(R)-2-[(2H-1,3-Benzodioxol-5-yl)methyl]pyrrolidine and its preparation process, composition and use

Abstract

This application encompasses an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof. Also included are compositions of an enantiomerically pure compound of formula (R)-I, and methods of using a compound of formula (R)-I or a composition thereof for treating, for example, diseases, disorders or medical conditions for which psychotherapy is beneficial. The application also encompasses a composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof, and a compound of (S)-I or a salt and / or solvate thereof, wherein the (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount, expressed in enantiomeric equivalents, compared to the (S)-I or a salt and / or solvate thereof, and the use thereof. Further included is a process for preparing a compound of formula (R)-I or (S)-I. JPEG2025524763000070.jpg5277 JPEG2025524763000071.jpg72155

Description

Technical Field

[0001] This application relates to enantiomerically pure (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine or a salt and / or solvate thereof, and compositions and uses thereof. This application also relates to compositions comprising a non-racemic mixture of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, and methods of using such compositions for therapeutic treatment, for example, for treating mental disorders. This application also relates to a process for preparing 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine.

Background Art

[0002] Related Applications This application claims the benefit of priority from co-pending U.S. Provisional Patent Application No. 63 / 392,948, filed Jul. 28, 2022, the content of which is hereby incorporated by reference in its entirety into this disclosure.

[0003] 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (E) or molly, is a psychostimulant first developed by Merck in 1912. MDMA is today often used recreationally. However, MDMA's first use was as an adjunct to psychotherapy. More recently, MDMA has been tested in various clinical trials investigating MDMA-assisted psychotherapy for, for example, post-traumatic stress disorder (PTSD), anxiety associated with advanced disease, and social anxiety in adults with autism. MDMA now has breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of PTSD.

[0004] MDMA is generally available and is taken as a racemate. The racemate of MDMA is also known to have the potential for harmful effects such as hyperthermia and neurotoxicity. However, qualitative differences in the effects between the enantiomers of MDMA have been shown by tests. The evidence suggests that the R enantiomer of MDMA may provide an improved therapeutic index by maintaining some of the therapeutic effects of the MDMA racemate while reducing the side effect profile (Pitts et al. Psychopharmacology 235, 377 - 392, 2018 and Curry et al. Neuropharmacology. 2018 January;128:196 - 206).

[0005] Analogues of MDMA are known. For example, N - methyl - 1,3 - benzodioxolylbutanamine (MBDB), commonly known as Eden or Methyl - J, is an analogue of MDMA that has an ethyl group instead of a methyl group attached to the alpha - carbon adjacent to the amine. Like MDMA, MBDB is also classified as an entactogen. MBDB is also generally available and is taken as a racemate.

[0006] The synthetic processes for 2 - [(2H - 1,3 - benzodioxol - 5 - yl)methyl]pyrrolidine, a cyclic analogue of MDMA, and its S - enantiomer are disclosed in Williams et al., Med. Chem. Commun., 2015, 6, 1054 and Dolby L.J. et al, J. Org. Chem., 37(23), 1972 p3691.

[0007] Further development of MDMA analogues and further investigation to determine the therapeutic potential of the enantiomers of MDMA and its analogues are also needed. SUMMARY OF THE INVENTION

[0008] The applicant has investigated an analogue of MDMA, namely (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, and provides enantiomerically pure (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, as well as its preparation process, composition and use.

[0009] The applicant further investigates a composition comprising a non-racemic mixture of enantiomers of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine containing a greater amount of the R enantiomer in order to develop a composition containing an amount of the R enantiomer sufficient to achieve an improved toxicity profile, such as a reduction in cardiotoxicity, compared to the racemic mixture of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine. The applicant develops a composition having an optimal range for the ratio between the two enantiomers of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine in order to minimize undesirable effects while providing the desired efficacy.

[0010] In the present application, the applicant also describes new therapeutic uses for enantiomerically pure (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine and its compositions, as well as new therapeutic uses for compositions comprising a non-racemic mixture of enantiomers of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, which include uses as treatments for autism spectrum disorder, clinical depression in palliative patients, and substance use disorders (e.g., opioid use disorder).

[0011] Accordingly, the present application encompasses an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof. [Chemical formula]

[0012] This application further encompasses a composition comprising an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof and a carrier.

[0013] This application also relates to a method of treating a disease, disorder or medical condition treatable by activation of a serotonin receptor, the method comprising administering to a subject in need thereof an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof. which is included in this application.

[0014] This application also relates to a composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof, wherein:

Chemical formula

[0015] This application also relates to a method of activating an intracellular serotonin receptor, the method comprising administering to a subject in need thereof a composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof, wherein the cell may be a cell in a biological sample or a cell in a patient. which is included in this application.

[0016] This application also relates to A method for treating a disease, disorder or medical condition treatable by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof comprising.

[0017] In some embodiments, the disease, disorder or medical condition treated by activation of the serotonin receptor is a disease, disorder or medical condition for which treatment with racemic MDMA is beneficial, a disease, disorder or medical condition for which treatment with racemic MBDB is beneficial, any disease, disorder or medical condition for which psychotherapy is beneficial, and any disease, disorder or medical condition for which treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is beneficial, such as Parkinson's disease.

[0018] This application relates to a compound of formula (R)-I or (S)-I:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0019] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while representing embodiments of the present application, are given by way of illustration only, and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the entire specification

Brief Description of the Drawings

[0020] The present application will be described in more detail with reference to the accompanying drawings and tables

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Mode for Carrying Out the Invention

[0044] I. Definitions Unless otherwise indicated, the definitions and embodiments described in this section and other sections are intended to be applicable to all of the embodiments and aspects of the present application described in the present disclosure to which those definitions and embodiments are suitable, as understood by those skilled in the art.

[0045] For the purpose of understanding the scope of the present application, the term "comprising" and its derivatives are intended to be open-ended terms that, when used in the present disclosure, specify the presence of the described features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other un-described features, elements, components, groups, integers, and / or steps. The above also applies to words having similar meanings such as the terms "including", "having", and their derivatives.

[0046] When used in this disclosure, the term "compound of the application" or "compound of the present application" refers to an enantiomerically pure compound of formula (R)-I, including its pharmaceutically acceptable salts or solvates.

[0047] When used in this disclosure, the term "composition of the application" refers to an enantiomerically pure compound of formula (R)-I and / or its salts and / or solvates as described in this disclosure, and / or any composition containing its salts and / or solvates, as well as any composition containing a non-racemic mixture of the compounds of formula (R)-I and (S)-I and / or their salts and / or solvates as described in this disclosure.

[0048] As used in this disclosure, the term "non-racemic" for a mixture containing two enantiomeric compounds means that the mixture contains the two enantiomeric compounds in a ratio other than 1:1.

[0049] As used in this disclosure, the term "racemic" for a mixture containing two enantiomeric compounds means that the mixture contains the two enantiomeric compounds in a ratio of 1:1 or in equal amounts.

[0050] When used in this disclosure, the terms "consisting" and its derivatives are intended to be closed terms that specify the presence of the described features, elements, components, groups, integers, and / or steps, while excluding the presence of other un-described features, elements, components, groups, integers, and / or steps.

[0051] When used in this disclosure, the term "consisting essentially of" is intended to specify the presence of the described features, elements, components, groups, integers, and / or steps, as well as the presence of those that do not substantially affect the basic and novel features of the features, elements, components, groups, integers, and / or steps.

[0052] Terms such as "substantially", "about", and "approximately" when used in this disclosure mean a reasonable amount of deviation from the modified term such that the end result does not vary significantly. These terms of degree should be construed to include a deviation of at least ±5% from the term being modified, provided that such deviation does not negate the meaning of the term being modified.

[0053] As used in this application, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include the case of referring to a plurality.

[0054] In embodiments that include an "additional" or "second" component, the second component used in this disclosure is chemically different from other components or the first component. The "third" component is different from other components, the first component, and the second component, and further listed or "additional" components are likewise different.

[0055] The term "and / or" when used in this disclosure means that the listed items are present or used individually or in combination. In effect, this term means that "at least one" or "one or more" of the listed items is used or present.

[0056] The term "subject" when used in this disclosure includes all members of the animal kingdom including mammals, and preferably refers to humans. Accordingly, the methods of the present application are applicable to both human treatment and veterinary use.

[0057] The term "compound of formula (R / S)-I" when used in this disclosure refers to a compound having the chemical name (R / S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, or (R / S)-2-(benzod[d][1,3]dioxol-5-ylmethyl)pyrrolidine, and having the following chemical structure. [Chemistry]

[0058] The term "compound of formula (R)-I", as used in this disclosure, refers to a compound having the chemical name (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, or (R)-2-(benzod[d][1,3]dioxol-5-ylmethyl)pyrrolidine, and having the following chemical structure. [Chemistry]

[0059] The term "compound of formula (S)-I", as used in this disclosure, refers to a compound having the chemical name (S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, or (S)-2-(benzod[d][1,3]dioxol-5-ylmethyl)pyrrolidine, and having the following chemical structure. [Chemistry]

[0060] The term "MDMA" or "racemic MDMA", as used in this disclosure, refers to a compound having the chemical name: 1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine, or the chemical name 3,4-methylenedioxymethamphetamine, and having the following chemical structure. [Chemistry]

[0061] The term "MBDB", as used in this disclosure, refers to a compound having the chemical name: 1-(1,3-benzodioxol-5-yl)-N-methylbutan-2-amine, or N-methyl-1,3-benzodioxolylbutanamine, and having the following chemical formula. [Chemistry]

[0062] As used in this disclosure, the term "reducing agent" means any compound or combination of compounds that reduces a desired functional group. A reducing agent as a whole causes a total addition of electrons to the functional group, or in the case of organic chemistry, a total addition of hydrogen atoms.

[0063] As used in this disclosure, the term "inert solvent" means a solvent that does not interfere with or otherwise inhibit the reaction. Thus, the identity of the inert solvent varies depending on the reaction being carried out. The selection of an inert solvent is within the skill of one of ordinary skill in the art.

[0064] The term "solvent" encompasses both a single solvent and a mixture containing two or more solvents.

[0065] As used in this disclosure, terms such as "protecting group" or "PG" refer to a chemical moiety that prevents side reactions at a reactive portion of a molecule by protecting or masking that reactive portion of the molecule while operating on or reacting different portions of the molecule. After the operation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remainder of the molecule. The selection of an appropriate protecting group can be made by one of ordinary skill in the art. For example, as described in "Protective Groups in Organic Chemistry" McOmie, J.F.W. Ed., Plenum Press, 1973, Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999 and Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas), many conventional protecting groups are known in the art.

[0066] As used in the present disclosure, the term "enantiomerically pure" means one enantiomer of a compound that is substantially free of the opposite enantiomer of the compound.

[0067] As used in the present disclosure with respect to an enantiomerically pure compound, "substantially" should be construed to mean that the enantiomerically pure compound contains less than 1% of the opposite enantiomer of the compound.

[0068] The term "enantiomeric excess" or "ee" is the absolute difference between the mole fractions of each enantiomer in a racemic compound.

[0069] As used in the present disclosure, the term "pharmaceutical composition" refers to a composition of matter for pharmaceutical use.

[0070] The term "for pharmaceutical use" means being suitable for the treatment of a subject.

[0071] The term "pharmaceutically acceptable" means being suitable for the treatment of a subject.

[0072] The term "pharmaceutically acceptable salt" means an acid addition salt that is suitable for or compatible with the treatment of a subject.

[0073] An acid addition salt that is suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0074] As used in the present disclosure, the term "solvate" means a compound or a salt of a compound in which molecules of a suitable solvent are incorporated into the crystal lattice. The suitable solvent is physiologically tolerable at the dosage administered.

[0075] As used in the present disclosure, the term "administered" means administering the composition of the present application, or a compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof, to cells that may be in a cell culture or within a subject.

[0076] As used herein, "to treat," "treating," and "treatment," as well known in the art, mean a method for obtaining a beneficial or desired result such as a clinical outcome. Beneficial or desired clinical outcomes for a disease, disorder, or medical condition can include, but are not limited to, a decrease in degree, a stabilized (i.e., not worsening) state, prevention of spread, delay or slowing of progression, improvement or alleviation of the condition, and remission (partial or complete), and these can be detectable or undetectable. "To treat," "treating," and "treatment" may also mean an extended survival time compared to the expected survival time without treatment.

[0077] "Alleviating" a disease, disorder, or medical condition means that the degree and / or undesirable clinical findings of the disease, disorder, or medical condition are reduced and / or the time course of progression is slowed or lengthened compared to not treating the disease, disorder, or medical condition.

[0078] The terms "prevent" or "prevention," or synonyms thereof, as used in this disclosure, refer to a decrease in the risk or probability that a patient will suffer from a disease, disorder, or medical condition or exhibit symptoms associated with the disease, disorder, or medical condition.

[0079] The term "treating a disease, disorder, or condition treatable by activation of a serotonin receptor" as used in this disclosure means that the disease, disorder, or condition to be treated is affected, regulated, and / or has some biological basis involving serotonin activity, particularly an increase in serotonin activity, whether directly or indirectly, by serotonin activity. These diseases preferably respond when the serotonin activity associated with the disease, disorder, or condition is agonized by one or more of the compounds or compositions of the present application.

[0080] The term "activation" as used in this disclosure includes agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0081] The term "5-HT 2A " as used in this disclosure means the 5-HT 2A HT 2A receptor subtype of the 5-HT2 serotonin receptor.

[0082] The term "therapeutic agent" as used in this disclosure refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0083] The term "ON-time" as used in this disclosure means the duration of the anti-Parkinson's disease effect of L-DOPA.

[0084] For example, when used with respect to the treatment methods, uses, compositions, and / or kits of the present application, a subject, such as a "subject in need thereof", is a subject diagnosed with and / or treated for a disease, disorder, or condition treatable by activation of a serotonin receptor, such as 5-HT 2A ,.

[0085] As used in this disclosure, the term "enantiomer equivalent" refers to the molar amount of each enantiomer of the basic compound, namely the compound of formula (R)-I and the compound of formula (S)-I, regardless of whether the enantiomers are present as salts and / or solvates. Thus, the percentage of the enantiomer equivalent of each of (R)-I and (S)-I is defined by dividing the molar amount of (R)-I or (S)-I by the total molar amount of both (R)-I and (S)-I. The amount of the anion forming the salt and / or the solvating solvent is excluded and not taken into account in calculating the percentage of the enantiomer equivalent of each of (R)-I and (S)-I.

[0086] II. Compounds of the present application The applicant of the present application has investigated an analogue of MDMA, namely (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, and provides enantiomerically pure (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, as well as its compositions and uses.

[0087] This application encompasses an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof.

Chemical formula

[0088] In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof comprises about 99 wt% or more of the compound of formula (R)-I and about 1 wt% or less of the compound of formula (S)-I or a salt and / or solvate thereof.

Chemical formula

[0089] In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof comprises more than 99% by weight of the compound of formula (R)-I or a salt and / or solvate thereof and less than 1% by weight of the compound of formula (S)-I or a salt and / or solvate thereof. In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof comprises 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.91%, 99.92%, 99.93%, 99.94%, 99.95%, 99.96%, 99.97%, 99.98%, 99.9% or 100% by weight of the compound of formula (R)-I or a salt and / or solvate thereof and 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, 0.01% or less or 0% by weight of the compound of formula (S)-I or a salt and / or solvate thereof.

[0090] In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof has an enantiomeric excess (ee) of 98% or more. In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof has an enantiomeric excess (ee) of from 98% to 100%. In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof has an enantiomeric excess (ee) of 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.7%, 99.8%, 99.9% or about 100%.

