Effective aminoglycoside antibiotic for multidrug-resistant bacteria
Inventors
Takahashi, Yoshiaki • Umemura, Eijiro • Ida, Takashi • Igarashi, Masayuki
Assignees
Microbial Chemistry Research Foundation • Meiji Seika Pharma Co Ltd
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Publication Number
US-11135234-B2
Publication Date
2021-10-05
Expiration Date
Abstract
A compound represented by the following general formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical composition thereof, and the use thereof to prevent or treat infectious diseases and a method to prevent or treat infectious diseases using those regimen are disclosed. The compound represented by formula (I) has an antibacterial activity against both gram-positive and gram-negative bacteria, and is useful in the prevention or treatment of infectious diseases caused by these bacteria.
Core Innovation
The document describes synthesized apramycin derivatives and modified apramycin/aminoglycoside structures represented by Formula (I) and related subformulas, with variable substituents defined by R1-R11 and a possible double bond between R1 and R4. The derivatives are derived from apramycin and epiapramycin, and the compound set includes salts and solvates.
The disclosure presents modified apramycin derivatives distinguished by substituents at defined positions, including guanidino, glycyl, sarcosyl, alanyl, seryl, beta-alanyl, isoseryl, cycloalkyl, azetidinyl, and related variants. It also describes 4''-functionalization and 5,6-region modifications, including N-substituted and deoxy/apramycin-related compounds.
The document further presents synthetic schemes for producing modified apramycin/aminoglycoside derivatives, including cyclohexylidene removal, selective benzoylation/protection, methanesulfonylation followed by inversion, selective chlorination and reduction, cyclic carbamate formation and hydrolysis, and protecting-group removal. Example compounds are provided, and analytical characterization is reported with MS, 1H NMR, and sometimes 13C NMR, together with yields and salt forms such as TFA salt or pharmaceutically acceptable salt or hydrate.
Claims Coverage
One independent claim is provided across the input items. It covers a method for treating bacterial infectious disease by administering a therapeutically effective dose of a compound represented by Formula (I) or a pharmaceutically acceptable salt or hydrate, with a defined R1-R11 substituent framework, an allowed double bond between R1 and R4, and explicit exclusions for particular hydroxyl/hydrogen combinations.
Treatment of bacterial infectious disease with Formula (I) compounds
A method for the treatment of bacterial infectious disease comprising administering a therapeutically effective dose of a compound represented by Formula (I) or a pharmaceutically acceptable salt or hydrate thereof.
Defined substituent framework for Formula (I)
R1 through R11 are defined by allowed hydrogen, hydroxyl, amino, halogen, fluorine, guanidino-C1-6 alkyl, glycyl, sarcosyl, L/D-alanyl, L/D-seryl, beta-alanyl, and L/D-isoseryl substituent options, with R1 and R4 optionally forming a double bond together.
Explicit exclusions of specific hydroxyl/hydrogen combinations
The Formula (I) framework excludes cases where R5, R8, and R11 are hydroxyl groups and the remaining listed positions are hydrogen atoms, and cases where R1, R5, R8, and R11 are hydroxyl groups and the remaining listed positions are hydrogen atoms.
The claim coverage centers on administering Formula (I) compounds, or salts or hydrates, for bacterial infectious disease treatment, with structural scope defined by R1-R11, the R1-R4 double-bond option, and explicit exclusion conditions.
Stated Advantages
Broad antibacterial activity against both gram-positive and gram-negative bacteria, including multidrug-resistant strains.
Antibacterial activity against gram-positive and gram-negative pathogens.
Documented Applications
Prevention and treatment of bacterial infectious diseases, including sepsis, infectious endocarditis, respiratory infections, urinary tract infections, enteral infections, peritonitis, meningitis, ophthalmological infections, otolaryngological infections, dermatological infections, surgical site infections including orthopedic surgical site infections, and tuberculosis.
Antibacterial activity assessment of the described compound set against multiple Gram-positive and Gram-negative strains, including methicillin-resistant Staphylococcus aureus (MRSA), carbapenemase-producing (KPC) and metallo-β-lactamase-producing (NDM) Klebsiella, multidrug-resistant Acinetobacter, AMK/GM-resistant Serratia and Pseudomonas, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, with MIC tables compared to aminoglycoside comparators.
Use in pharmaceutical compositions for bacterial infectious diseases.
Treating or preventing bacterial infectious diseases.
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