Substituted tetracycline compounds

Abstract

The present invention pertains, at least in part, to novel 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 tetracycline compounds such as blocking tetracycline efflux and modulation of gene expression.

1 . A substituted tetracycline compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is CHC(R 13 Y′Y), 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, 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 ethyl, perhalogenated alkenyl, substituted pyridinyl, pyrazinyl, furanyl, or pyrazolyl;  
 R 8  is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;  
 R 9 —CH 2 NR 9a R 9b ;  
 R 9a  and R 9b  are each independently hydrogen, alkyl, alkenyl or linked to form a heterocycle;  
 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.  
 
     
     
         2 . The tetracycline compound of  claim 1 , wherein 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  is NR 4′ R 4″ ; R 4′  and R 4″  are lower alkyl; and R 5  is hydroxy 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 ethyl and R 9a  is alkyl and R 9b  is alkenyl.  
     
     
         5 . The tetracycline compound of  claim 1 , wherein R 7  is substituted pyrazinyl.  
     
     
         6 . The tetracycline compound of  claim 5 , wherein R 7  is substituted with a fluorine.  
     
     
         7 . The tetracycline compound of  claim 5  or  6 , wherein R 9a  is alkyl and R 9b  is alkenyl.  
     
     
         8 . The tetracycline compound of  claim 5  or  6 , wherein R 9a  and R 9b  are linked to form a heterocycle.  
     
     
         9 . The tetracycline compound of  claim 5  or  6 , wherein R 9a  is hydrogen and R 9b  is alkyl.  
     
     
         10 . The tetracycline compound of  claim 1 , wherein R 7  is furanyl, and R 9a  is hydrogen or alkyl and R 9b  is alkenyl.  
     
     
         11 . The tetracycline compound of  claim 1 , wherein R 7  is 1,2,2-trifluoroethenyl.  
     
     
         12 . The tetracyline compound of  claim 11 , wherein R 9a  is hydrogen or alkyl and R 9b  is alkenyl.  
     
     
         13 . The tetracycline compound of  claim 1 , wherein R 7  is pyrazolyl and R 9a  is hydrogen or alkyl and R 9b  is alkenyl or alkyl.  
     
     
         14 . A tetracycline compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters, and prodrugs thereof.  
     
     
         15 . A tetracycline compound of formula II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O;  
 R 2 , R 4′ , R 4″ , R 7′  and R 7″  are each 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 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 8  is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;  
 R 9  is —CH 2 NR 9a R 9b  or linked with R 10  to form a furanyl ring;  
 R 9a  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, or heteroaromatic;  
 R 9b  is hydrogen or alkyl;  
 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, and pharmaceutically acceptable salts, esters and prodrugs thereof.  
 
     
     
         16 . The tetracycline compound of  claim 15 , wherein R 4  is NR 4′ R 4″ ; X is CR 6 R 6′ ; R 7  is NR 7′ R 7″ , R 2 , R 2′ , R 5 , R 6 , R 6′ , R 8 , R 9 , R 10 , R 11 , and R 12  are each hydrogen; and, R 4′ , R 4″ , R 7′ , and R 7″  are each lower alkyl.  
     
     
         17 . The tetracycline compound of  claim 15 , wherein R 4  is NR 4′ R 4″ ; X is CR 6 R 6′ , is hydrogen, R 2 , R 2′ , R 7 , R 6′, R   8 , R 9 , R 10 , R 11 , and R 12  are each hydrogen; R 5  is hydroxy, and R 4′ , R 4″ , and R 6  are each lower alkyl.  
     
     
         18 . The tetracycline compound of  claim 15 , wherein R 9a  is alkyl, alkenyl, or arylalkyl.  
     
     
         19 . The tetracycline compound of  claim 18 , wherein R 9a  is alkyl substituted with an alkoxy, alkenyl, heterocyclic, cyano, halogen, amido, carbonyl, or hydroxy moiety.  
     
     
         20 . The tetracycline compound of  claim 18 , wherein R 9a  is substituted or unsubstituted benzyl.  
     
     
         21 . The tetracycline compound of  claim 18 , wherein R 9b  is hydrogen or substituted or unsubstituted alkyl.  
     
     
         22 . The tetracycline compound of  claim 15 , wherein R 9a  and R 9b  are linked to form a pyrrolidinyl, piperazinyl, piperidinyl, pyrazinyl, azapanyl, thiomorpholinyl, morpholinyl, tetrahydroquinolinyl, or decahydroquinolinyl ring.  
     
     
         23 . The tetracycline compound of  claim 22 , wherein said ring is substituted with one or more halogens or halogenated alkyl groups.  
     
     
         24 . The tetracycline compound of  claim 15 , wherein R 9  is 4′trifluoromethyl-piperdin-1-yl) methyl, (4′,4′-difluoro-piperdin-1-yl) methyl, or (4′-fluoropiperdin-1-yl) methyl.  
     
     
         25 . A tetracycline compound, selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters, and prodrugs thereof.  
     
