Substituted oxazolidines as anti-bacterial agents
Inventors
Peer Mohamed, Shahul Hameed • Bharatham, Nagakumar • KATAGIHALLIMATH, NAINESH • SHARMA, SREEVALLI • NANDISHAIAH, RADHA
Assignees
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Publication Number
US-10711011-B2
Publication Date
2020-07-14
Expiration Date
Abstract
The present disclosure relates to compounds of Formula I, its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms 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 disclosure provides compounds of Formula I, including pharmaceutically acceptable salts, stereoisomers, chiral enantiomers, tautomers, hydrates, solvates, polymorphs, racemic mixtures, and active derivatives thereof, with Ring A and the variables X, Y1-Y3, Z1-Z2, R1-R6, W, and n defined within specified ranges. The scaffold includes a pyrido[3,2-b][1,4]oxazinone core and substituted oxazolidine antibacterial agents, with a substituent noted as absent.
The disclosure also provides processes for preparing compounds of Formula I. The processes include reacting defined precursors in the presence of a reducing agent selected from NaBH4 and NaCNBH3, and an alternative process includes oxidation with m-chloroperoxybenzoic acid followed by further reaction in the presence of at least one protic solvent to provide the Formula I compound.
The compounds are described as medicaments for killing or inhibiting microbes, including bacteria, virus, fungi, and protozoa, with administration to a mammal, preferably human. In the examples, the compounds are prepared and subjected to analytical characterization, including NMR, LCMS, and HPLC purity determination, and biological characterization includes MIC results against Gram-positive and Gram-negative strains and enzyme inhibition results including IC50 values against E. coli DNA gyrase and Topo IV.
Claims Coverage
The provided claim set includes independent claims directed to a compound of Formula I and to processes for preparing compounds of Formula I. The inventive coverage centers on the defined Formula I scaffold with Ring A selection and explicit constraints on X, Y1-Y3, Z1-Z2, R1-R6, W, and n, together with preparation routes using NaBH4 or NaCNBH3, and an alternative route using m-chloroperoxybenzoic acid followed by reaction in at least one protic solvent.
Defined Formula I compound scaffold
A compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, polymorph, racemic mixture, chiral enantiomer, or active derivative thereof, wherein Ring A is selected from the stated group; X is —CR3R4—, —NH—, —N(C1-6 alkyl)—, or —O—; Y1 is CR5 or N; Y2 is CH or N; Y3 is CR6 or N; Z1-Z2 is —(C1-6alkylene)-NH— with optional OH substitution on the alkylene; R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C3-6 cycloalkyl, each optionally substituted with 1, 2, or 3 substituents; R2 is hydrogen, NH2, or OH; R3 and R4 are hydrogen, halogen, or C1-6 alkyl; R5 and R6 are hydrogen, halogen, CN, C1-6 alkyl, or OC1-6 alkyl or OC1-6haloalkyl; W is —O—; n is 1 or 2; and a certain substituent is absent.
Reducing agent process to prepare Formula I compounds
A process for preparing a compound of Formula I by reacting defined precursor compounds in the presence of a reducing agent selected from NaBH4 and NaCNBH3 to provide the compound of Formula I.
mCPBA oxidation followed by protic-solvent step to prepare Formula I compounds
A process for preparing a compound of Formula I comprising reacting a defined precursor compound with m-chloroperoxybenzoic acid to provide an intermediate, and then reacting the intermediate with a defined reagent in the presence of at least one protic solvent to provide the compound of Formula I.
Claim coverage is anchored in the chemically defined Formula I scaffold and in preparation routes using NaBH4 or NaCNBH3, plus an alternative route using m-chloroperoxybenzoic acid followed by a protic-solvent reaction step. The claims collectively cover the compound definition and the associated processes for making the Formula I compounds.
Stated Advantages
The compounds are medicaments for killing or inhibiting microbes.
MIC activity is described against clinical strains and Gram-negative and Gram-positive categories.
Infection efficacy is described using a mouse thigh infection model.
Antimicrobial activity, including bactericidal use, against Gram-positive bacteria.
Antimicrobial activity, including bactericidal use, against Gram-negative bacteria.
Documented Applications
Use as medicaments for killing or inhibiting microbes, including bacteria, virus, fungi, and protozoa.
Therapeutic administration to a mammal, preferably human.
MIC activity testing against clinical strains, including Gram-negative and Gram-positive categories.
Efficacy in a mouse thigh infection model.
Use as an antimicrobial/bactericidal agent against specified Gram-positive and Gram-negative pathogens, including E. coli and Staphylococcus aureus, as well as Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Clostridium difficile, Neisseria gonorrhoeae, and Enterococcus faecalis.
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