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-10617704-B2
Publication Date
2020-04-14
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 invention relates to compounds represented by formula (I), or pharmaceutically acceptable salts or hydrates thereof, based on aminoglycoside apramycin derivatives and modified apramycin-like compounds. The substituent positions R1 through R11 are defined by hydrogen atom, hydroxyl group, amino group, halogen atom, fluorine atom, and specified C1-6 alkyl, amino-C1-6 alkyl, guanidino-C1-6 alkyl, cycloalkyl, amidino, azetidino, glycyl, sarcosyl, and amino acid conjugate classes, with R1 and R4 able to form a double bond together and with multiple explicit exclusion combinations.
The document further narrows the formula (I) framework through variants such as (I-1), (I-2), and (I-4), each with tightened definitions for selected R positions and additional exception cases. The claimed compound family includes specific modified apramycin compounds and N-substituted derivatives, including epimeric, deoxy, fluoro, amino, and guanidino variants, as well as named aminoalkyl and amino acid conjugates.
The described compounds are presented as useful for preventing or treating infectious diseases, including sepsis and localized infections. The applications include infections caused by methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, and multidrug-resistant gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
Claims Coverage
The consolidated claim set centers on one principal independent compound claim of formula (I) with detailed R1-R11 substituent definitions and multiple explicit exclusion combinations, together with dependent narrowing through formula variants (I-1), (I-2), and (I-4). The claim set also includes specific modified apramycin derivatives and N-substituted derivatives, plus a pharmaceutical composition claim; six inventive features are present.
Apramycin-derivative compound of formula (I) with defined substituent scope
A compound represented by formula (I), or a pharmaceutically acceptable salt or hydrate thereof, with R1-R11 defined by hydrogen atom, hydroxyl group, amino group, halogen atom, fluorine atom, and specified substituent classes such as C1-6 alkyl, amino-C1-6 alkyl, guanidino-C1-6 alkyl, cycloalkyl, amidino, azetidino, glycyl, sarcosyl, and amino acid conjugate groups, and with R1 and R4 able to form a double bond together, subject to multiple explicit exclusion combinations.
Formula (I-1) variant
A compound represented by formula (I-1), or a pharmaceutically acceptable salt or hydrate thereof, with specified substituent definitions for selected R positions and explicit exception conditions.
Formula (I-2) variant
A compound represented by formula (I-2), or a pharmaceutically acceptable salt or hydrate thereof, with restricted substituent classes at selected R positions, including aminoalkyl and guanidino-containing groups.
Formula (I-4) variant
A compound represented by formula (I-4), or a pharmaceutically acceptable salt or hydrate thereof, with constrained R1-R4 options and explicit exception cases, including the possibility that R1 and R4 form a double bond together.
Specific modified apramycin and N-substituted derivatives
A compound within the formula scope that is one of the specifically listed modified apramycin derivatives, including epimeric, deoxy, fluoro, amino, and guanidino variants, and N-substituted derivatives including aminoalkyl and amino acid conjugates.
Pharmaceutical composition containing the claimed compound
A pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof.
The claims cover a formula (I) apramycin-derivative compound class with detailed substituent definitions and exclusions, refined by formula variants (I-1), (I-2), and (I-4), and further anchored by enumerated modified apramycin and N-substituted derivatives. The scope also extends to a pharmaceutical composition containing the claimed compound or its salt or hydrate.
Stated Advantages
Broad antibacterial spectrum.
Activity against multidrug-resistant gram-positive and gram-negative bacteria.
Activity against multidrug-resistant bacteria not treated by current antibiotics.
Shows antibacterial activity against both sensitive strains and resistant or low-susceptibility strains compared with existing aminoglycosides.
Documented Applications
Preventing or treating infectious diseases, including sepsis.
Preventing or treating localized infections including infectious endocarditis.
Preventing or treating dermatological infections, surgical site infections, orthopedic surgical site infections, respiratory infections, urinary tract infections, enteral infections, peritonitis, meningitis, ophthalmological infections, and otolaryngological infections.
Use for infections caused by MRSA and Staphylococcus aureus.
Use for infections caused by multidrug-resistant gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
Antibacterial activity testing by MIC across multiple Gram-positive and Gram-negative strains, including MRSA and NDM-producing Klebsiella and multidrug-resistant Acinetobacter.
Antimicrobial/antibacterial use against infectious diseases, including MRSA, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
Use as an antimicrobial agent for conditions and infectious diseases including sepsis, infective endocarditis, pneumonia, and tuberculosis.
Pharmaceutical composition containing the claimed compound(s).
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