Prodrugs of fencamfamine
Inventors
Patil, Sandeep • Bihovsky, Ron • Smith, Steven A • Ji, YuHua • Stella, Valentino • Long, Daniel D. • Marquess, Daniel
Assignees
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Publication Number
US-11919836-B2
Publication Date
2024-03-05
Expiration Date
Abstract
Disclosed herein are pharmaceutical compositions comprising fencamfamine or fencamfamine related prodrug derivatives for targeted therapeutic applications and methods of synthesizing the compositions.
Core Innovation
The invention relates to a prodrug composition comprising at least one conjugate of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine or any of its stereoisomers. The conjugate is selected from a defined group of conjugate compounds, including stereoisomeric (+)/(−) forms, amino acid conjugates, carboxylic-acid-linked prodrugs, carbamate and aryl-carbamate linked prodrugs, and acyloxymethoxy or acyloxyethyl ester linked prodrugs.
The disclosed prodrugs also include long-chain and unsaturated oxycarbonyl ester conjugates and peptide-derived linkers, with fatty-acid/aliphatic chain conjugates and variable Y moieties. Representative entries include octadecanoyloxymethoxycarbonyl oxycarbonyl conjugate, octadec-9-enoyloxymethoxycarbonyl (E/Z) conjugate, decanoyloxyethoxycarbonyl, butanoyloxyethoxycarbonyl, octanoyloxyethoxycarbonyl, dodecanoyloxyethoxycarbonyl, hexadecanoyloxyethoxycarbonyl, glycyl-glycyl, alanyl-glycyl, valyl-valyl, lysyl-lysyl, and Phenylalanyl-phenylalanyl conjugates.
The disclosure further provides representative prodrug examples and enantiomer-related entries for PRX-001 and PRX-002, including PRX-P1-001 and amino-acid linked prodrugs PRX-P1-005, PRX-P1-006, PRX-P1-012, and PRX-P1-013. It also describes synthetic examples of 1-acyloxyethoxycarbonyl prodrugs and dipeptide prodrugs, with PRX-P5-001 to PRX-P5-011 and PRX-P6-001 to PRX-P6-011 shown with structures, yields, and characterization.
Claims Coverage
The claim coverage centers on prodrug compositions comprising at least one conjugate of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine or any of its stereoisomers, selected from a defined group of conjugate compounds. Dependent features further specify pharmaceutical dosage forms, higher plasma or blood concentration of released drug after oral administration, reduced abuse potential, and treatment of specified disorders.
Prodrug composition comprising selected conjugates
A prodrug composition comprising at least one conjugate of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine or any of its stereoisomers, wherein the conjugate is selected from a defined group of conjugate compounds.
Pharmaceutical dosage form selection
The prodrug composition is provided in specified pharmaceutical dosage forms.
Higher released drug plasma or blood concentration after oral dosing
The prodrug composition provides a higher plasma or blood concentration of released N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine after oral administration than after intravenous administration and compared to the unconjugated drug given in equimolar amounts.
Reduced abuse potential compared to unconjugated drug
The prodrug composition provides less abuse potential than an unconjugated N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine drug composition.
Therapeutic treatment of specified diseases and disorders
A method treats Alzheimer's disease, Parkinson's disease, major depressive disorder, or attention deficit hyperactivity disorder by administering an effective amount of the compound to a subject in need.
Overall, the claims are directed to prodrug compositions containing conjugates of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine and stereoisomers selected from a defined group, with dependent refinements for dosage forms and functional outcomes such as higher oral released-drug exposure, reduced abuse potential, and therapeutic methods for specified indications.
Stated Advantages
Slower and reduced release after intravenous administration versus unconjugated fencamfamine.
Extended or controlled Tmax after oral dosing at equimolar amounts versus unconjugated dosing.
Reduced side effects versus unconjugated fencamfamine.
Reduced abuse potential versus unconjugated fencamfamine.
Higher plasma or blood concentration of released N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine after oral administration than after intravenous administration and compared to the unconjugated drug given in equimolar amounts.
Altered release kinetics with slower active release.
Higher oral plasma levels and/or extended Tmax.
Documented Applications
Treatment of cancer-related fatigue.
Treatment of chronic fatigue syndrome.
Treatment of major depressive disorder.
Treatment of narcolepsy.
Treatment of Parkinson's disease.
Treatment of attention deficit hyperactivity disorder.
Treatment of Alzheimer's disease (apathy/cognitive impairment).
Treatment of Alzheimer's disease.
Treatment of Alzheimer’s apathy.
Treatment of dopamine responsive dystonia.
Treatment of substance-abuse disorders.
Treatment of binge-eating disorder.
Comparative in vivo pharmacokinetic evaluation in male Sprague-Dawley rats to characterize oral versus intravenous conversion/release and isomer-dependent pharmacokinetics for prodrug conjugates.
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