Combination therapy comprising oxazolidinone-quinolones for use in treating bacterial infections

Abstract

The present invention provides a combination of at least one oxazolidinone-quinolone hybrid with at least one further antibacterial compound and the use thereof as drug, especially for the treatment or prophylaxis of bacterial infections.

1 . (canceled) 
     
     
         2 . A combination of
 i) at least one oxazolidinone-quinolone hybrid of 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 alkylcycloalkylene group, a heteroalkylcycloalkylene group, an arylene group or a heteroarylene group all of which groups may be substituted;
 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 alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may be substituted with one, two or more halogen atoms like F or Cl or amino groups; 
         R 4  is hydrogen, a group of formula PO 3 R 9   2  or SO 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 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  alkyl, a C 1-6  heteroalkyl or a heteroaralkyl group; 
         or a pharmacologically acceptable salt, solvate or hydrate thereof; and 
         ii) at least one further antibacterial compound which is different from compound (i) and selected from the ceftriaxone, ampicillin, fosfomycin, polypeptides, linezolid and moxifloxacin. 
       
     
     
         3 . The combination according to  claim 2 , wherein the at least one oxazolidinone-quinolone hybrid is a compound of formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         B is CH 2  or CH 2 CH 2 ; 
         X is CH, N or C—OMe and R 3  is cyclopropyl or 
         X is CR 7  and R 7  and R 3  together form a bridge of the formula —O—CH 2 —CH(Me)-; 
         n is 1, 2 or 3; 
         m is 2 and 
         R 4  is hydrogen or a group of formula PO 3 H 2    
         or a pharmacologically acceptable salt, solvate or hydrate thereof. 
       
     
     
         4 . (canceled) 
     
     
         5 . The combination according to  claim 2  wherein the at least one further antibacterial compound (ii) is selected from the following compounds:
 ß-lactams:
 penems including carba-, thio-, and oxapenems such as imipenem, meropenem, ertapenem, faropenem, biapenem; 
 cephalosporines such as cefazolin, cefepime, cefotaxime, cefoxitine, ceftaroline, ceftazidime, ceftobiprole, ceftriaxone, cefuroxime and cephalexine; 
 monobactames such as aztreonam, BAL30072; 
 penicillines such as penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin); acylaminopenicillines such as piperacillin, mezlocillin, azlocillin; aminopenicillines such as ampicillin, amoxicillin; isoxazolylpenicillines such as oxacillin, cloxacillin, dicloxacillin, flucloxacillin; methicillin; sultamicillin; ticarcillin, carbenicillin, temocillin; 
 combinations of ß-lactams with a ß-lactamase inhibitor such as clavulanic acid+amoxicillin, sulbactam+ampicillin, tazobactam+piperacillin, ticarcillin+clavulanate, ceftazidime+avibactam, ceftaroline+avibactam, imipenem+MX-7655, biapenem+RPX7009, aztreonam+avibactam; 
 
 fosfomycin; 
 fosmidomycin; 
 glycopeptides such as teicoplanin, vancomycin; 
 lipopeptides such as daptomycin; 
 lipoglycopeptides such as telavancin, oritavancin, dalbavancin; 
 other agents active against Gram-positive bacteria such as GSK-1322322, AFN-1252, MUT-056399; 
 polypeptides such as bacitracin, colistin, gramicidin, polymyxin B, tyrothricin; 
 other membrane-acting agents such as brilicidin, POL7080, ACHN-975; 
 aminoglykosides such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin; 
 chloramphenicol, thiamphenicol; 
 fusidic acid; 
 macrolides such as azithromycin, clarithromycin, erythromycin, roxythromycin, ketolides such as cethromycin, narbomycin, telithromycin, solithromycin; 
 lincosamides such as clindamycin, lincomycin; 
 Streptogramines such as dalfopristin, quinupristin; 
 polyketides 
 oxazolidinones such as linezolid, tedizolid, radezolid; 
 tetracyclines such as doxycyclin, minocyclin, tetracyclin, oxytetracyclin; 
 glycylcyclines such as tigecyclin, omadacycline; 
 type II topopisomerase inhibitors:
 quinolones (especially fluoroquinolones) such as norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, grepafloxacin, moxifloxacin, delafloxacin, finafloxacin, nemonoxacin, zabofloxacin, ozenoxacin, chinfloxacin, JNJ-Q2, DS-8587, KPI-10, GSK2140944, ACH-702; 
 coumarins such as novobiocin, clorobiocin, coumermycin A; 
 
 nitroimidazoles such as metronidazole, tinidazole, ornidazole, nimorazole; 
 folic acid agonists:
 sulfonamides such as sulfadiazin, sulfadoxin, sulfamethoxazole, sulfasalazin; 
 diaminopyrimidines such as pyrimethamin, trimethoprim; 
 
 ansamycines:
 rifamycines such as rifampicin,rifabutin, rifapentin, rifamixin; 
 
 additional classes:
 pleuromutilines such as BC-3781, BC-7013; 
 leucyl-t-RNA synthase inhibitors such as AN3365. 
 
