Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections

Abstract

The present invention relates to the use of compounds, in which the pharmacophores of quinolone and oxazolidinone are chemically linked together through a linker that is stable under physiological conditions, for the treatment of anthrax and other infections.

1 - 27 . (canceled)  
   
   
       28 . A method for treating a subject suffering or susceptible to anthrax, comprising administering to the subject one or more compounds of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       A is a bond, a NH, O, S, SO, SO 2 , SO 2 NH, PO 4 , —NH—CO—NH—, —CO—NH—, —CO—, —CO—O—, —NH—CO—O—, —O-Z-heterocycloalkylen, an alkylen group, an alkenylen group, an alkinylen group, a heteroalkylen group, an arylen group, a heteroarylen group, a cycloalkylen group, a heterocycloalkylen group, an alkylarylen group or a heteroarylalkylen group or a combination of two or more of these atoms or groups;  
       L is selected from the following groups:  
       
         
           
           
               
               
           
         
       
       X is CR5 or N;  
       Y is CR6 or N;  
       U is F or Cl;  
       Z is a C 1-4  alkylene group, a C 2-4  alkenylene group, a C 2-4  alkynylene group or a C 1-4  heteroalkylene group, all of which may be substituted by one or more hydroxy or amino groups;  
       n is 0, 1, 2 or 3;  
       R1 is H, F, Cl, Br, I, OH, NH 2 , an alkyl group or a heteroalkyl group;  
       R2 is H, F or Cl;  
       R3 is H, an alkyl group, an alkenyl group, an alkinyl 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 may be substituted with one, two or more halogen atoms like F or Cl;  
       R4 is a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group;  
       R5 is H, F, Cl, OH, NH 2 , an alkyl group or a heteroalkyl group, or  
       R3 and R5 can be linked via an alkylen, an alkenylen or a heteroalkylen group or be a part of a cycloalkylen or heterocyclo-alkylen group; in case R3 is no H and R5 is no H, F, OH, NH 2  or Cl;  
       R6 is H, F, Cl or OMe;  
       R8 is a C 1-6  heteroalkyl or a heteroarylalkyl group;  
       or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof.  
     
   
   
       29 . The method of  claim 28  wherein R1 is H.  
   
   
       30 . The method of  claim 28  wherein R2 is F or H.  
   
   
       31 . The method of  claim 28  wherein R3 is an ethyl, a 2-propyl, a C 3 -C 6  cycloalkyl, a phenyl or a pyridyl group, all of which may be substituted by one, two or more fluorine atoms or amino groups.  
   
   
       32 . The method of  claim 28  wherein R3 is a cyclopropyl group.  
   
   
       33 . The method of  claim 28  wherein R3 and R5 together form a group of the formula —O—CH 2 —N(Me)- or —O—CH 2 —CH(Me)-.  
   
   
       34 . The method of  claim 28  wherein R4 is an acetylamino group.  
   
   
       35 . The method of  claim 28  wherein the absolute configuration at C-5 of the oxazolidinone ring is (S) according to the Cahn-Ingold-Prelog nomenclature system.  
   
   
       36 . The method of  claim 28  wherein X is N or CH.  
   
   
       37 . The method of  claim 28  wherein Y is CF or CH.  
   
   
       38 . The method of  claim 28  wherein n is 0.  
   
   
       39 . The method of  claim 28  wherein A is a group of the formula  
     
       
         
         
             
             
         
       
       wherein  
       the group B is an alkylene, which may be substituted by one, two or more fluorine atoms, an O, S, SO, SO 2 , SO 2 NH group, or a heteroalkylen group, which may be substituted by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group;  
       the groups D independently of each other are optionally anellated heterocycloalkylen groups with 1, 2, 3 or 4 nitrogen atoms, which heterocycloalkylen groups may each be substituted by one, two or more fluorine atoms and/or which each may be substituted at one, two, three or four nitrogen atoms by an alkyl or an acyl group; 
 the groups E independently of each other are an alkylene, which may be substituted by one, two or more fluorine atoms, an O, S, SO, SO 2 , SO 2 NH group, or a heteroalkylen group, which may be substituted by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group;  
 
       the groups G independently of each other are optionally anellated heterocycloalkylen groups with 1, 2, 3 or 4 nitrogen atoms, which heterocycloalkylen groups may each be substituted by one, two or more fluorine atoms and/or which each may be substituted at one, two, three or four nitrogen atoms by an alkyl or an acyl group;  
       the group K is an alkylene, which may be substituted by one, two or more fluorine atoms, an O, S, SO, SO 2 , SO 2 NH group, or a heteroalkylen group, which may be substituted by one, two or more fluorine atoms and/or at the optionally present nitrogen atoms by an alkyl or an acyl group; and m=1, 2, 3 or 4.  
     
   
   
       40 . The method of  claim 28  wherein A is a group of the formula —V—W—, wherein V is a direct bond or a group of the formula NH, O, S, SO, SO 2 , SO 2 NH, PO 4 , —NH—CO—NH—, —CO—NH—, —CO—, —CH 2 —, —CO—O—, —(CH 2 ) 1-3 —O—, —CH═CH—C(O)—, or —NH—CO—O— and W is a heterocycloalkyl group with 4 to 7 ring atoms or a alkylheterocycloalkyl group with 4 to 7 ring atoms and 1 to 4 carbon atoms in the alkyl chain; all these groups may be substituted by 1, 2, 3 or 4 fluorine atoms, methyl or methoxy groups.  
   
