Combination of a pyrroloquinoline compound and an aminoglycodise antimicrobial agent
Inventors
Hu, Yanmin • Coates, Anthony R. M.
Assignees
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Publication Number
US-9216186-B2
Publication Date
2015-12-22
Expiration Date
Abstract
This invention relates to the use of 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline or a pharmaceutically acceptable derivative thereof in combination with an aminoglycoside antimicrobial agent for the prevention and/or treatment of microbial infections.
Core Innovation
The invention relates to the prevention and treatment of microbial infections using a combination comprising 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline, or a salt thereof, with an aminoglycoside antimicrobial agent. Pharmaceutically acceptable derivatives are described, including hydrochloride and mesylate salts.
The invention addresses microbial infections that require effective antimicrobial activity, including killing of microorganisms associated with log phase, stationary phase, and clinically latent states. The aminoglycoside antimicrobial activity is unexpectedly improved when combined with 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline, and the document describes synergistic killing of log-phase and stationary phase/clinically latent microorganisms.
The synergy is supported by in vitro antimicrobial testing including MIC/MBC and time-kill curves, together with chequerboard analysis. The document describes synergy against S. aureus and P. aeruginosa, including a clinical isolate of P. aeruginosa, with aminoglycosides such as kanamycin, gentamicin, and tobramycin.
The document also describes pharmaceutical compositions comprising the compound and an aminoglycoside antimicrobial agent with a pharmaceutically acceptable adjuvant, diluent, or carrier, and methods of manufacture and treatment using simultaneously, separately, or sequentially administering the combination. Administration routes are described as oral/topical and inhalation.
Claims Coverage
The provided set includes five independent claims, covering a combination product, manufacture of a medicament, a general method of treatment, a pharmaceutical composition formulation, and a more specific method of treating infections caused by specified microorganisms. Across these claims, the inventive subject matter is centered on combining 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline, or a salt thereof, with an aminoglycoside antimicrobial agent.
Combination of the pyrroloquinoline with an aminoglycoside antimicrobial agent
A combination comprising 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline, or a salt thereof, and an aminoglycoside antimicrobial agent.
Manufacturing a medicament by combining the pyrroloquinoline with an aminoglycoside antimicrobial agent
A method of manufacture of a medicament comprising combining 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline, or a pharmaceutically salt or solvate thereof, with an aminoglycoside antimicrobial agent, or a pharmaceutically acceptable salt or solvate thereof.
Method of treating a microbial infection by administering the combination to a patient
A method of treatment of a microbial infection comprising simultaneously, separately or sequentially administering a combination comprising 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline and an aminoglycoside antimicrobial agent to a patient in need thereof.
Pharmaceutical composition with pyrroloquinoline, aminoglycoside, and pharmaceutically acceptable carrier
A pharmaceutical composition comprising 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline, an aminoglycoside antimicrobial agent, and a pharmaceutically acceptable adjuvant, diluent or carrier.
Treatment of infections caused by specified microorganisms using the combination
A method of treating a Staphylococci, Streptococci, Pseudomonas, Bacillaceae, Enterobacteriaceae, Haemophilis influenzae, Enterococci, Mycobacteria, Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum or Pneumocystis jiroveci infection comprising simultaneously, separately or sequentially administering a combination comprising 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline and an aminoglycoside antimicrobial agent.
Overall, the claim coverage centers on a combination of the specified pyrroloquinoline, or its salts, with an aminoglycoside antimicrobial agent, extended to manufacturing, treatment by administration of the combination, and pharmaceutical compositions including the combination with a pharmaceutically acceptable adjuvant, diluent, or carrier.
Stated Advantages
Unexpected improvement in aminoglycoside antimicrobial activity.
Synergistic killing of log-phase and stationary-phase/clinically latent microorganisms.
Documented Applications
Prevention and treatment of microbial infections using the combination comprising 4-methyl-8-phenoxy-1-(2-phenylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline and an aminoglycoside antimicrobial agent.
Treatment of infections associated with log phase (multiplying) microorganisms, stationary phase (non-multiplying) microorganisms, and clinically latent microorganisms.
Treatment of infections involving S. aureus and P. aeruginosa, including a P. aeruginosa clinical isolate.
Pharmaceutical administration for microbial infection using oral/topical administration or inhalation administration of the pharmaceutical composition.
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