 
     
     
         6 . The combination according to  claim 2 , wherein the at least one further antibacterial compound (ii) is selected from the following compounds: colistin, fosfomycin, ampicillin, ceftriaxone, moxifloxacin and linezolid. 
     
     
         7 . The combination according to  claim 2 , wherein the at least one further antibacterial compound (ii) is selected from the following compounds: colistin and other polycations (or polycationic antibacterials) such as bacitracin, gramicidin, polymyxin B, tyrothricin, and aminoglycosides (e.g. amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin and tobramycin). 
     
     
         8 . The combination according to  claim 2 , wherein the at least one further antibacterial compound (ii) is selected from the following compounds: fluoroquinolones such as norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, grepafloxacin, moxifloxacin, delafloxacin, nemonoxacin, zabofloxacin, ozenoxacin, chinfloxacin, JNJ-Q2, DS-8587, KPI-10, GSK2140944, ACH-702 and finafloxacin, as well as oxazolidinones such as linezolid, tedizolid and radezolid. 
     
     
         9 . The combination according to  claim 2 , wherein the at least one further antibacterial compound (ii) is selected from the following compounds: ß-lactams such as amoxicillin, ampicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), piperacillin, mezlocillin, azlocillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, sultamicillin, carbenicillin, temocillin, ticarcillin, imipenem, meropenem, ertapenem, faropenem, biapenem, cefazolin, cefepime, cefotaxime, cefoxitine, ceftaroline, ceftazidime, ceftobiprole, ceftriaxone, cefuroxime and cephalexine, aztreonam and BAL30072 as well as combinations of ß-lactams with a ß-lactamase inhibitor such as clavulanic acid+amoxicillin, sulbactam+ampicillin, tazobactam+piperacillin, ticarcillin+clavulanate, ceftazidime+avibactam, ceftaroline+avibactam, imipenem+MX-7655, biapenem+RPX7009, and aztreonam+avibactam. 
     
     
         10 . The combination according to  claim 2 , wherein the at least one further antibacterial compound (ii) is selected from the following compounds: vancomycin, daptomycin, tobramycin, ciprofloxacin, tigecycline, imipenem, piperacillin-tazobactam, telavancin, dalbavancin, oritavancin and ceftazidime. 
     
     
         11 . The combination according to  claim 2 , wherein the at least one further antibacterial compound (ii) is selected from the following compounds: fosfomycin and other cell wall synthesis inhibitors, such as ß-lactams, e.g. amoxicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), piperacillin, mezlocillin, azlocillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, sultamicillin, carbenicillin, temocillin, ticarcillin, imipenem, meropenem, ertapenem, faropenem, biapenem, cefazolin, cefepime, cefotaxime, cefoxitine, ceftaroline, ceftazidime, ceftobiprole, ceftriaxone, cefuroxime and cephalexine, aztreonam, BAL30072 as well as combinations of ß-lactams with a ß-lactamase inhibitor such as clavulanic acid+amoxicillin, sulbactam+ampicillin, tazobactam+piperacillin, ticarcillin+clavulanate, ceftazidime+avibactam, ceftaroline+avibactam, imipenem+MX-7655, biapenem+RPX7009, aztreonam+avibactam. 
     
     
         12 . (canceled) 
     
     
         13 . A pharmaceutical composition comprising a combination according to  claim 2  and a carrier and/or diluent and/or adjuvant. 
     
     
         14 . A kit-of-parts comprising:
 i) at least one oxazolidinone-quinolone hybrid according to  claim 2  and   ii) at least one further antibacterial compound which is different from compound (i) according to  claim 2 .   
     
     
         15 . A combination or a pharmaceutical composition or a kit-of-parts according to  claim 2  for use in the treatment and/or prophylaxis of bacterial infections. 
     
     
         16 . A method for treating a subject suffering from or susceptible to a bacterial infection, comprising administering to the subject a combination according to  claim 2 . 
     
     
         17 . A method for treating a subject suffering from or susceptible to a bacterial infection, comprising administering to the subject a pharmaceutical composition of  claim 13 . 
     
     
         18 . A method for treating a subject suffering from or susceptible to a bacterial infection, comprising administering to the subject a kit of  claim 14 . 
     
     
         19 . The pharmaceutical composition of  claim 13  further comprising a carrier and/or diluent and/or adjuvant. 
     
     
         20 . The combination according to  claim 2 , wherein the at least one further antibacterial compound (ii) is selected from the following compounds:
 carba-, thio-, and oxapenems;   cefazolin, cefepime, cefotaxime, cefoxitine, ceftaroline, ceftazidime, ceftobiprole, ceftriaxone, cefuroxime and cephalexine;   aztreonam and BAL30072;   penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin);   acylaminopenicillines such as piperacillin, mezlocillin, azlocillin; aminopenicillines, amoxicillin; isoxazolylpenicillines;   clavulanic acid+amoxicillin, sulbactam+ampicillin, tazobactam+piperacillin, ticarcillin+clavulanate, ceftazidime+avibactam, ceftaroline+avibactam, imipenem+MX-7655, biapenem+RPX7009n and, aztreonam+avibactam.   
     
     
         21 . The combination of  claim 2 , wherein R 3  is F or Cl. 
     
     
         22 - 26 . (canceled)