Amino-methyl substituted tetracycline compounds

Abstract

Aminomethyl substituted tetracycline compounds, pharmaceutical compositions, and methods of use thereof are discussed.

1 . A tetracycline compound of the formula (I):  
       
         
           
           
               
               
           
         
         wherein 
 R 1  and R 2  are linked to form a ring, or pharmaceutically acceptable salts, prodrugs and esters thereof.  
 
       
     
     
         2 . The tetracycline compound of  claim 1 , wherein R 1  and R 2  are linked to form a five membered ring.  
     
     
         3 . The tetracycline compound of  claim 1 , wherein R 1  and R 2  are linked to form a six membered ring.  
     
     
         4 . The tetracycline compound of  claim 3 , wherein R 1  and R 2  are linked to form a piperidine ring, morpholine ring, pyridine ring, or a pyrazinyl ring.  
     
     
         5 . The tetracycline compound of  claim 4 , wherein said compound is:  
       
         
           
           
               
               
           
         
       
     
     
         6 . A tetracycline compound of the formula:  
       
         
           
           
               
               
           
         
       
       pharmaceutically acceptable salts, esters or prodrugs thereof.  
     
     
         7 . A tetracycline compound of the formula (II):  
       
         
           
           
               
               
           
         
       
       wherein: 
 J 1  and J 2  are each independently hydrogen, aryl, sulfonyl, acyl, or linked to form a ring, provided that at least one of J 1  or J 2  is not hydrogen;  
 J 3  and J 4  are each alkyl, halogen, or hydrogen;  
 X is CHC(R 13 Y′Y), CR 6′ R 6 , C═CR 6′ R 6 , S, NR 6 , or O;  
 R 2 , R 2′ , R 4′ , and R 4″  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;  
 R 4  is NR 4′ , R 4″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;  
 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 9  is hydrogen, 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 , NR 9b  or O;  
 Z′ is O, S, or NR 9f ;  
 R 9a , R 9b , R 9c , R 9d , and R 9e  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.  
 
     
     
         8 . The tetracycline compound of  claim 7 , wherein R 4  is NR 4′ R 4″ , X is CR 6 R 6′ ; R 2 , R 2′ , R 6 , R 6′ , R 8 , R 9 , R 10 , R 11 , and R 12  are each hydrogen; R 4′  and R 4″  are lower alkyl; and R 5  is hydroxy or hydrogen.  
     
     
         9 . The tetracycline compound of  claim 8 , wherein R 4′  and R 4″  are each methyl and R 5  is hydrogen.  
     
     
         10 . The tetracycline compound of  claim 7 , wherein J 3  and J 4  are hydrogen.  
     
     
         11 . The tetracycline compound of  claim 7 , wherein J 1  is substituted or unsubstituted alkyl.  
     
     
         12 . The tetracycline compound of  claim 7 , wherein J 1  is sulfonyl.  
     
     
         13 . The tetracycline compound of  claim 7 , wherein J 1  and J 2  are linked to form a ring.  
     
     
         14 . The tetracycline compound of  claim 7 , wherein J 1  is heteroaryl.  
     
     
         15 . A tetracycline compound, wherein said compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
 R is substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, alkoxy; and Y is N, O, or S, or pharmaceutically acceptable salts, esters, or prodrugs thereof.  
 
       
     
     
         16 . A tetracycline compound of formula (III):  
       
         
           
           
               
               
           
         
       
       wherein: 
 J 5  and J 6  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, sulfonyl, acyl, alkoxycarbonyl, alkaminocarbonyl, alkaminothiocarbonyl, substituted thiocarbonyl, substituted carbonyl, alkoxythiocarbonyl, or linked to form a ring;  
 J 7  and J 8  are each alkyl, halogen, or hydrogen;  
 X is CHC(R 13 Y′Y), CR 6′ R 6 , C═CR 6′ R 6 , S, NR 6 , or O;  
 R 2 , R 2′ , R 4′ , and R 4″  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;  
 R 4  is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or hydrogen;  
 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 hydrogen;  
 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 thereof.  
 
     
     
         17 . The tetracycline compound of  claim 16 , wherein R 4  is NR 4′ R 4″ , X is CR 6 R 6′ ; R 2 , R 2′ , R 6 , R 6′ , R 8 , R 10 , R 11 , and R 12  are each hydrogen; R 4′  and R 4″  are lower alkyl; and R 5  is hydroxy or hydrogen.  
     
     
         18 . The tetracycline compound of  claim 17 , wherein R 4′  and R 4″  are each methyl and R 5  is hydrogen.  
     
     
         19 . The tetracycline compound of  claim 16 , wherein J 7  and J 8  are hydrogen.  
     
     
         20 . The tetracycline compound of  claim 16 , wherein J 5  is substituted or unsubstituted alkyl.  
     
     
         21 . The tetracycline compound of  claim 16 , wherein J 5  is sulfonyl.  
     
     
         22 . The tetracycline compound of  claim 16 , wherein J 5  and J 6  are linked to form a ring.  
     
     
         23 . The tetracycline compound of  claim 16 , wherein J 5  is heteroaryl.  
     
     
         24 . The tetracycline compound of  claim 16 , wherein J 5  is substituted carbonyl.  
     
     
         25 . The tetracycline compound of  claim 16 , wherein said compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
 R is substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, alkoxy; and Y is N, O, or S, or pharmaceutically acceptable salts or prodrugs thereof.  
 
       
     
     
         26 . A tetracycline compound of Table 1, or a pharmaceutically acceptable salt thereof.  
     
     
         27 . A pharmaceutical composition comprising an effective amount of a tetracycline compound of any one of claims  1 ,  15 ,  16 ,  25  or  26 , and a pharmaceutically acceptable carrier.  
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said effective amount is effective to treat a tetracycline responsive state.  
     
     
         29 . A method for treating a tetracycline responsive state in a subject, comprising administering to said subject a tetracycline compound of any one of claims  1 ,  15 ,  16 ,  25  or  26 , such that said subject is treated.  
     
     
         30 . The method of  claim 29 , wherein said tetracycline responsive state is an inflammatory process associated state.  
     
     
         31 . The method of  claim 29 , wherein said tetracycline responsive state is cancer, a lung injury, an eye disorder, neurological disorder or stroke.  
     
     
         32 . The method of  claim 29 , wherein said tetracycline responsive state is a bacterial infection.  
     
     
         33 . The method of  claim 32 , wherein said bacterial infection is associated with  E. coli.    
     
     
         34 . The method of  claim 32 , wherein said bacterial infection is associated with  S. aureus.    
     
     
         35 . The method of  claim 32 , wherein said bacterial infection is associated with  E. faecalis.    
     
     
         36 . The method of  claim 32 , wherein said bacterial infection is resistant to other tetracycline antibiotics.  
     
     
         37 . The method of  claim 32 , wherein said bacterial infection is associated with gram positive bacteria.  
     
     
         38 . The method of  claim 32 , wherein said bacterial infection is associated with gram negative bacteria.  
     
     
         39 . The method of  claim 29 , wherein said tetracycline responsive state is a viral or fungal infection.  
     
     
         40 . The method of  claim 29 , wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.  
     
     
         41 . The method of  claim 29 , wherein said subject is a human.