Oxazolidinones having a benzannulated 6- or 7-membered heterocycle

Abstract

The present invention provides oxazolidinones having a benzannelated 6- or 7-membered heterocycle as antibacterial agents.

We claim:  
     
         1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein 
 Y is 
 a) —NHC(═W)R 1 ,  
 b) —O-het, —S-het, or —NH-het;  
 
 X is 
 a) —NR 3 —,  
 
 W is 
 a) O, or  
 b) S;  
 
 R 1  is 
 a) H,  
 b) C 1-8 alkyl,  
 c) C 3-6 cycloalkyl,  
 d) OC 1-4  alkyl,  
 e) SC 1-4  alkyl,  
 f) NH 2 ,  
 g) NHC 1-6  alkyl, or  
 h) N(C 1-6  alkyl) 2 ;  
 
 R 2  is 
 a) H,  
 b) halo, or  
 c) C 1-4  alkyl;  
 
 R 3  is 
 a) H,  
 b) C 1-8 alkyl,  
 c) aryl,  
 d) het,  
 e) C(═W)R 5 ,  
 f) C(═O)OR 6 , or  
 g) S(═O) i R 7 ;  
 
 R 4  is 
 a) H, or  
 b) C 1-8 alkyl;  
 
 R 5  is 
 a) H,  
 b) aryl,  
 c) het,  
 d) NR 8 R 9 , or  
 e) C 1-8 alkyl;  
 
 R 6  is 
 a) C 1-8 alkyl,  
 b) aryl, or  
 c) het;  
 
 R 7  is 
 a) aryl,  
 b) het,  
 c) NR 8 R 9 , or  
 d) C 1-8 alkyl;  
 
 R 8  and R 9  are independently 
 a) H,  
 b) C 1-8 alkyl, or  
 c) aryl;  
 
 wherein >G-E is >C═C— and Q is a nitrogen atom;  
 aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic;  
 het is a C-linked five- (5) or six- (6) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring;  
 at each occurrence, alkyl or cycloalkyl is optionally substituted with one or more OR 8 , halo, aryl, S(═O) i R 7 , C(═W)R 8 , OC(═O)C 1-6 alkyl, or NR 8 R 9 ;  
 at each occurrence, aryl is optionally substituted with one or more halo, OH, CF 3 , OC 1-6 alkyl, CN, C 1-6  alkyl, S(═O) i R 7 , C(═W)R 8 , OC(═O)R 8 , NHC(═O)R 8 , or NR 8 R 9 ;  
 at each occurrence, het is optionally substituted with one or more halo, OH, CF 3 , OC 1-6 alkyl, CN, C 1-6  alkyl, S(═O) i R 7 , C(═W)R 8 , OC(═O)R 8 , NHC(═O)R 8 , or NR 8 R 9 , oxo, or oxime;  
 m is 0, 1,3, or 4;  
 n is 0, 1, 3, or 4; with the proviso that m and n taken together are 3 or 4; if m is 2 n is not 2, and if n is 2 m is not 2; and  
 i is 0, 1, or 2.  
 
     
     
         2 . A compound of  claim 1  which is a compound of formula IA:  
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 2  wherein R 2  is H.  
     
     
         4 . A compound of  claim 2  wherein R 1  is CH 1-6 alkyl.  
     
     
         5 . A compound of  claim 2  wherein R 1  is methyl.  
     
     
         6 . A compound of  claim 4  wherein R 3  is C(═O)R 5 , or C(═O)OR 5 .  
     
     
         7 . A compound of  claim 4  wherein R 3  is C(═O)CH 2 OH.  
     
     
         8 . A compound of  claim 4  wherein R 3  is CHO.  
     
     
         9 . A compound of  claim 4  wherein R 5  is C 1-4 alkyl, optionally substituted with C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, C(═O)phenyl, or phenyl, wherein said phenyl is optionally substituted with I, or CF 3 .  
     
     
         10 . A compound of  claim 4  wherein R 5  is phenyl.  
     
     
         11 . A compound of  claim 4  wherein R 3  is C(═S)R 5 , wherein R 5  is aryl, alkyl or NR 8 R 9 , wherein R 8  and R 9  are independently H, C 1-4 alkyl or aryl.  
     
     
         12 . A compound of  claim 4  wherein R 3  is S(═O) i C 1-4 alkyl,  
     
     
         13 . A compound of  claim 4  wherein R 3  is H, C 1-8 alkyl, or aryl,.  
     
     
         14 . A compound of  claim 4  or  6  wherein m is 1 and n is 3.  
     
     
         15 . A compound of  claim 4  or  6  wherein m is 0 and n is 4.  
     
     
         16 . A compound of  claim 4  or  6  wherein m is 1 and n is 2.  
     
     
         17 . A compound of  claim 4  or  6  wherein m is 2 and n is 1.  
     
     
         18 . A compound of  claim 1  which is a compound of formula IB:  
       
         
           
           
               
               
           
         
       
       wherein A is O, S or NH and het is isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl, 1,2,4-thiadiazol-3-yl or 1,2,5-thiadiazol-3-yl.  
     
     
         19 . A compound of  claim 1  which is a compound of formula IC:  
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound of  claim 1  which is a compound of formula ID  
       
         
           
           
               
               
           
         
       
       wherein A is O, S or NH and het is isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl, 1,2,4-thiadiazol-3-yl or 1,2,5-thiadiazol-3-yl.  
     
     
         21 . A method for treating microbial infections comprising: administering to a mammal in need thereof an effective amount of a compound of  claim 1 .  
     
     
         22 . The method of  claim 21  wherein said compound is administered orally, parenterally, transdermally, or topically.  
     
     
         23 . The method of  claim 21  wherein said compound is administered in an amount of from about 0.1 to about 150 mg/kg of body weight/day.  
     
     
         24 . The method of  claim 21  wherein said compound is administered in an amount of from about 3 to about 100 mg/kg of body weight/day.  
     
     
         25 . The method of  claim 21  wherein said infection is skin infection.  
     
     
         26 . The method of  claim 21  wherein the infection is eye infection.  
     
     
         27 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         28 . The method of  claim 21  wherein said compound is administered in an amount of 600 mg per day by IV or by oral.  
     
     
         29 . The method of  claim 21  wherein said mammal is human.