[0091] In some embodiments, the enantiomerically pure compound of formula (R)-I is in the free base form. In some embodiments, the enantiomerically pure compound of formula (R)-I is in its acid salt form or solvate.

[0092] In certain embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by those skilled in the art (see, for example, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19).

[0093] Suitable or pharmaceutically acceptable acid addition salts for treating a subject are any non-toxic organic or inorganic acid addition salts of any basic compound. Examples of basic compounds that form acid addition salts include, for example, compounds containing an amine group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In certain embodiments, monoacid salts or diacid salts are formed, and such salts exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. Criteria for selecting suitable salts are known to those of ordinary skill in the art. Other non-pharmaceutically acceptable salts, such as but not limited to oxalates, may be used, for example, for experimental purposes or in the isolation of the compounds of the present application for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0094] In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof is an enantiomerically pure salt of the compound of formula (R)-I or a solvate thereof. Accordingly, the present application encompasses enantiomerically pure salts of the compound of formula (R)-I or a solvate thereof. In some embodiments, the enantiomerically pure salt of the compound of formula (R)-I is the HCl salt. Accordingly, in some embodiments, the present application encompasses the enantiomerically pure HCl salt of the compound of formula (R)-I or a solvate thereof.

[0095] In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof is provided as a solvate. Solvates of the compounds of the present application include, for example, those prepared using pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is referred to as a hydrate) and ethanol. Suitable solvents are physiologically tolerable at the dosage administered.

[0096] The compounds of the present application may further exist in various polymorphic or amorphous forms, and any polymorphic form or amorphous form or a mixture thereof is contemplated and encompassed within the scope of the present application.

[0097] In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof is crystalline. In some embodiments, the enantiomerically pure crystalline compound of formula (R)-I is an enantiomerically pure crystalline salt of the compound of formula (R)-I or a solvate thereof. In some embodiments, the enantiomerically pure crystalline salt of the compound of formula (R)-I is the enantiomerically pure crystalline HCl salt of the compound of formula (R)-I or a solvate thereof.

[0098] In some embodiments, the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof is amorphous.

[0099] In some embodiments, the enantiomeric excess of the enantiomers is determined using various analytical techniques known in the art, such as NMR spectroscopy, chiral column chromatography, or optical rotation measurement. In some embodiments, the enantiomeric excess of the enantiomers is determined using a polarimeter, using methods known in the art.

[0100] III. Compositions of the Present Application (i) A composition of an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof The enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof is suitably formulated into a composition in a conventional manner using one or more carriers. Accordingly, the present application also encompasses a composition comprising an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof and a carrier.

Chemical Formula

[0101] The enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof is suitably formulated into a pharmaceutical composition for administration to a subject in a biocompatible form suitable for in vivo administration. Accordingly, the present application further encompasses a pharmaceutical composition comprising an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier. In certain embodiments of the present application, the pharmaceutical composition is used for the treatment of any of the diseases, disorders, or conditions described in the present disclosure.

[0102] In some embodiments of the present application, a pharmaceutical composition comprising an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is used for the treatment of any of the diseases, disorders, or conditions described in the present disclosure.

[0103] (ii) A composition of a non-racemic mixture of the compounds of formula (R)-I and (S)-I of the present application This application further encompasses a composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof: [Chemical formula] The compound of formula (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount, expressed in enantiomeric equivalents, compared to (S)-I or a salt and / or solvate thereof.

[0104] In some embodiments, the composition comprises more than 50% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0105] In some embodiments, the composition comprises from 51% to 99% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from 1% to about 49% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents. In some embodiments, the composition comprises from 55% to 99%, about 60% to 99%, about 65% to 99%, about 70% to 99%, about 75% to 99%, about 80% to 99%, about 85% to 99%, about 90% to 99% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from 1% to 45%, 1% to about 40%, 1% to about 35%, 1% to about 30%, 1% to about 25%, 1% to about 20%, 1% to about 15%, or 1% to about 10% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents, respectively.

[0106] In some embodiments, the composition comprises from 51% to 99% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from 1% to 49% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0107] In some embodiments, the composition comprises from about 60% to 99% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 1% to about 40% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0108] In some embodiments, the composition comprises from about 60% to about 69.9% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 30.1% to about 40% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0109] In some embodiments, the composition comprises from about 70% to 99% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 1% to about 30% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0110] In some embodiments, the composition comprises from about 70% to about 79.9% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 20.1% to about 30% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0111] In some embodiments, the composition comprises from about 70% to about 75% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from 25% to about 30% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0112] In some embodiments, the composition comprises from about 75% to about 79.9% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 20.1% to about 25% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0113] In some embodiments, the composition comprises from about 75% to about 85% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 15% to about 25% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0114] In some embodiments, the composition comprises from about 80% to about 89.9% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 10.1% to about 20% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0115] In some embodiments, the composition comprises from about 80% to about 85% of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 15% to about 20% of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0116] In some embodiments, the composition comprises about 80% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and about 20% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0117] In some embodiments, the composition comprises from about 85% to about 89.9% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from about 10.1% to about 15% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0118] In some embodiments, the composition comprises from about 90% to 99% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and from 1% to about 10% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0119] In some embodiments, the composition comprises about 90% to 95% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and 5% to about 10% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0120] In some embodiments, the composition comprises 95 to 99% of the compound of formula (R)-I or a salt and / or solvate thereof in enantiomeric equivalents, and 1% to 5% of the compound of formula (S)-I or a salt and / or solvate thereof in enantiomeric equivalents.

[0121] In some embodiments, both the compound of formula (R)-I or a salt and / or solvate thereof and the compound of formula (S)-I or a salt and / or solvate thereof in the composition of the present application, which is a non-racemic mixture thereof, are in the free base form. In some embodiments, both the compound of formula (R)-I and the compound of formula (S)-I or a salt and / or solvate thereof are in the acid salt form or a solvate thereof.

[0122] In some embodiments, the enantiomeric excess of the enantiomers is determined using various analytical techniques known in the art, such as NMR spectroscopy, chiral column chromatography, or optical rotation measurement. In some embodiments, the enantiomeric excess of the enantiomers is determined using the optical rotation measured with a polarimeter using methods known in the art.

[0123] (iii) the composition of the present application In some embodiments, compounds of formula (R)-I and / or (S)-I, including enantiomerically pure compounds of formula (R)-I, are provided as salts. The selection of suitable salts may be made by those skilled in the art. Acids generally considered suitable for the formation of pharmaceutically acceptable salts from basic pharmaceutical compounds are, for example, discussed in P. Stahl et al, Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al, Journal of Pharmaceutical Sciences 1977 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0124] In some embodiments, acid addition salts suitable for or adapted to the treatment of a subject are any non-toxic organic or inorganic acid addition salts. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In some embodiments, the salts exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms.

[0125] Salts of the compounds of formula (R)-I or (S)-I, including the enantiomerically pure compound of formula (R)-I, may be formed by methods known to those skilled in the art, for example, including the enantiomerically pure compound of formula (R)-I, (R)-I or (S)-I may be reacted in a medium, for example, a medium in which the salt precipitates or an aqueous medium, with an amount of an acid, for example an equivalent amount of acid, followed by lyophilization.

[0126] In some embodiments, the compounds of formula (R)-I and / or (S)-I, including the enantiomerically pure compound of formula (R)-I, are provided as solvates. Examples of solvates include solvates prepared using pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is termed a hydrate) and ethanol. Suitable solvents are physiologically tolerable at the dosage administered.

[0127] Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an anti-solvent. Solvates are typically dried or azeotroped under ambient conditions. Selection of appropriate conditions for forming a particular solvate can be carried out by those skilled in the art.

[0128] The compounds of formula (R)-I and (S)-I, including the enantiomerically pure compound of formula (R)-I, or pharmaceutically acceptable salts and / or solvates thereof, may further exist in various polymorphic and amorphous forms, and any polymorphic or amorphous form or mixtures thereof are contemplated and encompassed within the scope of the present application. In some embodiments of the present application, the pharmaceutical compositions of the present application are used for the treatment of any of the diseases, disorders or conditions described in the present disclosure.

[0129] Compounds of formula (R)-I and (S)-I, including the enantiomerically pure compound of formula (R)-I, and / or their pharmaceutically acceptable salts and / or solvates are suitably formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Thus, in certain embodiments, the compositions of the present application are pharmaceutical compositions and further comprise one or more pharmaceutically acceptable carriers.

[0130] The pharmaceutical compositions of the present application are administered to a subject in various forms according to the selected route of administration, as will be understood by those skilled in the art. For example, the compositions of the present application are administered by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal administration, and the pharmaceutical compositions are formulated accordingly. In some embodiments, the administration is by pump for periodic or continuous delivery. Conventional procedures and components for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition), and The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0131] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period.

[0132] In some embodiments, the compositions of the present application may be administered orally, for example, together with an inert diluent or an absorbable edible carrier, or the compositions of the present application may be encapsulated in hard or soft shell gelatin capsules, or the compositions of the present application may be compressed into tablets, or may be directly incorporated with food in the diet. For oral therapeutic administration, the compositions may be incorporated with pharmaceutical excipients and may be used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gums, powders, syrups, elixirs, wafers, aqueous solutions or suspensions, and the like. In the case of tablets, carriers used include lactose, corn starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH-sensitive enteric coatings such as Eudragits (trademark), designed to control the release of the active ingredient, are optionally used. Oral formulations also include release-modulating formulations, for example, immediate-release formulations and timed release formulations.Examples of modified release formulations include, for example, sustained release (SR), extended-release (ER, XR or XL), time-release or timed-release, controlled release (CR), or continuous release (CR or Contin), and are used, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles (e.g., aggregated particles of molecular sieve-type particles), or fine hollow permeable fiber bundles, or in the form of chopped hollow permeable fiber groups that are aggregated or held in fibrous packets. Timed release compositions may be formulated, for example, within liposomes or in formulations where the composition is protected by a differentially degradable coating (e.g., by microencapsulation, multiple coating, etc.). Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholine. For oral administration in capsule form, useful carriers or diluents include lactose and dry corn starch.

[0133] In some embodiments, the liquid preparation for oral administration may take the form of, for example, a solution, syrup or suspension, or may be suitably presented as a dry product for reconstitution with water or other suitable vehicle before use. When orally administering an aqueous suspension and / or emulsion, the compositions of the present application are suitably suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. Optionally, certain sweeteners and / or flavoring agents and / or coloring agents may be added. In some embodiments, such liquid preparations for oral administration are prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or edible hard fat); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycol.

[0134] In some embodiments, the compositions of the present application are formulated as solid compositions or semi-solid compositions. In some embodiments, the compositions of the present application are formulated as tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gums, powders, syrups, elixirs, wafers, aqueous solutions or suspensions. In some embodiments, the compositions of the present application are formulated as tablets or capsules. In some embodiments, the compositions of the present application are formulated as tablets.

[0135] It is also possible to lyophilize the compositions of the present application and use the resulting lyophilizate, for example, in the preparation of injectable products.

[0136] In some embodiments, the compositions of the present application are administered parenterally. For example, a solution of the composition of the present application is prepared with water as a solvent, appropriately mixed with a surfactant such as hydroxypropylcellulose (in water). In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without alcohol), and in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms. Those skilled in the art know how to prepare appropriate formulations. For parenteral administration, a sterile solution of the composition of the present application is usually prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to make the preparation isotonic. For ocular administration, an ointment or a droppable liquid is delivered by an ocular delivery system known in the art, such as an applicator or an eye dropper. In some embodiments, such formulations include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzalkonium chloride, and a normal amount of diluent or carrier. For pulmonary administration, a diluent or carrier will be selected to be suitable for enabling the formation of an aerosol.

[0137] In some embodiments, the compositions of the present application are formulated for parenteral administration by injection, which also includes the use of conventional catheterization techniques or infusions. Injectable compositions are provided, for example, in unit dosage forms, such as in ampoules or in multiple-dose containers with preservatives. In some embodiments, the composition is formulated as a sterile suspension, solution or emulsion in an oily or aqueous vehicle and contains formulating agents such as suspending agents, stabilizers and / or dispersing agents. In any case, the form must be sterile and must be fluid enough to be easily injectable. Alternatively, the compositions of the present application are preferably in sterile powder form for reconstitution prior to use with a suitable vehicle, such as pyrogen-free sterile water.

[0138] In some embodiments, the compositions of the present application are for nasal administration.

[0139] Accordingly, in some embodiments, the present application also encompasses intranasal compositions comprising an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof, and a carrier. In some embodiments, the present application further encompasses intranasal pharmaceutical compositions comprising an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier.

[0140] In some embodiments, the present application is an intranasal composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof, wherein: The compound of formula (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount, expressed in enantiomeric equivalents, compared to (S)-I or a salt and / or solvate thereof, further encompassing the intranasal composition.

[0141] In some embodiments, the enantiomeric excess is as described under the section "Compositions of Non-Racemic Mixtures of the Compounds of Formula (R)-I and (S)-I of the Present Application".

[0142] In certain embodiments of the present application, the nasal composition is used for the treatment of any of the diseases, disorders or conditions described in the present disclosure.

[0143] In some embodiments, the composition for nasal administration is conveniently formulated as an aerosol, drops, gel, and powder. For nasal administration or administration by inhalation, the compositions of the present application are in the form of a solution, dry powder formulation, or suspension from a pump spray container that is constricted or pumped by the subject, or in the form of an aerosol spray from a pressurized container or nebulizer, and are conveniently delivered. The aerosol composition typically comprises a solution or fine suspension of the composition of the present application in a physiologically acceptable aqueous or non-aqueous solvent, and is usually provided in a sterile form as a single-dose or multi-dose in a sealed container, which takes the form of, for example, a cartridge or refill for use with a nebulizing device. Alternatively, the sealed container is a unit dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve intended to be discarded after use. When the dosage form includes an aerosol dispenser, it will contain a propellant, which is, for example, a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoralkane, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit is appropriately determined by providing a valve that delivers a measured amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the composition of the present application. Capsules and cartridges (e.g., made of gelatin) for use in inhalers or injectors are formulated, for example, to contain a powder mixture of the composition of the present application and a suitable powder base such as lactose or starch. The aerosol dosage form can also take the form of a pump atomizer.

[0144] In some embodiments, the intranasal pharmaceutical composition is formulated as an aerosol for use with a pump atomizer.

[0145] In some embodiments, the intranasal pharmaceutical composition is a powder. In some embodiments, the intranasal pharmaceutical composition is a dry powder. In some embodiments, the dry powder is formulated to be reconstituted with a suitable vehicle prior to use or administration. In some embodiments, the suitable vehicle is sterile water free of pyrogens.

[0146] In some embodiments, the powder is formulated for use or administration using an inhaler or injector. Thus, in some embodiments, the dry powder is formulated for use or administration as a capsule and cartridge for use with an inhaler or injector.

[0147] In some embodiments, the dry powder further comprises a suitable powder base. In some embodiments, the suitable powder base comprises lactose or starch.

[0148] In some embodiments, the intranasal pharmaceutical composition further comprises water. Thus, in some embodiments, the intranasal pharmaceutical composition further comprises water and is an aqueous intranasal pharmaceutical composition.

[0149] In some embodiments, the intranasal pharmaceutical composition is a solution, suspension or emulsion. In some embodiments, the intranasal pharmaceutical composition is a solution.

