Gram-negative bacteria have an outer membrane composed of a lipid bilayer, which does not exist in Gram-positive bacteria, and therefore tend to have stronger drug resistance, as compared to Gram-positive bacteria. Gram-negative bacteria are also known to have a plurality of drug efflux proteins, which are involved in drug resistance (Antimicrobial Resistance, 2002, Mar. 1, 34, pp. 634-640).
Among Gram-negative bacteria, Pseudomonas aeruginosa, in particular, has a strong tendency to show intrinsic resistance to various antimicrobial drugs. In recent years, Pseudomonas aeruginosa which has gained resistance to carbapenem drugs, quinolone drugs, aminoglycoside drugs, or the like has been often isolated in medical settings (J. Antimicrob. Chemother., 2003, Vol. 51, pp. 347-352). Moreover, multi-drug resistant Pseudomonas aeruginosa has been isolated (Jpn. J. Antibiotics, 2006, Vol. 59, No. 5, pp. 355-363) and has posed worldwide major problems.
UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an enzyme in charge of the synthesis of lipid A (the hydrophobic anchor of LPS, which is the constituent of the outer membrane).
Lipid A biosynthesis consists of reactions in 10 stages, and LpxC catalyzes the second stage to remove the acetyl group of UDP-3-O-acyl-N-acetylglucosamine (J. Biol. Chem., 1995, Vol. 270, pp. 30384-30391). Lipid A is a component essential for the formation of the outer membrane, and is indispensable for the survival of Gram-negative bacteria (J. Bacteriol., 1987, Vol. 169, pp. 5408-5415). LpxC is one of the rate-determining important enzymes during the process of lipid A biosynthesis, and is an indispensable enzyme for lipid A biosynthesis. Thus, a drug inhibiting the activity of LpxC is highly expected to be capable of becoming an antimicrobial agent effective against Gram-negative bacteria including Pseudomonas aeruginosa, particularly against drug resistant Pseudomonas aeruginosa, because such a drug has a mechanism of action different from those of conventional drugs.
Compounds having LpxC inhibitory activity have been known so far (Patent Documents 1 to 7).
To provide its medicinal efficacy, a drug is required to dissolve at an absorption site. Thus, when a sparingly water-soluble drug is orally administered, the drug may be insufficiently absorbed from the gastrointestinal tract and have a difficulty in providing its medicinal efficacy. Also, in the case of parenteral administration, particularly intravenous administration, the drug is required to be administered in a dissolved form.
Cyclodextrins (sometimes referred to as “CDs” hereinbelow), or cyclodextrin derivatives (sometimes referred to as “CD derivatives” hereinbelow), are known to be used for solubilizing compounds (International J. Pharmaceutics., 2013, Vol. 453, pp. 167-180; Yakugaku Zasshi, 2012, Vol. 132, No. 1, pp. 85-105).
USPTO Backgrounds
USPTO Backgrounds