Methods of preventing bacterial infections with florfenicol-type antibiotics

Abstract

The present invention relates to novel florfenicol compounds having the chemical structure: wherein the compounds are useful for the treatment and/or prevention of bacterial infections in a broad range of patients such as, without limitation, birds, fish, shellfish and mammals.

1 - 25 . (canceled)  
   
   
       26 . A method of preventing a bacterial infection in a nonhuman patient comprising administering to the nonhuman patient a pharmaceutically effective amount of a compound having the chemical formula:  
     
       
         
         
             
             
         
       
       wherein R 2  and R 3  are independently selected from the group consisting of hydrogen, (1C-4C)alkyl, halo, —CF 3 , —NH 2 , —CN and N 3 ;  
       wherein R 4  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein A 1  is carbon or nitrogen, and carbon atoms in the ring are independently substituted with an entity selected from the group consisting of hydrogen, (1C-4C)alkyl, (3C-6C)cycloalkyl, (1C-4C)alkylO—, —CF 3 , —OH, —CN, halo, (1C-4C)alkylSO—, (1C-4C)alkylSO 2 —, NH 2 SO 2 —, (1C-4C)alkylNHSO 2 —, ((1C-4C)alkyl) 2 NSO 2 —, —NH 2 , (1C-4C)alkylNH—, ((1C-4C)alkyl) 2 N—, (1C-4C)alkylSO 2 NH—, (1C-4C)alkylC(O)—, (3C-6C)cycloalkylC(O)—, (1C-4C)alkylOC(O)—, (1C-4C)alkylC(O)NH—, —C(O)NH 2 , (1C-4C)alkylNHC(O)— and ((1C-4C)alkyl) 2 NC(O)—, wherein any of the alkyl groups within the substituents may be unsubstituted or substituted with a group selected from halo and hydroxy;  
       wherein A 2 , A 3 , A 4 , and A 5  are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur, provided that at least one of A 1 -A 5  is not carbon, that the total number of nitrogen, oxygen and sulfur atoms in the ring does not exceed 4 and that the ring is aromatic; and wherein if A 1  is carbon and the ring does not contain oxygen or sulfur, one of the nitrogen atoms may optionally be substituted with an entity selected from the group consisting of (1C-4C)alkyl, (1C-4C)alkylSO 2 — and —NH 2 ; and  
       wherein A 6 , A 7 , A 8 , A 9  and A 10  are independently selected from the group consisting of carbon, nitrogen and  
       
         
           
           
               
               
           
         
       
       provided that only one of A 6 -A 10  at a time can be  
       
         
           
           
               
               
           
         
       
       and that one, two, or three of the A 6 -A 10  atoms are nitrogen; and wherein the carbon atoms in the ring are independently substituted with an entity selected from the group consisting of hydrogen, (1C-4C)alkyl, (3C-6C)cycloalkyl, (1C-4C)alkylO—, —CF 3 , —OH, —CN, halo, (1C-4C)alkylSO—, (1C-4C)alkylSO 2 —, NH 2 SO 2 —, (1C-4C)alkylNHSO 2 —, ((1C-4C)alkyl) 2 NSO 2 —, —NH 2 , (1C-4C)alkylNH—, ((1C-4C)alkyl) 2 N—, (1C-4C)alkylSO 2 NH—, (1C-4C)alkylC(O)—, (3C-6C)cycloalkylC(O)—, (1C-4C)alkylOC(O)—, (1C-4C)alkylC(O)NH—, —C(O)NH 2 , (1C-4C)alkylNHC(O)—, ((1C-4C)alkyl) 2 NC(O)— and —OCH 2 O—, wherein the oxygen atoms with the —OCH 2 O— substituent being bonded to adjacent ring carbon atoms, and wherein any of the alkyl groups within any of the substituents may be unsubstituted or substituted with a group selected from halo and hydroxy; and  
       wherein R 8  is hydrogen in all compounds, except when R 2  and R 3  are both F, in which case R 8  is hydrogen or F; and, the compound is either a racemate having the relative stereochemistry shown or is substantially enantiomerically pure and has the absolute stereochemistry shown.  
     
   
   
       27 . The method of  claim 26 , wherein R 2  and R 3  are independently selected from the group consisting of Cl and F; and wherein R 8  is hydrogen.  
   
