl, alkenyl, alkynyl, hydroxyl, halogen or hydrogen; 
 R 5  and R 5′  are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy or aryl carbonyloxy; 
 R 6  and R 6′  are each independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 
 R 7  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ; 
 R 8  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, 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, alkylthiol, 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, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 13  is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 
 W is CR 7d R 7e , S, NR 7b  or O; 
 W′ is O, NR 7f  or S; 
 E is CR 8d R 8e , S, NR 8b  or O; 
 E′ is O, NR 8f  or S; 
 Z is CR 9d R 9e , S, NR 9b  or O; 
 Z′ is O, NR 9f  or S; 
 Q is a double bond when R 2  is absent, or Q is a single bond when R 2  is hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, formyl, alkoxy, amino, alkylamino, cyano, nitro or heterocyclic; 
 X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6  or O; and 
 Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl, or pharmaceutically acceptable salts, esters and enantiomers thereof. 
 
   
   
       2 . The compound of  claim 1 , wherein R 4  is NR 4a R 4b ; R 4a  and R 4b  are each alkyl; R 5  is hydroxyl; X is CR 6′ R 6 ; R 6  is methyl; and R 5′  and R 6′  are each hydrogen. 
   
   
       3 . The compound of  claim 1 , wherein R 1 , R 7  and R 8  are each hydrogen. 
   
   
       4 . The compound of  claim 1 , wherein R 9  is hydrogen. 
   
   
       5 . The compound of  claim 1 , wherein R 9  is alkyl substituted with unsubstituted or substituted amino. 
   
   
       6 . The compound of  claim 5 , wherein R 9  is alkyl substituted with alkylamino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino or arylcarbonylamino. 
   
   
       7 . The compound of  claim 1 , wherein R 9  is unsubstituted amino. 
   
   
       8 . The compound of  claim 1 , wherein R 9  is substituted amino selected from alkylamino, dialkylamino, arylamino, alkylcarbonylamino, arylcarbonylamino and alkyl aminocarbonylamino. 
   
   
       9 . The compound of  claim 1 , selected from: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts, esters and enantiomers thereof. 
   
   
       10 . The compound of  claim 1 , wherein R 1  and R 2  are linked to form a 3, 4, 5, 6, 7, 8 or 9 membered ring. 
   
   
       11 . The compound of  claim 1 , wherein R 1  and R 2  are linked to form a ring selected from an epoxide ring, a lactam ring, a lactone ring and a carboxylic ring. 
   
   
       12 . A compound of formula III: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, amino, alkylamino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthiol, arylthiol, alkenyl, heterocyclic, hydroxyl or halogen; 
 R 2′ , R 2″ , R 4a  and R 4b  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 3 , R 10 , R 11  and R 12  are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl or a pro-drug moiety; 
 R 4  and R 4′  are each independently NR 4a R 4b , alkyl, alkenyl, alkynyl, hydroxyl, halogen or hydrogen; 
 R 5  and R 5′  are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy or aryl carbonyloxy; 
 R 6  and R 6′  are each independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 
 R 7  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ; 
 R 8  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, 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, alkylthiol, 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, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 13  is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 
 W is CR 7d R 7e , S, NR 7b  or O; 
 W′ is O, NR 7f  or S; 
 E is CR 8d R 8e , S, NR 8b  or O; 
 E′ is O, NR 8f  or S; 
 Z is CR 9d R 9e , S, NR 9b  or O; 
 Z′ is O, NR 9f  or S; 
 X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6  or O; and 
 Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl, or pharmaceutically acceptable salts, esters and enantiomers thereof. 
 
   
   
       13 . The compound of  claim 12 , wherein R 4  is NR 4a R 4b ; R 4a  and R 4b  are each alkyl; R 5  is hydroxyl; X is CR 6′ R 6 ; R 6  is methyl; and R 5′  and R 6′  are each hydrogen. 
   
   
       14 . The compound of  claim 12 , wherein R 7 , R 8 , and R 9  are each hydrogen. 
   
   
       15 . The compound of  claim 12 , wherein R 1  is amino or alkylamino. 
   
   
       16 . The compound of  claim 12 , selected from: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts, esters and enantiomers thereof. 
   
   
       17 . A compound of formula IV: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, amino, alkylamino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthiol, arylthiol, alkenyl, heterocyclic, hydroxyl or halogen; 
 R 2′ , R 2″ , R 4a  and R 4b  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 10 , R 11  and R 12  are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl or a pro-drug moiety; 
 R 4  is NR 4a R 4b , alkyl, alkenyl, alkynyl, hydroxyl, halogen or hydrogen; 
 R 5  and R 5′  are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy or aryl carbonyloxy; 
 R 6  and R 6′  are each independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 
 R 7  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ; 
 R 8  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthiol, 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, alkylthiol, 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, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 13  is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl; 
 W is CR 7d R 7e , S, NR 7b  or O; 
 W′ is O, NR 7f  or S; 
 E is CR 8d R 8e , S, NR 8b  or O; 
 E′ is O, NR 8f  or S; 
 Z is CR 9d R 9e , S, NR 9b  or O; 
 Z′ is O, NR 9f  or S; 
 Q is a double bond when R 2  is absent, or Q is a single bond when R 2  is hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, formyl, alkoxy, amino, alkylamino or heterocyclic; 
 X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6  or O; and 
 Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl, or pharmaceutically acceptable salts, esters and enantiomers thereof. 
 
   
   
       18 . A pharmaceutical composition comprising an effective amount of a compound of any one of  claims 1 ,  12  and  17  and a pharmaceutically acceptable carrier.