Antimycobacterial heterocyclic amides
Inventors
Day, Joshua • Graham, James • Jarvis, Thale • Mcfaddin, Elizabeth • Ochsner, Urs • Sun, Xicheng • Wong, Christina
Assignees
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Publication Number
US-11655225-B2
Publication Date
2023-05-23
Expiration Date
Abstract
The present invention provides novel heterocylic amide compounds having useful antimycobacterial activity. Use of these compounds as pharmaceutical compositions and method of their production are also provided.
Core Innovation
The invention relates to substituted heterocyclic amide compounds represented by Formula (I) for use as antimycobacterial agents. The compounds are defined by heteroatom selections X and Y, ring-size index n, and multiple substituent variables R1-R8, with explicit rules for when certain substituents are null or restricted. The definition further includes a proviso that R7 and R8 can link together to form rings under specified conditions.
Formula (I) includes variable choices for X selected from C or N and Y selected from N, O or S. R1-R4 are selected from groups including H, halogens, small alkyl (C1-C6), small alkyloxy (C1-C6), halogenated small alkyl (C1-C6), halogenated small alkyloxy (C1-C6), and carboxylates. R5 depends on whether X is carbon or nitrogen; R6 depends on whether Y is nitrogen or oxygen/sulfur; and R7 is restricted relative to n. The definitions include an explicit excluded set of carbonyl-containing cyclic structures.
The documented examples and study content focus on antimycobacterial activity against mycobacteria including Mycobacterium tuberculosis and nontuberculous mycobacteria (NTM). Representative benzothiazol-2-amine amide analogs are described as inhibiting MmpL3-mediated transfer of mycolic acids, with metabolic labeling evidence. In vivo lung infection content is provided using CRS400226 (compound 45), showing CFU reduction and tolerability after intratracheal delivery in a specified emulsion context.
Claims Coverage
The independent claim set comprises one independent compound claim defining a Formula (I) antimycobacterial compound, together with dependent claims that refine the compound structure and add composition and patient-treatment uses. Across these claims, the inventive content is concentrated in the Formula (I) heterocyclic amide scaffold with specific heteroatom/substituent options and explicit exclusions, while downstream claim coverage addresses pharmaceutical composition and therapeutic/prophylactic methods for mycobacterial infection.
Formula (I) heterocyclic amide with defined heteroatoms and substituents
A compound of Formula (I) in which X is selected from C or N, Y is selected from N, O or S, n=1-6, R1-R4 are independently selected from H, halogens, small alkyl (C1-C6), small alkyloxy (C1-C6), halogenated small alkyl (C1-C6), halogenated small alkyloxy (C1-C6), and carboxylates, R5 is selected from H, alkyl, halogens, and cyano when X is carbon with R5 null when X is nitrogen, R6 is selected from H, alkyl, and substituted alkyl when Y is nitrogen with R6 null when Y is O or S, R7 is selected from H, small alkyl (C1-C6), halogenated small alkyl (C1-C6) with R7 not H when n<3, each R8 is independently selected from H, small alkyl (C1-C6), and halogenated small alkyl (C1-C6), and m is 1-6 with the additional ring-linking proviso and an explicit set of excluded carbonyl-containing cyclic structures.
Specific benzo[d]thiazol-2-amine substitution variants within Formula (I)
The compound according to claim 1 is selected from substituted benzo[d]thiazol-2-amine species having the specific substituent options shown in the provided structural representations.
Enumerated carbonyl-containing cyclic moieties
The compound according to claim 1 is selected from the enumerated carbonyl-containing cyclic compounds and carbonyl substituent structures listed in the claim refinement.
Pharmaceutical composition with therapeutically effective amount
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt of the compound according to claim 1.
Treatment of a patient diagnosed with mycobacterial infection by administration
A method for treating a patient diagnosed with a mycobacterial infection comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.
Protection/prophylaxis without diagnosed mycobacterial infection by administration
A method for protecting a patient from a mycobacterial infection comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof to a patient without a diagnosed mycobacterial infection.
Overall claim coverage protects a Formula (I) antimycobacterial heterocyclic amide scaffold defined by precise heteroatom and substituent options plus explicit exclusions, narrows to specific benzo[d]thiazol-2-amine variants and enumerated carbonyl-containing cyclic moieties, and extends coverage to pharmaceutical compositions and methods of treating diagnosed mycobacterial infection and protecting patients prophylactically.
Stated Advantages
In vivo efficacy evidence is described as CFU reduction in a lung infection model.
In vivo tolerability is described in connection with intratracheal delivery of the tested compound.
Benzothiazole amide analogs inhibit MmpL3-mediated transfer of mycolic acids.
Documented Applications
Treating a patient diagnosed with a mycobacterial infection by administering a therapeutically effective amount of a Formula (I) compound (or acceptable salt/solvate).
Protecting a patient from a mycobacterial infection by administering a therapeutically effective amount of a Formula (I) compound (or acceptable salt/solvate) to a patient without a diagnosed mycobacterial infection.
Use as an antimycobacterial agent against mycobacterial infections including Mycobacterium tuberculosis and nontuberculous mycobacteria (NTM), supported by MIC ranges against multiple mycobacteria.
Lung infection study use case: intratracheal delivery in a specified emulsion context in a described animal model, with CFU reduction and tolerability reported.
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