Deuterated analogs of etifoxine, their derivatives and uses thereof
Inventors
Assignees
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Publication Number
US-11672805-B2
Publication Date
2023-06-13
Expiration Date
Abstract
This invention relates to deuterated analogs of etifoxine of Formula 1, solvates, prodrugs, and pharmaceutically acceptable salts thereof, as well as to methods for their preparation and use, and to pharmaceutical compositions. Briefly, this invention is generally directed to deuterated analogs of etifoxine as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same.
Core Innovation
The invention relates to deuterated analogs of etifoxine, including solvates, prodrugs, and pharmaceutically acceptable salts. The deuterated analogs are defined by general chemical structures in which substituents are hydrogen or deuterium, and include 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine and enantiomerically pure deuterated S- and R-etifoxine forms.
The invention also relates to multi-step synthetic routes to deuterated and labeling variants of 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine and related Formula I compounds. The document describes incorporation of deuterium at specified positions, including deuterium labeling at the ethyl moiety and related variants of the Formula I compounds.
The document states that the deuterated analogs retain etifoxine’s therapeutic effects while having “surprisingly superior” ADME properties. It also describes use for treatment of conditions amenable to GABA_A modulation by administering the specified deuterated etifoxine or its pharmaceutically acceptable salt, including anxiety disorders among CNS indications, and reports biological evaluation results for metabolic stability and rat pharmacokinetics.
Claims Coverage
The independent claim family member covers treating anxiety by administering a specific deuterated etifoxine compound or a pharmaceutically acceptable salt, and dependent claims refine the treated anxiety subtype and the deuterium/enantiomer specification. One inventive feature is identified.
Treating anxiety with deuterated benzoxazin-2-amine
A method of treating anxiety in a subject in need thereof comprising administering an effective amount of 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage centers on administering an effective amount of the specified deuterated etifoxine or a pharmaceutically acceptable salt to treat anxiety, with dependent refinements that identify particular anxiety disorder subtypes and specify deuterium abundance and enantiomerically pure deuterated S-etifoxine.
Stated Advantages
The deuterated analogs retain etifoxine’s therapeutic effects.
The deuterated analogs have “surprisingly superior” ADME properties.
Increased half-life and increased exposure (AUC0-12 and Cmax) for Example 1 hydrochloride compared with etifoxine hydrochloride, as reflected in rat pharmacokinetics.
Documented Applications
Treatment of anxiety in a subject in need thereof, including anxiety disorders listed as CNS indications.
Treatment of panic disorder without agoraphobia.
Treatment of posttraumatic stress disorder.
Biological evaluation for metabolic stability in human liver microsomes and rat liver microsomes, including metabolic stability half-life.
Rat pharmacokinetic evaluation comparing Example 1 hydrochloride versus etifoxine hydrochloride, including AUC0-12 and Cmax.
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