JAK kinase inhibitor compounds for treatment of respiratory disease
Inventors
Fatheree, Paul R. • Jacobsen, John R. • Beausoleil, Anne-Marie • Brandt, Gary E. L. • Fleury, Melissa • Jiang, Lan • Smith, Cameron • Sullivan, Steven D. E. • VAN ORDEN, Lori Jean • Colson, Pierre-Jean • Fass, Gene Timothy • Rapta, Miroslav • Benjamin, Noah • Dabros, Marta • Thalladi, Venkat R.
Assignees
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Publication Number
US-11718616-B2
Publication Date
2023-08-08
Expiration Date
Abstract
The invention provides compounds of formula (I): wherein X is and the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are useful as JAK kinase inhibitors. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat respiratory diseases, and processes and intermediates useful for preparing such compounds.
Core Innovation
The invention provides a method of treating a respiratory disease modulated by Janus kinases in a subject by administering an inhaled pharmaceutical composition formulated as a nebulizer composition. The composition comprises a formula (I) diamino compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Disclosed examples include substituted indazole-imidazopyridine compounds, 5-ethyl-2-fluoro-4-(indazolyl)phenol derivatives, and a crystalline hydrate of a representative inhibitor.
The compounds inhibit JAK1, JAK2, JAK3, and TYK2, providing cellular inhibition of IL-13-induced STAT6 phosphorylation and reduction of allergen-induced BALF eosinophils. Designed for local lung activity with limited systemic exposure, the molecules demonstrate lung exposure exceeding plasma levels by one to two orders of magnitude and extended lung retention. The crystalline hydrate form is characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis.
Claims Coverage
The claims identify one independent claim directed to a method of treating a Janus-kinase-modulated respiratory disease using a nebulizer composition, comprising three inventive features.
Treatment of a Janus-kinase-modulated respiratory disease
The method comprises treating a respiratory disease modulated by Janus kinases in a subject having said disease.
Formula (I) compound and pharmaceutical carrier
The pharmaceutical composition comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Nebulizer composition
The pharmaceutical composition is formulated as a nebulizer composition, wherein dependent claims further specify particular compounds and respiratory diseases.
The independent claim requires the administration of a nebulizer composition containing a formula (I) compound or pharmaceutically acceptable salt and a carrier to treat Janus-kinase-modulated respiratory conditions.
Stated Advantages
The compounds are designed for local lung activity with limited systemic exposure.
Preclinical findings report lung exposure one to two orders of magnitude above plasma and a lung half-life greater than about five hours.
The compounds inhibit IL-13-induced STAT6 phosphorylation.
Documented Applications
Treatment of respiratory diseases modulated by Janus kinases, specifically asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, and bronchiolitis obliterans.
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