[0150] In some embodiments, the aqueous intranasal pharmaceutical composition is formulated for administration to the nose in the form of drops. In some embodiments, the aqueous intranasal pharmaceutical composition is formulated for administration as a nasal spray. In some embodiments, the nasal spray is delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or in the form of an aerosol spray from a pressurized container or nebulizer. In some embodiments, the aqueous intranasal pharmaceutical composition is formulated as an aerosol for use with a pump atomizer.

[0151] In some embodiments, water is present in an amount of about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 33% to about 75%, about 55% to about 70%, or about 55% to about 65% by weight of the composition. In some embodiments, water is present in an amount of about 50%, about 60%, about 65% or about 70% by weight of the composition. In some embodiments, water is present in an amount of about 55% to about 65% by weight of the composition. In some embodiments, water is about 60% by weight of the composition.

[0152] Compositions suitable for buccal or sublingual administration include tablets, lozenges and troches, and the compositions of the present application are formulated with carriers such as sugars, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0153] In some embodiments, the compositions of the present application are for sublingual administration.

[0154] Accordingly, in some embodiments, the present application also encompasses a sublingual composition comprising an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof and a carrier. In some embodiments, the present application further encompasses a sublingual pharmaceutical composition comprising an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier.

[0155] In some embodiments, the present application is a sublingual composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof, wherein: The compound of formula (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount, expressed in enantiomeric equivalents, compared to (S)-I or a salt and / or solvate thereof, and further encompasses the sublingual composition.

[0156] In some embodiments, the enantiomeric excess is as described under the section "Compositions of Non-Racemic Mixtures of the Compounds of Formula (R)-I and (S)-I of the Present Application".

[0157] In some embodiments, the sublingual dosage form is formulated as a tablet, a drop, strips, a spray, a lozenge, or an effervescent tablet.

[0158] In certain embodiments of the present application, the sublingual composition is used for the treatment of any of the diseases, disorders, or medical conditions described in this disclosure.

[0159] In some embodiments, the intranasal composition and / or the sublingual composition provide a more rapid onset of activity, exhibit reduced neurotoxicity, and / or exhibit reduced cardiotoxicity compared to an oral composition. In some embodiments, the required dosage of the compound of formula (R)-I, or the dosage of the non-racemic combination of the compound of formula (R)-I and the compound of formula (S)-I, in the intranasal composition and / or the sublingual composition is lower than the dosage of the compound of formula (R)-I, or the dosage of the non-racemic combination of the compound of formula (R)-I and the compound of formula (S)-I, in the oral composition to achieve the same beneficial effect.

[0160] The suppository form of the compositions of the present application is useful for administration into the vagina, urethra, and rectum. Such suppositories are generally constructed from a mixture of substances that are solid at room temperature but melt at body temperature. Substances commonly used to make such vehicles include, but are not limited to, cocoa butter (also known as cocoa butter), glycerinated gelatin, other glycerides, vegetable hard fats, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For example, for further description of suppository dosage forms, see Remington’s Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0161] In some embodiments, the composition of the present application contains from about 40 mg to about 180 mg of the compound of formula (R)-I, or both the compounds of formula (R)-I and (S)-I, and / or its salts and / or solvates. In some embodiments, the composition of the present application contains 40 mg, 60 mg, 75 mg, 80 mg, 100 mg, 120 mg or 125 mg of the compound of formula (R)-I, or both the compounds of formula (R)-I and (S)-I, and / or its salts and / or solvates. In some embodiments, depending on the mode of administration, the composition of the present application contains from about 0.05 wt% to about 99 wt%, or from about 0.10 wt% to about 70 wt% of the compound of formula (R)-I, or both the compounds of formula (R)-I and (S)-I, and / or its pharmaceutically acceptable salts and / or solvates, and from about 1 wt% to about 99.95 wt%, or from about 30 wt% to about 99.90 wt% of one or more pharmaceutically acceptable carriers, where the weight percentages are all values relative to the whole composition.

[0162] In some embodiments, the enantiomerically pure compound of formula (R)-I and / or its salts and / or solvates, or both the compounds of formula (R)-I and (S)-I and / or its salts and / or solvates are present in the composition in an effective amount, for example, in an effective amount for treating or preventing a disease, disorder or condition treatable by activation of a serotonin receptor (especially 5-HT 2A ).

[0163] In some embodiments, the composition of the present application is a pharmaceutical composition containing an additional therapeutic agent and optionally one or more pharmaceutically acceptable carriers. In some embodiments, the additional therapeutic agent is a known drug useful for treating a disease, disorder or condition for which treatment with racemic MDMA and / or its pharmaceutically acceptable salts and / or solvates is beneficial, or for which treatment with psychotherapy combined with racemic MDMA and / or its pharmaceutically acceptable salts and / or solvates is beneficial.

[0164] IV. Methods and Uses of the Present Application (i) Method and use of (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine Using homology modeling, 5-HT 1B / 5-HT 2B / 5-HT 2C Based on the existing crystal structure data of, three-dimensional models of all 5-hydroxytryptamine (5-HT) receptor subtypes have been constructed and validated, and the residues contributing to the selectivity of each receptor have been identified (Wang, Y-q et al. Acta Pharmacologica Sinica (2019) 40:1138-1156). Using such models, the Applicants conducted molecular docking tests using the (R) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (compound of formula (R)-I). The Applicants have shown that the (R) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine binds to the 5-hydroxytryptamine 2B receptor (5-HT 2B ) and the 5-hydroxytryptamine 2A receptor (5-HT 2A ) with lower and more balanced affinity compared to its opposite enantiomer, where the opposite enantiomer has a higher affinity for the 5-hydroxytryptamine 2B receptor (5-HT 2B ).

[0165] 5-HT 2B has been shown to be involved in the mediating toxicity associated with racemic MDMA, such as cardiotoxicity, such as valvular heart disease (Setola V et al. Molecular Pharmacology, 63, 1223-1229, 2003, Huot et al. Journal of Neuroscience, 2011, 31(19)7190-7198). However, the therapeutic activity involves binding to both 5-HT 2B and 5-HT 2A . Therefore, compounds with a more balanced affinity between 5-HT 2B and 5-HT 2A would be advantageous.

[0166] Thus, the (R) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine is expected to have an improved toxicity profile compared to its racemate (i.e., the compound of formula (R / S)-I), while maintaining the therapeutic effect of the racemate.

[0167] Indeed, the Applicant conducted tests on C57 mice, which are a general population mouse model, and BTBR mice, which are a mouse model of autism spectrum disorder. In tests of deep body temperature and spontaneous locomotor activity in both C57 mice and BTBR mice, the (R) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (the compound of formula (R)-I) did not cause a dose-dependent increase in deep body temperature in any of the mouse models, unlike MDMA. An increase in body temperature, i.e., hyperthermia, is known to cause cell damage and neurotoxicity (Walter and Carraretto, Crit Care. 2016 Jul 14;20(1):199). Furthermore, the compound of formula (R)-I showed a dose-dependent hypothermic effect, but no decrease in deep body temperature was observed at a dose of about 5.6 mg / kg (R)-I in any of the mouse strains. In contrast, the (S) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (the compound of formula (S)-I) was found to induce a significant decrease in body temperature at a low dose of about 5.6 mg / kg. Thus, the Applicant demonstrated that at a dose of about 5.6 mg / kg, (R)-I did not cause an increase or decrease in deep body temperature in the test mouse strains.

[0168] These tests further showed that neither (R)-I nor (S)-I caused a significant dose-dependent stimulatory effect on spontaneous locomotion.

[0169] In the cardiovascular toxicity test, the compound of formula (R)-I was shown to have a significantly lower impact on cardiovascular effects compared to the compound of formula (S)-I, MDMA, and S-methamphetamine when measured by systolic pressure, diastolic pressure, and mean arterial pressure in both C57 and BTBR mouse models. This is consistent with the above-mentioned predictive docking test and further predictive IC 50 tests conducted by the applicant, whereby it was shown that (S)-I binds more strongly to the 5-HT 2B receptor than (R)-I.

[0170] In the social interaction test, (R)-I was shown to induce similar prosocial responses at lower doses compared to MDMA in both C57 and BRTB mouse models, suggesting that (R)-I is a more potent drug than MDMA with respect to prosocial responses. Furthermore, (R)-I was shown to exhibit social preference without an accompanying locomotor stimulant effect in both C57 and BRTB mouse models.

[0171] Accordingly, the applicant has shown that in the mouse strains tested, (R)-I exhibits equivalent social preference to MDMA at lower doses and, advantageously, is accompanied by a reduction in adverse effects (as shown in the deep body temperature, locomotor activity, and cardiovascular tests), particularly at doses up to about 5.6 mg / kg.

[0172] The compound of formula (R)-I is useful for treating a disease, disorder, or condition treatable by activating serotonin receptors such as 5-HT 2A . Therefore, the compounds of the present application are useful as medicaments. Accordingly, the present application also encompasses the compounds of the present application for use as medicaments.

[0173] Accordingly, the present application encompasses a method for treating a disease, disorder or medical condition treatable by activation of a serotonin receptor, which comprises administering to a subject in need thereof an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0174] The present application also encompasses the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for the treatment of a disease, disorder or medical condition treatable by activation of a serotonin receptor, and the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for the treatment of a disease, disorder or medical condition treatable by activation of a serotonin receptor. The present application further encompasses an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof of the present application for use in treating a disease, disorder or medical condition treatable by activation of a serotonin receptor.

[0175] In some embodiments, the serotonin receptor is 5-HT 2A . Accordingly, the present application encompasses a method for activating the 5-hydroxytryptamine 2A receptor (5-HT 2A ) in a cell, which may be in a biological sample or in a patient, which method comprises administering to the cell an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof. The present application also encompasses an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof for activating 5-HT 2A in a cell, and the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for activating 5-HT 2A in a cell. The present application further encompasses an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof of the present application for use in activating 5-HT 2A in a cell.

[0176] This application also relates to a method of treating a disease, disorder or medical condition treatable by activation of 5-HT 2A which comprises administering to a subject in need thereof an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof. This application also relates to the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for the treatment of a disease, disorder or medical condition treatable by activation of 5-HT 2A and to the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for the treatment of a disease, disorder or medical condition treatable by activation of 5-HT 2A This application further relates to an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof for use in treating a disease, disorder or medical condition treatable by activation of 5-HT 2A

[0177] In some embodiments, treatment with an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof results in a lower risk of adverse side effects compared to treatment with the racemate 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (i.e., the compound of formula (R / S)-I), or treatment with an enantiomerically pure compound of formula (S)-I.

[0178] In some embodiments, treatment with an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof results in a lower risk of adverse side effects compared to treatment with the racemate 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (i.e., the compound of formula (R / S)-I).

[0179] ​In some embodiments, treatment with an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof has a reduced risk of adverse side effects compared to treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA).

[0180] In some embodiments, the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, hypothermia, cardiotoxicity, and substance use disorder. In some embodiments, the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, and substance use disorder. In some embodiments, the substance use disorder is drug abuse or drug dependence. In some embodiments, the substance use disorder is drug abuse of racemic MDMA. In some embodiments, the adverse side effect is neurotoxicity.

[0181] In some embodiments, the adverse side effects are hyperthermia or hypothermia. In some embodiments, the adverse side effect is hyperthermia. In some embodiments, the adverse side effect is hypothermia.

[0182] Some reports suggest that long-term use of MDMA may result in fibroproliferation and dysfunction of the heart valves, such as valvular heart disease (VHD) (Setola et al. Mol. Pharmacol. 63:1223-1229, 2003). Thus, in some embodiments, the adverse side effect is cardiotoxicity. In some embodiments, the cardiotoxicity is fibroproliferation and dysfunction of the heart valves. In some embodiments, the cardiotoxicity is valvular heart disease. Thus, in some embodiments, the adverse side effect is valvular heart disease. In some embodiments, the cardiotoxicity is tachycardia or tremor.

[0183] In some embodiments, the reduced risk of adverse side effects is due to the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof having a lower affinity for the 5-hydroxytryptamine 2B receptor (5-HT 2A ) compared to the compound of formula (R / S)-I or a salt and / or solvate thereof, or compared to the enantiomerically pure compound of formula (S)-I or a salt and / or solvate thereof, by binding to the 5-hydroxytryptamine 2B receptor (5-HT 2B ).

[0184] In some embodiments, the reduced risk of adverse side effects is due to the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof providing a more balanced binding between the 5-hydroxytryptamine 2B (5-HT 2B ) receptor and the 5-hydroxytryptamine 2A (5-HT 2A ) receptor compared to the compound of formula (R / S)-I or a salt and / or solvate thereof, or compared to the enantiomerically pure compound of formula (S)-I or a salt and / or solvate thereof.

[0185] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are those diseases, disorders or conditions in which treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof is beneficial.

[0186] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are those diseases, disorders or conditions in which treatment with racemic MBDB or a pharmaceutically acceptable salt and / or solvate thereof is beneficial.

[0187] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are those for which treatment with racemic MDMA is beneficial, and the method has a reduced risk of adverse side effects compared to treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA).

[0188] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are any diseases, disorders or conditions for which psychotherapy is beneficial, including but not limited to one or more of post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction and eating disorders.

[0189] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered or used in combination with psychotherapy for treating said diseases, disorders or conditions. In some embodiments, the compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the effectiveness of psychotherapy. In some embodiments, the psychotherapy is directed to mental disorders.

[0190] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are one or more mental disorders. In some embodiments, the one or more mental disorders are selected from one or more of anxiety disorders, mood disorders, developmental disorders, substance use disorders and addictions, eating disorders, personality disorders, and psychotic disorders. In some embodiments, the substance use disorder is drug abuse or drug dependence.

[0191] In some embodiments, the anxiety disorder is selected from one or more of obsessive-compulsive disorder (OCD), social anxiety disorder, phobia, panic disorder and post-traumatic stress disorder (PTSD). In some embodiments, the anxiety disorder is social anxiety disorder. In some embodiments, the anxiety disorder is PTSD.

[0192] In some embodiments, the mood disorder is selected from one or both of depression and bipolar disorder.

[0193] In some embodiments, the developmental disorder is selected from one or both of autism spectrum disorder (ASD) and Asperger's syndrome.

[0194] In some embodiments, the substance use disorder and addiction are selected from one or more of alcohol dependence, drug abuse, drug dependence, and compulsive gambling. In some embodiments, the drug dependence is opioid dependence. In some embodiments, the substance use disorder is opioid use disorder.

[0195] In some embodiments, the eating disorder is selected from anorexia and bulimia.

[0196] In some embodiments, the personality disorder is selected from borderline personality disorder and dependent personality disorder.

[0197] In some embodiments, the psychotic disorder is selected from schizophrenia and other disorders that cause detachment from reality.

[0198] In some embodiments, one or more mental disorders are selected from one or more of autism spectrum disorder (ASD), depression, and drug dependence. In some embodiments, the depression is clinical depression, such as clinical depression in a palliative care setting.

[0199] In some embodiments, one or more mental disorders are selected from post-traumatic stress disorder (PTSD), eating disorder, and alcohol dependence. In some embodiments, one or more mental disorders are post-traumatic stress disorder (PTSD).

[0200] In some embodiments, one or more mental disorders are selected from autism spectrum disorder (ASD), depression, and substance dependence. In some embodiments, the depression is clinical depression, such as clinical depression in a palliative care setting. In some embodiments, the substance use disorder is opioid use disorder.

[0201] In some embodiments, a disease, disorder, or condition treatable by activation of a serotonin receptor is autism spectrum disorder.

[0202] In some embodiments, the autism spectrum disorder is selected from autism, Asperger's syndrome, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified.

