Bis(pentahydroxyhexyl)amino substituted 2-{[(3-amino-pyrazin-2-yl)formamido]methyl}-1H-1,3-benzodiazol-3-ium derivatives as ENaC inhibitors for treating respiratory diseases
Inventors
HAY, Duncan Alexander • SCHOFIELD, Thomas Beauregard • Went, Naomi • McCarthy, Clive
Assignees
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Publication Number
US-11370778-B2
Publication Date
2022-06-28
Expiration Date
Abstract
The present invention discloses bis(pentahydroxyhexyl)amino substituted 2-{[(3-amino-pyrazin-2-yl)formamido]methyl}-1H-1,3-benzodiazol-3-ium derivatives of formula (I) as inhibitors of ENaC and are of use in the treatment of respiratory diseases and conditions, skin conditions or ocular conditions, wherein the respiratory disease or condition is e.g. cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis bronchiectasis, and asthma; the skin condition is e.g. psoriasis, atopic dermatitis and ichthyosis; and the ocular condition is e.g. dry eye disease.
Core Innovation
The invention is directed to benzodiazolium derivatives that act as epithelial sodium channel (ENaC) inhibitors. The compounds are defined as compounds of general formula (I), including all tautomeric forms, all enantiomers, isotopic variants, and salts thereof, with an anion X− and variable substituents R1, R2, R3, and R4 together with a linker group L1 and associated structural variables Z1, Z2, Z3, Q1, Q2, and Q3.
A key aspect of the disclosed framework is the use of a defined L1 linker architecture that includes multiple forms of C(O)-, amide-containing, and heteroatom-containing connectivity patterns involving the Z and Q structural variables. The structural concept also incorporates bis(pentahydroxyhexyl)amino sugar residues within the benzodiazolium derivative framework, while maintaining extensive variability in the remaining structural regions.
The disclosure further grounds the claimed framework by naming specific benzodiazolium-containing salt forms and their anion counter-ions, including bromide and related salt species, along with multiple exemplary intermediates and final compounds that share the benzodiazolium core and employ variations in the piperidine or pyrrolidine side-chain, linker modifications, and related amide or carboxamide linkages. The compounds are positioned for treatment or prophylaxis of respiratory diseases and conditions including cystic fibrosis, COPD, asthma, and bronchiectasis, and are also framed for skin or ocular conditions including psoriasis, atopic dermatitis, ichthyosis, and dry eye disease.
Claims Coverage
The claim coverage centers on broad compound class coverage under general formula (I), including tautomeric forms, enantiomers, isotopic variants, and salts. Consolidated independent and dependent claim features reflect five inventive features covering the core benzodiazolium scaffold, substituent ranges, linker definitions, formula sub-variants, and a pharmaceutical composition.
General formula (I) compounds including tautomeric forms, enantiomers, isotopic variants, and salts
A compound of general formula (I) including all tautomeric forms, all enantiomers and isotopic variants and salts thereof, wherein X− is an anion and R1, R2, R3, R4, and L1 are defined as specified by the general structural variables of claim 1.
Counter-ion selection via X−
X− is defined as an anion for the compounds of general formula (I), and the document further specifies benzodiazolium salt forms with anion counter-ion X− in named exemplars, including bromide-containing species in the partial disclosure.
Substituent definition for R1–R4 and optional CH2 replacements
R1 is halo, cyano, C1-3 alkyl, C1-3 haloalkyl, or −S(C1-3 alkyl); R2 is H or NH2; each of R3 and R4 is independently C1-10 alkyl with one or more −CH2− groups optionally replaced by −O− or −S− under the restriction that adjacent −CH2− groups are not so replaced.
Linker group L1 with Z1–Z3 and Q1–Q3 structural patterns
L1 is selected from multiple specified groups built from Z1, Q1, Q2, Q3, and Z2/Z3 with the enumerated heteroatom-containing variants and acyl and amide-containing options; Z1, Z2 and Z3 are independently C1-12 alkylene, C2-12 alkenylene, or C2-12 alkynylene optionally substituted by halo, OH, C(O)NR11R12, C(O)OR11 or NR11R12; and Q1, Q2 and Q3 are independently carbocyclyl, heterocyclyl, aryl or heteroaryl optionally substituted by the listed substituent classes.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition that includes the compound of claim 1 together with a pharmaceutically acceptable excipient.
Overall, the claim coverage centers on broad structural Markush definition of benzodiazolium-containing compounds by general formula (I), with core variability in substituents R1–R4, anion X−, and linker and heteroatom construction L1 with Z1–Z3 and Q1–Q3. Dependent coverage further narrows the scope to sub-variants of general formula (IA)/(TB), restricts R1 selection, constrains L1 to specified linker structures, and adds a pharmaceutical composition dependent form.
Stated Advantages
Improves airway mucus hydration and mucociliary clearance (MCC).
Prolonged lung retention assessed via epithelial lining fluid levels.
Enables smaller dosing.
Reduces kidney exposure.
Addresses hyperkalaemia risk concerns associated with ENaC blockade.
Documented Applications
Treatment or prophylaxis of respiratory diseases and conditions including cystic fibrosis, COPD, asthma, and bronchiectasis.
Treatment or prophylaxis of skin conditions including psoriasis, atopic dermatitis, and ichthyosis.
Treatment or prophylaxis of an ocular condition including dry eye disease.
ENaC inhibition evaluation using an ENaC short-circuit current assay in human bronchial epithelial cells (HBEC).
Rat bronchoalveolar lavage dosing with LC-MS/MS bioanalysis workflow and measurement of ENaC inhibitor levels in BAL at 6 hours across examples 1–7.
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