Ketamine compounds and processes for making and using them
Inventors
Chi, Guochen • Guenther, Sven • Mickle, Travis • Smith, Adam
Assignees
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Publication Number
US-11753378-B2
Publication Date
2023-09-12
Expiration Date
Abstract
Disclosed are compounds comprising ketamine (2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) chemically conjugated to one or more oxoacids, amino acids, polyethylene glycols (PEG or PEO), peptides, phosphates, and/or vitamin compounds, and salts of such compounds. Also disclosed are compositions comprising at least one ketamine compound, or a salt thereof, methods of making such compounds, and methods of using such ketamine compounds and compositions.
Core Innovation
The patent discloses ketamine prodrug/conjugate compounds in which ketamine, including ketamine having the structure 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone, is covalently linked to a ligand moiety. The disclosed compound structures include nicotinoyl- and isonicotinoyl-conjugates, with examples labeled as KTM-CO2CH2-nicotinoyl-AA derivatives and related conjugates, and the compounds are defined by chemical structure formulas with a linker (L) connecting to a moiety (M).
The disclosure includes structural classes including Formula I and Formula II–V with substituent-variable sets such as R1–R6, together with pharmaceutically acceptable salt forms and stereochemical and counterion variants. It also describes ketamine conjugates in which HN–R1R2 is derived from a standard, non-standard, or synthetic amino acid or peptide, including peptide examples such as Gly-Gly-OH, and related substituted amides and halogenated and functionalized side chains.
The patent characterizes functional outcomes including in vivo enzymatic/metabolic release of free ketamine, altered pharmacokinetics, improved oral bioavailability, reduced formation and exposure of the metabolite norketamine, and modulation of the concentration-time profile, including reduced Cmax peaks and delayed/extended release profiles. It further addresses differences in ketamine exposure and norketamine exposure associated with administration route, including oral, intranasal, and intravenous exposure characteristics and relative bioavailability values versus ketamine HCl.
The document further characterizes behavior under abuse-relevant routes by describing reduced abuse potential and resistance to abuse routes, including intravenous and intranasal administration. It also describes pharmaceutical composition and administration forms, including oral liquid, oral thin film, tablets, and capsules, together with dosing frequency limitations and comparative exposure metrics relative to unconjugated ketamine and norketamine.
Claims Coverage
The provided claim set includes independent claims directed to ketamine-related compound structures defined by Formula III or Formula IV, or to compounds selected from a group of structures. Across these claims, six inventive features are identified, focused on formula-based structural variables, selected pharmaceutically acceptable salts, composition-level excipients, dosing frequency, and intranasal exposure reduction.
Formula III compound definition
A compound having a structure of Formula III, or a pharmaceutically acceptable salt thereof, wherein L is alkyl, Z is selected from hydrogen, and R4, R5, and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, aryl, substituted aryl, and cycloalkyl.
Formula IV compound definition
A compound having a structure of Formula IV, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, aryl, substituted aryl, and cycloalkyl.
Selected structure group compound definition
A compound having a structure selected from the group consisting of a specified group of structures.
Specific pharmaceutically acceptable salt selection
The compound is a pharmaceutical salt selected from a specified group of named salts and salt mixtures, including acetate and other named inorganic and organic counterion salts.
Pharmaceutical composition with specified excipient types
A pharmaceutical composition includes one or more excipients chosen from anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners, their derivatives, or combinations.
Dosing regimen constraint
A composition is defined as having a dosing regimen of about two times per day or less.
Intranasal exposure reduction versus unconjugated ketamine
A composition, when given intranasally at an equimolar dose, reduces the maximal exposure (Cmax) and/or total exposure (AUC) to ketamine compared with unconjugated ketamine.
Overall claim coverage is directed to ketamine-related compound structures defined by Formula III or Formula IV, or compounds selected from a group of structures, with defined substituent categories and salt selections. The dependent claims additionally address pharmaceutical compositions with selected excipient types and impose dosing-frequency and intranasal exposure constraints relative to unconjugated ketamine.
Stated Advantages
Improved oral bioavailability.
Reduced formation and exposure of the metabolite norketamine.
Reduced maximal exposure (Cmax) and/or total exposure (AUC) to ketamine compared with unconjugated ketamine after intranasal administration at an equimolar dose.
Delayed/extended release.
Reduced abuse potential and resistance to abuse routes including intravenous and intranasal administration.
Documented Applications
Oral administration forms including oral liquid, oral thin film, tablets, and capsules.
Intranasal administration, with comparative exposure reductions to ketamine versus unconjugated ketamine at an equimolar dose.
Comparative pharmacokinetic assessment after oral, intranasal, and intravenous administration, including measurement of ketamine and norketamine Cmax, AUC, and Tmax and derived exposure ratios.
Intravenous and intranasal abuse-route context, described via reduced abuse potential and resistance to abuse routes.
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