[0203] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered before, during, and / or after psychotherapy. In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered during and / or after psychotherapy.

[0204] In some embodiments, the psychotherapy is selected from behavioral psychotherapy, exposure-based psychotherapy, cognitive psychotherapy, and psychodynamic-oriented psychotherapy.

[0205] In some embodiments, a disease, disorder, or condition treatable by activation of a serotonin receptor is any disease, disorder, or condition in which treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is beneficial.

[0206] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered or used in combination with L-DOPA for treating a disease, disorder or condition for which treatment with L-DOPA is beneficial. In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of L-DOPA. In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered or used in combination with L-DOPA to improve the efficacy of L-DOPA.

[0207] In some embodiments, the disease, disorder or condition for which treatment with L-DOPA is beneficial is Parkinson's disease.

[0208] The present application also encompasses a method of treating Parkinson's disease, the method comprising administering to a subject in need thereof an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0209] The present application further encompasses the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for treating Parkinson's disease, the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating Parkinson's disease, and an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for use in treating Parkinson's disease.

[0210] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered or used in combination with L-DOPA for treating Parkinson's disease. In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of L-DOPA for treating Parkinson's disease. In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered or used in combination with L-DOPA to improve the efficacy of L-DOPA for treating Parkinson's disease.

[0211] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of L-DOPA by reducing L-DOPA-induced dyskinesia.

[0212] Thus, in some embodiments, the disease, disorder or condition for which treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof is beneficial is dyskinesia. In some embodiments, the dyskinesia is L-DOPA-induced dyskinesia.

[0213] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of L-DOPA by increasing the duration of the anti-Parkinson's disease effect of L-DOPA (e.g., the on-time). In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of L-DOPA by increasing the duration of the anti-Parkinson's disease effect of L-DOPA without disabling dyskinesia.

[0214] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of L-DOPA by reducing L-DOPA-induced Parkinson's disease psychosis.

[0215] Accordingly, in some embodiments, the disease, disorder or condition for which treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof is beneficial is L-DOPA-induced Parkinson's disease psychosis.

[0216] "Reducing L-DOPA-induced dyskinesia" or "reducing L-DOPA-induced Parkinson's disease psychosis" means any decrease in the degree of dyskinesia, a stabilized (i.e., non-worsening) state of dyskinesia, a delay or slowing in the progression of dyskinesia, an improvement or alleviation of dyskinesia, and a remission (partial or complete) of dyskinesia in the presence of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof as compared to the same conditions except for the absence of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof, and these may be detectable or undetectable.

[0217] "Increasing the duration of the anti-Parkinson's disease effect of L-DOPA" means any increase in the duration of the anti-Parkinson's disease effect of L-DOPA as compared to the same conditions except for the absence of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0218] "Increasing the duration of the anti-Parkinson's disease effect of L-DOPA without causing dyskinesia that causes impairment" means an increase in the duration of the anti-Parkinson's disease effect of L-DOPA without causing dyskinesia that causes impairment compared to the same conditions except for the absence of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0219] Methods for the evaluation of L-DOPA-induced dyskinesia and / or psychosis are well known in the art to those skilled in the art, such as those found in, for example, Fox et al. 2006 Arch Neurol 63:1343-1344; Gomez-Ramirez et al. 2006, Mov Disord 21:839-846; Visanji et al. 2006, Mov Disord 21:1879-1891; Huot et al. Journal of Neuroscience, 2011, 31(19)7190-7198 and Fox et al. 2010 Can J Neurol Sci 37:86-95).

[0220] The applicant has shown that the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof promotes prosocial behavior in vivo in both C57 mice (a general population mouse model) and BRTB mice (a mouse model of autism spectrum disorder). (R)-I has also been shown to induce prosocial effects at lower doses compared to MDMA. The enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof has further been shown not to affect spontaneous locomotor activity in both the C57 mouse model and the BRTB mouse model. The applicant has further shown that the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof does not cause a significant effect on core temperature. Furthermore, the applicant has shown that the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof has less impact on cardiovascular events compared to the compound of formula (S)-I, (racemic) MDMA, and methamphetamine.

[0221] Accordingly, the present application also encompasses a method of treating one or more signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor, the method comprising administering to a subject in need thereof an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0222] The present application relates to the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for treating one or more signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor, the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating one or more signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor, and further encompasses an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for use in treating one or more signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor.

[0223] In some embodiments, at least one sign or symptom of a disease, disorder or medical condition treatable by activation of a serotonin receptor is reduced upon administration of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0224] Accordingly, in some embodiments, the methods and uses provided herein reduce at least one sign or symptom of a disease, disorder or medical condition treatable by activation of a serotonin receptor. In some embodiments, the methods and uses provided herein reduce at least one sign or symptom of a disease, disorder or medical condition treatable by activation of a serotonin receptor by about 5% to about 100%, such as about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100% or more compared to a treatment without using an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0225] In some embodiments, the signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor are reduced or disappear in a subject within about 1 hour, within about 2 hours, within about 3 hours, within about 6 hours, within about 12 hours, within about 24 hours, within about 48 hours, within about 3 days, within about 1 week, within about 2 weeks, within about 3 weeks, within about 4 weeks, within about 5 weeks, within about 6 weeks, within about 7 weeks, within about 8 weeks, or within about 3 months after administration of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0226] In some embodiments, the signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor are reduced or disappear in a subject over a period of about 1 day, about 3 days, about 7 days, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months or about 48 months after administration of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0227] "Reducing at least one sign or symptom of a disease, disorder or medical condition treatable by activation of a serotonin receptor" means some reduction or diminution of the signs or symptoms of the disease, disorder or medical condition compared to the same conditions except for the absence of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0228] In some embodiments, the signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor are neurotoxicity, hyperthermia, hypothermia, cardiotoxicity and substance use disorder.

[0229] In some embodiments, the disease, disorder or condition treatable by activation of a serotonin receptor is autism spectrum disorder, and the present application also provides a method for treating one or more signs or symptoms of autism spectrum disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0230] The present application further encompasses the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for treating one or more signs or symptoms of autism spectrum disorder, the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating one or more signs or symptoms of autism spectrum disorder, and the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for use in treating one or more signs or symptoms of autism spectrum disorder.

[0231] In some embodiments, one or more signs or symptoms of autism spectrum disorder are selected from general anxiety, clinical anxiety, irritability, inappropriate speech, echolalia, social withdrawal, repetitive behaviors, and hyperactivity.

[0232] In some embodiments, one or more signs or symptoms of autism spectrum disorder are selected from echolalia and social withdrawal. In some embodiments, one or more signs or symptoms of autism spectrum disorder are echolalia. In some embodiments, one or more signs or symptoms of autism spectrum disorder are social withdrawal. Thus, in some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is for use in promoting prosocial activity.

[0233] This application further encompasses treating one or more symptoms of autism spectrum disorder while reducing the harmful side effects of treatment with racemic MDMA or (R / S)-I, including administering or using to a subject in need thereof an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0234] In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the harmful side effects are selected from hyperthermia, stereotypies, and neurotoxicity. In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the harmful side effects are selected from hyperthermia and neurotoxicity. In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the harmful side effects are selected from hyperthermia.

[0235] In some embodiments, the autism spectrum disorder is as defined by DSM-IV, and one or more symptoms are selected from (i) qualitative impairment in social interaction; (ii) qualitative impairment in communication; and (iii) restricted, repetitive, and stereotyped patterns of behavior, interests, and activities.

[0236] In some embodiments, one or more symptoms are selected from qualitative impairment in social interaction.

[0237] In some embodiments, the qualitative impairment in social interaction includes one or more of marked impairment in the use of multiple non-verbal behaviors, including eye contact, facial expressions, body postures, and gestures, to regulate social interaction; the inability to form friendships appropriate to developmental level; the lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by the lack of showing, bringing, or pointing out things of interest); and the lack of social or emotional reciprocity.

[0238] In some embodiments, qualitative impairments in communication include one or more of: a delay or complete absence of spoken language development (without attempts to compensate through alternative communication modalities such as gestures or signs); a marked impairment in the ability to initiate or sustain a conversation with others in an individual who otherwise speaks appropriately; the stereotyped and repetitive use of language or idiosyncratic phrases; and the absence of diverse and spontaneous pretend play or social imitative play commensurate with the developmental level.

[0239] In some embodiments, restricted, repetitive, and stereotyped patterns of behavior, interests, and activities include one or more of: an intense and exclusive preoccupation with one or more stereotyped and restricted interest patterns, where either the intensity or focus is abnormal; an apparently inflexible adherence to specific non-functional routines or rituals; stereotyped and repetitive motor mannerisms (e.g., flapping or twisting of hands or fingers, or complex whole-body movements); and a persistent preoccupation with parts of objects.

[0240] In some embodiments, a disease, disorder, or medical condition treatable by activation of a serotonin receptor is an anxiety disorder, and the present application also encompasses a method of treating one or more symptoms or signs of an anxiety disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of an enantiomerically pure form of a compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0241] This application further encompasses the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for treating one or more signs or symptoms of an anxiety disorder, the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating one or more signs or symptoms of an anxiety disorder, and the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for treating one or more signs or symptoms of an anxiety disorder.

[0242] In some embodiments, one or more signs or symptoms of an anxiety disorder are measured according to diary evaluations, evaluations by a clinician or caregiver, or clinical scales.

[0243] In some embodiments, one or more signs or symptoms of an anxiety disorder are fears including fear of social interaction or context, avoidance of anxiety triggers, feeling stressed, being easily agitated, catastrophizing, being nervous, having a rapid heartbeat, palpitations of the heart, trembling, fatigue, worry, irritability, obsessions, compulsions, muscle tension, sweating, dizziness, shortness of breath, sleep disruption, or combinations thereof.

[0244] Accordingly, in some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is for use in promoting prosocial activity in a subject having an anxiety disorder.

[0245] In some embodiments, the anxiety disorder is selected from one or more of obsessive-compulsive disorder (OCD), social anxiety disorder, phobia, panic disorder, and post-traumatic stress disorder (PTSD) as described above. In some embodiments, the anxiety disorder is social anxiety disorder.

[0246] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered or used as a second agent or an "add-on" therapy.

[0247] In some embodiments, the enantiomerically pure compound of formula (R)-I comprises more than 99% by weight of the compound of formula (R)-I and less than 1% by weight of the compound of formula (S)-I. In some embodiments, the enantiomerically pure compound of formula (R)-I comprises 99.1% by weight, 99.2% by weight, 99.3% by weight, 99.4% by weight, 99.5% by weight, 99.6% by weight, 99.7% by weight, 99.8% by weight, 99.9% by weight, 99.91% by weight, 99.92% by weight, 99.93% by weight, 99.94% by weight, 99.95% by weight, 99.96% by weight, 99.97% by weight, 99.98% by weight, 99.9% by weight or 100% by weight of the compound of formula (R)-I and, respectively, 0.9% by weight or less, 0.8% by weight or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, 0.1% by weight or less, 0.09% by weight or less, 0.08% by weight or less, 0.07% by weight or less, 0.06% by weight or less, 0.05% by weight or less, 0.04% by weight or less, 0.03% by weight or less, 0.02% by weight or less, 0.01% by weight or less or 0% by weight of the compound of formula (S)-I.

[0248] In some embodiments, the enantiomerically pure compound of formula (R)-I has an enantiomeric excess (ee) of 98% or more. In some embodiments, the enantiomerically pure compound of formula (R)-I has an enantiomeric excess (ee) of from 98% to 100%. In some embodiments, the enantiomerically pure compound of formula (R)-I has an enantiomeric excess (ee) of 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.7%, 99.8%, 99.9% or about 100%.

[0249] In some embodiments, the enantiomeric purity of the compound is determined by its optical rotation.

[0250] In some embodiments, an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof, when administered to a subject, is used or administered in an amount sufficient to provide beneficial or desired results, including clinical outcomes, and thus the amount depends on the circumstances in which it is applied. Accordingly, the amount administered or used is an amount of the compound sufficient to treat, prevent or inhibit a disease or medical condition. In some embodiments, the amount of the compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof administered will vary depending on factors such as the pharmaceutical formulation, route of administration, medical condition, type of disease or disorder, the identity of the subject being treated, etc., but can be determined routinely by one of ordinary skill in the art. In certain embodiments, the amount administered or used is an amount that results in an improvement or reduction of the symptoms of any disease, disorder or medical condition, particularly as compared to the symptoms of the disease, disorder or medical condition that is not being treated, as manifested after treatment therewith.

[0251] In certain embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutically acceptable salt and / or solvate thereof, is administered at least once a week. However, in another embodiment, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject approximately once every two weeks, three weeks, or one month. In another embodiment, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered from approximately once a week to approximately once a day. In another embodiment, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered 2, 3, 4, 5, or 6 times a day. The length of the treatment period depends on various factors such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or activity of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof, and / or combinations thereof. It is understood that the effective dosage of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof used in the treatment may increase or decrease during the course of a particular treatment regimen. Changes in dosage may occur and become apparent by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject in an amount and for a period sufficient to treat the subject.

[0252] In certain embodiments, the subject is a mammal. In another embodiment, the subject is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a dog. In certain embodiments, the subject is a cat. Accordingly, the methods and uses of the present application are directed to diseases, disorders and conditions in both human and veterinary medicine.

[0253] The enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is used alone or in combination with other known agents useful for treating a disease, disorder or condition treatable by activation of a serotonin receptor.

[0254] In some embodiments, when used in combination with other agents useful for treating a disease, disorder or condition treatable by activation of a serotonin receptor, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered simultaneously with those agents, which is one embodiment. As used in this disclosure, "simultaneous administration" of two substances to a subject means administering each of the two substances such that both substances are active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two substances in the presence of each other and may include administering the two substances within a few hours of each other if the pharmacokinetics are suitable, and may even include administering one substance within 24 hours of the other administration. Designing an appropriate dosing regimen is routine for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within a few minutes of each other, or in a single composition containing both substances. Administering the combination of agents to the subject in a non-simultaneous manner is a further embodiment of the present application.

[0255] The dosage of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof varies depending on many factors such as the pharmacodynamic properties of the compound in the subject being treated, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of treatment, and the type, if any, of co-treatment, as well as the clearance rate of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof. Those skilled in the art can determine an appropriate dosage based on the above factors.

[0256] As a representative example, the oral dosage of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is about 1 mg to about 50 mg per day for an adult, preferably about 1 mg to about 40 mg per day, more preferably about 2 mg to about 30 mg per day. In some embodiments, the weight of the subject is 55 kg to 65 kg, preferably 60 kg. For oral administration, representative amounts are about 0.01 mg / kg to about 1 mg / kg, about 0.05 mg / kg to about 1 mg / kg, about 0.05 mg / kg to about 0.75 mg / kg, or about 0.05 mg / kg to about 0.5 mg / kg.

[0257] In some embodiments of the present application, the pharmaceutical composition of the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof of the present application is used for the treatment of any of the diseases, disorders or conditions described in the present disclosure as described below.

[0258] (ii) Methods and uses of the compositions of the present application In some embodiments, the compositions of the present application, including pharmaceutical compositions, are useful for treating diseases, disorders or conditions treatable by activating serotonin receptors such as 5-HT 2A and the like.

[0259] Accordingly, the present application encompasses the above method, which is a method for treating a disease, disorder or condition treatable by activating a serotonin receptor, comprising administering a therapeutically effective amount of the composition of the present application to a subject in need thereof.

