Deuterated analogs of etifoxine, their derivatives and uses thereof
Inventors
Assignees
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Publication Number
US-10736901-B2
Publication Date
2020-08-11
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 6-chloro-N-(ethyl-d5)-4-methyl-4-aryl-4H-3,1-benzoxazin-2-amine analogs of Formulae I–II, solvates, prodrugs, and pharmaceutically acceptable salts. The compounds are defined by structures in which X1–X3 are independently hydrogen or deuterium, and the disclosure identifies deuterated compound structures, isotopologues, isotopic enrichment, and enantiomerically pure S- or R-analogs, mixtures thereof.
The disclosure includes synthetic preparation routes that introduce deuterium via deuterated ethylamine/isothiocyanate and via deuterated aryl intermediates, using protected aniline intermediates and conversion through cyanamide/thiourea intermediates. An explicit Scheme 2 is referenced for the preparation pathway.
The therapeutic scope described in the disclosure includes modulation of the GABA-A receptor complex and an increase in endogenous neurosteroid and neuroactive steroid levels. The stated therapeutic target areas include CNS disorders, PNS disorders, and inflammatory conditions, including anxiety, through administration of the disclosed deuterated etifoxine analogs.
Claims Coverage
The independent claim coverage centers on one specific deuterated benzoxazin-2-amine compound, or pharmaceutically acceptable salt thereof, defined by a fixed structure and stereochemical limitation. Across the provided claim sets, one inventive feature is consistently recited with dependent refinements to salt form, pharmaceutical compositions, dosage forms, and therapeutic use.
Enantiomerically pure deuterated etifoxine analog structure
6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine or a pharmaceutically acceptable salt thereof, where the compound is an enantiomerically pure S- or R- analog, or a mixture thereof.
Claim coverage centers on the specific deuterated etifoxine analog scaffold with defined stereochemical limitation and extends to dependent refinements including racemic mixture and hydrochloride salt, as well as pharmaceutical compositions and methods involving GABA-A receptor complex modulation and increased endogenous neurosteroid and neuroactive steroid levels.
Stated Advantages
Improved ADME by reducing rapid metabolism while retaining etifoxine’s therapeutic effects.
Increased exposure (AUC0-12) in rat pharmacokinetics for the Example 1 hydrochloride salt versus etifoxine hydrochloride.
Increased Cmax in rat pharmacokinetics for the Example 1 hydrochloride salt versus etifoxine hydrochloride.
Documented Applications
Metabolic stability evaluation in liver microsomes, including measurement of half-life.
Rat pharmacokinetics evaluation in Sprague-Dawley rats using AUC0-12 and Cmax comparisons between the Example 1 hydrochloride salt and etifoxine hydrochloride.
Modulating the GABA-A receptor complex in a subject in need by administering an effective amount of the compound of claim 1.
Treating anxiety and disorders described as CNS disorders, PNS disorders, and inflammatory conditions, via modulation of the GABA-A receptor complex and increased endogenous neurosteroid/neuroactive steroid levels.
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