Novel oxazolidinone derivatives

Abstract

The present invention relates to novel derivatives of oxazolidinone, a method thereof and pharmaceutical compositions comprising the derivatives for use in an antibiotic. The oxazolidinone derivatives of the present invention show inhibitory activity against a broad spectrum of bacteria and lower toxicity. The prodrugs, prepared by reacting the compound having hydroxyl group with amino acid or phosphate, have an excellent efficiency on solubility thereof against water. Further, the derivatives of the present invention may exert potent antibacterial activity versus various human and animal pathogens, including Gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganisms such as Bacteroides and Clostridia, and acid-resistant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium . Accordingly, the compositions comprising the oxazolidinone are used in an antibiotic.

What is claimed: 
     
         1 . An oxazolidinone derivative of Formula I, or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
       
       wherein,
 Het is pyrrolyl, furanyl, piperazinyl, piperidinyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, thiazolyl or pyrazinyl; 
 ring A is unsubstituted or has at least one fluorine substituent; 
 R 7  is H or a prodrug substituent; 
 R 3  is hydrogen, or at least one C 1-4  alkyl group that is unsubstituted, or substituted with cyano, —(CH 2 )m-OR 7  or ketone; and 
 m is 0, 1, 2, 3, or 4. 
 
     
     
         2 . The oxazolidinone derivative of  claim 1 , wherein R 7  is a prodrug substituent, and wherein the oxazolidinone derivative has a solubility of greater than 30 mg/mL. 
     
     
         3 . The oxazolidinone derivative of  claim 2 , wherein the oxazolidinone derivative has a solubility of greater than 50 mg/mL. 
     
     
         4 . The oxazolidinone derivative of  claim 1 , wherein R 7  is a prodrug substituent, the prodrug substituent is PO(OH) 2  or PO(O) 2   −2 (M + ) 2 , and M +  is a metal cation. 
     
     
         5 . The oxazolidinone derivative of  claim 4 , wherein M +  is Na + . 
     
     
         6 . An active metabolite of the oxazolidinone derivative of  claim 1 . 
     
     
         7 . The oxazolidinone derivative of  claim 1 , wherein Het is triazolyl. 
     
     
         8 . An oxazolidinone derivative which is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof;
 wherein 
 R 1  and R 1 ′ are each independently H or F; 
 Het is pyrrolyl, furanyl, piperazinyl, piperidinyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, thiazolyl or pyrazinyl; 
 R 7  is H or a prodrug substituent; 
 R 3  is hydrogen, or at least one C 1-4  alkyl group that is unsubstituted, or substituted with cyano, —(CH 2 )m-OR 7  or ketone; and 
 m is 0, 1, 2, 3, or 4. 
 
       
     
     
         9 . A pharmaceutical composition comprising the oxazolidinone derivative of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the pharmaceutical composition is an injectable composition. 
     
     
         11 . A method of treating a bacterial infection in a subject, comprising administering to the subject the oxazolidinone derivative of  claim 1 . 
     
     
         12 . The method of  claim 11 , wherein the bacterium is selected from the group consisting of  Staphylococcus, Enterococcus , and  Streptococcus.    
     
     
         13 . The method of  claim 12 , wherein the bacterium is MRSA or VRE. 
     
     
         14 . A pharmaceutical composition comprising the oxazolidinone derivative of  claim 8  and a pharmaceutically acceptable carrier. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutical composition is an injectable composition. 
     
     
         16 . A method of treating a bacterial infection in a subject, comprising administering to the subject the oxazolidinone derivative of  claim 8 . 
     
     
         17 . The method of  claim 16 , wherein the bacterium is selected from the group consisting of  Staphylococcus, Enterococcus , and  Streptococcus.    
     
     
         18 . The method of  claim 17 , wherein the bacterium is MRSA or VRE. 
     
     
         19 . An active metabolite of the oxazolidinone derivative of  claim 8 . 
     
     
         20 . The oxazolidinone derivative of  claim 8 , wherein Het is triazolyl. 
     
     
         21 . The oxazolidinone derivative of  claim 20 , wherein the compound is selected from Compound 17, 22, 24 or 29.