[0260] The present application also encompasses the use of the composition of the present application for the treatment of a disease, disorder or condition treatable by activating a serotonin receptor, and the use of the composition of the present application for the preparation of a medicament for the treatment of a disease, disorder or condition treatable by activating a serotonin receptor. The present application further encompasses the composition of the present application for use in treating a disease, disorder or condition treatable by activating a serotonin receptor.

[0261] In some embodiments, the serotonin receptor is 5-HT 2A . Accordingly, the present application encompasses methods of activating the 5-hydroxytryptamine 2A receptor (5-HT 2A ) in cells, which may be in a biological sample or in a patient, the method comprising administering to a subject in need thereof one or more compositions of the present application.

[0262] The present application also encompasses the use of one or more compositions of the present application for activating 5-HT 2A in cells, and the use of one or more compositions of the present application for the preparation of a medicament for activating 5-HT 2A in cells. The present application further encompasses one or more compositions of the present application for use in activating 5-HT 2A in cells.

[0263] The present application also encompasses methods of treating a disease, disorder or condition treatable by activation of 5-HT 2A , the method comprising administering to a subject in need thereof a composition of the present application. The present application also encompasses the use of a composition of the present application for the treatment of a disease, disorder or condition treatable by activation of 5-HT 2A , and the use of a composition of the present application for the preparation of a medicament for the treatment of a disease, disorder or condition treatable by activation of 5-HT 2A . The present application further encompasses a composition of the present application for use in treating a disease, disorder or condition treatable by activation of 5-HT 2A .

[0264] In some embodiments, the disease, disorder or condition treatable by activation of 5-HT 2A is any disease, disorder or condition for which treatment with racemic MDMA is beneficial.

[0265] In some embodiments, treatment with a composition of the present application has a reduced risk of adverse side effects compared to treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA).

[0266] In some embodiments, the treatment with the compositions of the present application has a reduced risk of adverse side effects compared to the treatment with racemic 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (i.e., the compound of formula (R / S)-I).

[0267] In some embodiments, the treatment with the compositions of the present application has a reduced risk of adverse side effects compared to the treatment with racemic 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (i.e., the compound of formula (R / S)-I), or the treatment with the enantiomerically pure compound of formula (S)-I).

[0268] In some embodiments, the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, hypothermia, cardiotoxicity, and substance use disorder. In some embodiments, the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, and substance use disorder. In some embodiments, the substance use disorder is drug abuse or drug dependence. In some embodiments, the substance use disorder is drug abuse of racemic MDMA.

[0269] In some embodiments, the adverse side effects are hyperthermia or hypothermia. In some embodiments, the adverse side effects are hyperthermia. In some embodiments, the adverse side effects are hypothermia.

[0270] Reports have suggested that long-term use of MDMA may lead to heart valve fibroplasia and dysfunction, such as valvular heart disease (VHD) (Setola et al. Mol. Pharmacol. 63:1223-1229, 2003). Thus, in some embodiments, the adverse side effect is cardiotoxicity. In some embodiments, the cardiotoxicity is heart valve fibroplasia and dysfunction. In some embodiments, the cardiotoxicity is valvular heart disease. Thus, in some embodiments, the adverse side effect is valvular heart disease. In some embodiments, the cardiotoxicity is tachycardia or tremor.

[0271] In some embodiments, the reduced risk of adverse side effects is due to the use of the compositions of the present application compared to compositions containing the racemic compound of formula (R / S)-I, and binding to the 5-hydroxytryptamine 2B (5-HT 2A ) receptor with lower affinity compared to the 5-hydroxytryptamine 2A (5-HT 2B ) receptor.

[0272] In some embodiments, the reduced risk of adverse side effects is due to the use of the compositions of the present application compared to compositions containing the racemic compound of formula (R / S)-I, and providing a more balanced binding between the 5-hydroxytryptamine 2B (5-HT 2B ) receptor and the 5-hydroxytryptamine 2A (5-HT 2A ) receptor.

[0273] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are those diseases, disorders or conditions for which treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof is beneficial.

[0274] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are those diseases, disorders or conditions for which treatment with racemic MBDB or a pharmaceutically acceptable salt and / or solvate thereof is beneficial.

[0275] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are those diseases, disorders or conditions for which treatment with racemic MDMA is beneficial, and the method has a reduced risk of adverse side effects compared to treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA).

[0276] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are any diseases, disorders or conditions for which psychotherapy is beneficial, including but not limited to one or more of post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction and eating disorders.

[0277] In some embodiments, the one or more compositions are administered or used in combination with psychotherapy for treating a disease, disorder or condition. In some embodiments, the one or more compositions improve the effectiveness of psychotherapy. In some embodiments, the psychotherapy is directed to mental disorders.

[0278] In some embodiments, the diseases, disorders or conditions treatable by activation of serotonin receptors are one or more mental disorders. In some embodiments, the one or more mental disorders are selected from one or more of anxiety disorders, mood disorders, developmental disorders, substance use disorders and addictions, eating disorders, personality disorders, and psychotic disorders. In some embodiments, the substance use disorder is drug abuse or drug dependence.

[0279] In some embodiments, the anxiety disorder is selected from one or more of obsessive-compulsive disorder (OCD), social anxiety disorder, phobia, panic disorder and post-traumatic stress disorder (PTSD). In some embodiments, the anxiety disorder is social anxiety disorder. In some embodiments, the anxiety disorder is PTSD.

[0280] In some embodiments, the mood disorder is selected from one or both of depression and bipolar disorder.

[0281] In some embodiments, the developmental disorder is selected from one or both of autism spectrum disorder (ASD) and Asperger's syndrome.

[0282] In some embodiments, the substance use disorder and addiction are selected from one or more of alcohol dependence, drug abuse, drug dependence, and compulsive gambling. In some embodiments, the drug dependence is opioid dependence. In some embodiments, the substance use disorder is opioid use disorder.

[0283] In some embodiments, the eating disorder is selected from anorexia nervosa and bulimia nervosa.

[0284] In some embodiments, the personality disorder is selected from borderline personality disorder and dependent personality disorder.

[0285] In some embodiments, the psychotic disorder is selected from schizophrenia and other disorders that cause detachment from reality.

[0286] In some embodiments, one or more mental disorders are selected from one or more of autism spectrum disorder (ASD), depression, and drug dependence. In some embodiments, the depression is clinical depression, such as clinical depression in a palliative care setting. In some embodiments, the substance use disorder is opioid use disorder.

[0287] In some embodiments, 5-HT 2A The diseases, disorders, or conditions treatable by activation of are autism spectrum disorder.

[0288] In some embodiments, the autism spectrum disorder is selected from autism, Asperger's syndrome, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified.

[0289] In some embodiments, one or more mental disorders are selected from post-traumatic stress disorder (PTSD), eating disorder, and alcohol dependence. In some embodiments, one or more mental disorders are post-traumatic stress disorder (PTSD).

[0290] In some embodiments, one or more mental disorders are selected from autism spectrum disorder (ASD), depression, and substance use disorder. In some embodiments, the depression is clinical depression, such as clinical depression in palliative care patients. In some embodiments, the substance use disorder is opioid use disorder.

[0291] In some embodiments, the compositions of the present application are administered before, during, and / or after psychotherapy. In some embodiments, the compositions of the present application are administered during and / or after psychotherapy.

[0292] In some embodiments, the psychotherapy is selected from behavioral psychotherapy, exposure-based psychotherapy, cognitive psychotherapy, and psychodynamic-oriented psychotherapy.

[0293] In some embodiments, a disease, disorder, or condition treatable by activation of a serotonin receptor is any disease, disorder, or condition in which treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is beneficial.

[0294] In some embodiments, the composition is administered or used in combination with L-DOPA to treat a disease, disorder, or condition in which treatment with L-DOPA is beneficial. In some embodiments, the composition improves the efficacy of L-DOPA. In some embodiments, the composition is administered or used in combination with L-DOPA to improve the efficacy of L-DOPA.

[0295] In some embodiments, a disease, disorder, or condition in which treatment with L-DOPA is beneficial is Parkinson's disease.

[0296] The present application also encompasses a method of treating Parkinson's disease, the method comprising administering one or more compositions of the present application to a subject in need thereof.

[0297] This application further encompasses the use of one or more compositions of the present application for the treatment of Parkinson's disease, the use of one or more compositions of the present application for the preparation of a medicament for treating Parkinson's disease, and the use of one or more compositions of the present application for the use of treating Parkinson's disease.

[0298] In some embodiments, the one or more compositions are administered or used in combination with L-DOPA for treating Parkinson's disease. In some embodiments, the one or more compositions improve the efficacy of L-DOPA for treating Parkinson's disease. In some embodiments, the one or more compositions are administered or used in combination with L-DOPA to improve the efficacy of L-DOPA for treating Parkinson's disease.

[0299] In some embodiments, the one or more compositions improve the efficacy of L-DOPA by reducing L-DOPA-induced dyskinesia.

[0300] Thus, in some embodiments, the disease, disorder or condition for which treatment with racemic MDMA is beneficial is dyskinesia. In some embodiments, the dyskinesia is L-DOPA-induced dyskinesia.

[0301] In some embodiments, the one or more compositions improve the efficacy of L-DOPA by increasing the duration of the anti-Parkinson's disease effect of L-DOPA (e.g., the on-time). In some embodiments, the one or more compositions improve the efficacy of L-DOPA by increasing the duration of the anti-Parkinson's disease effect of L-DOPA without causing dyskinesia that causes a disorder.

[0302] In some embodiments, the one or more compositions improve the efficacy of L-DOPA by reducing L-DOPA-induced Parkinsonian psychosis.

[0303] Accordingly, in some embodiments, the disease, disorder or medical condition for which treatment with one or more of the compositions of the present application is beneficial is L-DOPA-induced Parkinsonian psychosis.

[0304] "Reducing L-DOPA-induced dyskinesia" or "reducing L-DOPA-induced Parkinsonian psychosis" means any decrease in the degree of dyskinesia, a stabilized (i.e., non-worsening) state of dyskinesia, a delay or slowing in the progression of dyskinesia, an improvement or alleviation of dyskinesia, and remission (whether partial or complete) of dyskinesia in the presence of one or more of the compositions of the present application compared to the same conditions except for the absence of one or more of the compositions of the present application, and these may be detectable or undetectable.

[0305] "Increasing the duration of the anti-Parkinson's disease effect of L-DOPA" means any increase in the duration of the anti-Parkinson's disease effect of L-DOPA compared to the same conditions except for the absence of one or more of the compositions of the present application.

[0306] "Increasing the duration of the anti-Parkinson's disease effect of L-DOPA without dyskinesia causing the disorder" means any increase in the duration of the anti-Parkinson's disease effect of L-DOPA without dyskinesia causing the disorder compared to the same conditions except for the absence of one or more of the compositions of the present application.

[0307] Methods for the evaluation of L-DOPA-induced dyskinesia and / or psychosis are well known to those skilled in the art, such as those found in, for example, Fox et al. 2006 Arch Neurol 63:1343-1344; Gomez-Ramirez et al. 2006, Mov Disord 21:839-846; Visanji et al. 2006, Mov Disord 21:1879-1891; Huot et al. Journal of Neuroscience, 2011, 31(19)7190-7198 and Fox et al. 2010 Can J Neurol Sci 37:86-95).

[0308] The Applicant has shown that the composition of the present application promotes social behavior in an in vivo mouse model of autism spectrum disorder. The composition of the present application has further been shown not to affect spontaneous motor activity in a mouse model of autism spectrum disorder. The Applicant has further shown that the composition of the present application did not cause a significant effect on deep body temperature. Furthermore, the Applicant has shown that the composition of the present application has less impact on cardiovascular events compared to the compound of formula (S)-I, MDMA and methamphetamine.

[0309] Accordingly, the present application also encompasses a method for treating one or more signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor, the method comprising administering the composition of the present application to a subject in need thereof.

[0310] The present application further encompasses the use of the composition of the present application for the treatment of one or more signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor, the use of the composition of the present application for the preparation of a medicament for treating one or more signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor, and the above composition of the present application for use in treating one or more signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor.

[0311] In some embodiments, at least one sign or symptom of a disease, disorder or medical condition treatable by activation of a serotonin receptor is reduced following administration of the compositions of the present application.

[0312] In some embodiments, the methods and uses provided herein reduce at least one sign or symptom of a disease, disorder or medical condition treatable by activation of a serotonin receptor. In some embodiments, the methods and uses provided herein reduce at least one sign or symptom of a disease, disorder or medical condition treatable by activation of a serotonin receptor by about 5% to about 100%, such as about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100% or more as compared to treatment without the compositions of the present application.

[0313] In some embodiments, signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor are reduced or disappear in a subject within about 1 hour, within about 2 hours, within about 3 hours, within about 6 hours, within about 12 hours, within about 24 hours, within about 48 hours, within about 3 days, within about 1 week, within about 2 weeks, within about 3 weeks, within about 4 weeks, within about 5 weeks, within about 6 weeks, within about 7 weeks, within about 8 weeks or within about 3 months following administration of the compositions of the present application.

[0314] In some embodiments, signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor are reduced or disappear in a subject over a period of about 1 day, about 3 days, about 7 days, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months or about 48 months following administration of the compositions of the present application.

[0315] "Reducing at least one sign or symptom of a disease, disorder or medical condition treatable by activation of a serotonin receptor" means some reduction or decrease in the signs or symptoms of the disease, disorder or medical condition as compared to the same conditions except for the absence of the composition of the present application.

[0316] In some embodiments, the signs or symptoms of a disease, disorder or medical condition treatable by activation of a serotonin receptor are neurotoxicity, hyperthermia, hypothermia, cardiotoxicity and substance use disorder.

[0317] In some embodiments, the disease, disorder or medical condition treatable by activation of a serotonin receptor is an autism spectrum disorder, and the present application also encompasses a method of treating one or more signs or symptoms of an autism spectrum disorder, the method comprising administering a therapeutically effective amount of the composition of the present application to a subject in need thereof.

[0318] The present application further encompasses the use of the composition of the present application for treating one or more signs or symptoms of an autism spectrum disorder, the use of the composition of the present application for the preparation of a medicament for treating one or more signs or symptoms of an autism spectrum disorder, and the composition of the present application for use in treating one or more signs or symptoms of an autism spectrum disorder.

[0319] In some embodiments, one or more signs or symptoms of an autism spectrum disorder are selected from general anxiety, clinical anxiety, irritability, inappropriate speech, echolalia, social withdrawal, repetitive behavior and hyperactivity.

[0320] In some embodiments, one or more signs or symptoms of an autism spectrum disorder are selected from echolalia and social withdrawal. In some embodiments, one or more signs or symptoms of an autism spectrum disorder are echolalia. In some embodiments, one or more signs or symptoms of an autism spectrum disorder are social withdrawal. Thus, in some embodiments, the composition of the present application is for use in promoting prosocial activity.

[0321] This application further encompasses a method or use for treating one or more symptoms of autism spectrum disorder while reducing the harmful side effects of treatment with racemic MDMA or (R / S)-I.

[0322] In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the harmful side effects are selected from hyperthermia, stereotypies, and neurotoxicity. In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the harmful side effects are selected from hyperthermia and neurotoxicity. In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the harmful side effects are selected from hyperthermia.

[0323] In some embodiments, the autism spectrum disorder is as defined by DSM-IV, and one or more symptoms are selected from: (i) qualitative impairments in social interaction; (ii) qualitative impairments in communication; and (iii) restricted, repetitive, and stereotyped patterns of behavior, interests, and activities.

[0324] In some embodiments, one or more symptoms are qualitative impairments in social interaction.

