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-11459296-B2
Publication Date
2022-10-04
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 compounds of formula (I), including pharmaceutically acceptable salts, hydrates or solvates thereof, and to a pharmaceutical composition comprising a compound of Formula (I) together with pharmaceutically acceptable excipients. The disclosed scaffold defines multiple structural variables, including one of X and Y being N and the other C, a linker group selected from —(CH2)a-Q-(CH2)b— or Q being absent, and constrained ring selection for R1 and substituent selections for R2, R3, R4, R5, R6, and R7 with integer indices a, b, d, e, f, g, h and n governing bond representation and valence requirements.
A key structural element is the definition of R1 as a ring system that follows explicit heteroatom pattern conditions using T, V, W and Z, including cases where all are C, where T is C and one or two of V, W and Z are N, or where T is absent and one or two of V, W and Z are C with the other two N. The ring system for R1 is additionally described as mono- or bicyclic and substituted by one R3 group and 0, 1, or 2 R4 groups. The compounds are exemplified by substituted pyrrole sulfonamide/tetrazole-containing compounds, including free tetrazole and carboxylic acid and sodium salt forms.
The compounds of Formula (I) inhibit metallo-β-lactamases to enhance β-lactam antibacterial activity, and the document links them to metallo-β-lactamase inhibition including NDM-1 inhibition. The content also reports combination antibacterial activity with antibiotics, improved MICs for meropenem and imipenem, and cytotoxicity evaluation with limited cytotoxicity. The description further includes administration concepts for inhibiting MBL activity and preventing or treating infections or diseases, including combination with meropenem, as well as kits, dosage forms, and salt interconversion concepts.
Claims Coverage
The provided set includes one independent claim defining a compound of formula (I) and additional claim coverage for pharmaceutical composition and treatment use. Across the independent claims, the main inventive features count is three: compound definition, pharmaceutical composition, and treatment/combination use.
Formula (I) compounds with defined linker and substituent sets
A compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein one of X and Y is N and the other is C; L is a linker group selected from —(CH2)a-Q-(CH2)b— or Q being absent, with Q selected from O, NH, SO2, C≡C and C=C; R1 follows defined ring/heteroatom patterns; R2 is —C(O)OH or —C(O)OM with M as a group 1 cation; and R3, R4, R5, R6 and R7 are defined within enumerated substitution sets with integer ranges for a, b, d, e, f, g and h and n taking 0 to 2.
Pharmaceutical composition with pharmaceutically acceptable excipients
A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof together with one or more pharmaceutically acceptable excipients.
Treating bacterial infections using Formula (I) with an antibacterial agent
A method of treating a bacterial infection in a patient by administering a therapeutically effective amount of an antibacterial agent combined with a compound of formula (I) or its pharmaceutically acceptable salt, hydrate or solvate, or administering an antibacterial agent with a pharmaceutical composition containing the compound of formula (I) or its salt, hydrate or solvate.
The claim coverage is anchored on Formula (I) compounds defined by constrained linker and substituent options, extended to a pharmaceutical composition including pharmaceutically acceptable excipients, and further extended to treating bacterial infections via administration in combination with an antibacterial agent.
Stated Advantages
Restores activity of carbapenems, including meropenem, against carbapenem-resistant Gram-negative pathogens.
Inhibits metallo-β-lactamases (MBLs) to enhance β-lactam antibacterial activity.
Improved meropenem MICs and imipenem MICs versus antibiotics alone in combination antibacterial activity.
Limited cytotoxicity as indicated by HepG2 cytotoxicity CC50 values.
Documented Applications
Use of metallo-β-lactamase inhibitor compounds with carbapenems, including meropenem, to restore activity against carbapenem-resistant Gram-negative pathogens.
Treatment of a bacterial infection in a patient by administering an antibacterial agent combined with a compound of Formula (I) or by administering the antibacterial agent with a pharmaceutical composition containing the compound.
Metallo-β-lactamase inhibition evaluation for NDM-1 using an assay context including nitrocefin and ZnSO4, reported as IC50 values.
Combination antibacterial activity evaluation showing improved MICs for meropenem and imipenem versus antibiotics alone against bacterial strains including E. coli, Klebsiella pneumoniae, and Acinetobacter baumannii, with targets including VIM-1 and IMP.
HepG2 cytotoxicity assay evaluation reporting CC50 values and limited cytotoxicity.
Preventing or treating infections/diseases associated with metallo-β-lactamase activity, including infections described for Gram-positive and Gram-negative bacteria.
Use in methods of inhibiting MBL activity.
Use in combination including combination with meropenem.
Use in patient treatment of bacterial infection by administering a therapeutically effective amount of an antibacterial agent combined with a compound of formula (I).
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