Isoxazole hydroxamic acid compounds as LpxC inhibitors
This invention pertains generally to compounds of Formula I as described herein and compositions containing such compounds, as well as methods of using such compounds to treat bacterial infections. In certain aspects, the invention provides methods and compositions comprising these compounds for treating infections caused by Gram-negative bacteria.
1. A compound (R)-4-(5-(cyclopropylethynyl)isoxazol-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide of Formula (I):
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition, comprising:
a compound of claim 1 and
a pharmaceutically acceptable carrier.
3. A pharmaceutical combination composition, comprising:
a compound of claim 1 ,
an antibacterially effective amount of a second therapeutic agent, and
a pharmaceutically acceptable carrier.
4. The pharmaceutical combination composition of claim 3 , wherein the second therapeutic agent is selected from the group consisting of Ampicillin, Piperacillin, Penicillin G, Ticarcillin, Imipenem, Meropenem, Azithromycin, Erythromycin, Aztreonam, Cefepime, Cefotaxime, Ceftriaxone, Ceftazidime, Ciprofloxacin, Levofloxacin, Clindamycin, Doxycycline, Gentamycin, Amikacin, Tobramycin, Tetracycline, Tigecycline, Rifampicin, Vancomycin and Polymyxin.
5. A method of inhibiting a deacetylase enzyme in a Gram-negative bacterium, comprising contacting the Gram-negative bacteria with the compound of claim 1 .
6. A method for treating a subject with a Gram-negative bacterial infection, comprising:
administering to the subject in need thereof an antibacterially effective amount of the compound of claim 1 .
7. The method of claim 6 , wherein the Gram negative bacterial infection is an infection comprising at least one bacterium selected from the group consisting of Pseudomonas aeruginosa and other Pseudomonas spp., Stenotrophomonas maltophilia, Burkholderia cepacia and other Burkholderia spp., Alcaligenes xylosoxidans, Acinetobacter spp., Achromobacter spp., Aeromonas spp., Enterobacter spp., Eschericia coli, Haemophilus spp., Klebsiella spp., Moraxella spp., Bacteroides spp., Francisella spp., Shigella spp., Proteus spp., Porphyromonas spp., Prevotella spp., Mannheimia haemolyiticus, Pastuerella spp., Providencia spp., Vibrio spp., Salmonella spp., Bordetella spp., Borrelia spp., Helicobacter spp., Legionella spp., Citrobacter spp., Cedecea spp., Serratia spp., Campylobacter spp., Yersinia spp., Fusobacterium spp., and Neisseria spp.
8. The method of claim 7 , wherein the bacterium is an Enterobacteriaceae which is selected from the Pseudomonadales and Enterobacteriaceae species which is selected from the group consisting of organisms such as Pseudomonas, Acinetobacter, Stenotrophomonas, Burkholderia, Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Shigella, Providencia, Morganella, Cedecea, Yersina and Edwardsiella species and Escherichia coli.