Compounds for the treatment of multi-drug resistant bacterial infections

Abstract

The present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.

1 .- 20 . (canceled) 
     
     
         21 . A method of treating a bacterial infection comprising administering a therapeutically effective amount of a compound of formula V(A), or a pharmaceutically acceptable salt thereof, to a mammal in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 2 b is H, halo, cyano, nitro, (C 1 -C 6 )alkanoyl, carboxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, hydroxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy, NHCO—(C 1 -C 6 )alkyl, SO 2 (C 1 -C 6 )alkyl, SO 2 NH(C 1 -C 6 )alkyl, or SO 2 N((C 1 -C 6 )alkyl) 2 ; 
 Z is CH or N when “- - - -” is a bond, or, when “- - - -” is absent, Z is O or NH; 
 Ry is fluoro, hydroxy, methoxy, carbomethoxy, or carboxy; 
 R′ is H or (C 1 -C 6 )alkyl; and 
 R is 
 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 21 , wherein the compound of formula V(A) is cis(±)1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 21 , wherein the bacterial infection is caused by gram positive bacteria. 
     
     
         24 . The method of  claim 23 , wherein the gram positive bacteria is  Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes , or  Enterococcus faecium    
     
     
         25 . The method of  claim 21 , wherein the bacterial infection is caused by gram negative bacteria. 
     
     
         26 . The method of  claim 21 , wherein the gram negative bacteria is  Haemophilus influenzae, Escherichia coli  and  Moraxella catarrhalis.    
     
     
         27 . A method of treating a bacterial infection in a warm-blooded animal in need of such treatment, comprising administering to said animal an effective amount of a compound of formula V(A), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 2 b is H, halo, cyano, nitro, (C 1 -C 6 )alkanoyl, carboxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, hydroxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy, NHCO—(C 1 -C 6 )alkyl, SO 2 (C 1 -C 6 )alkyl, SO 2 NH(C 1 -C 6 )alkyl, or SO 2 N((C 1 -C 6 )alkyl) 2 ; 
 Z is CH or N when “- - - -” is a bond, or, when “- - - -” is absent, Z is O or NH; 
 Ry is fluoro, hydroxy, methoxy, carbomethoxy, or carboxy; 
 R′ is H or (C 1 -C 6 )alkyl; and 
 R is 
 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 27 , wherein the compound of formula V(A) is cis(±)1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method of  claim 27 , wherein the bacterial infection is caused by gram positive bacteria. 
     
     
         30 . The method of  claim 29 , wherein the gram positive bacteria is  Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes , or  Enterococcus faecium    
     
     
         31 . The method of  claim 27 , wherein the bacterial infection is caused by gram negative bacteria. 
     
     
         32 . The method of  claim 31 , wherein the gram negative bacteria is  Haemophilus influenzae, Escherichia coli  or  Moraxella catarrhalis.    
     
     
         33 . The method of  claim 27 , wherein the warm-blooded animal is a human. 
     
     
         34 . A method for inhibiting bacterial DNA gyrase in a warm-blooded animal in need of such treatment comprising administering to said animal an effective amount of a compound of formula V(A), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 2 b is H, halo, cyano, nitro, (C 1 -C 6 )alkanoyl, carboxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkyl, hydroxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy, NHCO—(C 1 -C 6 )alkyl, SO 2 (C 1 -C 6 )alkyl, SO 2 NH(C 1 -C 6 )alkyl, or SO 2 N((C 1 -C 6 )alkyl) 2 ; 
 Z is CH or N when “- - - -” is a bond, or, when “- - - -” is absent, Z is O or NH; 
 Ry is fluoro, hydroxy, methoxy, carbomethoxy, or carboxy; 
 R′ is H or (C 1 -C 6 )alkyl; and 
 R is 
 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 34 , wherein the compound of formula V(A) is cis(±)1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method of  claim 34 , wherein the bacterial infection is caused by gram positive bacteria. 
     
     
         37 . The method of  claim 36 , wherein the gram positive bacteria is  Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes , or  Enterococcus faecium    
     
     
         38 . The method of  claim 34 , wherein the bacterial infection is caused by gram negative bacteria. 
     
     
         39 . The method of  claim 38 , wherein the gram negative bacteria is  Haemophilus influenzae, Escherichia coli  or  Moraxella catarrhalis.    
     
     
         40 . The method of  claim 34 , wherein the warm-blooded animal is a human.