Novel bicyclic oxazolidinones as antibacterial agents

Abstract

The present invention provides compounds of formula I useful as antimicrobial agents wherein W, X, Y, R 1 , R 2 and n are as defined in thereof.

We claim:  
     
         1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 W is 
 a) O, or  
 b) S;  
 
 X is 
 a) —(═O) m—, or    
 b) —NR 3 —;  
 
 Y is 
 a) —O—,  
 b) —NH—,  
 c) —CH 2 —, or  
 d) —(═O) m —;  
 
 R is C 1-4  alkyl, optionally substituted with 1-3 R 5 ;  
 R 2  is 
 a) H,  
 b) C 1-6  alkyl, optionally substituted with 1-3 halo;  
 c) cyclopropyl,  
 d) —C 1-4  alkyl,  
 e) —NH 2 ,  
 f) —NHC 1-6  alkyl, or  
 g) —N(C 1-6  alkyl) 2 ;  
 
 R 3  is 
 a) C 1-8  alkyl, optionally substituted with 1-3 halo, CN, NO 2 , OH, SH or NH 2 ,  
 b) —C(═O)R 4 , or  
 c) —C(═S)NHC 1-4  alkyl;  
 
 R 4  is 
 a) H,  
 b) C 1-6  alkyl, optionally substituted with OH, C 1-4  alkoxy, NH 2 , SH or halo, or  
 c) —CH 2  OC(═O)C 1-4  alkyl;  
 
 R 5  is 
 j) halo,  
 k) —CN,  
 l) —OH,  
 m) —SH,  
 n) —NH 2 ,  
 o) —OR 6 ,  
 p) —NHR 6 ,  
 q) —N(R 6 ) 2 , or  
 r) —S(═O) m R 6 ;  
 
 R 6 is 
 g) C 1-6  alkyl,  
 h) —C(═O) C 1-4  alkyl,  
 i) —C(═O)O C 1-4  alkyl,  
 j) —C(═O)NH 2 ,  
 k) —C(═O)NH C 1-4  alkyl, or  
 l) —SO 2  C 1-4  alkyl;  
 
 m is 0, 1 or 2;  
 n is or 1;  
 with the proviso that where n is 0, Y is —CH 2 —.  
 
     
     
         2 . A compound of  claim 1  wherein R 1  is methyl; X is —NR 3 ; R 3  is formyl or acetyl; R 2  is methyl or ethyl; Y is —CH 2 —; W is sulfur, and n is 0 or 1.  
     
     
         3 . A compound of  claim 1  wherein R 1  is methyl; X is —NR 3 ; R 3  is formyl or acetyl; R 2  is methyl or ethyl; Y is —O—; W is sulfur; and n is 1.  
     
     
         4 . A compound of  claim 1  wherein W is sulfur, R 1 , R 2 , n, X and Y are the same as in  claim 1 .  
     
     
         5 . A compound of  claim 1  wherein X is —NR 3 —; R 3  is 2-fluoroethyl, glycolyl, formyl, methoxyacetyl, oxoethylacetate, acetyl, or methylaminocarbothioyl, R 1 , R 2 , n, W and Y are the same as in  claim 1 .  
     
     
         6 . A compound of  claim 1  wherein X is —NR 3 —; R 3  is is formyl or acetyl; R 1 , R 2 , n, W and Y are the same as in  claim 1 .  
     
     
         7 . A compound of  claim 1  wherein X is —NR 3 —; R 3  is as defined in  claim 1:  R 1 , R 2 , n, W and Y are the same as in  claim 1 .  
     
     
         8 . A compound of  claim 1  wherein Y is —CH 2 —; R 1 , R 2 , n, W and X are the same as in  claim 1 .  
     
     
         9 . A compound of  claim 1  wherein Y is oxygen, R 1 ,R 2 , n W and X are the same as in  claim 1 .  
     
     
         10 . A compound of  claim 1  which is 
 a) N-({(5S)-3-[(2R)-1-(2-fluoroethyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 b) N-{[(5S)-3-((2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide;  
 c) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 d) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 e) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)propanamide;  
 f) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;  
 g) N-({(5S)-3-[(2R)-1-(2-methoxyacetyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 h) 2-((2R)-5-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3dihydro-1H-indol-1-yl)-2-oxoethyl acetate;  
 i) N-({(5S)-3-[(2R)-1-acetyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 j) N-[((5S)-3-{(2R)-2-methyl-1-[(methylamnino)carbothioyl]-2,3-dihydro-1H-indol-5-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;  
 k) 2-((2R)-5-{(5S)-5-[(ethanethioylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate;  
 l) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;  
 m) N-{[(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3oxazolidin-5-yl]methyl}acetamide;  
 n) N-{[(5S)-3-[(2R)-1-glycoloyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3oxazolidin-5-yl]methyl}acetamide;  
 o) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 p) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3oxazolidin-5-yl}methyl)ethanethioamide;  
 q) N-{[(5S)-3-[(3R)4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-1,3-oxazolidin-5-yl]methyl}acetamide;  
 r) N-({(5S)-3-[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamiide;  
 s) N-({(5S)-3-[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;  
 t) N-({(5S)-3-[(2R)2-(fluoromethyl)-1-formyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 u) N-{[(5R)-3-(2(+)-methyl-2,3-dihydro-1-benzothien-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide; or  
 v) N-[[(5S)-3-[2-( 1,1-dimethylethyl)-1-formyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide.  
 
     
     
         11 . A compound of  claim 1  which is 
 a) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3oxazolidin-5-yl}methyl)ethanethioamide;  
 b) N-({(5S)-3-[(2R)-1-(2-methoxyacetyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 c) 2-((2R)-5-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3dihydro-1H-indol-1-yl)-2-oxoethyl acetate;  
 d) N-({(5S)-3-[(2R)-1-acetyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo- 1 , 3 -oxazolidin-5-yl}methyl)acetamide;  
 e) N-[((5S)-3-{(2R)-2-methyl-1-[(methylamino)carbothioyl]-2,3-dihydro-1H-indol-5-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;  
 f) 2-((2R)-5-{(5S)-5-[(ethanethioylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate;  
 g) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2oxo- 1 , 3 -oxazolidin-5-yl}methyl)ethanethioamide;  
 h) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 i) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;  
 j) N-({(5S)-3-[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;  
 k) N-({(5S)-3-[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide; or  
 l) N-[[(5S)-3-[2-(1,1-dimethylethyl)-1-formyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide.  
 
     
     
         12 . A compound of  claim 1  which is 
 a) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;  
 b) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;  
 c) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide; or  
 e) N-({(5S)-3-[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide.  
 
     
     
         13 . A compound of  claim 1  which N-({(5S)-3 -[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide.  
     
     
         14 . A method for treating microbial infections in patients comprising: administering to a human or warn blood animals in need thereof an effective amount of a compound of formula I as shown in  claim 1 .  
     
     
         15 . The method of  claim 14  wherein said compound of formula I is administered orally, parenterally, transdermally, or topically in a pharmaceutical composition.  
     
     
         16 . The method of  claim 14  wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.  
     
     
         17 . The method of  claim 14  wherein said compound is administered in an amount of from about 1 to about 50 mg/kg of body weight/day.  
     
     
         18 . A method for treating microbial infections of  claim 14  wherein the infection is skin infection.  
     
     
         19 . A method for treating microbial infections of  claim 14  wherein the infection is eye infection.  
     
     
         20 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.