D-amphetamine compounds, compositions, and processes for making and using the same
Inventors
Guenther, Sven • Chi, Guochen • Mickle, Travis
Assignees
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Publication Number
US-11136295-B2
Publication Date
2021-10-05
Expiration Date
Abstract
Disclosed are d-amphetamine compounds and compositions comprising at least one organic acid covalently bound to d-amphetamine, a salt thereof, a derivative thereof, or a combination thereof. Methods of making and using the same are also disclosed.
Core Innovation
The patent describes d-amphetamine conjugate compounds that include an isonicotinoyl linker and AMP-CO2CH2-isonicotinate frameworks. The disclosed compounds are defined by structural formulas including Formula I and related variants, with X selected from esters, carboxylic acids, amino acids, amino acid residues, amides, and derivatives thereof, and Y selected from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle.
The disclosure includes AMP-CO2CH2-isonicotinoyl conjugates and related derivatives, including amino-acid, peptide, and morpholine conjugates such as AMP-CO2CH2-isonicotinoyl-Val-NH2, AMP-CO2CH2-isonicotinoyl-morpholine, AMP-CO2CH2-isonicotinoyl-Gly, AMP-CO2CH2-isonicotinoyl-Sar, AMP-CO2CH2-isonicotinoyl-Leu, AMP-CO2CH2-isonicotinoyl-Thr, and AMP-CO2CH2-isonicotinoyl-Ile. It also includes structural variants with pyridine ring attachment patterns and, in some descriptions, stereochemical notes for chiral centers and salt forms such as HCl.
The patent identifies oral controlled/sustained release as a key context for these covalent conjugates, with gradual hydrolysis described as reducing blood concentration spikes, rebound effects, cardiovascular stress, and abuse potential. It further states that the covalent linkage can reduce or abolish activity for parenteral routes, including intravenous and intranasal administration, and that pharmacokinetic comparisons use Cmax and AUC relative to unconjugated d-amphetamine and lisdexamfetamine.
Claims Coverage
The claim set covers Formula I d-amphetamine conjugate compounds and related compound groupings, with independent claims centered on X and Y substituent selections and on positional constraints for X on the pyridine ring. The claims also extend to pharmaceutically acceptable salts, oral dosage forms, selected-structure families, and kit formats providing individual doses of therapeutically effective amounts.
Formula I compound with X and Y substituent selection
A compound having the structure of Formula I or a pharmaceutically acceptable salt, where X is selected from esters, carboxylic acids, amino acids, amino acid residues, amides, and derivatives thereof, and Y is selected from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle.
Formula I compound with positional X placement on pyridine ring
A compound having the structure of Formula I or a pharmaceutically acceptable salt, where X is located at the C-2 or C-4 position of the pyridine ring or at two or more of the C-2, C-3, C-4, C-5, or C-6 positions of the pyridine ring, and Y is selected from the listed substituent classes.
Selected structure set compound
A compound having a structure selected from the group consisting of specified structures.
Kit providing individual doses of a therapeutically effective amount
A kit comprising individual doses of a therapeutically effective amount of a composition including at least one claimed compound, its pharmaceutically acceptable salt, or combinations thereof.
Overall, the claims cover Formula I compound families defined by X and Y selection, variants with specific pyridine ring placement of X, selected-structure compound groupings, and kits that provide individual doses of therapeutically effective amounts containing the claimed compounds or their salts.
Stated Advantages
Reduces blood concentration spikes via oral controlled/sustained release through gradual hydrolysis.
Reduces rebound effect.
Reduces cardiovascular stress.
Reduces abuse potential.
Reduces or abolishes activity for parenteral routes.
Provides oral bioavailability.
Decreases Cmax while providing similar or reduced AUC compared to unconjugated d-amphetamine after oral administration at equimolar doses.
Similar or decreased AUC and/or Cmax versus unconjugated d-amphetamine.
Decreased abuse potential while providing central nervous system stimulation.
Documented Applications
Oral controlled/sustained release delivery of d-amphetamine conjugates.
Oral administration compositions and dosage forms.
A therapeutic-dosage kit providing individual doses of a therapeutically effective amount containing at least one claimed compound or its pharmaceutical salt.
Comparative evaluation after oral administration versus unconjugated d-amphetamine using Cmax and AUC.
Parenteral route contexts including intravenous and intranasal administration.
Treatment or use context for attention-deficit hyperactivity disorder.
Treatment or use context for narcolepsy.
Treatment or use context for sleep disorder.
Treatment or use context for insomnia.
Treatment or use context for schizophrenia.
Treatment or use context for major depressive disorder.
Treatment or use context for obesity.
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