Aztreonam derivatives and uses thereof

Abstract

Disclosed herein are aztreonam derivatives, therapeutic methods of using the aztreonam derivatives, particularly in combination with β-lactamase inhibitors, and pharmaceutical compositions thereof. The aztreonam derivatives can be administered orally to provide orally bioavailable aztreonam.

What is claimed is: 
     
         1 . A compound of Formula (2): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein,
 each R 1  is independently selected from C 1-3  alkyl; 
 R 2  is selected from —C(R 8 ) 2 — and —CH 2 —C(R 8 ) 2 —, wherein each R 8  can be independently selected from C 1-3  alkyl; and 
 R 3  is —O—C(O)—R 4 , wherein R 4  can be selected from C 1-10  alkyl, C 1-10  heteroalkyl, substituted C 1-10  alkyl, substituted C 1-10  heteroalkyl, 4(yl-methyl)-5-methyl-1,3-dioxol-2-one, and phenyl; and 
 R 7  can be selected from hydrogen, C 1-6  alkyl, C 1-6  heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is selected from methyl and ethyl. 
     
     
         3 . The compound of  claim 1 , wherein each R 1  is methyl. 
     
     
         4 . The compound of  claim 1 , wherein R 2  can be —C(R 8 ) 2 —, wherein each R 8  is hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is —CH 2 —C(R 8 ) 2 —, wherein each R 8  is hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein each R 1  is methyl and each R 8  is hydrogen. 
     
     
         7 . The compound of  claim 1 , wherein each R 1  is methyl and each R 8  is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein R 4  is C 1-6  alkyl. 
     
     
         9 . The compound of  claim 1 , wherein R 4  is phenyl. 
     
     
         10 . The compound of  claim 1 , wherein R 4  is C 1-10  heteroalkyl. 
     
     
         11 . The compound of  claim 1 , wherein R 7  is hydrogen. 
     
     
         12 . The compound of  claim 1 , wherein R 7  can be selected from C 1-6  alkyl and C 1-6  heteroalkyl. 
     
     
         13 . The compound of  claim 1 , wherein the compound is selected from:
 2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzoyloxy)-2,2-dimethylpropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (2);   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-(benzoyloxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (5);   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-4-(propionyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (6); and   6-(4-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino) acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-3,3-dimethylbutoxy)-6-oxohexanoic acid (8);   or a pharmaceutically acceptable salt of any of the foregoing.   
     
     
         14 . A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutical composition comprises an oral formulation. 
     
     
         16 . A method of treating a bacterial infection in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 16 , wherein the bacterial infection is capable of being treated by administering aztreonam to the patient. 
     
     
         18 . The method of  claim 16 , wherein administering comprises orally administering. 
     
     
         19 . The method of  claim 16 , further comprising orally administering a therapeutically effective amount of a β-lactamase inhibitor to the patient. 
     
     
         20 . The method of  claim 16 , wherein administering comprises orally administering a prodrug of the β-lactamase inhibitor.