Antimicrobial 4-oxoquinolizines

Abstract

This invention provides novel 4-oxoquinolizine compounds and their uses for a series of broad-spectrum antibiotics having no cross-resistance to existing or emerging classes of antibiotics. In addition the novel 4-oxoquinolizine compounds are useful against CDC Category A and B pathogens The invention also provides pharmaceutical compositions comprising certain 4-oxoquinolizines in combination with subinhibitory concentrations of polymyxin B against clinical isolates which are resistant to quinolones, carbapenems and other antimicrobial agents.

We claim: 
     
         1 . A compound of formula IIIc: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 (a) R 1  is halogen, cyano, C 1-8  alkyl, C 1-8  haloalkyl, —OR X , —N(R X ) 2 , —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 , wherein each R X  is independently hydrogen, C 1-8  alkyl, or C 1-8 haloalkyl;
 Y is phenyl, which is substituted with either —N(R Y1 ) 2  or —C 1 -C 8  alkyl-R Y  and further optionally substituted by one to four groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8  cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y , 
 wherein R Y  is nitro, cyano, —OR Y1 , —SR Y1 , —C(O)R Y1 , —C(O)OR Y1 , —C(O)N(R Y1 ) 2 , —OC(O)R Y1 , —OC(O)OR Y1 , —OC(O)N(R Y1 ) 2 , —N(R Y1 )C(O)R Y1 , —N(R Y1 )C(O)OR Y1 , —N(R Y1 )C(O)N(R Y1 ) 2 , —S(O) 2 R Y1 , —S(O) 2 OR Y1 , —S(O) 2 N(R Y1 ) 2 , —OS(O) 2 R Y1 , —OS(O) 2 OR Y1 , —OS(O) 2 N(R Y1 ) 2 , —N(R Y1 )S(O) 2 R Y1 , —N(R Y1 )S(O) 2 OR Y1 , or —N(R Y1 )S(O) 2 N(R Y1 ) 2 ; and 
 wherein each R Y1  is independently hydrogen, C 1-8  alkyl, or C 1-8  haloalkyl; or 
 
 (b) R 2  is hydrogen, halogen, cyano, C 1-8  alkyl, C 1-8  haloalkyl, —OR X , —N(R X ) 2 , —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 , wherein each R X  is independently hydrogen, C 1-8  alkyl, or C 1-8 haloalkyl;
 Y is 5-membered or 6-membered heterocyclyl, each of which is substituted with either —N(R Y1 ) 2  or —C 1 -C 8  alkyl-R Y  and further optionally substituted by one to four groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8  cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y , 
 wherein R Y  is nitro, cyano, —OR Y1 , —SR Y1 , —C(O)R Y1 , —C(O)OR Y1 , —C(O)N(R Y1 ) 2 , —OC(O)R Y1 , —OC(O)OR Y1 , —OC(O)N(R Y1 ) 2 , —N(R Y1 )C(O)R Y , —N(R Y1 )C(O)OR Y1 , —N(R Y1 )C(O)N(R Y1 ) 2 , —S(O) 2 R Y1 , —S(O) 2 OR Y1 , —S(O) 2 N(R Y1 ) 2 , —OS(O) 2 R Y1 , —OS(O) 2 OR Y1 , —OS(O) 2 N(R Y1 ) 2 , —N(R Y1 )S(O) 2 R Y1 , —N(R Y1 )S(O) 2 OR Y1 , or —N(R Y1 )S(O) 2 N(R 1 ) 2 ; and 
 wherein each R Y1  is independently hydrogen, C 1-8  alkyl, or C 1-8  haloalkyl; or 
 
 (c) R 1  is hydrogen, halogen, cyano, C 1-8  alkyl, C 1-8  haloalkyl, —OR X , —N(R X ) 2 , —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 , wherein each R X  is independently hydrogen, C 1-8  alkyl, or C 1-8  haloalkyl;
 Y is a bicyclic heteroaryl, each of which is substituted with either —N(R Y1 ) 2  or —C 1 -C 8  alkyl-R Y  and further optionally substituted by one to four groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8  cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y , 
 wherein R Y  is nitro, cyano, —OR Y1 , —SR Y1 , —NR Y1 , —C(O)R Y1 , —C(O)OR Y1 , —C(O)N(R Y1 ) 2 , —OC(O)R Y1 , —OC(O)OR Y1 , —OC(O)N(R Y1 ) 2 , —N(R Y1 )C(O)R Y1 , —N(R Y1 )C(O)OR Y1 , —N(R Y1 )C(O)N(R Y1 ) 2 , —S(O) 2 R Y1 , —S(O) 2 OR Y1 , —S(O) 2 N(R Y1 ) 2 , —OS(O) 2 R Y1 , —OS(O) 2 OR Y1 , —OS(O) 2 N(R 1 ) 2 , —N(R Y1 )S(O) 2 R Y1 , —N(R Y1 ) S(O) 2 OR Y1 , or —N(R Y1 )S(O) 2 N(R Y1 ) 2 ; and 
 wherein each R Y1  is independently hydrogen, C 1-8  alkyl, or C 1-8  haloalkyl. 
 