   
       28 . The method of  claim 27 , wherein: 
 R 4  is                          and,    wherein any of A 6 -A 10  that is a carbon atom is substituted with an entity selected from the group consisting of hydrogen, —NH 2 , halo-, —CN, (1C-4C)alkyl-, (1C-4C)alkylC(O)—, (1C-4C)alkylSO—, (1C-4C)alkylSO 2 , NH 2 SO 2 —, (1C-4C)alkylSO 2 NH—, (1C-4C)alkylNHSO 2 —, ((1C-4C)alkyl) 2 NSO 2 —, wherein any of the alkyl groups within any of the substituents may be unsubstituted or substituted with halo or hydroxy.    
   
   
       29 . The method of  claim 27 , wherein R 4  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       30 . The method of  claim 27  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       31 . The method of  claim 30 , wherein all carbon atoms and nitrogen atoms are unsubstituted.  
   
   
       32 . The method of  claim 30 , wherein one of the A 2 -A 5  atoms that is carbon is substituted with an —NH 2  group, and all other carbon and nitrogen atoms in the ring are unsubstituted.  
   
   
       33 . The method of  claim 30 , wherein R 4  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       34 . The method of  claim 27  selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein the compound is either a racemate having the relative stereochemistry shown or is substantially enantiomerically pure and has the absolute stereochemistry shown.  
     
   
   
       35 . The method of  claim 34  selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein the compound is either a racemate having the relative stereochemistry shown or is substantially enantiomerically pure and has the absolute stereochemistry shown.  
     
   
   
       36 . The method of  claim 26 , wherein: 
 R 4  is                          and, wherein any of A 6 -A 10  that is a carbon atom is substituted with an entity selected from the group consisting of hydrogen, —NH 2 , halo-, —CN, (1C-4C)alkyl-, (1C-4C)alkylC(O)—, (1C-4C)alkylSO—, (1C-4C)alkylSO 2 , NH 2 SO 2 —, (1C-4C)alkylSO 2 NH—, (1C-4C)alkylNHSO 2 —, ((1C-4C)alkyl) 2 NSO 2 —, wherein any of the alkyl groups within any of the substituents may be unsubstituted or substituted with halo or hydroxy.    
   
   
       37 . The method of  claim 26 , wherein: 
 R 4  is                          wherein any of A 6 -A 10  that are carbon atoms are optionally substituted with —NH 2 , and wherein all remaining A 6 -A 10  carbon atoms are unsubstituted.    
   
   
       38 . The method of  claim 26 , wherein R 4  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       39 . The method of  claim 26 , wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       40 . The method of  claim 39 , wherein all carbon atoms and nitrogen atoms are unsubstituted.  
   
   
       41 . The method of  claim 39 , wherein one of the A 2 -A 5  atoms that is carbon is substituted with an —NH 2  group, and all other carbon and nitrogen atoms in the ring are unsubstituted.  
   
   
       42 . The method of  claim 39 , wherein R 4  is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       43 . The method of  claim 26 , selected from the group consisting of:  
     
       
         
         
             
             
         
       
       wherein the compound is either a racemate having the relative stereochemistry shown or is substantially enantiomerically pure and has the absolute stereochemistry shown.  
     
   
   
       44 . A method of preventing a bacterial infection in a nonhuman patient comprising administering to the nonhuman patient a pharmaceutically effective amount of a compound having the chemical formula:  
     
       
         
         
             
             
         
       
     
   
   
       45 . The method of  claim 44 , wherein the compound is a racemate having the relative stereochemistry shown.  
   
   
       46 . The method of  claim 44 , wherein the compound is substantially enantiomerically pure and has a 1-(R)-2-(S) absolute configuration.  
   
   
       47 . The method of  claim 26 , wherein the bacterial infection is caused by a bacteria of the genus  Pasteurella, Haemophilus, Fusobacterium, Bacterioides, Aeromonas, Enterobacter, Escherichia, Klebsiella, Salmonella, Shigella, Actinobacillus, Streptococcus, Mycoplasma, Edwardsiella, Staphylococcus, Enterococcus, Bordetella, Proteus,  or  Mannheimia.    
   
   
       48 . The method of  claim 47 , wherein the bacterial infection is caused by  Mannhemia haemolytica, Pasteurella multocida, Haemophilus somnus, Fusobacterium necrophorum, Bacterioides melaninogenicus, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cholerasuis, Mycoplasma bovis, Mycoplasma hyopneumoniae, Mycoplasma hyorhinis, Mycoplasma gallisepticum, Edwardsiella ictaluri, Escherichia coli, Enterobacter cloacae, Staphylococcus aureus, Staphylococcus intermedius, Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Proteus mirabilis , or  Aeromonas salmonicida.