Penam derivatives for treating bacterial infections
Inventors
Ai, Huibing • Ding, Jun • He, Shijie • Liu, Yu • Wan, Dawei • WANG, Huan • Yuan, Ying • Zhang, Qian • Zhuang, Zhijun • Ma, Zhenkun
Assignees
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Publication Number
US-11040987-B2
Publication Date
2021-06-22
Expiration Date
Abstract
Novel iron chelating group conjugated penam derivatives described herein show antibacterial activity, and could be used as antibacterial agents or beta-lactamase inhibitors (BLIs) which are of value for application in combination with other antibacterial agents.
Core Innovation
The disclosure relates to (2S,3R,5R)-substituted bicyclic carboxylic acid 4,4-dioxide derivatives having a 7-oxo-4-thia-1-azabicyclo[3.2.0]heptane core. The compounds include hydrazono, hydrazinecarbonyl, hydrazone, isoxazol-3-yl, and dihydroisoxazol-3-yl linkage motifs, with defined aromatic or heteroaromatic benzoyl-derived substituent patterns including hydroxyl, halogen, alkoxy, and heterocycle substitution patterns.
The compound set also includes a broader formula built from defined substituent parts including R1, Y, linker group L, and iron chelating moiety Z. The disclosure includes stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, and deuterium-exchanged compounds, and describes aromatic iron-chelating moieties with optional substituents or ring formation.
The document further reports synthetic preparation and characterization for multiple representative compounds, including 1H NMR and LC-MS characterization used to confirm product identity and mass. The background states a rationale for siderophore-like iron chelation to influence antibiotic or periplasmic penetration and to support beta-lactamase inhibition.
Claims Coverage
The claims cover structurally defined compound classes centered on the bicyclic carboxylic acid 4,4-dioxide scaffold and a broader R1, Y, L, and Z formula. The claim set includes selected hydrazono, hydrazinecarbonyl, isoxazolyl, and dihydroisoxazolyl derivatives, together with pharmaceutical compositions, optional additional antibacterial agents, and methods of treating or preventing microbial infection.
Compound structure with R1, Y, L, and iron chelating moiety Z
A compound having a formula wherein R1 is hydrogen, a pharmaceutically acceptable salt forming agent, or an ester residue; Y is selected from —S—, —SO—, and —SO2—; L is one or a combination of groups selected from (C1-C8)alkylene, (C3-C8)cycloalkylene containing one to three heteroatoms, arylene, heteroarylene, (C3-C8)heterocycloalkylene, —C(=O)—, —O—, —S(O)n—, —N(R2)—, —C(R3)=C(R4)—, and —C≡N—; and Z is an iron chelating moiety with defined substituents and possible ring formation, including stereoisomers, salts, solvates, prodrugs, and deuterium-exchanged compounds thereof.
Selected (2S,3R,5R)-substituted bicyclic carboxylic acid 4,4-dioxide derivatives
A compound selected from specific (2S,3R,5R)-substituted bicyclic carboxylic acid 4,4-dioxide derivatives bearing hydrazono or hydrazinecarbonyl motifs and defined aromatic substituent patterns.
Aromatic isoxazolyl or dihydroisoxazolyl substitution variants
Compounds selected that include isoxazol-3-yl or 4,5-dihydroisoxazol-3-yl structural variants on the bicyclic carboxylic acid 4,4-dioxide scaffold.
Pharmaceutical composition containing a pharmaceutically effective amount and pharmaceutically acceptable carrier
A pharmaceutical composition comprising a pharmaceutically effective amount of the compound and a pharmaceutically acceptable carrier.
Optional inclusion of one or more additional antibacterial agents
The pharmaceutical composition further includes one or more additional antibacterial agents.
Treating or preventing a microbial infection in a subject by administering the pharmaceutical composition
A method of treating or preventing a microbial infection in a subject by administering the pharmaceutical composition.
Overall claim coverage centers on constrained compound scaffolds defined by hydrazono, hydrazinecarbonyl, isoxazolyl, and dihydroisoxazolyl substitution patterns, as well as a broader R1/Y/L/Z compound definition, with downstream coverage for pharmaceutical compositions and microbial infection treatment or prevention.
Stated Advantages
Improved antibiotic or periplasmic penetration and beta-lactamase inhibition are stated as the rationale for the siderophore-like iron chelation approach.
Documented Applications
MIC determination against an ESKAPE panel (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, E. coli).
Combination MICs with antibiotics against A. baumannii clinical isolates.
β-lactamase inhibition with IC50 data across multiple β-lactamase classes, including AmpC_AB, AmpC_PA, KPC-2, OXA24/40, NDM-1, IMP-1, and VIM-1.
Treating or preventing a microbial infection in a subject by administering the pharmaceutical composition.
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