Over the past several decades, the frequency of antimicrobial resistance and its association with serious infectious diseases has increased at alarming rates.
For example, in the United States, the Centers for Disease Control and Prevention estimate that roughly 1.7 million hospital-associated infections, from all types of microorganisms, including bacteria, combined, cause or contribute to 99,000 deaths each year. In Europe, where hospital surveys have been conducted, the category of Gram-negative infections are estimated to account for two-thirds of the 25,000 deaths each year. Nosocomial infections can cause severe pneumonia and infections of the urinary tract, bloodstream and other parts of the body. Many types are difficult to attack with antibiotics, and antibiotic resistance is spreading to Gram-negative bacteria that can infect people outside the hospital (see, Pollack, Andrew. “Rising Threat of Infections Unfazed by Antibiotics” New York Times, Feb. 27, 2010). This high rate of resistance increases the morbidity, mortality, and costs associated with nosocomial infections.
The problem of antibacterial resistance is compounded by the existence of bacterial strains resistant to multiple antibacterials. It is conventionally taught in the art that among:                Gram-positive organisms, resistant pathogens include methicillin-(oxacillin) resistant Staphylococcus aureus, beta-lactam-resistant and multidrug-resistant pneumococci, and vancomycin-resistant enterococci; and that        Gram-negative resistance includes extended-spectrum beta-lactamases (ESBLs) in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis, high-level third-generation cephalosporin (Amp C) beta-lactamase resistance among Enterobacter species and Citrobacter freundii, and multidrug-resistance genes observed in Pseudomonas aeruginosa, Acinetobacter, and Stenotrophomonas maltophilia.         
To date, a variety of beta-lactam drugs have been developed and beta-lactam drugs have become clinically extremely important antimicrobial drugs.
However, there are increasing number of bacterial types which have obtained resistance against β-lactam drugs by producing β-lactamase, which degrade β-lactam drugs.
According to the Ambler molecular classification, β-lactamases are largely classified into four classes. Specifically, these are Class A (TEM type, SHV type, CTX-M type and the like), Class B (IMP type, VIM type, L-1 type and the like), Class C (AmpC type) and Class D (OXA type and the like). Amongst these, Classes A, C and D types are largely classified into serine-β-lactamase, and on the other hand, Class B type is classified into metallo-β-lactamase. It has been known that both have respectively different mechanisms to each other in terms of hydrolysis of β-lactam drugs.
Recently, clinical problems have been occurring due to the existence of Gram negative bacteria which have become highly resistant to β-lactam drugs including Cephems and Carbapenems, by production of Class A (ESBL) or D type serine-β-lactamases and Class B type metallo-β-lactamases which have extended their substrate spectrum. Particularly, metallo-β-lactamases are known to be one of the causes of obtaining multi-resistant Gram negative bacteria. Cephem compounds which exhibit intermediate activity against metallo-β-lactamase producing Gram negative bacteria are known (i.e., e.g., see, International Patent Publication No. WO 2007/119511 to Astellas Pharma. Inc. and Wakunaga Pharmaceuticals Inc., Intern.'l Pub. Date: Oct. 25, 2007 and Takeda et al., “In Vitro Antibacterial Activity of a New Cephalosporin, FR 295389, against IMP-type Metallo-β-Lactamase-Producters”, The Journal of Antibiotics, vol. 61, pp. 36-39 (January 2008)).
However, there is a demand for development of Cephem compounds which exhibit more potent antimicrobial activity, in particular effectiveness against a variety of β-lactamase producing Gram negative bacteria.
One of the known antimicrobials to have poetnt anti-Gram negative bactericidal activity are Cephem compounds having a catechol group intramolecularly (i.e., e.g., see Sanada et al., “Comparison of Transport Pathways of Catechol-Substituted Cephalosporins. BO-1236 AND BO-1341, Through the Outer Membrane of ESCHERICHIA COLI”, The Journal of Antibiotics, vol. 43, No. 12, pp. 1617-1620 (1990); Weissberger et al, “L-658, 310, A New Injectable Cephalosporin I. In Vitro Antibacterial Properties”, The Journal of Antibiotics, vol. 42, No. 5, pp. 795-806 (1989); Okita et al., “Synthesis and Antibacterial Activity of Cephalosporins Having a Catechol in the C3 Side Chain”, The Journal of Antibiotics, vol. 46, No. 5, pp. 833-839 (1993)). The action thereof is that the catechol group forms a chelate with Fe3+, thereby the compound is efficiently incorporated into the bacterial body by means of the Fe3+ transportation system across the cellular membrane (tonB-dependent iron transport system).
Thus there is a need for new antibacterials, particularly antibacterials with novel mechanisms of action.
In light of the above, a need exists to develop compounds of the present invention, which provides Cephem compounds that exhibit potent antimicrobial spectrum against a variety of bacteria including Gram negative bacteria and/or Gram positive bacteria, corresponding pharmaceutical compositions and treatment methods for bacterial infections. More importantly, there is a need to develop Cephem compounds of the present invention, which exhibit:                potent antimicrobial activity against beta-lactamase producing Gram negative bacteria;        potent antimicrobial activity against multi-drug resistant microbes, in particular, Class B type metallo-beta-lactamase producing Gram negative bacteria;        effective antimicrobial activity against extended-spectrum beta-lactamase (ESBL) producing bacteria; and        a lack of cross-resistance against known Cephem drug or Carbapenem drugs.        
The present invention is directed to overcoming these and other problems encountered in the art.
USPTO Backgrounds
USPTO Backgrounds