Ion channel modulators
Inventors
Griffin, Andrew Mark • Marron, Brian Edward • MARTINEZ BOTELLA, Gabriel • Reddy, Kiran
Assignees
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Publication Number
US-12030881-B2
Publication Date
2024-07-09
Expiration Date
Abstract
Provided, in part, are compounds of Formula I: pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of conditions associated with the activity of sodium channels. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.
Core Innovation
The invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, in a unit dosage form and administered in a therapeutically effective amount. The Formula I framework defines R1, R2, R3, R4, R5, R6, and t, with optional substitution by Ra, Rb, and Rc.
The compounds and pharmaceutical compositions are intended for treating diseases or conditions associated with aberrant sodium channel activity, especially abnormal late sodium current (INaL). The patent also describes a combination-therapy approach for treating acute coronary disease events and associated secondary metabolic, pulmonary, peripheral vascular, and gastrointestinal disorders using ranolazine together with one or more additional therapeutic agents.
The co-therapeutic agent categories include antihypertensive agents such as ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, and diuretics, as well as pulmonary drugs, diabetes/metabolic drugs, gastrointestinal drugs, antibiotics, analgesics, NSAIDs and COX-2 inhibitors, antidepressants, and benzodiazepines. The document also discloses chemical synthesis and characterization of multiple triazolopyridine derivatives, including intermediates and final products, followed by biological activity evaluation.
An Example 12 Biological Activity section describes electrophysiology patch-clamp assessment of sodium channel late currents (INaL) using recombinant sodium channels, with results categorized as A/B/C inhibition levels for exemplary compounds presented in a table along with compound structures.
Claims Coverage
The claim set includes one independent claim directed to a unit-dosage pharmaceutical composition with defined Formula I structural substituent features.
Unit-dosage pharmaceutical composition with Formula I compound
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in a unit dosage form.
Substituent-defined Formula I structural class
R1 is selected from —CR2R3R4, a monocyclic C3-6 cycloalkyl, or a 4- to 7-membered monocyclic heterocyclyl, with each cycloalkyl and heterocyclyl optionally substituted with one or more Ra; R2 is a C1-4 haloalkyl or a monocyclic C3-6 cycloalkyl optionally substituted with one or more Rb; R3 and R4 are each selected from hydrogen, a C1-4 alkyl, and a C1-4 haloalkyl; R5 is a halogen; R6 is a C1-4 haloalkyl or a C3-6 monocyclic cycloalkyl optionally substituted with one or more Rc; and t is 1 or 2.
Optional substitution by Ra, Rb, and Rc
Ra, Rb, and Rc are each independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.
Overall, the independent claim covers a unit-dosage pharmaceutical composition defined by a carrier plus a pharmaceutically acceptable salt of a Formula I compound with a specified R1–R6 structural pattern, optional substitutions via Ra, Rb, and Rc, and t = 1 or 2.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating diseases or conditions associated with aberrant sodium channel activity, especially abnormal late sodium current (INaL).
Treating neurological disorders including epilepsy and epilepsy syndromes including Dravet syndrome, infantile spasms, and Lennox-Gastaut syndrome.
Treating pain.
Treating neuromuscular disorders.
Treating acute coronary disease events and associated secondary metabolic, pulmonary, peripheral vascular, and gastrointestinal disorders using ranolazine together with one or more additional therapeutic agents.
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