7-quinolyl ketolide antibacterial agents
Inventors
Shaw, Simon James • Ashley, Gary W • Burlingame, Mark A.
Assignees
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Publication Number
US-7595300-B2
Publication Date
2009-09-29
Expiration Date
Abstract
15-fluoroketolides of the formula having improved activity and safety, compositions comprising them, and methods for their preparation and use in the treatment of bacterial infections.
Core Innovation
The invention relates to 7-quinolyl ketolide antibacterial agents based on a modified 15-fluoroerythromycin nucleus. Compounds are defined by formula (I), including variants where R1 is H or F and R2 is H or a hydroxyl protecting group. The disclosed framework centers on an erythromycin-like macrolide nucleus modified to carry a 7-quinolyl heterocycle substituent.
The document frames the problem as achieving improved safety for ketolide antibacterial agents, including reduced cardiac safety liabilities associated with QT interval/QTc prolongation and torsades de pointes risk. It further addresses hepatotoxicity and positions the disclosed 7-quinolyl ketolide agents as improvements over comparator ketolides. The text explicitly references hERG/IKr ion channel effects as part of the safety rationale and also includes preclinical safety comparisons.
The disclosure also provides a preparation strategy for the 15-fluoroerythromycin derivative scaffolds leading to compounds of formula (I)/(II)/(III), including intermediate chemistry. It includes oxime formation, hydroxyl protection, 6-O-allylation, oxime removal, formation of an 11,12-cyclic carbamate, and a Heck-type arylation step to install the 7-quinolyl group. The document includes subsequent deprotection/oxidation and optional fluorination steps to obtain the targeted members, with illustrative intermediate compound formulas (IV) and (V)/(VIa)-(VIc).
Claims Coverage
The partial content identifies two independent claims: one directed to a compound defined by a structural formula, and one directed to a multi-step method of preparing a specific 15-fluoroerythromycin derivative bearing a 7-quinolyl substituent. Across these, the claim set includes the core structural definitions for formula-based compounds as well as specific transformation features that install the 7-quinolyl group via Heck coupling and build the cyclic carbamate framework.
Formula-defined 7-quinolyl ketolide scaffold with R1 and R2 substitution pattern
A compound or pharmaceutically acceptable salt thereof having a formula wherein R1 is H or F and R2 is H or a hydroxyl protecting group.
Stepwise conversion of 15-fluoroerythromycin to a 7-quinolyl Heck-coupled 15-fluoroerythromycin cyclic carbamate
A method of preparing a compound of a formula wherein R1 is H or F, comprising sequential steps including reacting 15-fluoroerythromycin with hydroxylamine to form a 15-fluoroerythromycin 9-oxime, protecting hydroxyl groups, reacting with an allylating reagent to provide a 6-O-allyl oxime protected derivative, deprotecting and removing the oxime, reacting with a carbonylating reagent to obtain a 11,12-cyclic carbamate, treating with an arylating reagent under Heck coupling conditions to produce a 6-O-(1-(7-quinolyl)-3-propenyl) derivative, followed by acid treatment, oxidation, optional fluorination, removal of a 2′-O-benzoate, and isolating the product.
Overall claim coverage spans (i) formula-based definitions for compounds with R1 (H or F) and R2 (H or a hydroxyl protecting group), and (ii) a multi-step preparation route that converts 15-fluoroerythromycin into a Heck-coupled 7-quinolyl substituted 15-fluoroerythromycin 11,12-cyclic carbamate framework, including oxime, protection/deprotection, carbonylation, and optional fluorination.
Stated Advantages
Improved cardiac safety characterized by no significant QTc prolongation in guinea pigs up to 30 mg/kg for representative invention compounds.
Improved hepatic/cardiac safety versus comparator ketolides.
Improved pharmacokinetics (mouse plasma/lung Cmax/AUC).
In vivo efficacy demonstrated by inhibition of S. pneumoniae growth in infected rat lungs.
Documented Applications
Therapeutic use against pulmonary infections selected from pneumonia, bronchitis, tonsillitis, and pharyngitis.
Therapeutic use against skin infections including acne.
Pharmaceutical compositions including topical application and other administration routes (solid/liquid/oral/parenteral/inhalation) for the disclosed antibacterial agents.
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