Phthalanilate compounds and methods of use

Abstract

The invention provides antimicrobial compounds and compositions, and methods of using them. The compounds and compositions include, for example, a compound of any one of Formulas I-X. The invention further provides methods of preparing the compounds, and useful intermediates for their preparation. The compounds can possess highly specific and selective activity, such as antibacterial activity and/or enzymatic inhibitory activity. Accordingly, the compounds and compositions can be used to treat bacterial infections, or to inhibit or kill bacteria, either in vitro or in vivo.

What is claimed is: 
     
         1 . A compound of Formula III: 
       
         
           
           
               
               
           
         
       
       wherein
 W is absent, oxygen, (C 1 -C 24 )alkylene, or carbonyl; 
 Y is oxygen or sulfur; 
 Z is carbon or nitrogen, provided that when Z is nitrogen, R 8  is absent or oxygen; 
 R 1  is carboxylic acid, thiocarboxylic acid, or a salt thereof; 
 R 2  is hydrogen, halo, or nitro; 
 R 3  and R 4  are each independently hydrogen, halo, or (C 1 -C 24 )alkyl; 
 R 5  is hydrogen or halo; 
 R 6  is hydrogen or (C 1 -C 24 )alkyl; 
 R 7  is hydrogen or halo; 
 R 8  is absent, hydrogen, or oxygen; 
 R 9  is hydrogen, halo, (C 1 -C 24 )alkyl, —O(C 1 -C 24 )alkyl, or (C 1 -C 24 )alkylene(C 1 -C 24 )cycloalkyl; 
 R 10  is hydrogen, cyano, halo, halo(C 1 -C 24 )alkyl, (C 1 -C 24 )alkylhydroxyl, or (C 1 -C 24 )alkyl; 
 R 11  is hydrogen; or 
 R 10 , R 11 , and the atoms in between form a fused (C 6 -C 30 )aryl; 
 wherein any (C 1 -C 24 )alkyl, (C 1 -C 24 )alkylene, (C 6 -C 30 )aryl, or (C 1 -C 24 )cycloalkyl is optionally substituted on carbon with one or more oxo, hydroxyl, halo, (C 6 -C 30 )aryl, nitro, cyano, (C 1 -C 6 )alkoxy, or trifluoromethyl groups or any combination thereof, and optionally exchanged on carbon with one or more oxo, imino, or thio groups; 
 or a pharmaceutically acceptable salt, a prodrug, or a metabolite thereof. 
 
     
     
         2 . The compound of  claim 1  wherein:
 W is absent, oxygen, —CH 2 —, or carbonyl; 
 Y is oxygen or sulfur; 
 Z is carbon or nitrogen; 
 R 1  is —CO2H, —CS2H, —CO2Na, or —COSH; 
 R 2  is hydrogen, fluorine, chlorine, bromine, or nitro; 
 R 3  and R 4  are each independently hydrogen, fluorine, chlorine, bromine, or methyl; 
 R 5  is hydrogen, fluorine, chlorine, or bromine; 
 R 6  is hydrogen or methyl; R 7  is hydrogen or chlorine; 
 R 8  is absent, hydrogen, or oxygen; 
 R 9  is hydrogen, chlorine, —(CH 2 ) 7 CH 3 , —(CH 2 ) 9 CH 3 , —(CH 2 ) 15 CH 3 , —O(CH 2 ) 3 CH 3 , —CH 2 CH(OH)CH 2 OCH 2 (cyclopropyl); or —CH 2 CH(OH)CH 2 O(CH 2 ) 3 CH 3 ; 
 R 10  is hydrogen, cyano, chlorine, trifluoromethyl, —CH 2 OH, or methyl; 
 R 10 , R 11 , and the atoms in between form a fused 3-hydroxyphenyl; and 
 R 11  is hydrogen. 
 
     
     
         3 . The compound of  claim 1  wherein Y is oxygen, Z is carbon, and R 6  is hydrogen. 
     
     
         4 . The compound of  claim 1  wherein R 1  is —CO 2 H or —CO 2 Na. 
     
     
         5 . The compound of  claim 1  wherein R 2  is hydrogen, fluoro, chloro, bromo, or nitro. 
     
     
         6 . The compound of  claim 1  wherein R 3 , R 4 , and R 5  are halo. 
     
     
         7 . The compound of  claim 1  wherein R 3 , R 4 , and R 5  are hydrogen. 
     
     
         8 . The compound of  claim 1  wherein R 7  and R 11  are each hydrogen. 
     
     
         9 . The compound of  claim 1  wherein —WR 9  is —O(C 1 -C 24 )alkyl. 
     
     
         10 . The compound of  claim 1  wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 10  and a pharmaceutically acceptable carrier. 
     
     
         13 . The compound: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt or solvate thereof. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 13  and a pharmaceutically acceptable carrier. 
     
     
         15 . A method of treating an animal inflicted with a bacterial infection comprising administering to an animal in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         16 . A method of killing or inhibiting a bacteria comprising contacting the bacteria with an effective amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the contacting is in vitro. 
     
     
         18 . The method of  claim 16 , wherein the contacting is in vivo. 
     
     
         19 . A pharmaceutical composition suitable for oral administration comprising a compound of  claim 1  effective against anti-vancomycin-resistant methicillin-resistant  Staphylococcus aureus , and a pharmaceutical acceptable diluent or carrier.