Substituted benzodiazoliums as ENaC inhibitors
Inventors
McCarthy, Clive • HARGRAVE, Jonathan David • HAY, Duncan Alexander • SCHOFIELD, Thomas Beauregard • Went, Naomi
Assignees
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Publication Number
US-11739094-B2
Publication Date
2023-08-29
Expiration Date
Abstract
Compounds of general formula (I) wherein R1, R2, R3, R4, R5 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 a method for the treatment of a disease or condition in a patient by administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. The disease or condition is mediated by epithelial sodium channel (ENaC) activity and is selected from an ocular condition, a respiratory disease, a respiratory condition, and a skin condition. The disclosure defines the compounds of formula (I) through extensive structural variables, including R1, R2, R3, R4, R5, L1, R7, R8, R9, R10, R12, R13, Q1, Q2, Q3, Z1, Z2, Z3, and X−, together with a proviso concerning an additional X− in defined circumstances.
The compounds are characterized as ENaC inhibitors that block ENaC activity and are described for use in methods of treating or preventing diseases or conditions mediated by ENaC activity. The description emphasizes respiratory diseases and conditions, while also stating that the compounds are suitable for skin and ocular conditions. The text further highlights improved ADME, improved mucociliary clearance, prolonged lung retention, reduced dosing burden, and reduced hyperkalaemia risk.
The document also includes exemplary ENaC-blocker compounds corresponding to formula (I) with cationic structures pairing with anions X−, together with example aryl substituent variants. The disclosed compounds are framed as suitable for therapeutic treatment and prophylaxis in the therapeutic setting described.
Claims Coverage
Three independent claims are reflected across the input items. They center on administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to treat an ENaC-mediated disease or condition; the scope further includes claims to a compound having the cation for ENaC-mediated respiratory disease or respiratory condition. In total, the independent claims present three inventive features.
ENaC-mediated treatment using a formula (I) compound
A method for the treatment of a disease or condition in a patient by administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the disease or condition is mediated by epithelial sodium channel (ENaC) activity.
Structural diversity of formula (I) defined by substituents and linkers
The compound of formula (I) is defined by extensive substituent and linker variables, including R1, R2, R3, R4, R5, L1, R10, R12, R13, R7, R8, R9, Q1, Q2, Q3, Z1, Z2, Z3, R15, R16, R17, and X−, with defined allowable ranges and a proviso concerning an additional X− when R10 has specified forms.
Respiratory disease selection and specified cation claims
The disease or condition is selected from an ocular condition, a respiratory disease, a respiratory condition, and a skin condition, and separate independent claims cover a compound having the cation for respiratory diseases or respiratory conditions selected from asthma, bronchiectasis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and primary ciliary dyskinesia.
The claims collectively cover ENaC-mediated treatment by administering a formula (I) compound or a specified cation compound, with broad structural definitions and disease selection focused on ocular, respiratory, and skin conditions, and with separate respiratory-only claims narrowing the scope to an enumerated disease list.
Stated Advantages
Improved ADME.
Improved mucociliary clearance.
Prolonged lung retention.
Reduced dosing burden.
Reduced hyperkalaemia risk.
Documented Applications
Treatment or prevention of ENaC-mediated diseases or conditions.
Treatment or prevention of ocular conditions mediated by ENaC activity.
Treatment or prevention of respiratory diseases or conditions mediated by ENaC activity.
Treatment or prevention of skin conditions mediated by ENaC activity.
Treatment of respiratory diseases or conditions selected from asthma, bronchiectasis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and primary ciliary dyskinesia.
Treatment of cystic fibrosis.
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