Substituted phenylether-thienopyridone compounds with antibacterial activity
Inventors
Guiles, Joseph • Sun, Xicheng • Janjic, Nebojsa • STRONG, Sarah
Assignees
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Publication Number
US-8697720-B2
Publication Date
2014-04-15
Expiration Date
Abstract
Novel bicyclic heteroaromatic compounds are provided that are inhibitors of bacterial methionyl tRNA synthetase (MetRS). Compounds of the invention generally have a left hand side phenylether constituent and a right hand side thienopyridone constituent. Also disclosed are methods for their preparation and their use in therapy as antibacterial agents, particularly as anti-Clostridium difficile agents.
Core Innovation
The disclosure concerns substituted MetRS inhibitor candidates constructed on a 4H-thieno[3,2-b]pyridin-7-one scaffold and defined by a general structural formula (I) with related preferred formula (IA). The compounds include variable substituents R1, R2, and R3 and indices n and m, with example compounds shown as specific derivatives of the scaffold. The invention relates to novel bicyclic heteroaromatic antibacterial compounds comprising a left-hand phenylether moiety and a right-hand thienopyridone moiety.
The compounds are described as antibacterial agents that target bacterial methionyl tRNA synthetase (MetRS), including activity against Clostridium difficile and C. difficile methionyl-tRNA synthetase (MetRS). The disclosure indicates that the compounds are designed to inhibit MetRS and thereby suppress C. difficile toxin production. The document also states therapeutic context for treating bacterial infections using compounds and pharmaceutical compositions comprising the described structures, while noting limited activity versus mammalian MetRS.
The disclosure also describes synthetic preparation routes that proceed from the aldehyde intermediate XVII, and then use reductive amination to yield multiple substituted MetRS inhibitor candidates. It includes approaches involving benzaldehyde protection/deprotection and side-chain installation, with further examples prepared via methods (Methods A–C) from intermediates such as XVII and XVIII.
Claims Coverage
The provided claim coverage centers on a family of substituted MetRS inhibitor candidate compounds defined by formula (I), with narrower formula (IA) substituent constraints, optional salt and pharmaceutically acceptable salt coverage, a set of specifically enumerated 4H-thieno[3,2-b]pyridine-7-one derivatives, and pharmaceutical composition coverage for antibacterial use.
Compound of formula (I) with defined substituents
A compound of formula (I) in which R1 is selected from aryl and heteroaryl groups including substituted and unsubstituted benzene, toluene, phenol, anisole, thiazole, thiazolidine and pyridine; R2 is selected from halo, cyano, hydroxyl, (C1-6) alkyl and other functional group options including (C1-6) alkylthio and sulphane-related substituents; R3 is selected from halo, (C1-3)alkyl, (C2-3)alkenyl, and (C2-3)alkynyl; n is one, two or three; and m is 0 or an integer from 1 to 3.
Compound of formula (IA) with restricted R1 and R2
A compound of formula (I) characterized by formula (IA), where R1 is selected from specified substituted and unsubstituted aromatic and heteroaromatic groups and R2 is selected from halogen and/or sulfane substituents.
Salt forms of the compound
A salt of the compound described by the claim to a compound of formula (I), including pharmaceutically acceptable salt forms.
Enumerated substituted 4H-thieno[3,2-b]pyridine-7-one derivatives
A compound of formula (I) selected from a listed set of specific substituted 4H-thieno[3,2-b]pyridin-7-one derivatives having defined benzylamino-propylamino substitution and various bromo and other substituents, including methylsulfanyl and ether-linked aromatic and heteroaromatic groups.
Antibacterially effective pharmaceutical composition
A pharmaceutical composition comprising an antibacterially effective amount of a compound of claim 1 together with a pharmaceutically accepted carrier or excipient.
Overall, the claim coverage is centered on a formula (I) bicyclic heteroaromatic scaffold with variable substituents R1, R2, and R3 and indices n and m, refined to a preferred formula (IA) and further narrowed to enumerated specific thienopyridone derivatives. The coverage additionally includes salt forms and pharmaceutical compositions containing an antibacterially effective amount of the compounds.
Stated Advantages
Antibacterial targeting of bacterial methionyl tRNA synthetase (MetRS).
Activity against Clostridium difficile.
Limited mammalian MetRS activity.
In vitro and enzyme inhibition performance against C. difficile MetRS with reported IC50 values in the nanomolar range.
Selectivity versus rat mammalian MetRS with no inhibition up to 1 μM.
Antibacterial effectiveness shown by reported MIC90 values.
In vivo efficacy in a C. difficile hamster model, including survival versus vancomycin.
Suppression of C. difficile toxin production (toxins A and B).
Documented Applications
Treating bacterial infections using antibacterial compounds and pharmaceutical compositions comprising the described structures.
Therapeutic use context specifically including activity against Clostridium difficile.
Antibacterial use against C. difficile, including MetRS tRNA charging assay results and C. difficile antibacterial activity with reported MIC90 values.
In vivo testing in a C. difficile hamster model, including survival comparisons versus vancomycin.
Suppression of C. difficile toxin production (toxins A and B), assessed using an ELIFA assay.
Use as a pharmaceutical composition comprising an antibacterially effective amount of a compound and a pharmaceutically accepted carrier or excipient.
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