Compounds with activity as inhibitors of the epithelial sodium channel (ENaC)
Inventors
McCarthy, Clive • HAY, Duncan Alexander • SCHOFIELD, Thomas Beauregard
Assignees
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Publication Number
US-12037336-B2
Publication Date
2024-07-16
Expiration Date
Abstract
Compounds of general formula (I) wherein R1, R2, R3, R4 and X are as defined herein are inhibitors of the epithelial sodium channel (ENaC) and are useful for the treatment or prevention respiratory diseases and conditions, skin conditions and ocular conditions.
Core Innovation
The invention relates to compounds of formula (I) or tautomeric forms, enantiomers, isotopic variants, or salts thereof, wherein X− is an anion. The compounds include a cationic benzodiazol-3-ium framework and defined substituent patterns for R1, R2, R3, and R4, together with linker and group options defined through L1, R10, Z1, Z2, Z3, Q1, Q2, Q3, R7, R8, and R9.
The structure is defined by broad but explicit connectivity and substitution rules, including L1 architectures such as Z1, Q1, Z2, Q2, Z3, and related O- and N-containing motifs, and O(CH2CH2O)n motifs where n is 1 to 6. Z1, Z2, and Z3 are independently C1-12 alkylene, C2-12 alkenylene, or C2-12 alkynylene optionally substituted by halo, OH, C(O)NR15R16, C(O)OR15, and NR15R16, while Q1, Q2, and Q3 are independently carbocyclyl, heterocyclyl, aryl, or heteroaryl optionally substituted by halo, OH, C1-4 alkyl, C1-4 haloalkyl, C(O)NR15R16, C(O)OR15, and NR15R16.
The document also describes cationic group variants in R10, including −N(R7)−C(O)−(C1-3 alkylene)−N+(R8)3 and −N+(R8)3, where an additional anion X− is required. The disclosed content further shows preparation of general formula (I) compounds from intermediate formulae through derivatization, coupling, hydrolysis, and protection/deprotection, including activated acid intermediates and reductive amination routes.
Claims Coverage
The consolidated claim coverage includes one compound claim of formula (I) and one medical-use claim. The inventive features are the structurally defined formula (I) framework with X− as an anion, the defined linker and substituent sets, and the method of treating or preventing respiratory, skin, or ocular conditions by administering an effective amount of the claimed compound.
Compounds of formula (I) with anion X−
A compound of formula (I) or tautomeric form, enantiomer, isotopic variant, or salt thereof, wherein X− is an anion and the compound includes defined substituent patterns for R1, R2, R3, and R4.
Defined linker architecture via L1 and R10
R1 is H or halo, or is -L1R10, wherein L1 includes the specified Z/Q connectivity patterns and related O- and N-containing motifs, and R10 is selected from H, -N(R7)R8, -N(R7)C(=NR9)N(R8)2, -N(R7)-C(O)OR8, OR7, -C(O)OR7, or a cationic group requiring an additional anion X−.
Substituent scope for Z1, Z2, Z3 and Q1, Q2, Q3
Z1, Z2, and Z3 are independently C1-12 alkylene, C2-12 alkenylene, or C2-12 alkynylene optionally substituted by halo, OH, C(O)NR15R16, C(O)OR15, and NR15R16; Q1, Q2, and Q3 are independently carbocyclyl, heterocyclyl, aryl, or heteroaryl optionally substituted by halo, OH, C1-4 alkyl, C1-4 haloalkyl, C(O)NR15R16, C(O)OR15, and NR15R16.
Defined terminal groups R7, R8, and R9
R7 and R8 are independently H or C1-12 alkyl optionally substituted with halo or OH, with optional 5- or 6-membered heterocyclic ring formation when attached to nitrogen, and R9 is H or C1-6 alkyl.
Defined substitutions for R2, R3, and R4
R2 and R3 are independently C1-10 alkyl with optional replacement of one or more CH2 groups by O, S, or NR7 and with defined optional substituents; R4 is H, halo, cyano, C1-6 alkyl, C(O)OR16, or C(O)N(R16)R17.
Treatment or prevention by administering the claimed compound
A method for treating or preventing respiratory, skin, or ocular conditions in a patient by administering an effective amount of a compound according to claim 1.
The consolidated claim coverage centers on a structurally defined compound genus of formula (I) with X−-paired cationic framework and exhaustive linker and substituent definitions, plus a medical-use claim for respiratory, skin, or ocular conditions.
Stated Advantages
Provides ENaC blocking activity.
Motivated as supporting mucus hydration and mucociliary clearance.
May improve ADME properties and lung retention.
Discusses mitigation relative to renal hyperkalaemia risk associated with amiloride.
Documented Applications
Treating or preventing respiratory diseases or conditions by administering an effective amount of a compound according to claim 1.
Treating or preventing skin conditions by administering an effective amount of a compound according to claim 1.
Treating or preventing ocular conditions by administering an effective amount of a compound according to claim 1.
Treating or preventing respiratory, skin, or ocular conditions in a patient by administering an effective amount of a compound according to claim 1.
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