Heterocyclic compounds useful as anti-bacterial agents and method for production thereof
Inventors
Peer Mohamed, Shahul Hameed • Bharatham, Nagakumar • KATAGIHALLIMATH, NAINESH • SHARMA, SREEVALLI • NANDISHAIAH, RADHA • Ramachandran, Vasanthi • Venkataraman, Balasubramanian
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Publication Number
US-10912780-B2
Publication Date
2021-02-09
Expiration Date
Abstract
The present disclosure relates to compounds of Formula I, or their stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof, and pharmaceutical compositions containing them as the active ingredient which can be used as medicaments. The aforementioned substances can also be used in the manufacture of medicaments for treatment, prevention or suppression of diseases, and conditions mediated by microbes. The present disclosure also relates to the synthesis and characterization of aforementioned substances.
Core Innovation
The patent describes Formula I compounds, including stereoisomers and pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms, and pharmaceutically active derivatives. The compounds are characterized by specific substituent selections for R1–R8 and ring or connectivity variables X1–X4, Y2–Y3, Z1, n1, and n2, with explicit constraints on allowable chemical functionality and dotted-line bond conditions. Multiple embodiments narrow the scope to defined heterocyclic scaffolds and substituent variability, including oxazinone, pyrido[3,2-b][1,4]oxazin-3(4H)-one, pyrazino[2,3-b][1,4]oxazin-3(4H)-one, oxazolidinyl substituted variants, and related heteroaryl fused scaffolds.
The disclosure also includes a process for preparing a compound of Formula I by reacting Formula (A) with Formula (B) in the presence of at least one reducing agent and an adsorbent. The claims and description specify dotted-line bond conditions that determine whether X4 is CH, C1-6 alkyl, CH2, or O, and in some embodiments whether X3 is CH2. The partial content also ties the structural scope to specifically named example compounds and stereochemically defined members within the Formula I family.
The patent frames the compounds as heterocyclic antibacterial or antimicrobial compounds for killing or inhibiting microorganisms, including bacteria, viruses, fungi, and protozoa. It also describes pharmaceutical compositions containing the compounds with a pharmaceutically acceptable carrier, together with treatment methods for infections in patients for diseases or conditions mediated by microbes. The document reports synthetic examples, analytical characterization, biological evaluation, and formulation-related notes for selected example compounds.
Claims Coverage
The consolidated claim coverage includes two main inventive features: a Formula I compound family with extensive stereochemical, solid-form, and chemical-variant coverage, and a preparation claim using Formula (A), Formula (B), at least one reducing agent, and an adsorbent.
Formula I compound family with defined substituent and connectivity constraints
A compound of Formula I, including stereoisomers and pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms, and pharmaceutically active derivatives thereof, wherein R1–R8, X1–X4, n1–n2, Y2–Y3, and Z1 are selected according to the recited group definitions and dotted-line bond conditions.
Preparing Formula I derivatives by reacting Formula (A) with Formula (B) in presence of reducing agent and adsorbent
A process for preparing a compound of Formula I, including its stereoisomers and pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms, and pharmaceutically active derivatives, by reacting Formula (A) with Formula (B) in the presence of at least one reducing agent and an adsorbent.
The claim set is anchored by the Formula I compound definition, which fixes a large but explicitly bounded substituent and connectivity space and includes stereoisomeric and solid-form variants. It also includes a preparation claim directed to obtaining Formula I compounds by reacting Formula (A) and Formula (B) with a reducing agent and an adsorbent.
Stated Advantages
Killing or inhibiting bacteria, including Gram-positive and Gram-negative, viruses, fungi, and protozoa.
Use in a treatment method for infections in patients for diseases or conditions mediated by microbes.
Formulation as pharmaceutical compositions including a pharmaceutically acceptable carrier.
Selectivity for hERG as supported by the reported hERG IC50 results.
In vivo efficacy supported by rat infection model outcomes connected to bacterial topoisomerase inhibition, as supported by DNA gyrase and Topo IV inhibition data.
Documented Applications
Treatment method for infections in patients, for diseases or conditions mediated by microbes, using the disclosed compounds.
Antibacterial or antimicrobial use against bacteria (Gram-positive and Gram-negative), viruses, fungi, and protozoa.
Pharmaceutical composition use with a pharmaceutically acceptable carrier.
Antibacterial evaluation against multiple Gram-positive pathogens as reported by MIC measurements in Table 1.
Rat infection models for in vivo efficacy and pharmacokinetics, including thigh, UTI, and lung models, as reported for Example 15.
Intravenous formulation context, including a vehicle described with 10% L-ascorbic acid.
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