9-Aminomethyl Substituted Minocycline Compounds

Abstract

The present invention pertains, at least in part, to novel 9-substituted minocycline compounds. These minocycline 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 minocycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       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 3 , R 10 , R 11  and R 12  are each hydrogen or a pro-drug moiety; 
 R 4  is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, halogen, or 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 independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 R 8  is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 R 9  is aminoalkyl; 
 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. 
 
     
     
         2 . The compound of  claim 1 , 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 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. 
     
     
         3 . The compound of  claim 2 , wherein R 4′ , R 4″ , R 7′ , and R 7″  are each methyl. 
     
     
         4 . The compound of  claim 3 , wherein said aminoalkyl is aminomethyl. 
     
     
         5 . The compound of  claim 3  or  4 , wherein said aminoalkyl is substituted with an alkyl group. 
     
     
         6 .- 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein said aminoalkyl is of the formula
   —CH 2 NR 9c C(=Z′)ZR 9a ,   
       wherein
 Z is CR 9d R 9e , S, NR 9b  or O; 
 Z′ is NR 9f , O or S; and 
 R 9a , R 9b , R 9c , R 9d , R 9e  and R 9f  are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 
     
     
         17 .- 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         27 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       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 3 , R 10 , R 11  and R 12a  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  and R 8  are each independently hydrogen, dialkylamino, 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. 
 
     
     
         28 . The compound of  claim 27 , 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; R 7  is dialkylamino; and R 5  is hydroxy or hydrogen. 
     
     
         29 . The compound of  claim 28 , wherein R 4′  and R 4″  are each methyl and R 5  is hydrogen. 
     
     
         30 . The compound of  claim 28 , wherein J 7  and J 8  are hydrogen. 
     
     
         31 . The compound of  claim 28 , wherein J 5  is substituted or unsubstituted alkyl. 
     
     
         32 .- 34 . (canceled) 
     
     
         35 . The compound of claim  33 , wherein J 6  is hydrogen. 
     
     
         36 . A compound of the formula (III): 
       
         
           
           
               
               
           
         
       
       wherein
 J 5  is alkyl; and 
 J 6  is hydrogen, or pharmaceutically acceptable salts, prodrugs and esters thereof. 
 
     
     
         37 . (canceled) 
     
     
         38 . A method for treating a tetracycline responsive state in a mammal, comprising administering to said subject a compound of  claim 1 , such that said subject is treated. 
     
     
         39 .- 47 . (canceled) 
     
     
         48 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , and a pharmaceutically acceptable carrier.