[0325] In some embodiments, the qualitative impairment in social interaction includes one or more of: marked impairment in the use of multiple non-verbal behaviors, such as eye contact, facial expressions, body postures, and gestures, to regulate social interaction; inability to form friendships appropriate to developmental level, and lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by lack of showing, bringing, or pointing out interesting objects); and lack of social or emotional reciprocity.

[0326] In some embodiments, qualitative impairments in communication include one or more of: delays or complete absence in the development of spoken language (without attempts to compensate through alternative communication modalities such as gestures or signs); significant impairments in the ability to initiate or sustain conversations with others in individuals who otherwise speak appropriately; stereotyped and repetitive use of language or idiosyncratic phrases; and absence of varied and spontaneous pretend play or social imitative play appropriate to the developmental level.

[0327] In some embodiments, restricted, repetitive, and stereotyped patterns of behavior, interests, and activities include one or more of: intense and excessive focus on one or more stereotyped and restricted interest patterns, where either the intensity or focus is abnormal; clearly inflexible adherence to specific non-functional routines or rituals; stereotyped and repetitive motor mannerisms (e.g., flapping or twisting of hands or fingers, or complex whole-body movements); and persistent focus on parts of objects.

[0328] In some embodiments, a disease, disorder, or medical condition treatable by activation of a serotonin receptor is an anxiety disorder, and the present application also encompasses a method of treating one or more symptoms or signs of an anxiety disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present application.

[0329] The present application further encompasses the use of a composition of the present application for treating one or more symptoms or signs of an anxiety disorder, the use of a composition of the present application for the preparation of a medicament for treating one or more symptoms or signs of an anxiety disorder, and a composition of the present application for use in treating one or more symptoms or signs of an anxiety disorder.

[0330] In some embodiments, one or more symptoms or signs of an anxiety disorder are measured according to diary assessments, assessments by a clinician or caregiver, or clinical scales.

[0331] In some embodiments, one or more signs or symptoms of an anxiety disorder are fears about social interactions or situations, avoidance of anxiety triggers, feeling stressed, being easily agitated, having a sense of impending doom, being nervous, having a rapid heartbeat, palpitations of the heart, trembling, fatigue, worry, irritability, obsessive thoughts, compulsive behaviors, muscle tension, sweating, dizziness, shortness of breath, interrupted sleep, or fears including combinations thereof.

[0332] Accordingly, in some embodiments, the compositions of the present application are for use in promoting prosocial activity in a subject having an anxiety disorder.

[0333] In some embodiments, the anxiety disorder is selected from one or more of obsessive-compulsive disorder (OCD), social anxiety disorder, phobia, panic disorder, and post-traumatic stress disorder (PTSD) as described above. In some embodiments, the anxiety disorder is social anxiety disorder.

[0334] In some embodiments, the compositions of the present application are administered or used as a second agent or “add-on” therapy.

[0335] In some embodiments, the compositions of the present application are used or administered in an amount sufficient to provide a beneficial or desired result, including clinical outcomes, when administered to a subject, and thus the amount depends on the circumstances in which it is applied. Accordingly, the amount administered or used is an amount of the composition sufficient to treat, prevent, or inhibit a disease or medical condition. In some embodiments, the amount of a given composition used or administered varies depending on factors such as the given composition, pharmaceutical formulation, route of administration, medical condition, type of disease or disorder, and the identity of the subject being treated, but nonetheless can be determined routinely by one of ordinary skill in the art. In one embodiment, the amount administered or used is an amount that appears as an improvement or reduction in the symptoms of any disease, disorder, or medical condition, particularly as compared to the symptoms of an untreated disease, disorder, or medical condition, after treatment therewith.

[0336] In some embodiments, the compositions of the present application are administered at least once a week. In some embodiments, the compositions of the present application are administered approximately once every two weeks, three weeks, or one month. In some embodiments, the compositions of the present application are administered from approximately once a week to approximately once a day. In some embodiments, the compositions of the present application are administered 2, 3, 4, 5, or 6 times a day. The length of the treatment period depends on various factors such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or activity of the compositions of the present application, and / or combinations thereof.

[0337] It is also understood that the effective dosage of the composition used for treatment may increase or decrease during the course of a particular treatment regimen. Changes in dosage may be revealed by standard diagnostic assays known in the art. In some cases, chronic administration is required. For example, the composition is administered to the subject in an amount and for a period sufficient to treat the subject.

[0338] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. Accordingly, the compositions, methods and uses of the present application are directed to diseases, disorders and conditions in both human and veterinary medicine. In some embodiments, "a subject in need thereof" is a subject having a disease, disorder or condition to be treated.

[0339] The composition of the present application is used alone or in combination with other known drugs useful for treating diseases, disorders or conditions treatable by activation of serotonin receptors. When used in combination with other drugs useful for treating diseases, disorders or conditions treatable by activation of serotonin receptors, it is one embodiment to administer the composition of the present application simultaneously with those drugs. As used in the present disclosure, "simultaneous administration" of two substances to a subject means administering each of the two substances such that both are active simultaneously in the individual. The exact details of administration depend on the pharmacokinetics of the substances in the presence of each other and may include administering the substances within a few hours of each other if the pharmacokinetics are suitable, and may even include administering one substance within 24 hours of the other administration. Designing an appropriate dosing regimen is routine for those skilled in the art. In certain embodiments, the substances are administered substantially simultaneously, i.e., within a few minutes of each other, or in a single composition containing all the substances. Administering a combination of drugs to a subject in a non-simultaneous manner is a further embodiment of the present application.

[0340] The dosage of the composition of the present application varies depending on many factors such as the pharmacodynamic properties of the compound in the subject being treated, the mode of administration, the age, health and weight of the recipient, the nature and degree of the symptoms, the frequency of treatment, and the type of co-treatment if any, as well as the clearance rate of the compound. Those skilled in the art can determine an appropriate dosage based on the above factors. In some embodiments, the composition of the present application is initially administered at an appropriate dosage that is adjusted according to the clinical response as needed.

[0341] As a representative example, the oral dosage of one or more of the compositions of the present application is about 1 mg per day to about 50 mg per day for adults, preferably about 1 mg per day to about 40 mg per day, and more preferably about 2 mg per day to about 30 mg per day. In some embodiments, the weight of the subject is 55 kg to 65 kg, preferably 60 kg. In the case of oral administration, representative amounts are about 0.01 mg / kg to about 1 mg / kg, about 0.05 mg / kg to about 1 mg / kg, about 0.05 mg / kg to about 0.75 mg / kg, or about 0.05 mg / kg to about 0.5 mg / kg.

[0342] V. Process of the Present Application The present application includes a novel process for preparing (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine ((R)-I) or (S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine ((S)-I). In particular, the present application includes a stereoselective and efficient two-step process for preparing the compounds of (R)-I or (S)-I using an aryl acylation reaction and subsequent carbonyl reduction.

[0343] Therefore, the present application relates to a compound of formula (R)-I or (S)-I:

Chemical formula

Chemical formula

[0344] In some embodiments, L is halo. In some embodiments, L is selected from Cl, Br, and I. In some embodiments, L is Cl. Thus, in some embodiments, the compound of formula (R)-B or (S)-B is an acyl chloride.

[0345] In some embodiments, L is C(O)OR 2 In some embodiments, R 2 is C 1~4 alkyl. In some embodiments, R 2 is CH3. In some embodiments, R 2 in the compound of formula (R)-A [Chemistry] or R 2in the compound of formula (S)-A [Chemical formula] That is. Therefore, in some embodiments, the compound of formula (R)-A or (S)-A is an anhydride.

[0346] In some embodiments, R 1 is an unsubstituted benzyl group, and the compound of formula (R)-A or (S)-A is a compound protected with benzyloxycarbonyl.

[0347] In some embodiments, R 1 is a substituted benzyl group. In some embodiments, the substituted benzyl group is substituted by one or more substituents selected from NO2, halo, C 1~4 alkyl and C 1~4 alkoxy. In some embodiments, R 1 is a benzyl group substituted by one or more substituents selected from NO2, Br, Cl, C 1~4 alkyl and C 1~4 alkoxy. In some embodiments, R 1 is benzyl substituted by NO2. In some embodiments, R 1 is p-nitrobenzyl or o-nitrobenzyl. In some embodiments, R 1 is p-nitrobenzyl. In some embodiments, R 1 is benzyl substituted by one or more of Cl and Br. In some embodiments, R 1 is 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2-bromobenzyl, or 4-bromobenzyl. In some embodiments, R 1 is a benzyl group substituted by one or more C 1~4 alkoxy. In some embodiments, R 1 is a benzyl group substituted by one or more OCH3. In some embodiments, R 1is 3,4-dimethoxybenzyl or p-methoxybenzyl. In some embodiments, R 1 is a benzyl group substituted by one or more CH3 and C(CH3)3. In some embodiments, R 1 is 3,5-di-t-butylbenzyl.

[0348] In some embodiments, the Lewis acid is any Lewis acid suitable for use in the Friedel-Crafts acylation reaction. In some embodiments, the Lewis acid is selected from BF3, AlCl3, SbCl5, SbF5, InCl3, GaCl3, BCl3, FeCl3, SnCl4, TiCl4, Mo2Cl 10 and AlBr3, and combinations thereof. In some embodiments, the Lewis acid is selected from BF3, AlCl3, SbCl5, FeCl3, SnCl4, TiCl4 and AlBr3, and combinations thereof. In some embodiments, the Lewis acid is AlCl3.

[0349] In some embodiments, the step of reacting a compound of formula (R)-A or (S)-A with a compound of formula B in the presence of a Lewis acid to give a compound of formula (R)-C and (S)-C, respectively, is carried out in a suitable solvent. In some embodiments, the suitable solvent is selected from methylene dichloride, carbon disulfide, 1,2-dichloroethane, tetrachloroethane, 1,1,2,2-tetrachloroethane, and mixtures thereof. In some embodiments, the suitable solvent is methylene dichloride.

[0350] In some embodiments, in the presence of an excess amount (e.g., about 1.2 to about 4 molar equivalents, about 1.5 to about 2.5 molar equivalents, about 1.2 to about 2 molar equivalents, about 1.2 to about 1.5 molar equivalents) of a Lewis acid, a compound of formula (R)-A or (S)-A is reacted with a compound of formula B to give a compound of formula (R)-C and (S)-C, respectively.

[0351] As a representative non-limiting example, the temperature for reacting a compound of formula (R)-A or (S)-A with a compound of formula B in the presence of a Lewis acid to give compounds of formula (R)-C and (S)-C, respectively, is from about -18 °C to about 25 °C, from about -10 °C to about 25 °C, from about -5 °C to about 10 °C, from about 0 °C to about 10 °C, from about 0 °C to about 20 °C, from about 0 °C to about 5 °C, or from about -10 °C to about -5 °C. In some embodiments, the temperature is the temperature of a mixture of ice and NaCl. In some embodiments, the temperature is the temperature of a cold water bath. In some embodiments, at from about -5 °C to about 10 °C, or from about 0 °C to about 10 °C, a compound of formula (R)-A or (S)-A is combined with a compound of formula B in the presence of a Lewis acid and then allowed to warm to room temperature, or from about 18 °C to about 25 °C.

[0352] In some embodiments, the compounds of formula (R)-C or (S)-C are prepared using any suitable conditions known in the art for acylating a compound of formula (R)-A or (S)-A with a compound of formula B in the presence of a Lewis acid to give compounds of formula (R)-C and (S)-C, respectively, for example, using the synthetic procedures found in Ookawa and Soai J.Chem.Soc.,Perkin Trans.1,1987,1465-1471.

[0353] In some embodiments, the compounds of formula (R)-A or (S)-A are commercially available or can be prepared using methods known in the art or can be readily prepared from available precursors using methods known in the art.

[0354] For example, in some embodiments, the compound of formula (R)-A or (S)-A where L is Cl is prepared by reacting D-proline or L-proline protected with benzyloxycarbonyl in a suitable solvent in the presence of a suitable chlorinating agent. In some embodiments, the compound of formula (R)-A or (S)-A where L is Cl is prepared by reacting D-proline or L-proline protected with benzyloxycarbonyl in a suitable solvent in the presence of an excess amount (e.g., about 1.2 to about 2 molar equivalents, about 1.2 to about 1.5 molar equivalents, or about 1.5 molar equivalents) of a suitable chlorinating agent. In some embodiments, the suitable chlorinating reagent is selected from thionyl chloride (SOCl2), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), or oxalyl chloride [(COCl)2]. In some embodiments, the suitable chlorinating reagent is oxalyl chloride. In some embodiments, the suitable solvent is an inert solvent such as methylene dichloride, carbon disulfide, 1,2-dichloroethane, tetrachloroethane, 1,1,2,2-tetrachloroethane, and mixtures thereof. In some embodiments, the suitable solvent is methylene dichloride.

[0355] In some embodiments, D-proline or L-proline protected with benzyloxycarbonyl can be commercially available or prepared using methods known in the art. For example, in some embodiments, D-proline protected with benzyloxycarbonyl (i.e., N-Cbz-D-proline), and L-proline protected with benzyloxycarbonyl (i.e., N-Cbz-L-proline) are available from Millipore-Sigma (Burlington, Massachusetts).

[0356] In some embodiments, the compound of formula (R)-A or (S)-A where L is Cl is prepared in situ. Thus, in some embodiments, the process comprises reacting D-proline protected with benzyloxycarbonyl or L-proline protected with benzyloxycarbonyl in a suitable solvent in the presence of a suitable chlorinating agent to give, respectively, a compound of formula (R)-A or (S)-A where L is Cl, and without isolation, further reacting the compound of formula (R)-A or (S)-A where L is Cl with a compound of formula B in the presence of a Lewis acid to give, respectively, a compound of formula (R)-C or (S)-C where L is Cl.

[0357] In some embodiments, a suitable solvent for reacting D-proline protected with benzyloxycarbonyl or L-proline protected with benzyloxycarbonyl in the presence of a suitable chlorinating agent to give, respectively, a compound of formula (R)-A or (S)-A where L is Cl, and without isolation, further reacting the compound of formula (R)-A or (S)-A where L is Cl with a compound of formula B in the presence of a Lewis acid to give, respectively, a compound of formula (R)-C or (S)-C where L is Cl, is methylene dichloride.

[0358] In some embodiments, the compound of formula B, namely 1,3-benzodioxole, may be commercially available or prepared using methods known in the art. For example, in some embodiments, 1,3-benzodioxole, the compound of formula B, is available from Millipore-Sigma (Burlington, Massachusetts).

[0359] In some embodiments, the compounds of formula (R)-C and (S)-C are each converted to a compound of formula (R)-I or (S)-I using a one-step or two-step method.

[0360] In some embodiments, the compounds of formula (R)-C and (S)-C are each converted to a compound of formula (R)-I or (S)-I using a step-by-step method. In some embodiments, the compounds of formula (R)-C and (S)-C are each converted to a compound of formula (R)-I or (S)-I using a one-step method in the presence of H2 and a catalyst. Thus, in some embodiments, the process comprises converting the compounds of formula (R)-C and (S)-C to a compound of formula (R)-I or (S)-I, respectively, in the presence of H2 and a catalyst.

[0361] In some embodiments, the catalyst is a nickel catalyst, a palladium catalyst or a platinum catalyst. In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is palladium on carbon (Pd / C), palladium hydroxide on carbon (Pd(OH)2 / C), or palladium acetate (Pd(OAc)2 on carbon. In some embodiments, the palladium catalyst is palladium on carbon (Pd / C). In some embodiments, the palladium on carbon (Pd / C) is about 5% - about 10% palladium on carbon (Pd / C). In some embodiments, the palladium on carbon (Pd / C) is about 10% palladium on carbon (Pd / C).

