Benzotriazine Oxides as Drugs Targeting Mycobacterium Tuberculosis

Abstract

Benzotriazine doxides are disclosed as drugs targeting mycobacterium tuberculosis , including novel compounds of formula I:

What is claimed is: 
     
         1 . A compound having the structure of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 each X is independently H, halogen, alkyl, OR, SR, NR′R, or BR′R, wherein each R and each R′ is independently H, halogen, or alkyl; 
 W is N; 
 each A and B is optionally substituted alkyl, or A and B are joined in an optionally substituted heterocycloalkyl; and 
 Z is an optionally present, optionally substituted 5 or 6-membered ring, saturated or unsaturated, fused to the bezotriazine ring at the 6,7 position, 
 
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         2 . The compound of  claim 1  wherein:
 each X is H; 
 W is N; 
 A and B are joined in an optionally substituted piperidinyl or pyrrolidinyl; and 
 Z is present as a 5-membered ring, fused to the bezotriazine ring at the 6,7 position, 
 
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         3 . The compound of  claim 1  selected from:
 3-(diethylamino)benzo[e][1,2,4]triazine 1,4-dioxide (17o); 
 3-morpholinobenzo[e][1,2,4]triazine 1,4-dioxide (17p); 
 3-(pyrrolidin-1-yl)benzo[e][1,2,4]triazine 1,4-dioxide (17q); 
 3-(pyrrolidin-1-yl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20q); 
 3-(piperidin-1-yl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20r); 
 3-(dimethylamino)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20s); 
 3-(benzyl(methyl)amino)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20t); 
 3-(methyl(phenethyl)amino)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20u); 
 3-(thiomorpholinosulfone-1-yl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20v); 
 3-(2-methylpiperidin-1-yl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20w); and 
 3-(4-(methylsulfonyl)piperazin-1-yl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20x), 
 or a pharmaceutically acceptable salt or stereoisomer thereof. 
 
     
     
         4 . The compound of  claim 1  that is:
 3-(pyrrolidin-1-yl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (20q), 
 or a pharmaceutically acceptable salt or stereoisomer thereof. 
 
     
     
         5 . A pharmaceutical composition or kit comprising a compound of  claim 1  and a second, different anti- mycobacterium tuberculosis  (Mtb) drug. 
     
     
         6 . A pharmaceutical composition or kit comprising a compound of  claim 2  and a second, different anti- mycobacterium tuberculosis  (Mtb) drug. 
     
     
         7 . A method of making a compound of  claim 1  according to the following scheme: 
       
         
           
           
               
               
           
         
       
       (a) HOF.ACN, DCM; b) HNR 2 R 3 , Et 3 N, DCM; wherein X is R 1 , W is N, A is R 3  and B is R 2 . 
     
     
         8 . A method of making a compound of  claim 2  according to the following scheme: 
       
         
           
           
               
               
           
         
       
       (a) HOF.ACN, DCM; b) HNR 2 R 3 , Et 3 N, DCM; wherein X is R 1 , W is N, A is R 3  and B is R 2 . 
     
     
         9 . A method of treating a  mycobacterium tuberculosis  (Mtb) infection, comprising: contacting a person in need thereof with an effective amount of compound of  claim 1 . 
     
     
         10 . A method of treating a  mycobacterium tuberculosis  (Mtb) infection, comprising: contacting a person in need thereof with an effective amount of compound of  claim 2 .