Antibacterial agents

Abstract

D-(threo)-1-aryl-2-disubstitutedacylamido-3-fluoro-1-propanol compounds compounds and analogues thereof (“Fenicol Compounds”), compositions comprising an effective amount of a Fenicol Compound, and methods for treating or preventing a bacterial infection in an animal comprising administering to an animal in need thereof an effective amount of a Fenicol Compound are disclosed.

1 . A compound of formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein
 A is (R) —CH(CH 3 )(CF 3 ) substantially free of (S) —CH(CH 3 )(CF 3 ), (R) —CH(CH 3 )(halo) substantially free of (S) —CH(CH 3 )(halo), (R) —CH(CF 3 )(halo) substantially free of (S) —CH(CF 3 )(halo), (R)—CH(CF 3 )(OH) substantially free of (S) —CH(CF 3 )(OH), (S) —CH(CH 3 )(CF 3 ) substantially free of (R) —CH(CH 3 )(CF 3 ), (S) —CH(CH 3 )(halo) substantially free of (R) —CH(CH 3 )(halo), (S) —CH(CF 3 )(halo) substantially free of (R) —CH(CF 3 )(halo), or (S)CH(CF 3 )(OH) substantially free of (R) —CH(CF 3 )(OH); 
 Z is hydrogen or an acyl group of formula —C(O)—R 2 , wherein R 2  is a C 1  to C 18  hydrocarbon group that may optionally be substituted with a —NH 2  or —COOH; 
 Y and Y 1  is —H; —NO 2 ; —SO 2 R 1 ; —SOR 1 ; —SR 1 ; —SONH 2 ; —SO 2 NH 2 ; —SONHR 1 ; —SO 2 NHR 1 ; —COR 2 ; —OR 1 ; —R 1 ; —CN, -halogen; -phenyl; or -phenyl substituted with -halogen, —NO 2 , —SO 2 CH 3 , -R 1 , or —OR 1 ; 
 halo is —Cl, —Br, —I, or —F; and 
 R 1  is a C 1  to C 3  hydrocarbon group. 
 
     
     
         2 . The compound of  claim 1 , wherein A is (R) —CH(CH 3 )(CF 3 ) substantially free of (S) —CH(CH 3 )(CF 3 ), (R) —CH(CH 3 )(halo) substantially free of (S) —CH(CH 3 )(halo), (R) —CH(CF 3 )(halo) substantially free of (S) —CH(CF 3 )(halo), or (R)—CH(CF 3 )(OH) substantially free of (S) —CH(CF 3 )(OH). 
     
     
         3 . The compound of  claim 2 , wherein Z is hydrogen. 
     
     
         4 . The compound of  claim 1 , wherein Z is hydrogen. 
     
     
         5 . The compound of  claim 3 , wherein Y is —SO 2 CH 3  and Y 1  is hydrogen. 
     
     
         6 . The compound of  claim 5 , wherein A is (R) —CH(CH 3 )(CF 3 ) substantially free of (S) —CH(CH 3 )(CF 3 ). 
     
     
         7 . The compound of  claim 5 , wherein A is (R) —CH(CH 3 )(halo) substantially free of (S) —CH(CH 3 )(halo). 
     
     
         8 . The compound of  claim 7 , wherein A is (R) —CH(CH 3 )(Cl) substantially free of (S) —CH(CH 3 )(Cl). 
     
     
         9 . The compound of  claim 7 , wherein A is (R) —CH(CH 3 )(F) substantially free of (S) -CH(CH 3 )(F). 
     
     
         10 . The compound of  claim 7 , wherein A is (R) —CH(CH 3 )(Br) substantially free of (S) —CH(CH 3 )(Br). 
     
     
         11 . The compound of  claim 7 , wherein A is (R) —CH(CH 3 )(I) substantially free of (S) -CH(CH 3 )(I). 
     
     
         12 . The compound of  claim 5 , wherein A is (R) —CH(CH 3 )(OH) substantially free of (S) —CH(CH 3 )(OH). 
     
     
         13 . The compound of  claim 5 , wherein A is (R) —CH(CF 3 )(halo) substantially free of (S) —CH(CF 3 )(halo). 
     
     
         14 . The compound of  claim 13 , wherein A is (R) —CH(CF 3 )(Cl) substantially free of (S) —CH(CF 3 )(Cl). 
     
