Neuro-attenuating ketamine and norketamine compounds, derivatives thereof, and methods
Inventors
Nivorozhkin, Alex • Landrau, Nelson
Assignees
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Publication Number
US-11613515-B2
Publication Date
2023-03-28
Expiration Date
Abstract
The present invention is directed to novel neuro-attenuating norketamine (NANKET) compounds according to any one of formulas (I—shown below), (I-A) and (I-B), or any of the compounds described in Tables A-D, or in any of the Examples provided herein, and pharmaceutically acceptable salts thereof, novel pharmaceutical formulations and novel methods of uses thereof. The present invention also features novel oral neuro-attenuating ketamine (NAKET) and neuro-attenuating norketamine (NANKET) modified-release pharmaceutical formulations, and novel methods of administration thereof, which ensure the steady release of a therapeutically effective amount of ketamine, norketamine, or derivatives thereof from the oral modified-release pharmaceutical formulations without neurologically toxic spikes in plasma concentration of the ketamine, norketamine, or derivatives during the release periods.
Core Innovation
The invention relates to deuterated compounds of formula (I) and related variants, including deuterated norketamine compounds, neuro-attenuating ketamine (NAKET), and neuro-attenuating norketamine (NANKET). The disclosed compositions comprise a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt thereof, with X1, X2, X3, and X4 as hydrogen and X5 through X14 each independently selected from hydrogen and deuterium, with at least one of X5 through X12 being deuterium.
The document describes exemplary deuterated compounds and isotopically enriched ketamine or norketamine derivatives, including compounds of Formula (I) and Formula (I-A), deuterated norketamine compounds 10, 11, and 12, and structural variants of a benzene-chloro moiety linked to a cyclohexanone/cyclohexane scaffold bearing an amino group. It also discloses NAKET and NANKET structural formulas, related variants, and pharmaceutically acceptable salts.
The invention further describes deuterium incorporation requirements, isotopologue distributions, and purified isotopologue compositions with deuterium incorporation thresholds for the recited positions. It also includes oral modified-release formulations intended to provide steady release, steady therapeutic plasma levels, and a steadier plasma concentration profile while avoiding toxic concentration spikes and reducing neurological adverse effects.
Claims Coverage
The claim coverage centers on 1 independent inventive concept: a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a defined hydrogen/deuterium substitution pattern. Dependent refinements add specific hydrogen assignments and minimum deuterium incorporation thresholds.
Pharmaceutical composition with formula (I) deuterated substitution pattern
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4 are hydrogen; X5 through X14 are each independently selected from hydrogen and deuterium; and at least one of X5 through X12 is deuterium.
Fixed hydrogen at X13 and X14
X13 and X14 are hydrogen.
Minimum deuterium incorporation threshold for each deuterium
Each deuterium has a deuterium incorporation of at least 52.5% or at least 90%.
Overall, the claims define a carrier-based pharmaceutical composition containing a formula (I) deuterated compound, with fixed hydrogen at X1 through X4, hydrogen/deuterium substitution across X5 through X14, at least one deuterium among X5 through X12, and dependent refinements that fix X13 and X14 to hydrogen and impose minimum deuterium incorporation levels.
Stated Advantages
About 80% half-life increase in rat liver microsomes for compound 11 versus non-deuterated norketamine.
About 40% terminal half-life prolongation in vivo in rats for compound 11 versus non-deuterated norketamine.
NMDA receptor functional activity largely retained despite deuteration.
Provides steady therapeutic plasma levels.
Avoids toxic concentration spikes over extended release periods.
Reduced neurological adverse effects via oral modified-release steady release to avoid plasma concentration spikes.
Addresses limitations of conventional oral ketamine, including short half-life, need for frequent dosing, and risk of plasma-side effects.
Documented Applications
In vitro metabolism assessment using rat liver microsomes.
In vivo rat pharmacokinetics evaluation.
NMDA receptor functional activity testing.
Oral modified-release pharmaceutical formulations for treatment of pain, depression, neurological disorders.
Use for neuropsychiatric and pain indications.
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