Isotopologues salts, crystalline forms, stereoisomers, of methylone and ethylone and methods of use thereof
Inventors
Clark, Samuel • Duncton, Matthew
Assignees
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Publication Number
US-12234216-B2
Publication Date
2025-02-25
Expiration Date
Abstract
Described herein are isotopically enriched analogs of methylone (e.g., deuterated analogs of methylone (e.g., (S)-methylone and (R)-methylone) with improved characteristics. Also described herein are salts (such as hydrochloride salt) and solid forms (e.g., crystalline forms) of methylone. Also described herein are stereoisomers (e.g., enantiomers) of methylone. The present disclosure also provides methods of making and methods of use of the methylone or methylone analogs and solid forms of 3,4-methylenedioxy-N-ethylcathinone hydrochloride described herein to treat brain and neurological disorders such as depression.
Core Innovation
The disclosure relates to crystalline forms of racemic 3,4-methylenedioxy-N-methylcathinone (methylone) hydrochloride. It specifically defines crystalline methylone hydrochloride Form A by an X-ray powder diffraction (XRPD) pattern measured with Cu Kα radiation, including characteristic peaks at 7.5±0.2 2-Theta, 10.3±0.2 2-Theta, and 15.1±0.2 2-Theta, with additional XRPD peaks at 14.7±0.2 and 14.9±0.2 2-Theta also described.
The disclosure further relates to stereochemical scope for Formula (II) compounds, including optical activity, (R)/(S) enantiomers, racemates, tautomers, stereoisomers, and isotopologues including deuterated analogs and tritiated analogs. It also includes pharmaceutically acceptable salt forms, solid-state forms including solvates, hydrates, amorphous and crystalline polymorphs, and crystalline Forms A–D of methylone hydrochloride, together with related structures designated Formula (II-A) and Formula (II-B).
The document also describes crystalline solid forms of methylone hydrochloride and related solid forms with DSC thermograms and TGA thermograms, including solvated, unsolvated, anhydrous, and non-hygroscopic states. In addition, it extends to methylone maleate, an (S)-methylone–gentisic acid cocrystal described as 1:1, and crystalline ethylone hydrochloride.
Claims Coverage
The claims coverage centers on one independent claim for a crystalline form of racemic methylone hydrochloride (Form A) defined by an XRPD peak pattern measured with Cu Kα radiation, with dependent claims adding additional XRPD peaks, solid dosage form limitations, and therapeutic use in post-traumatic stress disorder with optional co-administration of a serotonin receptor 2A antagonist. Four inventive features are covered.
Crystalline Form A of racemic methylone hydrochloride defined by XRPD peaks
A crystalline form of racemic 3,4-methylenedioxy-N-methylcathinone (methylone) hydrochloride (Form A), characterized as having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.5±0.2 2-Theta, 10.3±0.2 2-Theta, and 15.1±0.2 2-Theta as measured with Cu Kα radiation.
Crystalline Form A further characterized by additional XRPD peaks
The crystalline form of racemic methylone hydrochloride (Form A) characterized as having an XRPD pattern with additional characteristic peaks at 14.7±0.2 and 14.9±0.2 2-Theta as measured with Cu Kα radiation.
Solid dosage form comprising crystalline Form A and pharmaceutically acceptable excipient
A solid dosage form comprising crystalline Form A of methylone hydrochloride and at least one pharmaceutically acceptable excipient.
Treatment of post-traumatic stress disorder in a human using crystalline Form A
A method of treating post-traumatic stress disorder in a human by administering a therapeutically effective amount of the crystalline form of racemic methylone hydrochloride of claim 1, optionally with a serotonin receptor 2A antagonist.
Overall, the claims are anchored on the XRPD-defined crystalline Form A of racemic methylone hydrochloride, further refined by additional XRPD peaks. The remaining claim coverage extends the material to solid dosage forms with pharmaceutically acceptable excipients and to methods of treating post-traumatic stress disorder in a human, optionally with a serotonin receptor 2A antagonist.
Stated Advantages
Enables identification and characterization of the crystalline Form A by a specific XRPD pattern with characteristic peaks measured with Cu Kα radiation.
Provides polymorph/salt characterization using XRPD, DSC, TGA, and dynamic vapor sorption to distinguish solid forms.
Enables formulation of the crystalline Form A into solid dosage forms comprising pharmaceutically acceptable excipients.
Provides a therapeutic method for treating post-traumatic stress disorder by administering a therapeutically effective amount of crystalline Form A.
Allows additional therapeutic coverage by co-administering a serotonin receptor 2A antagonist.
Increasing neuronal plasticity.
Improved pharmacokinetic properties for certain (R)-methylone and deuterated analogs, including longer half-life (t1/2) and slower intrinsic clearance (CLint).
Documented Applications
Polymorph/salt characterization and generation/analysis of crystalline forms of methylone hydrochloride using XRPD, DSC, TGA, and dynamic vapor sorption.
Solid dosage formulations containing crystalline methylone hydrochloride Form A with pharmaceutically acceptable excipients, optionally as tablets, pills, capsules, or powder.
Therapeutic use for treating post-traumatic stress disorder in a human using a therapeutically effective amount of crystalline methylone hydrochloride Form A.
PTSD treatment method that further includes administering a serotonin receptor 2A antagonist to the human subject.
Treating brain/neurological disorders, including depression, psychological disorders, and post-traumatic stress disorder (PTSD).
Co-administration with a serotonin receptor 2A antagonist.
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