 
       
     
     
         2 . The compound of  claim 1 , wherein in (a) R 1  is halogen; or in (b) R 1  is hydrogen or halogen; or in (c) R 1  is hydrogen or halogen. 
     
     
         3 . The compound of  claim 1 , wherein
 (a) Y is phenyl substituted with one group which is —N(R Y1 ) 2  or —C 1-8  alkyl-N(R Y1 ) 2 , and optionally substituted by one or two groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8  cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y ; or   (b) Y is a 5-membered or 6-membered heterocyclyl each of which is substituted with either —N(R Y1 ) 2  or —C 1 -C 8  alkyl-R Y  and optionally substituted by one or two groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y ; or   (c) Y is a bicyclic heteroaryl substituted with either —N(R Y1 ) 2  or —C 1 -C 8  alkyl-R Y  and optionally substituted by one or two groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y .   
     
     
         4 . The compound of  claim 2 , wherein
 (a) Y is phenyl substituted with one group which is —N(R Y1 ) 2  or, —C 1-8  alkyl-N(R Y1 ) 2 , and optionally substituted by one or two groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y ; or   (b) Y is a 5-membered or 6-membered heterocyclyl each of which is substituted with either —N(R Y1 ) 2  or —C 1 -C 8  alkyl-R Y  and optionally substituted by one or two groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8  cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y ; or   (c) Y is a bicyclic heteroaryl substituted with either —N(R Y1 ) 2  or —C 1 -C 8  alkyl-R Y  and optionally substituted by one or two groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y .   
     
     
         5 . The compound of  claim 1  selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                 
                   Compound Structure 
                   Compound Name 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(4-amino-phenyl)-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(3-fluoro-4-amino-phenyl)-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(3-amino-phenyl)-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(6-amino-3-pyridyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(2-aminopyrimidin-5-yl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(6-amino-3-pyridyl)-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(2-amino-1,3-benzothiaol-5- yl)-1-cyclopropyl-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-[6-(methylamino)-3-pyridyl]-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(6-amino-5-methyl-3-pyridyl)- 1-cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(6-amino-3-pyridyl)-1- cyclopropyl-7,9-dimethyl-4-oxo- quinolizine-3-carboxylic acid 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   8-(6-amino-3-pyridyl)-1- cyclopropyl-9-methoxy-4-oxo- quinolizine-3-carboxylic acid 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         6 . The compound 8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid and pharmaceutically acceptable salts thereof. 
     
     
         7 . The compound 8-[5-(aminomethyl)-2-thienyl]-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid and pharmaceutically acceptable salts thereof. 
     
     
         8 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         9 . A method of treating a bacterial infection in an individual in need thereof comprising administering to the individual the compound of  claim 1 . 
     
     
         10 . The method of  claim 9 , wherein the infection is infection by a multi-drug resistant bacterial strain. 
     
     
         11 . The method of  claim 9 , wherein the bacterial infection is caused by one or more bacteria of a genus selected from the group consisting of  Acinetobacter, Bacillus, Bordetella, Borrelia, Brucella, Camphylobacter, Chlamydia, Clostridium, Corynebacterium, Enterococcus, Escherichia, Fransisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Propionibacterium, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Vibrio  and  Yersinia.    
     
     
         12 . A method of treating a bacterial infection in an individual in need thereof comprising administering to the individual the compound of  claim 7 . 
     
     
         13 . The method of  claim 12 , wherein the infection is infection by a multi-drug resistant bacterial strain. 
     
     
         14 . The method of  claim 12 , wherein the bacterial infection is caused by one or more bacteria of a genus selected from the group consisting of  Acinetobacter, Bacillus, Bordetella, Borrelia, Brucella, Camphylobacter, Chlamydia, Clostridium, Corynebacterium, Enterococcus, Escherichia, Fransisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Propionibacterium, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Vibrio  and  Yersinia.    
     
     
         15 . A method of treating a bacterial infection in an individual in need thereof comprising administering to the individual a compound selected from the group consisting of 8-(6-amino-3-pyridyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid, 8-[3-(aminomethyl)-4-hydroxy-phenyl]-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, 8-(2-amino-1,3-benzothiazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, 8-(6-amino-5-methyl-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 15 , wherein the infection is infection by a multiresistant strain. 
     
     
         17 . The method of  claim 15 , wherein the infection is infection by one or more bacteria of a genus selected from the group consisting of  Acinetobacter, Bacillus, Bordetella, Borrelia, Brucella, Camphylobacter, Chlamydia, Clostridium, Corynebacterium, Enterococcus, Escherichia, Fransisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Propionibacterium, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Vibrio  and  Yersinia.    
     
     
         18 . The method of  claim 15 , wherein the compound is 8-(6-amino-3-pyridyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 15 , wherein the compound is a hydrochloride acid salt of 8-(6-amino-3-pyridyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid. 
     
     
         20 . The method of  claim 15 , wherein the compound is 8-[3-(aminomethyl)-4-hydroxy-phenyl]-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 15 , wherein the compound is 8-(2-amino-1,3-benzothiazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 15 , wherein the compound is 8-(6-amino-5-methyl-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.