Derivative n-thiolated 2-oxazolidinone antibiotics

Abstract

This invention describes the discovery and synthesis of N-thiolated 2-oxazolidinones as a new class of anti bacterial agents. These compounds can be synthesized from 2-oxazolidinones by Ndeprotection and N-sulfenylation. These new substances were found to exhibit potent anti-bacterial activity, including bacteriostatic properties against Staphylococcus spp., including methicillin resistant Staphylococcus aureus (MRSA), and Bacillus spp., including Bacillus anthracis.

1 . A method of inhibiting a bacterial infection comprising administering an effective amount of an N-thiolated 2-Oxazolidinone compound of the formula: 
     
       
         
         
             
             
         
       
       or a salt or hydrate thereof, wherein: 
       —C(R 1 ) 3  is aryl, or heteroaryl, alkyl, CH 3 , CH(CH 3 )CH 2 CH 3 ; 
       —X(R 2 ) n  is hydrogen, methoxy, acetoxy, phenoxy, or OSO 2 R 6 ; 
       R 3  is alkynyl, alkenyl, acetyl, aryl, heteroaryl, aryl(C 1 -C 6 ) alkyl, heteroaryl(C 1 -C 6 ) alkyl, aryl(C 2 -C 6 ) alkenyl, heteroaryl(C 2 -C 6 )alkenyl, aryl(C 2 -C 6 ) alkynyl or heteroaryl(C 2 -C 6 )alkynyl; wherein any aryl or heteroaryl is optionally substituted with halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 15 )alkyl, (C 2 -C 15 )alkenyl, (C 2 -C 15 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 15 )alkoxy, (C 3 -C 8 )cycloalkyl-(C 2 -C 15 ) alkenyl, C 3 -C 8 )cycloalkyl(C 2 -C 15 )alkynyl, (C 1 -C 15 )alkoxy, (C 1 -C 15 )alkanoyl, (C 1 -C 15 )alkanoyloxy, C(O)O(C 1 -C 6 )alkyl, C(═O)N((C 1 -C 6 )alkyl) 2 , N((C 1 -C 6 )alkyl) 2  or H; 
       R 4  is hydrogen, CH 2 N 3 , CH 2 CH, CO 2 Me, or linked to X(R 2 ) n ; and 
       R 5  is hydrogen. 
     
   
   
       2 . The method of  claim 1 , wherein X(R 2 ) n  and R 4  form a spirocycle. 
   
   
       3 . The method of  claim 1 , wherein R 6  is alkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl is optionally substituted with halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 15 )alkyl, (C 2 -C 15 )alkenyl, (C 2 -C 15 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 2 -C 15 )alkoxy, (C 3 -C 8 )cycloalkyl-(C 2 -C 15 )alkenyl, (C 3 -C 8 )cycloalkyl(C 21 -C 15 )alkynyl, (C 1 -C 15 )alkoxy, (C 1 -C 15 )alkanoyl, (C 1 -C 15 )alkanoyloxy, C(O)O(C 1 -C 6 )alkyl, C(═O)N((C 1 -C 6 )alkyl) 2 , or N((C 1 -C 6 )alkyl) 2 . 
   
   
       4 . The method of  claim 1 , wherein the bacterium is a  Staphylococcus  bacterium. 
   
   
       5 . The method of  claim 4 , wherein the  Staphylococcus  bacterium is a methicillin resistant  Staphylococcus  bacterium. 
   
   
       6 . The method of  claim 4 , wherein the methicillin resistant  Staphylococcus  bacterium selected from the group consisting of MRSA USF919, MRSA USF920, MRSA USF652, MRSA USF653, MRSA USF654, MRSA USF655, MRSA USF656, MRSA USF657, MRSA USF658, and MRSA USF659. 
   
   
       7 . The method of  claim 1 , wherein the bacterium is a  Bacillus  bacterium. 
   
   
       8 . The method of  claim 1 , wherein the  Bacillus  bacterium is selected form the group consisting of  B. anthracis, B. globigii, B. thurigensis, B. megaterium, B. subtilis, B. cereus , and  B. coagulans .