     
         15 . The compound of  claim 13 , wherein A is (R) —CH(CF 3 )(F) substantially free of (S) —CH(CF 3 )(F). 
     
     
         16 . The compound of  claim 13 , wherein A is (R) —CH(CF 3 )(Br) substantially free of (S) —CH(CF 3 )(Br). 
     
     
         17 . The compound of  claim 13 , wherein A is (R) —CH(CF 3 )(I) substantially free of (S) —CH(CF 3 )(I). 
     
     
         18 . The compound of  claim 5 , wherein A is (R) —CH(CF 3 )(OH) substantially free of (S) —CH(CF 3 )(OH). 
     
     
         19 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         20 . The pharmaceutical composition of  claim 19  adapted for oral administration. 
     
     
         21 . The pharmaceutical composition of  claim 19  adapted for parenteral administration. 
     
     
         22 . The pharmaceutical composition of  claim 19  adapted for topical administration. 
     
     
         23 . A method of treating or preventing a bacterial infection in an animal, comprising administering to an animal in need thereof the compound of  claim 1 . 
     
     
         24 . The method of  claim 23 , wherein the animal is a dog or cat. 
     
     
         25 . The method of  claim 23 , wherein the compound of  claim 1  is administered at a dose ranging from about 0.1 mg/kg of body weight to about 50 mg/kg of body weight. 
     
     
         26 . The method of  claim 23 , wherein the compound of  claim 1  is administered daily until the bacterial infection is abated. 
     
     
         27 . A method of treating a bacterial infection in an animal comprising administering to an animal in need thereof a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein A is a group of formula —CH(CH 3 )(CF 3 ), —CH(CH 3 )(halo), —CH(CF 3 )(halo), or —CH(CF 3 )(OH); 
 Z is hydrogen or an acyl group of formula —C(O)—R 2 , wherein R 2  is a C 1  to C 18  hydrocarbon group that may optionally be substituted with a —NH 2  or —COOH; 
 Y and Y 1  is —H; —NO 2 ; —SO 2 R 1 ; —SOR 1 ; —SR 1 ; —SONH 2 ; —SO 2 NH 2 ; —SONHR 1 ; —SO 2 NHR 1 ; —COR 2 ; —OR 1 ; —R 1 ; —CN, -halogen; -phenyl; or -phenyl substituted with -halogen, —NO 2 , —SO 2 CH 3 , -R 1 , or —OR 1 ; 
 halo is —Cl, —Br, —I, or —F; and 
 R 1  is a C 1  to C 3  hydrocarbon group; and 
 wherein the group of formula A is in either the (R) configuration substantially free of the (S) configuration or the (S) configuration substantially free of the (R) configuration and is the configuration that is cleared more slowly when administered to an animal. 
 
     
     
         28 . A method of selecting a compound for treating a condition in an animal comprising:
 providing a first compound that has a first carbon atom that is achiral and bonded to four first substituents;   modifying the first compound that has a first carbon atom that is achiral by replacing a sufficient number of the first substituents with second substituents to provide a second compound wherein the first carbon atom has been changed to a chiral carbon atom, and wherein the second compound exists as a mixture of the second compound wherein the chiral carbon atom has the R stereochemical configuration and the second compound wherein the chiral carbon has the S stereochemical configuration;   separating the second carbon compound wherein the chiral carbon atom has the R stereochemical configuration and the second carbon compound wherein the chiral carbon atom has the S stereochemical configuration;   testing the second carbon compound that has the chiral carbon in the R stereochemical configuration and the second carbon compound that has the chiral carbon atom bonded in the S stereochemical configuration for activity at treating the condition;   selecting the second carbon compound that has the higher activity for treating the condition.   
     
     
         29 . The method of  claim 1 , wherein the condition is a bacterial infection. 
     
     
         30 . The method of  claim 1 , wherein the second carbon compound that has the higher activity for treating the condition is selected based on its rate of clearance in the animal. 
     
     
         31 . The method of  claim 30 , wherein the rate of clearance in the animal of the second carbon compound that has the higher activity for treating the condition is the second carbon compound that is cleared more slowly. 
     
     
         32 . A chemical compound selected using the method of  claim 28 .