Neuro-attenuating ketamine and norketamine compounds, derivatives thereof, and methods

Inventors

Nivorozhkin, Alex • Landrau, Nelson

Assignees

Acadia Pharmaceuticals Inc

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 deuterium-labeled compounds of formula (I), pharmaceutically acceptable salts thereof, and isotopically enriched ketamine and norketamine compounds. The disclosed compounds include formula (I), variants (I-A) and (I-B), and an isotopically enriched ketamine compound of formula (II), with representative deuterated compounds and listing tables. The examples include deuterium-labeled compounds corresponding to a cyclohexanecarboxamide-like or fused cyclohexanone-aniline scaffold with an amide carbonyl or carbonyl O, an NH2 substituent, and a chloro-substituted phenyl ring.

The compounds are characterized by X1, X2, X3, and X4 being hydrogen, while X5 through X14 are independently selected from hydrogen and deuterium, and at least one of X5 through X12 is deuterium. The disclosures present multiple deuterium-labeled exemplary compounds with D/2H placement at designated positions, including full and partial deuteration and D-labeled OH for I-A variants. Dependent variations further specify deuterium incorporation thresholds and fix X13 and X14 as hydrogen.

The invention also discloses oral immediate or modified-release formulations intended to provide steady therapeutic plasma concentrations without neurologically toxic plasma spikes. The concept relies on deuterium kinetic isotope effects to reduce metabolic oxidation associated with CYP-mediated metabolism, and formulation discussion highlights steady release, matrix-based composition, and maintaining plasma concentrations within a therapeutic window. Deuterium exchange is described as producing tetra/bi-deuterated norketamine and as demonstrating stability against exchange at neutral and acidic pH conditions.

Claims Coverage

The consolidated claim coverage centers on deuterium-labeled compounds of formula (I) or pharmaceutically acceptable salts thereof, with X1, X2, X3, and X4 fixed as hydrogen and X5 through X14 independently selected from hydrogen and deuterium, with at least one deuterium among X5 through X12. Dependent refinements add the depicted deuterium- and chloro-substituted framework, quantitative deuterium incorporation thresholds, and further restriction of X13 and X14 as hydrogen.

Overall, the claims cover deuterium-labeled compounds of formula (I) with X1-X4 fixed as hydrogen and a required deuterium presence among X5-X12, while dependent refinements define the depicted deuterium/chloro-containing structure, specify quantitative deuterium incorporation thresholds, and further restrict X13 and X14 as hydrogen.

Stated Advantages

Documented Applications