Novel oxazolidinone derivative with difluorophenyl moiety, pharmaceutically acceptable salt thereof, preparation method thereof and antibiotic composition containing the same as an active ingredient

Abstract

Novel oxazolidinone derivatives with a difluorophenyl moiety, represented by Chemical Formula 1, pharmaceutically acceptable salts thereof, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient are provided. Exhibiting potent inhibitory activity against Gram-positive bacteria including Haemophilus influenza and Coagulase negative staphylococci and resistant bacteria including vancomycin-resistant enterococci (VRE), the pharmaceutical composition is useful as an antibiotic. (wherein, R is as defined in the specification)

1 . An oxazolidinone compound, represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       wherein R is a hydroxy, an amino, a halogen, hydrazine, a hydroxyimine, an alkyloxyimine of C 1 ˜C 4  or an allyloxyimine. 
     
   
   
       2 . The oxazolidinone compound or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein R is hydroxy, amino, fluoro, chloro, bromo, hydrazine, hydroxyimine, methoxyimine, ethoxyimine, propoxyimine, isopropoxyimine, butoxyimine, isobutoxyimine or allyloxyimine. 
   
   
       3 . The oxazolidinone compound or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the oxazolidinone compound is selected from a group consisting of: 
     (1) (S)—N-{{3-[3,5-difluoro-4-(7-hydroxy-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide; 
     (2) (S)—N-{{3-[3,5-difluoro-4-(7-fluoro-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide; 
     (3) (S)—N-{{3-[3,5-difluoro-4-(7-hydroxyimino-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide; 
     (4) (S)—N-{{3-[3,5-difluoro-4-(7-methoxyimino-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide; 
     (5) (S)—N-{{3-[3,5-difluoro-4-(7-hydrazino-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide; 
     (6) (S)—N-{{3-[3,5-difluoro-4-(7-ethoxyimino-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide; 
     (7) (S)—N-{{3-[3,5-difluoro-4-(7-allyloxyimino-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide; and 
     (8) (S)—N-{{3-[3,5-difluoro-4-(7-amino-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide. 
   
   
       4 . A method for preparing the oxazolidinone compound of  claim 1 , as illustrated in the following Reaction Scheme 1, comprising:
 reacting a compound of Chemical Formula 2 with trifluoronitrobenzene of Chemical Formula 3 to give a compound of Chemical Formula 4 (Step 1);   reducing the compound of Chemical Formula 4 through hydrogenation to a compound of Chemical Formula 5 (Step 2);   introducing a carbobenzyloxy (CBZ) group into the amine group of the compound of Chemical Formula 5 to give a compound of Chemical Formula 6 (Step 3);   adding n-butyl lithium and (R)-glycidyl butyrate to the compound of Chemical Formula 6 to give a compound of Chemical Formula 7 (Step 4);   mesylating the hydroxy group of the compound of Chemical Formula 7 to give a compound of Chemical Formula 8 (Step 5);   azidating the compound of Chemical Formula 8 with sodium azide to a compound of Chemical Formula 9 (Step 6);   reducing and acetylating the compound of Chemical Formula 9 to a compound of Chemical Formula 10 (Step 7);   deprotecting the compound of Chemical Formula 10 to give a compound of Chemical Formula 11 (Step 8); and   reducing the compound of Chemical Formula 11 to a compound of Chemical Formula 1a (Step 9).   
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       (wherein the compound of Chemical Formula 1a is included within the range of Chemical Formula 1). 
     
   
   
       5 . The method according to  claim 4 , as illustrated in the following Reaction Scheme 2, further comprising:
 halogenating or aminating the compound of Chemical Formula 1a to a compound of Chemical Formula 1b (Step 10) after Step 9.   
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       (wherein X is a halogen or an amine, and the compounds of Chemical Formulas 1a and 1b are included within the range of Chemical Formula 1). 
     
   
   
       6 . The method according to  claim 4 , as illustrated in the following Reaction Scheme 3, further comprising:
 reacting the compound of Chemical Formula 11 with an amine chloride salt to give a compound of Chemical Formula 1c (Step 9′) after Step 8.   
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       (wherein R′ is a hydroxy, methoxy or amine group, and the compound of Chemical Formula 1c is included within the range of Chemical Formula 1). 
     
   
   
       7 . The method according to  claim 6 , as illustrated in the following Reaction Scheme 4, further comprising:
 reacting a nucleophile with the compound of Chemical Formula 1c in the presence of a base to give a compound of Chemical Formula 1d (Step 10′) after Step 9′.   
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       (wherein R″ is C 1 ˜C 4  alkyl or allyl, and the compounds of Chemical Formulas 1c and 1d are included within the range of Chemical Formula 1). 
     
   
   
       8 . A method for treating diseases caused by bacteria, comprising administering the oxazolidinone compound or pharmaceutically acceptable salt thereof of  claim 1  at a therapeutically effective dose to a subject in need thereof. 
   
   
       9 . The method according to  claim 8 , wherein the bacteria is a Gram-positive strain or a resistant strain. 
   
   
       10 . The method according to  claim 9 , wherein the Gram-positive strain is  Haemophilus influenza  or Coagulase negative staphylococi. 
   
   
       11 . The method according to  claim 9 , wherein the resistant strain is vancomycin-resistant enterococci. 
   
   
       12 . A method for killing a bacterial strain infecting a subject comprising administering the oxazolidinone compound of  claim 1  or the pharmaceutically acceptable salt thereof at a therapeutically effective dose to the subject. 
   
   
       13 . The method according to  claim 12 , wherein the bacterial strain is a Gram-positive strain or a resistant strain. 
   
   
       14 . The method according to  claim 13 , wherein the Gram-positive strain  Haemophilus influenza  or Coagulase negative staphylococi. 
   
   
       15 . The method according to  claim 13 , wherein the resistant strain is vancomycin-resistant enterococci.