Isoxazole beta-lactamase inhibitors

Abstract

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

1 - 50 . (canceled) 
     
     
         51 . An antibiotic composition comprising ceftolozane and a compound of formula CCC: 
       
         
           
           
               
               
           
         
       
     
     
         52 . The composition of  claim 51 , wherein the composition is formulated for intravenous delivery upon reconstitution. 
     
     
         53 . The composition of  claim 51 , wherein the composition is in a unit dosage form comprising 100-1000 mg of the compound of formula (CCC). 
     
     
         54 . The composition of  claim 51 , wherein the composition is in a unit dosage form comprising ceftolozane and the compound of formula (CCC) in a ratio between 1:4 and 8:1. 
     
     
         55 . The unit dosage form of  claim 54  comprising 100-1000 mg of the compound of formula (CCC). 
     
     
         56 . The composition of  claim 51 , wherein the composition is a reconstituted composition obtained by a process comprising dissolving a composition comprising the ceftolozane and the compound of formula (CCC) in a pharmaceutically appropriate carrier to obtain the reconstituted composition. 
     
     
         57 . A method of treating an infection comprising the administration of a therapeutically effective amount of a pharmaceutical composition comprising ceftolozane and a compound of formula CCC: 
       
         
           
           
               
               
           
         
       
     
     
         58 . The method of  claim 57 , wherein the composition is formulated for intravenous delivery upon reconstitution. 
     
     
         59 . The method of  claim 57 , wherein the pharmaceutical composition is administered in three equal doses per day. 
     
     
         60 . The method of  claim 57 , wherein the therapeutically effective amount comprises 100-1000 mg of the compound of formula (CCC) per unit dose. 
     
     
         61 . The method of  claim 57 , wherein the therapeutically effective amount comprises ceftolozane and the compound of formula (CCC) in a ratio between 1:4 and 8:1. 
     
     
         62 . The method of  claim 57 , wherein:
 a. the therapeutically effective amount comprises ceftolozane and the compound of formula (CCC) in a ratio of 1:4 to 8:1;   b. the therapeutically effective amount comprises 100-1000 mg of the compound of formula (CCC) per unit dose; and   c. the pharmaceutical composition is administered in three equal doses per day.   
     
     
         63 . The method of  claim 57 , wherein the composition has a MIC 90  of about 8 μg/mL or less. 
     
     
         64 . The method of  claim 57 , wherein the composition has a MIC 50  of about 2 μg/mL or less. 
     
     
         65 . The method of  claim 57 , wherein the infection is caused by a cephalosporin resistant pathogen. 
     
     
         66 . The method of  claim 57 , wherein the infection is selected from the group consisting of intra-abdominal infection, urinary tract infection, and pneumonia. 
     
     
         67 . The method of  claim 57 , wherein the infection is caused by a bacteria selected from the group consisting of  Klebsiella pneumoniae, Eschericia coli, Enterobacter  spp,  Citrobacter  spp, and  Pseudomonas aeruginosa.    
     
     
         68 . A method of treating an infection caused by a bacteria selected from the group consisting of  Klebsiella pneumoniae, Eschericia coli, Enterobacter  spp,  Citrobacter  spp, and  Pseudomonas aeruginosa , the method comprising the administration of a therapeutically effective amount of a pharmaceutical composition comprising ceftolozane and a compound of formula CCC: 
       
         
           
           
               
               
           
         
       
     
     
         69 . The method of  claim 68 , wherein:
 a. the therapeutically effective amount comprises ceftolozane and the compound of formula (CCC) in a ratio of 1:4 to 8:1; and   b. the therapeutically effective amount comprises 100-1000 mg of the compound of formula (CCC) per unit dose.   
     
     
         70 . The method of  claim 68 , wherein the infection is selected from the group consisting of intra-abdominal infection, urinary tract infection, and pneumonia.