   
       41 . The method of  claim 28  wherein A is a group of the formula  
     
       
         
         
             
             
         
       
       wherein  
       V is a group of the formula NH, O, S, SO, SO 2 , SO 2 NH, PO 4 , —NH—CO—NH—, —CO—NH—, —CO—, —CH 2 —, —CO—O—, —(CH 2 ) 1-3 —O—, —CH═CH—C(O)—, or —NH—CO—O—; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; c is 0, 1, 2, 3 or 4 and 1, 2, 3 or 4 hydrogen atoms may be substituted by F, a methyl- or a methoxy group.  
     
   
   
       42 . The method of  claim 28  wherein V is NH, O, S, SO or SO 2 .  
   
   
       43 . The method of  claim 28  wherein V is O or NH; a is 0 or 1; b is 1 or 2 and c is 1 or 2.  
   
   
       44 . The method of  claim 28  wherein A is selected from the following groups which may be substituted by one, two or more fluorine atoms or by an alkyl group which may be substituted by one or more fluorine atoms, and wherein the amino groups may be substituted by an alkyl or an acyl group:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       45 . The method of  claim 28  wherein one or more administered compounds are represented by Formula (II):  
     
       
         
         
             
             
         
       
       wherein  
       L is selected from following groups:  
       
         
           
           
               
               
           
         
       
       b is 1, 2 or 3;  
       c is 1, 2 or 3;  
       R7 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, wherein R 9  is H, alkyl, cycloalkyl, aryl, aralkyl, and wherein R 10  is H, alkyl, cycloalkyl, aryl, aralkyl;  
       X, Y, Z, R1, R2, R3, R5, R6, R8, and the possible linkage between R3 and R5 are as defined above;  
       or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof for the treatment of anthrax.  
     
   
   
       46 . The method of  claim 28  wherein R7 is hydrogen or a group of the formula SO 3 H, PO 3 H 2 , PO 3 (CH 2 C 6 H 5 ) 2 , CH 2 OPO 3 H or COCH 2 CH 2 COOH, or together with the oxygen to which it is bound forms an ester of a naturally occurring amino acid or a derivative thereof.  
   
   
       47 . The method of  claim 28  wherein R8 is a group of the formula —CH 2 NHCOCH═CHAryl, —CH 2 OHeteroaryl, —CH 2 NHSO 2 Me, —CH 2 NHCOOMe, —CH 2 NHCS 2 Me, —CH 2 NHCSNH 2 , —CH 2 NHCSOMe or —CH 2 NHCOMe.  
   
   
       48 . The method of  claim 28  wherein L is a group of the following formula:  
     
       
         
         
             
             
         
       
     
   
   
       49 . The method of  claim 28  wherein R5 is H, F, Cl or a methoxy group which may be substituted by one, two or three fluorine atoms.  
   
   
       50 . The method of  claim 28  wherein Z is CH 2  or CH 2 CH 2 .  
   
   
       51 . The method of  claim 28  wherein a pharmaceutical composition is administered to the subject, the pharmaceutical composition comprising one or more compounds of Formula (I) and optionally one or more carriers and/or adjuvants and/or diluents.  
   
   
       52 . The method of  claim 28  wherein a compound of formula (I) that comprises at least one pharmacologically acceptable protective group is administered to the subject.  
   
   
       53 . A method for treating a subject suffering or susceptible to an infection, comprising administering to the subject one or more compounds of Formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       A is a bond, a NH, O, S, SO, SO 2 , SO 2 NH, PO 4 , —NH—CO—NH—, —CO—NH—, —CO—, —CO—O—, —NH—CO—O—, —O-Z-heterocycloalkylen, an alkylen group, an alkenylen group, an alkinylen group, a heteroalkylen group, an arylen group, a heteroarylen group, a cycloalkylen group, a heterocycloalkylen group, an alkylarylen group or a heteroarylalkylen group or a combination of two or more of these atoms or groups;  
       L is selected from the following groups:  
       
         
           
           
               
               
           
         
       
       X is CR5 or N;  
       Y is CR6 or N;  
       U is F or Cl;  
       Z is a C 1-4  alkylene group, a C 2-4  alkenylene group, a C 2-4  alkynylene group or a C 1-4  heteroalkylene group, all of which may be substituted by one or more hydroxy or amino groups;  
       n is 0, 1, 2 or 3;  
       R1 is H, F, Cl, Br, I, OH, NH 2 , an alkyl group or a heteroalkyl group;  
       R2 is H, F or Cl;  
       R3 is H, an alkyl group, an alkenyl group, an alkinyl 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 may be substituted with one, two or more halogen atoms like F or Cl;  
       R4 is a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or a heteroarylalkyl group;  
       R5 is H, F, Cl, OH, NH 2 , an alkyl group or a heteroalkyl group, or  
       R3 and R5 can be linked via an alkylen, an alkenylen or a heteroalkylen group or be a part of a cycloalkylen or heterocyclo-alkylen group; in case R3 is no H and R5 is no H, F, OH, NH 2  or Cl;  
       R6 is H, F, Cl or OMe;  
       R8 is a C 1-6  heteroalkyl or a heteroarylalkyl group;  
       or a pharmacologically acceptable salt, solvate, hydrate or formulation thereof.