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-10662146-B2
Publication Date
2020-05-26
Expiration Date
Abstract
Disclosed herein are pharmaceutical compositions with fencamfamine or fencamfamine related prodrug derivatives. The pharmaceutical compositions are for targeted therapeutic applications including, but not limited to, treating cancer-related fatigue, apathy in Alzheimer's Disease, major depression, and attention deficit-hyperactivity disorder. Also disclosed are methods of synthesizing the pharmaceutical compositions with fencamfamine or fencamfamine related prodrug derivatives.
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 defined by formula (I) in which Y is —C(O)X, and X is selected from —OR1, —NHR1, —NR1R5, O(CR2R6)OR3, O(CR2R6)SR3, and —O(CR2R6)NR3.
In formula (I), R1 is independently selected from optionally substituted C1-16 alkyl, optionally substituted aryl, and optionally substituted cycloalkyl, while R2, R5, and R6 are independently selected from hydrogen and optionally substituted C1-6 alkyl. R3 is an optionally substituted C12-26 alkanoyl, thereby defining the prodrug linkage environment within formula (I).
The provided content describes example conjugates derived from N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, including long-chain acyloxy and acyloxyethyl ester prodrugs, stereoisomers, and peptide-based promoieties. The examples include decanoate, octadecanoate, oleate Z-isomer, acetate, butyrate, dodecanoate, octanoate, tetradecanoate, hexadecanoate, and peptide-linked conjugates such as Gly-Gly, Val-D-Val, Gly-Ala, Val-Val, and Lys-Lys.
Claims Coverage
The claim coverage centers on one independent claim directed to a prodrug composition defined by formula (I), with dependent claims refining substituent selection, linkage pattern, comparative oral-versus-intravenous outcome, and therapeutic indications.
Prodrug composition defined by formula (I)
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 of formula (I), Y is —C(O)X, X is selected from —OR1, —NHR1, —NR1R5, O(CR2R6)OR3, O(CR2R6)SR3, and —O(CR2R6)NR3, R1 is optionally substituted C1-16 alkyl, optionally substituted aryl, or optionally substituted cycloalkyl, R2/R5/R6 are hydrogen or optionally substituted C1-6 alkyl, and R3 is an optionally substituted C12-26 alkanoyl.
Oral administration increases released drug concentration
Oral administration increases the plasma or blood concentration of released N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine compared with intravenous administration and with an unconjugated drug at equimolar amounts.
Restricted R1 substituent set
R1 is selected from Me, Et, tBu, and substituted methylphenyl groups.
R3 chain length limited to C12 to C18
R3 has a chain length from C12 to C18.
Linkage pattern restricted to —O(CHR2)OR3
X is —O(CHR2)OR3.
Treatment of specified disorders
A method of treating Alzheimer’s disease, Parkinson’s disease, major depressive disorder, or attention deficit hyperactivity disorder by administering an effective amount of the compound of claim 1 to a subject in need.
The claims are directed to formula (I) conjugate prodrugs of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, with dependent claims narrowing substituent and linkage scope, stating an oral-versus-intravenous concentration increase, and reciting treatment of specified disorders.
Stated Advantages
Oral administration increases the plasma or blood concentration of released N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine compared with intravenous administration and with an unconjugated drug at equimolar amounts.
Documented Applications
Treating Alzheimer’s disease.
Treating Parkinson’s disease.
Treating major depressive disorder.
Treating attention deficit hyperactivity disorder.
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