     
         26 . A tetracycline compound of formula III:  
       
         
           
           
               
               
           
         
       
       wherein: 
 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 substituted or unsubstituted pyrazolyl, furanyl, thiophenyl, thiazolyl, aminoalkyl substituted phenyl;  
 R 8  is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;  
 R 9  is hydrogen;  
 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.  
 
     
     
         27 . The tetracycline compound of  claim 26 , wherein R 4  is NR 4′ R 4″ ; 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 4′ , and R 4  are each methyl.  
     
     
         28 . The tetracycline compound of  claim 26 , wherein R 7  is phenyl substituted with —CH 2 —N(CH 3 ) 2 , —CH 2 —NH—CH(CH 3 ) 2 , —CH 2 —N(CH 3 )—CH(CH 3 ) 2 , —CH 2 —N-piperdinyl), —CH 2 NH—CH 3 , —CH 2 —NH-cyclopropyl, CH 2 —NH-t-butyl, —CH 2 —N(CH 3 )-benzyl, —CH 2 —N(CH 3 )—CH 2 —CH═CH 2 , CH 2 —NH—(CH 2 ) 2 —CF 3 , CH 2 —NH—CH 2 —C(═O)—NH 2 , or —CH 2 —NH-cyclohexyl.  
     
     
         29 . The tetracycline compound of  claim 28 , wherein said phenyl is further substituted with a fluorine, methoxy, or alkyl group.  
     
     
         30 . The tetracycline compound of  claim 26 , wherein R 7  is substituted furanyl.  
     
     
         31 . The tetracycline compound of  claim 30 , wherein said furanyl is substituted with an aminoalkyl moiety.  
     
     
         32 . The tetracycline compound of  claim 26 , wherein R 7  is substituted or unsustituted thiophenyl.  
     
     
         33 . The tetracycline compound of  claim 26 , wherein R 7  is substituted pyridinyl.  
     
     
         34 . The tetracycline compound of  claim 26 , wherein said compound is:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         35 . A tetracycline compound is of formula IV:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is CHC(R 13 Y′Y), CR 6′ R 6 , S, NR 6 , or O;  
 R 2 , R 4 , R 4 , R 7′  and R 7″  are each 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 independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;  
 R 7  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or (CH 2 ) 0-3 (NR 7c ) 0-1 C(═W′)WR 7a ;  
 R 8  is an aminomethyl substituted phenyl or substituted pyridinyl;  
 R 9  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, 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 9a , R 9b , R 9c , R 9d , R 9e  and R 9f  are each independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;  
 Z is CR 9d R 9e , S, NR 9b  or O;  
 Z′ is O, NR 9f , or S;  
 W is CR 7d R 7e , S, O or NR 7b ;  
 W′ is O, NR 7f , or S;  
 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, and pharmaceutically acceptable salts, esters and prodrugs thereof.  
 
     
     
         36 . The tetracycline compound of  claim 35 , wherein 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  is NR 4′ R 4″ ; R 4′  and R 4″  are lower alkyl; and R 5  is hydroxy or hydrogen.  
     
     
         37 . The tetracycline compound of  claim 36 , wherein said substituted tetracycline compound is:  
       
         
           
           
               
               
           
         
       
     
     
         38 . A tetracycline compound of the formula V:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2 , R 4′, R   4″ , R 7′ , and R 7″  are each 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 7  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 (NR 7c ) 0-1 C(═W′)WR 7a ;  
 R 8  is substituted phenyl or substituted pyridinyl;  
 R 9  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, 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 9a , R 9b , R 9c , R 9d , R 9e , R 8f  are each independently absent, hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;  
 W is CR 7d R 7e , S, O or NR 7b ;  
 W′ is O, NR 7f  or S;  
 R 13  is 4-alkyl substituted phenyl, and pharmaceutically acceptable salts, esters and prodrugs thereof.  
 
     
     
         39 . The tetracycline compound of  claim 38 , wherein said tetracycline compound is:  
       
         
           
           
               
               
           
         
       
     
     
         40 . A method for treating a tetracycline responsive state in a subject, comprising administering to said subject an effective amount of a tetracycline compound of any one of claims  1 ,  14 ,  15 ,  25 ,  26 ,  34 ,  35 , or  38 , such that said subject is treated.  
     
     
         41 . The method of  claim 40 , wherein said tetracycline responsive state is a bacterial infection, a viral infection, or a parasitic infection.  
     
     
         42 . The method of  claim 41 , wherein said bacterial infection is associated with  E. coli.    
     
     
         43 . The method of  claim 41 , wherein said bacterial infection is associated with  S. aureus.    
     
     
         44 . The method of  claim 41 , wherein said bacterial infection is associated with  E. faecalis.    
     
     
         45 . The method of  claim 40 , wherein said bacterial infection is resistant to other tetracycline antibiotics.  
     
     
         46 . The method of  claim 40 , wherein said tetracycline associated state is malaria.  
     
     
         47 . The method of  claim 40 , wherein said subject is a human.  
     
     
         48 . The method of anyone of claims  40 , wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.  
     
     
         49 . A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of any one of claims  1 ,  14 ,  15 ,  25 ,  26 ,  34 ,  35 , or  38  and a pharmaceutically acceptable carrier.