Compounds
Inventors
McCarthy, Clive • HARGRAVE, Jonathan David • HAY, Duncan Alexander • SCHOFIELD, Thomas Beauregard • Went, Naomi
Assignees
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Publication Number
US-10759785-B2
Publication Date
2020-09-01
Expiration Date
Abstract
The invention relates to compounds of general formula (I): wherein R1, R2, R3, R10 and X− are as defined herein. The compounds are inhibitors of the epithelial sodium channel (ENaC) and are useful for the treatment or prevention respiratory diseases and conditions.
Core Innovation
The invention relates to compounds of formula (I), including a tautomer or enantiomer thereof, wherein X− is an anion. The compound definition permits a wide range of substituent patterns through R1, L1, R11, R5, R6, L2, L3, Z6, Z12, R2, R3, R10, R12, and related variables, subject to specific provisos that restrict selected combinations.
R1 is selected from H or halo; alkyl, alkenyl, alkynyl, or corresponding alkoxy groups optionally substituted by halo; or groups such as —L1R11, —O—L1R11, —OR5, —SO2R5, —C(O)OR5, —C(O)NR5R6, —C(=NR7)NR5R6, —L2—R12, and —L3—R13. L1, L2, L3, Z6, and Z12 include defined alkylene, alkenylene, alkynylene, aryl, heteroaryl, carbocyclyl, and heterocyclyl patterns, with optional oxo or other permitted substituents.
The document is linked to pharmaceutical compositions, combination-agent options, and administration for respiratory disease or condition. Therapeutic use is described across respiratory diseases, skin conditions, and an ocular condition, including cystic fibrosis, COPD, chronic bronchitis, emphysema, bronchiectasis, asthma, psoriasis, atopic dermatitis, ichthyosis, and dry eye disease.
The disclosure also includes substituted benzodiazolium-formamide derivatives consistent with the claimed scaffold, including anion or counterion forms such as bromide, iodide, chloride, and hydrobromide, and related substituted benzodiazol-3-ium structures and formamido-linked pyrazine or bromopyrazine-containing products.
Claims Coverage
The claim coverage centers on a compound of formula (I) with anion X− and broad substituent and linker definitions, together with explicit conditional exclusions. The inventive features include the core scaffold, R1 options, linker and ring constraints, and provisos that restrict selected R1 and related patterns.
Formula (I) compound with anion X−
A compound of formula (I), or a tautomer or enantiomer thereof, wherein X− is an anion.
R1 substituent definition
R1 is H or halo; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or corresponding alkoxy groups optionally substituted by halo; or —L1R11, —O—L1R11, —OR5, —SO2R5, —C(O)OR5, —C(O)NR5R6, —C(=NR7)NR5R6, —L2—R12, or —L3—R13.
Linker and ring constraints for L1, L2, L3, Z6, and Z12
L1 is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene; Z12 is C1-12 alkylene, C2-12 alkenylene, or C2-12 alkynylene; Z6 is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene, optionally substituted by NR8R9, C(O)NR8R9, OH, or halo; and L2 and L3 include aryl, heteroaryl, carbocyclyl, and heterocyclyl-related architectures.
Constrained substituent patterns for R2, R3, and R10
R2 is C1-10 alkyl optionally replacing one or more CH2 groups by O and optionally substituted with halo, aryl, heteroaryl, —OR7, and —NR7R8; R3 is H, halo, cyano, C1-3 alkyl, C1-3 haloalkyl, or —S(C1-3 alkyl); and R10 is C1-6 alkyl optionally substituted with halo, —OR7, and —NR7R8.
Conditional exclusions
When R2 is ethyl, R3 is chloro, and R10 is ethyl, R1 is not C(O)NR5R6 and is not L2R12 where L2 is C(O)heterocyclyl and R12 is N(CH3)2.
Overall, the claims define a formula (I) compound with anion X−, extensive R1 and linker definitions, and explicit provisos that narrow certain substituent combinations.
Stated Advantages
Increase airway mucus hydration and mucus clearance via ENaC blockade.
Address the challenge of renal side effects from inhaled ENaC blockers by providing longer-acting inhaled inhibitors and, for some compounds, purported faster metabolism to reduce renal exposure.
Enable long-acting inhaled ENaC inhibition for respiratory diseases and conditions.
Documented Applications
Treatment of respiratory diseases or conditions including cystic fibrosis, COPD, chronic bronchitis, emphysema, bronchiectasis, and asthma by administering a compound of formula (I).
Treatment of skin conditions including psoriasis, atopic dermatitis, and ichthyosis by administering a compound of formula (I).
Treatment of ocular conditions including dry eye disease by administering a compound of formula (I).
Pharmaceutical compositions and combination-agent options.
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