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-10941149-B2
Publication Date
2021-03-09
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 provides compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers or tautomers thereof, defined by extensive structural constraints on R1, R2, R3, R4, R5, L1, R7–R13, R10, Q1–Q3, Z1–Z3, and the anion X−. The scope includes permitted ring, linker, alkyl, heterocyclyl, aryl, and heteroaryl patterns, with optional substitution rules and a restriction on adjacent –CH2– replacements by –O–, –S–, or –NR7–. The definition also includes a provision for an additional X− under a stated R10 condition.
The compounds are further characterized by substituted 1H-1,3-benzodiazol-3-ium cations bearing a (formamido)methyl substituent linked to a {pyrrolo[2,3-b]pyrazin-2-yl} unit. The disclosed examples include benzodiazolium-related compounds with substituents such as fluoro, chloro, methoxy, trifluoromethyl, carbamoyl, and polyhydroxyhexyl-linked groups, together with counterions including iodide, bromide, hydrochloride, and trifluoroacetate. The partial content also reports synthetic intermediates and analytical characterization by 1H NMR and LC/MS (ESI+).
The compounds are described in relation to ENaC-mediated Na+ absorption, mucus hydration, and mucociliary clearance. ENaC inhibition is proposed to hydrate mucus and enhance mucociliary clearance in respiratory diseases such as chronic bronchitis and cystic fibrosis, and the document also mentions pseudohypoaldosteronism type 1 (PHA1) and Liddle’s syndrome. The background further notes limitations of prior ENaC blockers, including short lung duration and risk of renal hyperkalaemia.
Claims Coverage
The independent claim set defines one broad compound of formula (I) with extensive structural constraints and an anion X−, and includes a conditional additional X− requirement for certain R10 patterns. The covered inventive features also encompass the defined L1, Q1–Q3, and Z1–Z3 classes, the permitted R2/R3 substitution framework, and specific substituted 1H-1,3-benzodiazol-3-ium embodiments.
Compound of formula (I) with constrained substituent framework
A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, defined by extensive allowed substituent and structural constraints on R1, R2, R3, R4, R5, L1, R7–R13, R10, Q1–Q3, and Z1–Z3, with X− as an anion and an additional X− under a stated R10 condition.
Optional –CH2– replacement rule for R2 and R3
Each of R2 and R3 is independently C1-10 alkyl, optionally substituted, with one or more –CH2– groups optionally and independently replaced by –O–, –S–, or –NR7–, provided that adjacent –CH2– groups are not so replaced.
L1, Q1–Q3, and Z1–Z3 structural classes
L1 is selected from defined Z1/Q1/Q2/Q3-containing linker patterns, Q1, Q2, and Q3 are independently carbocyclyl, heterocyclyl, aryl, or heteroaryl with optional substitution patterns, and Z1, Z2, and Z3 are independently C1-12 alkylene, C2-12 alkenylene, or C2-12 alkynylene with optional substitution patterns.
Substituted 1H-1,3-benzodiazol-3-ium embodiments
The claim scope includes substituted 1H-1,3-benzodiazol-3-ium cations bearing a {3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl or related formamido)methyl-linked motif, with specified ring substituent patterns.
Overall claim coverage is centered on the formula (I) chemical space, defined by broad but explicit structural constraints, the anion X−, the restricted –CH2– replacement rule, and the permitted linker and ring classes. The claim set also narrows to substituted benzodiazolium cation embodiments and retains the conditional additional X− requirement for specified R10 forms.
Stated Advantages
ENaC inhibition is proposed to hydrate mucus and enhance mucociliary clearance.
In vivo effective mucociliary clearance.
Prolonged lung retention.
Reduced dose.
Avoidance of hyperkalaemia.
Good ENaC blocking activity.
Prolonged lung retention time.
Increased mucociliary clearance (MCC).
Documented Applications
ENaC inhibition in respiratory diseases including chronic bronchitis and cystic fibrosis.
Pseudohypoaldosteronism type 1 (PHA1).
Liddle’s syndrome.
Treating or preventing respiratory conditions including cystic fibrosis, COPD, chronic bronchitis, emphysema, bronchiectasis, asthma, and primary ciliary dyskinesia.
Treating or preventing skin conditions including psoriasis and atopic dermatitis, and ichthyosis.
Treating or preventing dry eye disease.
Pharmaceutical composition use as a dry powder or as an aerosol/spray for nasal, bronchial, and/or buccal administration.
ENaC inhibition evaluation using an HBEC short-circuit current assay, including comparison to an amiloride control and an IC50 table for Examples 1–67.
In vivo persistence/clearance evaluation using bronchoalveolar lavage and sheep mucociliary clearance models.
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