[0362] One skilled in the art will understand that in the step of converting the compounds of formula (R)-C and (S)-C to a compound of formula (R)-I or (S)-I, respectively, in the presence of H2 and a catalyst, a hydrogenolysis reaction to remove the benzyloxycarbonyl protecting group from the compounds of formula (R)-C and (S)-C and a hydrogenation reaction to reduce the arylcarbonyl group in the compounds of formula (R)-C and (S)-C occur simultaneously.

[0363] In some embodiments, the step of converting the compounds of formula (R)-C and (S)-C to give a compound of formula (R)-I or (S)-I, respectively, can be carried out in two steps.

[0364] In some embodiments, the compounds of formula (R)-C and (S)-C are each converted to a compound of formula (R)-I or (S)-I using a two-step method. Thus, in some embodiments, the process comprises converting the compounds of formula (R)-C and (S)-C to a compound of formula (R)-I or (S)-I, respectively, and said converting comprises reducing the compounds of formula (R)-C and (S)-C with a suitable reducing agent to give (R)-D and (S)-D, respectively [Chemical formula] (wherein R 1 is an unsubstituted benzyl group or a substituted benzyl group), and deprotecting the compounds of (R)-D and (S)-D to give a compound of formula (R)-I or (S)-I, respectively.

[0365] In some embodiments, the reducing agent for giving the compounds of (R)-D and (S)-D from the compounds of (R)-C and (S)-C, respectively, is any suitable reducing agent that reduces the aryl ketone of the compounds of (R)-C and (S)-C to alkylene. In some embodiments, the compounds of formula (R)-C and (S)-C are reduced with a suitable reducing agent under Clemmensen reduction conditions to give the compounds of (R)-D and (S)-D. In some embodiments, the suitable reducing agent for reacting with the compounds of (R)-C and (S)-C is zinc amalgam (Zn-Hg) in the presence of an acid. In some embodiments, the acid is concentrated hydrochloric acid.

[0366] In some embodiments, the step of deprotecting the compounds of (R)-D and (S)-D to give the compounds of formula (R)-I or (S)-I, respectively, is carried out in the presence of H2 and a catalyst. In some embodiments, the catalyst is a nickel catalyst, a palladium catalyst or a platinum catalyst. In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is palladium on carbon (Pd / C), palladium hydroxide on carbon (Pd(OH)2 / C), or palladium acetate (Pd(OAc)2 on carbon. In some embodiments, the palladium catalyst is palladium on carbon (Pd / C). In some embodiments, the palladium on carbon (Pd / C) is about 5% to about 10% palladium on carbon (Pd / C). In some embodiments, the palladium on carbon (Pd / C) is about 10% palladium on carbon (Pd / C).

[0367] In some embodiments, the step of deprotecting the compounds of (R)-D and (S)-D to give the compounds of formula (R)-I or (S)-I, respectively, is carried out in the presence of a Lewis acid and an acid. In some embodiments, the acid is hydrobromic acid.

[0368] In some embodiments, the process gives the compounds of formula (R)-I or (S)-I, respectively, as the main isomer. In some embodiments, the process gives the compound of formula (R)-I with an enantiomeric excess (ee) of greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98% or greater than 99% ee. In some embodiments, the process gives the compound of formula (S)-I with an enantiomeric excess (ee) of greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98% or greater than 99% ee.

[0369] In some embodiments, the enantiomeric excess of the enantiomers is determined using various analytical techniques known in the art, such as NMR spectroscopy, chiral column chromatography, or optical rotation measurement. In some embodiments, the enantiomeric excess of the enantiomers is determined using a polarimeter using methods known in the art.

[0370] In some embodiments, the process provides a compound of formula (R)-I. Accordingly, the present application relates to a process for preparing a compound of formula (R)-I:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0371] In some embodiments, the process provides a compound of formula (S)-I. Accordingly, the present application provides a process for preparing a compound of formula (S)-I:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0372] In an exemplary embodiment of the process of the present application, the present application provides a compound of formula (R)-I or (S)-I:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0373] In an exemplary embodiment of the process of the present application, the present application relates to a process for preparing a compound of formula (R)-I:

Chemical formula

Chemical formula

Chemical formula

[0374] In an exemplary embodiment of the process of the present application, the present application provides a compound of formula (S)-I: [Chemical formula] A process for preparing the compound of formula (S)-A [Chemical formula] (wherein, L is halo, R 1 is an unsubstituted benzyl group or a substituted benzyl group) and reacting the compound with a compound of formula B in the presence of a Lewis acid to give a compound of formula (S)-C respectively [Chemical formula] (wherein, R [Chemical formula] (wherein, R 1 is an unsubstituted benzyl group or a substituted benzyl group), and in the presence of H2 and a catalyst, convert the compound of formula (S)-C to the compound of formula (S)-I. A process comprising the above is included.

[0375] In an exemplary embodiment, R 1 is an unsubstituted benzyl group.

[0376] In some embodiments, the compound of formula (R)-I or (S)-I prepared by the process of the present application is further converted into its salts, solvates and / or prodrugs, for example, into its pharmaceutically acceptable salts, solvates and / or prodrugs. In some embodiments, the compound of formula (R)-I prepared by the process of the present application is further converted into its salts, solvates and / or prodrugs, for example, into its pharmaceutically acceptable salts, solvates and / or prodrugs. In some embodiments, the compound of formula (S)-I prepared by the process of the present application is further converted into its salts, solvates and / or prodrugs, for example, into its pharmaceutically acceptable salts, solvates and / or prodrugs.

[0377] In some embodiments, the pharmaceutically acceptable salts are acid addition salts, and the selection of suitable salts may be made by those skilled in the art (see, for example, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19).

[0378] A pharmaceutically acceptable acid addition salt suitable for or adapted to the treatment of a subject is any non-toxic organic or inorganic acid addition salt of any basic compound. Examples of basic compounds that form acid addition salts include, for example, compounds containing an amine group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In certain embodiments, mono- or di-acid salts are formed, and such salts exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts are more soluble in water and various hydrophilic organic solvents compared to their free base forms and generally exhibit higher melting points. Criteria for the selection of suitable salts are known to those of ordinary skill in the art. Other non-pharmaceutically acceptable salts, such as but not limited to oxalate salts, may be used, for example, in the isolation of the compounds of the present application for experimental use or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0379] In some embodiments, a compound of formula (R)-I or (S)-I is reacted with hydrochloric acid to give the hydrochloride salt of the compound of formula (R)-I or (S)-I. In some embodiments, a compound of formula (R)-I is reacted with hydrochloric acid to give the hydrochloride salt of the compound of formula (R)-I. In some embodiments, a compound of formula (S)-I is reacted with hydrochloric acid to give the hydrochloride salt of the compound of formula (S)-I. Solvates of the compound of formula (R)-I or (S)-I include, for example, solvates prepared using pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is termed a hydrate) and ethanol. Suitable solvents are physiologically tolerable at the dosage administered.

[0380] The formation of the desired compound salt is achieved using standard techniques. For example, a neutral compound is treated with an acid in a suitable solvent and the salt formed is isolated by filtration, extraction or any other suitable method.

[0381] The formation of solvates varies depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an anti-solvent. Solvates are typically dried or azeotroped under ambient conditions. The selection of appropriate conditions for forming a particular solvate can be made by one skilled in the art.

[0382] Prodrugs of the compound of formula (R)-I or (S)-I can be, for example, conventional esters formed using available amino groups. Some common esters that have been used as prodrugs include phenyl esters, aliphatic (C1-C 24 ) esters, acyloxymethyl esters, carbamates, and amino acid esters.

[0383] Examples of inert solvents include benzene, toluene, tetrahydrofuran, ethyl ether, ethyl acetate, dimethylformamide (DMF), acetonitrile, C 1~6Alkyl OH (e.g., methanol, ethanol, n-propanol, 2-propanol, n-butanol, butan-2-ol, and 2-methyl-1-propanol), diethyl carbonate, hexane, and dimethyl sulfoxide (DMSO) may be mentioned, but are not limited thereto. Further examples may include aqueous solutions, e.g., water and dilute acids and bases, and ionic liquids, provided that these solvents do not interfere with the reaction.

[0384] VI. The method and preparation of the present application The compound of formula (R)-I can also be prepared by various synthetic processes known in the art. The selection of a particular process is within the understanding of those skilled in the art. Some starting materials are available from commercial chemical suppliers. Other starting materials can be readily prepared from available precursors using straightforward conversions well-known in the art.

[0385] The compound of formula (R)-I can generally be prepared according to the process shown in the following scheme. Those skilled in the art will understand that many of the reactions shown in the following scheme are sensitive to oxygen and water and will know to conduct the reaction under an anhydrous inert atmosphere if necessary. The reaction temperature and reaction time are presented for illustrative purposes only and those skilled in the art will understand that they may be varied to optimize the yield.

[0386] Accordingly, in some embodiments, the compound of formula (R)-I is prepared as shown in Scheme 1. Thus, in some embodiments, (R)-prolinol ((R)-2-(hydroxymethyl)pyrrolidine) is reacted with sulfuryl chloride in a suitable solvent such as pyridine and dichloromethane or a mixture thereof at a suitable temperature such as about 60 °C to about 80 °C to give a sulfamate intermediate of formula A. Thereafter, in the presence of an organolithium reagent such as n-butyllithium, the sulfamate intermediate of formula A is reacted with a compound of formula B wherein X is a leaving group, and subsequently, the resulting sulfamic acid is subjected to acid hydrolysis at a suitable temperature such as about 70 °C to about 95 °C in the presence of a suitable acid such as HCl and a suitable solvent such as ethanol to give the compound of formula (R)-I.

Chemical formula

[0387] In some embodiments, the compound of formula (R)-I is prepared as shown in Scheme 2. Accordingly, in some embodiments, the condensation between an N,N-dimethylpiperonylamide compound of formula C and pyrrole in the presence of a coupling agent such as phosphorus oxychloride gives a 2-acylpyrrole compound of formula D. Removal of the keto oxygen from the compound of formula D in the presence of a suitable reducing agent such as sodium borohydride gives a compound of formula E. Hydrogenation of the pyrrole ring in the compound of formula E gives a racemic compound of formula (R / S)-I. The racemic compound of formula (R / S)-I can be optically resolved into the separate R and S enantiomers represented by formula (R)-I and (S)-I by methods known in the art.

Chemical formula

[0388] The compounds of formula (S)-I and formula (R / S)-I can be prepared according to the processes shown in the above scheme using starting materials having the corresponding (S) enantiomeric configuration or starting materials that are racemic, respectively, as will be understood by those skilled in the art. The compounds of formula (R)-I, formula (S)-I and formula (R / S)-I can also be prepared by methods known in the art, for example, by the methods disclosed in Williams et al., Med. Chem. Commun., 2015, 6, 1054 and Dolby L.J. et al, J. Org. Chem., 37(23), 1972 p3691.

[0389] The comparative racemic MDMA compound can be prepared by various synthetic processes. The selection of a particular process is within the understanding of those skilled in the art. For example, by the methods disclosed in Dunlap et al(2018), ACS Chem Neurosci;9(10):2408-2427; Llabres et al(2014), European J. of Med. Chem. 81(2014)35-46; Huot et al(2011), J Neurosci.(2011) May 11;31(19):7190-7198 and Felim et al., Chem Res Toxicol. 2010 23(1):211-9.

[0390] Nucleophilic substitution reaction conditions are any known method of reacting a nucleophile to substitute a leaving group to form a bond, which is compatible with the intermediates and products shown in the above scheme or can be used to prepare the compounds of the present application. In some embodiments, such conditions include combining the reactants in the presence of a base in a suitable solvent.

[0391] It should be understood that, through the processes described in this disclosure, where appropriate, suitable protecting groups are added to and then removed from various reactants and intermediates in a manner readily understandable by one of ordinary skill in the art. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are described, for example, in “Protective Groups in Organic Synthesis”, T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999).

[0392] For any intermediate product or final product on the synthetic route towards the final product, it is possible to convert a group or substituent to another group or substituent by chemical manipulation, and it should also be understood that the types of conversions possible are limited only by the inherent incompatibility of other functional groups the molecule has at that stage with the conditions or reagents used for the conversion. Such inherent incompatibilities, as well as ways to avoid them by performing appropriate conversions and synthetic steps in the appropriate order, will be readily understandable by one of ordinary skill in the art. Examples of conversions are shown in this disclosure, and it should be understood that the described conversions are not limited only to the general groups or substituents for which the conversion is exemplified. References and descriptions of other suitable conversions are shown in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994).

[0393] Techniques for the purification of the intermediates and final products include, for example, normal-phase chromatography and reverse-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid extraction or solid-liquid extraction, which will be readily understood by those skilled in the art.

[0394] The products of the process of the present application may be isolated according to known methods. For example, the compound may be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable methods.

[0395] Generally, the above reactions can be carried out in a suitable inert organic solvent at a temperature and for a time that optimize the yield of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0396] The formation of the desired compound salts is achieved using standard techniques. For example, a neutral compound is treated with an acid or a base in a suitable solvent, and the formed salt is isolated by filtration, extraction or any other suitable method.

[0397] The formation of solvates of the compounds of the present application varies depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using a poor solvent. Solvates are typically dried or azeotroped under ambient conditions. The selection of suitable conditions for forming a particular solvate can be carried out by those skilled in the art.

[0398] The prodrugs of the compounds of the present application can be, for example, conventional esters formed using available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and the acylation is optionally carried out in an inert solvent (e.g., acid chloride in pyridine).

[0399] One skilled in the art will recognize that when the reaction steps of the present application are carried out in various solvents or solvent systems, the reaction steps may be carried out in a mixture of suitable solvent(s) or solvent system(s).

Examples

[0400] The following non-limiting examples illustrate the present application:

[0401] Example 1: Exemplary Preparation of (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine-A (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine may be prepared using the method disclosed in Williams et al., Med. Chem. Commun., 2015, 6, 1054 for the preparation of (S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine.

[0402] (R)-Tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide Under argon, a solution of sulfuryl chloride (8 mL, 99 mmol) in DCM (40 mL) is added dropwise over 1.5 h to a well-stirred solution of (R)-2-(hydroxymethyl)pyrrolidine (10 g, 99 mmol) and pyridine (16 mL, 20 mmol) in DCM (60 mL) at -78 °C. After 3 h, the cooling bath is removed and the mixture is allowed to reach 0 °C. The reaction mixture is quenched into ice water and transferred to a separatory funnel. The layers are separated and the aqueous layer is subjected to extraction with DCM (2×). The combined organic extracts are washed with 1 M aqueous HCl, water, and brine. The organic layer is dried over Na2SO4, filtered, and evaporated in vacuo to give a yellow solid. This is then redissolved in THF (50 mL) and filtered through a sintered funnel to remove residual pyridine·HCl and concentrated in vacuo to give the title compound as a pale yellow solid (8.8 g, 55%).

