Leukotriene synthesis inhibitors
Inventors
Burgoyne, David L. • DEBRUIN, ERIN • Fonarev, Julia • Yee, James Gee Ken • LANGLANDS, JOHN MICHAEL
Assignees
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Publication Number
US-11976052-B2
Publication Date
2024-05-07
Expiration Date
Abstract
Provided are specific leukotriene synthesis inhibitor compounds and pharmaceutical compositions comprising the compounds and methods of using the compounds and the pharmaceutical compositions in treating, for example, inflammatory diseases or conditions.
Core Innovation
The invention provides compounds of formula (1) and pharmaceutically acceptable enantiomers, diastereomers, salts, and solvates. The compounds are defined by variable structural elements Ar, L, R1, A, E, R2, R3, R4, and R5, with Ar unsubstituted or substituted with one or two substituents selected from halide, C1-6 alkyl, S-C1-6 alkyl, O-C1-6 alkyl, and SO2-C1-6 alkyl; L is selected from a direct bond and CH2; and A is selected from a direct bond, CH2, and CH2CH2.
E is selected from C(O)R2 and C(OR3)R4R5, with R1 selected from hydrogen, halide, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; R2 selected from methyl, ethyl, and phenyl; R3 is H; R4 selected from hydrogen, C1-C7 alkyl, and phenyl; and R5 selected from C1-C7 alkyl, C1-C7 haloalkyl, phenyl, and halophenyl. The document includes specific substituted benzothiazole-, benzoxazole-, and quinoline-linked ether and related aryl compounds, including pure enantiomer and non-racemic mixture forms.
The disclosure further describes leukotriene synthesis inhibitor compounds and their pharmaceutical uses, with structural links to 5-lipoxygenase, FLAP, LTA4, LTC4/LTD4/LTE4, and LTB4. Biological results and assay contexts are provided for whole blood HPLC assay measurements, aminopeptidase assay—Alanine-4-Nitroanalide, human leukotriene A4 hydrolase, and in vivo inflammation and ocular models including LPS mouse lung inflammation, mouse ear edema, endotoxin-induced uveitis, rat experimental autoimmune uveitis, and ocular distribution.
Claims Coverage
The consolidated claim coverage centers on one independent claim defining a compound class of formula (1) with multiple variable structural elements. Across the dependent coverage, the content consistently refines the same chemical space through stereochemical form, specific compound embodiments, and a pharmaceutical composition in the form of an eyedrop.
Compound of formula (1) with pharmaceutically acceptable forms
A compound of formula (1), or a pharmaceutically acceptable enantiomer, diastereomer, salt, or solvate thereof.
Ar substitution and L linkage
Ar is unsubstituted or substituted with one or two substituents selected from halide, C1-6 alkyl, S-C1-6 alkyl, O-C1-6 alkyl, and SO2-C1-6 alkyl, and L is selected from a direct bond and CH2.
R1, A, and E substituent selections
R1 is selected from hydrogen, halide, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; A is selected from a direct bond, CH2, and CH2CH2; and E is selected from C(O)R2 and C(OR3)R4R5.
R2, R3, R4, and R5 definitions
R2 is selected from methyl, ethyl, and phenyl; R3 is H; R4 is selected from hydrogen, C1-C7 alkyl, and phenyl; and R5 is selected from C1-C7 alkyl, C1-C7 haloalkyl, phenyl, and halophenyl.
Pure enantiomer or non-racemic mixture of enantiomers
The compound corresponds to formula (1) and is provided as a pure enantiomer or as a non-racemic mixture of enantiomers.
Specific enumerated compound structures
Selected specific chemical compounds corresponding to the structurally defined variants are expressly listed, including benzothiazole-, benzoxazole-, and quinoline-linked ether and related aryl compounds.
Pharmaceutical composition formulated as an eyedrop
A pharmaceutical composition is provided in the form of an eyedrop.
The claims define a formula (1) compound class with constrained selections for Ar, L, R1, A, E, R2, R3, R4, and R5, and extend to pharmaceutically acceptable stereochemical and solid-form variants. The dependent coverage further includes pure or non-racemic enantiomeric forms, specific enumerated compounds, and an eyedrop pharmaceutical composition.
Stated Advantages
Not explicitly described in patent.
Included as isotopically-labelled variants, including positron emitting isotopes such as 11C and 18F, for mechanism/binding studies, tissue distribution, and PET/occupancy studies.
Crystallization can form solvates.
Documented Applications
Leukotriene inhibition.
Assay measurement including % inhibition of LTC4/LTB4 in an HPLC assay context.
Aminopeptidase assay—Alanine-4-Nitroanalide, including human leukotriene A4 hydrolase (LTA4H) model context.
In vivo inflammation models including LPS mouse lung inflammation with neutrophil infiltration.
Arachidonic acid induced mouse ear edema model context.
Endotoxin-induced uveitis and rat experimental autoimmune uveitis (EAU) context, including ocular distribution.
Mechanism/binding studies.
Tissue distribution.
PET/occupancy studies.
A pharmaceutical composition in the form of an eyedrop.
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