Analogs of dextromethorphan with balanced receptor activities
Inventors
Smith, Richard Alan • Rideout, Darryl C. • Myers, Kathleen J. • Kawasaki, Andrew
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11535596-B2
Publication Date
2022-12-27
Expiration Date
Abstract
Substituted analogs of dextromethorphan (DM) are disclosed, which are shown to have substantial binding affinity at both NMDA and sigma-1 receptors, and which are degraded by human liver enzymes more slowly than dextromethorphan. The analogs are useful as alternatives to dextromethorphan, and can provide the same benefits without requiring co-administration of a cytochrome P-450 enzyme inhibitor.
Core Innovation
The invention relates to compounds of formula I, wherein R1 is selected from H, CD3, C3-C4 alkenyl, C1-C4 alkyl, C3-C5 cycloalkyl, (C3-C5 cycloalkyl)methyl, and oxetanylmethyl. R2 is one or more substituents selected from halogen, pyridylmethyl, C1-C4 alkyl, and C1-C4 alkoxy, with the proviso that at least one R2 substituent is C2-C4 alkoxy substituted with one or more fluorine atoms and one or more deuterium atoms.
A related aspect is a pharmaceutical composition that includes one or more pharmaceutically acceptable excipients and a compound of formula I or a pharmaceutically acceptable salt thereof. The composition uses the same R1 and R2 definitions, including the proviso that at least one R2 alkoxy substituent bears one or more fluorine atoms and one or more deuterium atoms.
The disclosure focuses on deuterated, fluorinated dextromethorphan analogs, including CNS1-D5, N-desmethyl CNS1-D2, CNS27-D2, CNS28-D5, CNS29-D5, and CNS34-D2. It also addresses conversion to pharmaceutically acceptable oxalate salts, includes intermediates and product characterization, and reports in vitro pharmacology and ADME-style evaluations.
Claims Coverage
The consolidated claim set covers two independent claim categories: a compound of formula I and a pharmaceutical composition comprising that compound or a pharmaceutically acceptable salt thereof plus pharmaceutically acceptable excipients. Both independent claims center on the same inventive feature, namely a C2-C4 alkoxy substituent on R2 substituted with one or more fluorine atoms and one or more deuterium atoms, together with specified R1 options including CD3.
Formula I with fluorinated and deuterated alkoxy substituent on R2
A compound of formula I wherein R1 is selected from H, CD3, C3-C4 alkenyl, C1-C4 alkyl, C3-C5 cycloalkyl, (C3-C5 cycloalkyl)methyl, and oxetanylmethyl; and R2 is one or more substituents selected from halogen, pyridylmethyl, C1-C4 alkyl, and C1-C4 alkoxy, with the proviso that at least one R2 substituent is C2-C4 alkoxy substituted with one or more fluorine atoms and one or more deuterium atoms.
Pharmaceutical composition with compound of formula I and pharmaceutically acceptable excipients
A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, and a compound of formula I or a pharmaceutically acceptable salt thereof, with the same R1 and R2 definitions and the same fluorine- and deuterium-substituted C2-C4 alkoxy proviso on R2.
Overall, the claim coverage is anchored on formula I compounds featuring a C2-C4 alkoxy on R2 bearing fluorine and deuterium, combined with defined R1 substituent options, and extends to pharmaceutical compositions containing those compounds or pharmaceutically acceptable salts.
Stated Advantages
Improved metabolic stability is supported by human liver microsomal decomposition half-life relative to dextromethorphan.
Maintained receptor interactions are supported by sigma-1 and NMDA (PCP site) receptor binding/affinity results.
Potentially avoids co-administration of CYP2D6 inhibitors.
Alleviates pseudobulbar affect.
Alleviates pain.
Documented Applications
Alleviating pseudobulbar affect in a subject by administering an effective amount of a compound according to the claimed formula I definitions.
Alleviating pain in a subject by administering an effective amount of a compound according to the claimed formula I definitions.
Analgesic utility.
Treatment of pseudobulbar affect (PBA).
Pharmaceutical compositions comprising the claimed formula I compound or pharmaceutically acceptable salts with pharmaceutically acceptable excipients.
Interested in licensing this patent?