Dextrorphan prodrugs and processes for making and using them
Inventors
Mickle, Travis • Guenther, Sven • Bera, Sanjib
Assignees
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Publication Number
US-12012384-B2
Publication Date
2024-06-18
Expiration Date
Abstract
The presently described technology provides compositions of one or more of oxoacids, polyethylene glycols, and/or vitamin compounds chemically conjugated to dextrorphan, (+)-17-methylmorphinan-3-ol), to form novel prodrugs and compositions of dextrorphan.
Core Innovation
The invention relates to dextrorphan-derived prodrug/conjugate compounds functionalized at the C-3 hydroxyl and/or the N-17 tertiary amine. The disclosed compounds are defined by general chemical formulas with optional linker and substituent positions, repeating subunits, and pharmaceutically acceptable salt forms.
The repeating subunit Gm2 is selected independently from oxoacid, polyethylene glycol having from 2 to 5 ethylene oxide units, or a vitamin compound, and m is 1-4. The disclosure includes dextrorphan conjugates such as 3-Val-dextrorphan, N-acetyl-Val-dextrorphan, 3-(N-acetyl-Val)-dextrorphan, 3-(N-acetyl-Val-OCH2OC(O))-dextrorphan, and N-(acetyl-OCH2)-dextrorphanium, together with acetylated, pivaloylated, and quaternary salt forms.
The prodrug/conjugate design is intended to provide abuse-resistant delivery by requiring enzymatic or metabolic cleavage for dextrorphan release. The disclosure states that oral dosing can reduce crush/plasma spikes and improve resistance to non-oral abuse routes such as IV and intranasal administration, with potential improvements in solubility/bioavailability, reduced side effects, and controlled or sustained release.
Claims Coverage
The claims cover a broad class of dextrorphan-derived compounds defined by a general chemical formula with optional structural elements and repeating subunits, and they narrow to specific salts and named dextrorphanium compounds. The consolidated claim coverage includes three inventive feature sets.
General formula compound with repeating subunit selection
A compound having a general formula with optional linker and substituent positions, where repeating subunits Gm2 are selected independently from oxoacid, polyethylene glycol having from 2 to 5 ethylene oxide units, or a vitamin compound, with m being 1-4, and including pharmaceutically acceptable salts.
Specified absence conditions and oxoacid constraints
The compound is specified such that L2 and Y2 are absent, M is [-(CR3R4)q], G2 includes at least one oxoacid, m is in the range 1-3, and the at least one oxoacid is acetic acid.
N-(acetyl-OCH2)-dextrorphanium salt form
The compound is specified as N-(acetyl-OCH2)-dextrorphanium, or a pharmaceutically acceptable salt thereof.
Overall, the claims focus on dextrorphan-derived compounds defined by a broad general formula, repeating subunit selection from oxoacid, polyethylene glycol, or a vitamin compound, and narrower embodiments including acetic acid-linked and N-(acetyl-OCH2)-dextrorphanium salt forms.
Stated Advantages
Abuse-resistant delivery by requiring enzymatic or metabolic cleavage for dextrorphan release.
Reduced crush/plasma spikes after oral dosing.
Resistance to non-oral abuse routes such as IV and intranasal administration.
Potential improvements in solubility/bioavailability.
Reduced side effects.
Controlled or sustained release based on hydrolytic release of active dextrorphan.
Documented Applications
Treatment mediated by NMDA receptor antagonism, including anesthetic use.
Treatment of opioid dependence.
Treatment of neuropathic pain, including hyperalgesia and diabetic peripheral neuropathic pain.
Treatment related to PBA/PTSD.
Treatment of Alzheimer’s disease.
Treatment of depression.
Potentiation of certain opioids, including discussion of co-therapies such as quinidine and other listed agents.
Pharmaceutical indications including cough and NMDA antagonist indications, including neuropathic pain, diabetic peripheral neuropathic pain, and PTSD.
Pharmacokinetic comparison experiments in rats using oral and intranasal dosing of dextrorphan conjugates versus a dextrorphan tartrate comparator, with LC-MS/MS plasma analysis.
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