Antibacterial compounds
Inventors
Cooper, Ian • Orr, David • Wilkinson, Andrew • FINLAYSON, JONATHAN • BUNT, ADAM • APPELQVIST, PIA • Wallberg, Hans • WÅNGSELL, FREDRIK
Assignees
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Publication Number
US-11845725-B2
Publication Date
2023-12-19
Expiration Date
Abstract
This invention relates to compounds of formula (I) and methods of treatment using the compounds. The compounds of the invention can be used in combination with antibacterial agents to treat bacterial infections. More specifically, the compounds of formula (I) can be used in combination with a class of antibacterial agents known as carbapenems. The novel compounds of the present invention are enzyme inhibitors and more particularly are metallo-β-lactamase inhibitors.
Core Innovation
The invention relates to Formula (I) and Formula (IV) compounds, including pharmaceutically acceptable salts, hydrates, and solvates, and to pharmaceutical compositions and therapeutic uses of metallo-β-lactamase (MBL) inhibitors together with β-lactam antibacterials, including carbapenem antibacterial agents such as meropenem, imipenem, ertapenem, and doripenem. The compounds are described as antibacterial enzyme-inhibitor compounds, with a substituted hetero/aryl ring system and a SO2NH2 sulfonamide group, and the disclosure includes multiple named sub-formulas (II–VI).
The problem addressed is bacterial infections caused by Gram-positive and Gram-negative bacteria producing metallo-β-lactamases, including Gram-negative infections and carbapenem resistance contexts where β-lactam antibacterials alone are not sufficient. The invention positions the compounds for curative or prophylactic treatment and for use in vitro or in vivo, including treatment of infections associated with metallo-β-lactamase activity.
The therapeutic scope expressly covers community acquired pneumonia, nosocomial pneumonia, ventilator-acquired pneumonia, respiratory tract infections associated with cystic fibrosis and non-cystic fibrosis bronchiectasis, COPD, urinary tract infection, intra-abdominal infections, skin and soft tissue infections, bacteraemia, septicaemia, intra- and post-partum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis, and febrile neutropenia. The disclosure also enumerates bacterial genera and species, including Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and includes kit of parts concepts that include Formula (I) and a biologic (BLA).
Claims Coverage
The independent claims present in the provided items center on broad Formula (IV) compound claims, together with pharmaceutically acceptable salt or hydrate forms, a pharmaceutical composition comprising the compound with pharmaceutically acceptable excipients, and a method of treating bacterial infection. Across the merged claim coverage, the inventive features focus on detailed substituent selection for R1–R7, optional substitution patterns, and explicit infection-type limitations.
Formula (IV) compound with defined R1–R7 substituents
A compound of formula (IV) or a pharmaceutically acceptable salt, or hydrate thereof, where R1 is selected from the defined substituent options and R2 is —C(O)OH or —C(O)OM with M as a group 1 cation; R3 is selected to satisfy valence requirements from the listed alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and carbonyl-related groups; R4 is selected from H, halo, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C3-8 cycloalkyl; R5 is independently selected from H, halo, —OH, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, —(CH2)f-aryl, —(CH2)d-heteroaryl, and —(CH2)g-heterocyclyl; R7 is selected from H, C1-4 alkyl, C1-4 alkyl amine, C3-8 cycloalkyl, C6-10 aryl, and 5 to 10 membered heteroaryl; and d, e, f, g, h, and n are constrained to the stated integer ranges, with optional substitution where chemically possible using the stated group sets.
Pharmaceutical composition with pharmaceutically acceptable excipients
A pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt or hydrate thereof, together with one or more pharmaceutically acceptable excipients.
Treatment of bacterial infection by infection-type enumeration
A method of treating a bacterial infection using the compound or composition framework, where the bacterial infection is selected from the explicitly listed infection types including pneumonia, respiratory tract infections, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bacteraemia, septicaemia, intra- and post-partum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis, and febrile neutropenia.
The claim coverage centers on Formula (IV) compound definitions with detailed substituent selection and optional substitution rules for R1–R7, extended by a pharmaceutical composition concept and by treatment of enumerated bacterial infection types.
Stated Advantages
Prevention or treatment of bacterial infections as metallo-β-lactamase inhibitors.
Curative or prophylactic treatment.
Combination therapy with a carbapenem antibacterial agent.
Documented Applications
Community acquired pneumonia, nosocomial pneumonia, and ventilator-acquired pneumonia.
Respiratory tract infections associated with cystic fibrosis and non-cystic fibrosis bronchiectasis respiratory infections.
COPD.
Urinary tract infection.
Intra-abdominal infections.
Skin and soft tissue infection.
Bacteraemia and septicaemia.
Intra- and post-partum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis, and febrile neutropenia.
Treating bacterial infections caused by Gram-positive and Gram-negative bacteria producing metallo-β-lactamases.
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