Anti-bacterial heterocyclic compounds and their synthesis
Inventors
Peer Mohamed, Shahul Hameed • Bharatham, Nagakumar • KATAGIHALLIMATH, NAINESH • SHARMA, SREEVALLI • NANDISHAIAH, RADHA • Ramachandran, Vasanthi
Assignees
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Publication Number
US-11401277-B2
Publication Date
2022-08-02
Expiration Date
Abstract
The invention relates to compounds of Formula I and Formula (B) along with their stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms, and pharmaceutically active derivatives thereof. These compounds are useful for killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, virus, fungi, and protozoa.
Core Innovation
The invention relates to Formula I compounds, including their stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, and optically active forms. Formula I defines extensive structural constraints using substituent groups and ring or atom variables, including R1 to R8, X1 to X4, n1, Y1 and Y2, and Z1, and also includes defined options and substitution ranges. The disclosed scope covers multiple engineered variants by allowing different permitted selections for these structural parameters.
The disclosure also relates to Formula (B) compounds with constrained structural selections for key atoms and substituents, including Y1, Y2, R7, Z1, and R8. The compounds are described as antibacterial agents and bacterial topoisomerase inhibitors, and the document explicitly relates the claimed compounds to treating bacterial infection. The claims further connect the scaffold to therapeutic use and pharmaceutical compositions containing the compounds, including embodiments that can include antibiotic combinations.
The specification describes preparation approaches through reaction schemes and multistep synthetic sequences that link defined intermediates and formula groups to the claimed Formula I and Formula (B) compounds. The partial content further indicates the synthesis and isolation of chiral or engineered Formula I compounds, including compounds 5 to 10, with formation and isolation of salts such as formate or trifluoroacetic acid salt. Additional stereochemical variants are obtained by steps described in the examples and then characterized.
Claims Coverage
The independent claims identified in the provided claim set cover two structural regimes: Formula I compounds and Formula (B) compounds. In total, the independent claims provide structural scope for each formula class, plus therapeutic treatment and pharmaceutical composition coverage grounded in the chemical definitions.
Formula I compound definitions
A compound of Formula I, or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms, wherein R1 to R8, X1 to X4, n1, Y1 to Y2, and Z1 are defined with specified selectable options and substitution limits.
Formula (B) compound definitions
A compound of Formula (B), or its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, racemic mixtures, or optically active forms, wherein Y1 is selected from N or CR7, Y2 is N, R7 is selected from hydrogen, halogen, cyano, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, or C1-6 alkyl, Z1 is selected from O, S, NH, or CH2, and R8 is selected from hydrogen, hydroxyl, C1-6 alkyl, or fluorine.
Enumerated Formula I compounds
A compound according to claim 1, including any of its stereoisomers or related pharmaceutical forms, selected from Compounds 1 through 10 shown in the specification.
Therapeutic use against Gram-positive and Gram-negative microorganisms
A method for treating a disease or condition caused by a selected Gram-positive or Gram-negative microorganism by administering the compound of claim 1 or specified stereochemical and pharmaceutical forms.
Pharmaceutical composition including Formula (B) compounds
A pharmaceutical composition including a compound of Formula (B) with a pharmaceutically acceptable carrier, including a composition with at least one antibiotic.
Overall, the claim coverage is centered on defined heterocyclic antibacterial scaffolds specified by Formula I and Formula (B). The inventive scope is expressed primarily through detailed substituent and atom-selection constraints for the formula classes, with additional dependent coverage tying selected members, pharmaceutical compositions, and therapeutic use to the scaffold.
Stated Advantages
Potent antibacterial activity via dual topoisomerase inhibition.
hERG selectivity.
Favorable pharmacokinetics (PK).
In vivo efficacy in rat infection models.
Documented Applications
Antibacterial treatment, with MIC data for Gram-positive and Gram-negative strains and mechanistic or target IC50 assays using E. coli DNA gyrase and E. coli Topo IV.
In vivo antibacterial models in rats, including thigh infection, rat urinary tract infection (UTI) model, and rat lung P. aeruginosa model.
A pharmaceutical composition including a compound of Formula (B) with a pharmaceutically acceptable carrier.
A pharmaceutical composition including a compound of Formula (B) with a pharmaceutically acceptable carrier and, in combination with at least one antibiotic.
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