Oxazolidinone-quinolone hybrid antibiotics

Abstract

The present invention relates to compounds of the Formula (I) that are useful antimicrobial agents and effective against a variety of multi-drug resistant bacteria:

1 - 18 . (canceled) 
     
     
         19 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         A is an alkylene group, an alkenylene group, an alkynylene group, a heteroalkylene group, a cycloalkylene group, a heterocycloalkylene group, an arylene group or a heteroarylene group all of which groups may be substituted; 
         Q is CR 4 ; 
         X is CR 7  or N; 
         Y is CR 6  or N; 
         n is 1, 2 or 3; 
         m is 1, 2 or 3; 
         R 1  is H, F, Cl, Br, I, OH, NH 2 , an alkyl group or a heteroalkyl group; 
         R 2  is H, F or Cl; 
         R 3  is H, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group; all of which groups may be substituted with one, two or more halogen atoms or amino groups; 
         R 4  is hydroxy, a group of formula OPO 3 R 9   2  or OSO 3 R 10  or a heteroalkyl group carrying at least one OH, NH 2 , SO 3 R 10 , PO 3 R 9   2  or COOH group or an ester of a naturally occurring amino acid or a derivative thereof, wherein the groups R 9  independently of each other are H, alkyl, cycloalkyl, aryl or aralkyl and wherein R 10  is H, alkyl, cycloalkyl, aryl or aralkyl; 
         R 5  is selected from the following groups: 
       
       
         
           
           
               
               
           
         
         R 6  is H, F, Cl or OMe; 
         R 7  is H, F, Cl, OH, NH 2 , a substituted or unsubstituted alkyl group or a substituted or unsubstituted heteroalkyl group, or 
         R 3  and R 7  can be linked via an alkylene, an alkenylene or a heteroalkylene group or be a part of a cycloalkylene or heterocycloalkylene group; in case R 3  is no H and R 7  is no H, F, OH, NH 2  or Cl; and 
         R 8  is a C 1-6  heteroalkyl, a heteroarylalkyl, a heteroalkylaryl or a heteroalkylheteroaryl group; 
         or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof. 
       
     
     
         20 . A compound of  claim 19 , wherein R 1  is H. 
     
     
         21 . A compound according to  claim 19 , wherein R 2  is F or H. 
     
     
         22 . A compound of  claim 19 , wherein R 3  is an ethyl, a 2-propyl, a C 3 -C 6  cycloalkyl, a phenyl or a pyridyl group; all of which may be substituted with one, two, three or more fluorine atoms or amino groups. 
     
     
         23 . A compound according to  claim 19 , wherein R 3  is a cyclopropyl group. 
     
     
         24 . A compound of  claim 19 , wherein R 7  and R 3  together form a bridge of the formula —O—CH 2 —N(Me)— or —O—CH 2 —CH(Me)—, wherein the preferred stereochemistry at the chiral center is the one giving the (S) configuration in the final compound. 
     
     
         25 . A compound of  claim 19 , wherein R 7  is H, F, Cl or a methoxy group which may be substituted by one, two or three fluorine atoms. 
     
     
         26 . A compound of  claim 19 , wherein X is N or CH. 
     
     
         27 . A compound of  claim 19 , wherein R 4  is hydroxy or a group of formula OSO 3 H, OPO 3 H 2 , OCH 2 OPO 3 H 2 , OCOCH 2 CH 2 COOH or an ester of a naturally occurring amino acid or a derivative thereof. 
     
     
         28 . A compound of  claim 19 , wherein R 8  is a group of the formula —CH 2 NHCOCH═CHAryl, —CH 2 OHeteroaryl, —CH 2 NHSO 2 Me, —CH 2 NHCOOMe, —CH 2 NHCOMe, —CH 2 NHCS 2 Me, —CH 2 NHCSMe, —CH 2 NHCSNH 2 , —CH 2 NHCSOMe or —NHCOMe. 
     
     
         29 . A compound of  claim 19 , wherein R 5  has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         30 . A compound of  claim 19 , wherein Y is CH or N. 
     
     
         31 . A compound of  claim 19 , wherein A is C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, C 1-6  heteroalkylene, cyclopropylene, epoxide, aziridine, thioepoxide, lactame or lactone, all of which groups may be substituted. 
     
     
         32 . A compound of  claim 19 , wherein A is a group of formula —CH 2 CH 2 —, —OCH 2 —, —OCH 2 CH 2 —, —SCH 2 —, —SCH 2 CH 2 —, —CH═CH—, —CH(OH)CH(OH)— or —CH(NH 2 )CH(OH)—. 
     
     
         33 . A mono, di or tri sodium salt of a compound of formula (I) according to  claim 19 . 
     
     
         34 . A compound of  claim 33  wherein R 4  is OPO 3 H 2  or OSO 3 H or mixtures thereof. 
     
     
         35 . A pharmaceutical composition comprising a compound of  claim 19 . 
     
     
         36 . The pharmaceutical composition of  claim 35  further comprising one or more optionally carriers and/or adjuvants and/or diluents. 
     
     
         37 . A pro-drug comprising a compound of  claim 19  and at least one pharmacologically acceptable protective group. 
     
     
         38 . A method for treating a subject suffering from or susceptible to a bacterial infection, comprising administering to the subject a compound of  claim 19 .