[0403] (R)-2-(Benzod[d][1,3]dioxol-5-ylmethyl)pyrrolidine At a rate such that the internal temperature continues to be less than -70 °C, a solution of 1.6 M n-BuLi in hexane is added under argon to a solution of 4-bromo-1,2-(methylenedioxy)benzene (1.8 mL, 15 mmol) in THF. After several minutes, the mixture becomes turbid and a suspension is formed. After 30 minutes, a solution of (R)-tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (2.0 g, 12 mmol) in THF is added while maintaining the internal temperature below -70 °C. The cooling bath is removed and the mixture is slowly returned to room temperature (RT), where all the solids return to solution. The solution is stirred at room temperature for 1 hour and the volatile substances are removed in vacuo. The residue is dissolved in a 1:1 aqueous solution of 2 M HCl and ethanol and heated to 95 °C for 40 hours. The reaction mixture is cooled to room temperature, diluted with H2O, and the mixture is washed with TBME (1×). This extract is discarded, the aqueous phase is basified with 5 M aqueous NaOH, and re-extracted with TBME (3×60 mL). The combined organic extracts are dried over Na2SO4, filtered, and evaporated in vacuo to give the compound described in the heading.

[0404] Example 2: Exemplary Preparation of (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine - B (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine may be prepared using the method disclosed for (R / S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine by Dolby L.J. et al, J. Org. Chem., 37(23), 1972 p3691.

[0405] N,N-Dimethylpiperonylamide Thionyl chloride (270 ml) is added portionwise with stirring to piperonylic acid (63.8 g, 0.384 mol) over 20 minutes. The slurry is heated under reflux for 1 hour, during which time the acid gradually dissolves. The excess thionyl chloride is removed under reduced pressure and the residue is evaporated using anhydrous benzene. The crude acid chloride is added portionwise with stirring and cooling to a 40% aqueous dimethylamine solution over 15 minutes. The mixture is stirred at room temperature for 2 hours, then made strongly alkaline with 4N sodium hydroxide and saturated with sodium chloride. This aqueous solution is subjected to extraction with methylene chloride, the organic phase is filtered through paper and concentrated under reduced pressure to give the crude amide (57.1 g, 77%) as a dark oil. By distillation, the amide is obtained as a hygroscopic viscous liquid (53 g, 71%):

[0406] 2-(3,4-Methylenedioxybenzoyl)pyrrole To a cooled solution of N,N-dimethylpiperonylamide (58.5 g, 0.303 mol) in dichloroethane (60 ml), freshly distilled phosphorus oxychloride (46.5 g, 0.303 mol) is added dropwise with stirring over 15 minutes. The mixture is stirred under cooling for 10 minutes and then at room temperature for 1.5 hours. Additional dichloroethane is added (60 ml) and subsequently a solution of freshly distilled pyrrole (20.3 g, 0.303 mol) in dichloroethane (60 ml) is added over 10 minutes. The mixture is stirred at room temperature for 10 minutes and then refluxed for 1 hour. The dark red mixture is cooled and a solution of sodium acetate trihydrate (300 g) in water (600 ml) is added first slowly and then as rapidly as possible with vigorous stirring. The mixture is refluxed for about 15 minutes and then the phases are separated while still warm. The aqueous phase is subjected to extraction with chloroform, the combined organic solutions are washed with brine, dried and concentrated under reduced pressure. The dark solid residue is washed with a little cold methanol and then with ether and dried to give the acylpyrrole (51.7 g, 80%) as a yellow solid.

[0407] 2-(3,4-Methylenedioxybenzyl)pyrrole A mixture of 2-(3,4-methylenedioxybenzoyl)pyrrole (37.8 g, 0.175 mol), sodium borohydride (19 g, 0.50 mol), and dioxane (500 ml) is refluxed under nitrogen for 4 hours. The solution is concentrated under reduced pressure, diluted with water (500 ml), and subjected to extraction with ether-methylene chloride (2:1, 300 ml). The organic solution is washed with water, dried, and concentrated under reduced pressure to leave a dark viscous oil. Distillation under reduced pressure gives benzylpyrrole as a colorless liquid (20.8 g, 59%), bp 125-130° (0.03 mm).

[0408] 2-(3,4-Methylenedioxybenzyl)pyrrolidine A solution of 2-(3,4-methylenedioxybenzyl)pyrrole (28.9 g, 0.144 mol) in glacial acetic acid (100 ml) is hydrogenated with rhodium-alumina (5% Rh) (3 g) for 8 hours at an initial pressure of 50 psi in a Parr apparatus. The catalyst is filtered off and the filtrate is diluted to 500 ml with water. The aqueous solution is subjected to extraction with ether, then made strongly alkaline with 50% sodium hydroxide and subjected to extraction with methylene chloride. The organic solution is dried and concentrated under reduced pressure, and the dark oil is distilled under reduced pressure to give benzylpyrrolidine. The hydrochloride is prepared by adding saturated ethanolic hydrogen chloride to an ether solution of this pyrrolidine.

[0409] (R)-2-(3,4-Methylenedioxybenzyl)pyrrolidine Using enantiomeric separation methods known in the art, for example, chromatography methods (e.g., chiral chromatography), crystallization, synthetic techniques (e.g., by introducing an appropriate asymmetric group onto the N atom to form diastereomers that can be optically resolved using chromatography methods), or other such methods for obtaining the compound of formula (R)-1 from a racemic mixture, for example, as disclosed in Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S.H., et al, Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972 and Thompson, Wayne J. et al: Journal of Medicinal Chemistry, 33(2), 789-808; 1990), the (R)-2-(3,4-methylenedioxybenzyl)pyrrolidine (the compound of formula (R)-1) is optically resolved.

[0410] Example 3: Exemplary Preparation of (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine Using the Process of the Present Application* (R)-Benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (Cbz-(D)-Pro-OH) a (2.0 g, 8.0 mmol) is dissolved in DCM (10 mL), oxalyl chloride (6 mL of a 2 M solution, 12.0 mmol) is added, and then DMF (2 drops) is added. The mixture is stirred at room temperature for 30 minutes. The solution is concentrated to obtain (R)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate. This acid chloride is mixed with a solution of aluminum chloride (1.03 g, 8.4 mmol) in DCM (10 mL), and stirred until all of the aluminum chloride dissolves under a cooling water bath. Then, 2H-1,3-benzodioxole (1.074 g, 8.8 mmol) is added dropwise and stirred at room temperature. The reaction mixture is poured into water and ice. The organic layer is subjected to extraction with DCM and dried over sodium sulfate. When the solvent is evaporated under reduced pressure, *CBz-protected (R)-benzo[d][1,3]dioxol-5-yl(pyrrolidin-2-yl)methanone is produced.

[0411] A suspension of about 100 g of CBz-protected (R)-benzo[d][1,3]dioxol-5-yl(pyrrolidin-2-yl)methanone and 10% Pd / C (about 1.0 - 5 g) in about 1000 ml of methanol is subjected to hydrogenation at about 45 - 50 psi. When the reaction is complete, the catalyst is filtered and the solvent is distilled off under vacuum to obtain the compound described in the heading. *(S)-2-[(2H-1,3-Benzodioxol-5-yl)methyl]pyrrolidine is prepared in the same manner as (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine. Starting from (Cbz-(L)-Pro-OH), CBz-protected (S)-benzo[d][1,3]dioxol-5-yl(pyrrolidin-2-yl)methanone is prepared in the same manner from (S)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate.

[0412] Example 4: Exemplary Preparation of (R)-2-[(2H-1,3-Benzodioxol-5-yl)methyl]pyrrolidine and (S)-2-[(2H-1,3-Benzodioxol-5-yl)methyl]pyrrolidine Step 1: Preparation of (S)-tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide [Chemical formula] Under argon, a solution of sulfuryl chloride (8 mL, 99 mmol) in dichloromethane (DCM) (40 mL) was added dropwise over 1 hour to a well-stirred solution of (S)-(+)-prolinol (5 g, 49.43 mmol) and imidazole (6.73 g, 98.86 mmol) in DCM (75 mL) at -78 °C.

[0413] After 4 hours, the cooling bath was removed and the mixture was allowed to warm to room temperature overnight.

[0414] The reaction mixture was filtered through a short plug of silica to remove the precipitated imidazolium salt and washed with water (1×).

[0415] The aqueous layer was back-extracted with DCM (×3), and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a pale yellow oil.

[0416] This product was crystallized from ethanol / diethyl ether to give a white solid (4.22 g, 52%). The spectral data were consistent with those reported in the literature (Ferrari et al. (2022), Org. Process Res. Dev. 26, 9, 2614 - 2623).

[0417] The above procedure was modified so that the R-enantiomer (4.46 g, 55%) was produced starting from (R)-(-)-prolinol.

[0418] Step 2: Preparation of (S)-2-(benzo[d][1,3]dioxol-5-ylmethyl)pyrrolidine ((S)-I) [Chemical formula] At a rate such that the internal temperature continued to be less than -70 °C, nBuLi (2.5 M in hexane, 5.88 mL, 14.7 mmol) was added under nitrogen to a solution of 4-bromo-1,2-methylenedioxybenzene (2.95 g, 14.7 mmol) in THF (40 mL).

[0419] A white turbid suspension formed in the said solution. After stirring this suspension at -78 °C for about 90 minutes, sulfamidate (2.0 g, 12.25 mmol) (in THF) was added dropwise at -78 °C over 1 hour. This was left to warm to room temperature overnight and then concentrated in vacuo.

[0420] The residue was dissolved in 2 M aqueous HCl (25 mL) and ethanol (25 mL) and heated to reflux for 2 days. The reaction mixture was cooled to room temperature, concentrated in vacuo to remove ethanol, and diluted with H2O.

[0421] The aqueous layer was subjected to extraction with diethyl ether and the ether layer was discarded. The aqueous layer solution was basified with 5 N NaOH and subjected to extraction with DCM (5×).

[0422] The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow oil (1.1 g).

[0423] This oil was taken up in EtOH and 2 N HCl in diethyl ether was added, whereupon the hydrochloride salt was formed as an off-white solid ((S)-I. hydrochloride) (525 mg, 27%).

[0424] Following the same procedure, the hydrochloride salt of (R)-I. (610 mg, 31%) was formed as an off-white solid.

[0425] 11H NMR*(CD3OD) δ: 1.70 - 1.76 (m, 1 H), 1.99 - 2.17 (m, 3 H), 2.92 - 2.96 (m, 2 H), 3.24 - 3.35 (m, 3 H), 3.69 - 3.73 (pent, 1 H, J = 8 Hz, 15.2 Hz), 5.93 (s, 2 H), 6.75 - 6.81 (m, 3 H). 13 C: 24.27, 30.98, 38.67, 46.45, 63.63, 102.61, 109.67, 110.24, 123.29, 131.74, 148.49, 149.76 [M+H] + = 206.1 *HCl salt Final yield: (S)-I hydrochloride: 27%; (R)-I hydrochloride: 31%

[0426] Example 5: Exemplary compositions of the present application Exemplary composition 1: Enantiomerically pure compound of formula (R)-I (R enantiomer > 99%)

[0427] Exemplary composition 2: 90 - 99% of the compound of formula (R)-I and 1 - 10% of the compound of formula (S)-I

[0428] Exemplary composition 3: 80 - 89.9% of the compound of formula (R)-I and 10.1% - 20% of the compound of formula (S)-I

[0429] Exemplary composition 4: 70 - 79.9% of the compound of formula (R)-I and 20.1 - 30% of the compound of formula (S)-I

[0430] Exemplary composition 5: 60 - 69.9% of the compound of formula (R)-I and 30.1 - 40% of the compound of formula (S)-I

[0431] Exemplary composition 6: 51 - 59.9% of the compound of formula (R)-I and 40.1 - 49% of the compound of formula (S)-I

[0432] Comparative composition 1: Racemic compound of formula (R / S)-I

[0433] Comparative composition 2: Racemic MDMA

[0434] Comparative composition 2: racemic MBDB

[0435] Biological data Example 6: Computational analysis a. Docking analysis Using the compounds of formula (R)-I and (S)-I, the Glide® ligand docking program (e.g., Halgren T.A et al. J.Med.Chem. 2004, 47, 1750-1759) using the 6WHA cryo-EM structure of 5-HT2A at 3.4 Å resolution was used to perform docking analysis with the 5-HT 2A receptor (Figure 1). As shown in Figure 1, the basic alkylamine forms an ionic bridge to the highly conserved D155 side chain within TM3. There is a cluster of aromatic residues F243, W336, F339 and F340.

[0436] Using the compounds of formula (R)-I and (S)-I, the Glide® ligand docking program using the 6DRZ cryo-EM structure of 5-HT2B at 3.1 Å resolution was used to perform docking analysis with the 5-HT2B receptor (Figure 2). As shown in Figure 2, the basic alkylamine forms an ionic bridge to the highly conserved D135 side chain within TM3. There is a cluster of aromatic and aliphatic residues V136, I186, F340, F341, V366.

[0437] Similar docking analyses were performed using the (R)- and (S)-enantiomers of MDMA.

[0438] 5-HT 2A Table 1 shows the docking scores of the compounds of formula (R)-I and (S)-I and the (R)- and (S)-enantiomers of MDMA (R-MDMA and S-MDMA, respectively) when docked to the 5-HT

[0439] 5-HT 2BThe docking scores of the compounds of formula (R)-I and (S)-I, and the (R)- and (S)-enantiomers of MDMA when docked to the receptor are shown in Table 2. Table 1 [Table 1] *Glide evdw represents the van der Waals energy. **Glide ecoul represents the Coulomb energy. All items are related to the Glide gscore algorithm Table 2 [Table 2] *Glide evdw represents the van der Waals energy. **Glide ecoul represents the Coulomb energy. All items are related to the Glide gscore algorithm.

[0440] As can be seen from the docking scores in Table 1 and Table 2, similar to S-MDMA, the compound of the (S)-I molecule binds to 5HT with a stronger affinity compared to its corresponding R enantiomer. 2B with a stronger affinity.

[0441] b. Predicted IC 50 In silico analysis (QSAR and docking) is a useful tool for understanding drug mechanisms, and these analyses are relatively inexpensive and fast compared to experiments. QSAR models were created for each monoamine transporter. In addition, the docking properties of phenethylamine were investigated.

[0442] QSAR: For 73 phenethylamines, the IC of DAT, SERT and NET was obtained from the literature 50Values were collected. Three different softwares were used for the calculation of descriptors, and nearly 2000 descriptors were calculated. Prior to the multiple linear regression (MLR) analysis, highly correlated descriptors were removed. In the QSARiNS software, all descriptors were merged with the experimental inhibition values. The best model was selected using the multi-Criteria Decision-Making tool of QSARiNS.

[0443] Docking: The selected compounds were constructed by MOE as +1 charged (additional hydrogens were always on the amines). The molecular geometry was optimized using the energy minimization tool of MOE. As shown in Table 3, the 3D structures of the transporters and receptors were downloaded from the Protein Data Bank (PDB) website. Unnecessary components of the PDB files were removed. The 3D structure of the protein was optimized using the energy minimization tool. Table 3: Protein structures of the transporters and receptors selected for QSAR modeling

Table 3

[0444] The predicted IC 50 (mM) values of the analytical molecules generated based on the QSAR developed as described above are shown in Table 4. Table 4: Predicted IC 50 (μM) values of the analytical molecules based on the QSAR model developed in-house

Table 4

[0445] As described in Liechti 2015, "Many novel psychoactive substances interact with biogenic amine neurotransmitter transporters. Amphetamines, including methamphetamine and MDMA, inhibit the transporters of dopamine, serotonin, and norepinephrine (noradrenaline) (DAT, SERT, NET, respectively), and release these monoamines via their respective transporters. Methamphetamine mainly increases dopamine and norepinephrine. MDMA mainly increases serotonin and norepinephrine. The entactogenic effect of MDMA is generally thought to depend on its serotonergic effect. As a result, substances that mainly release serotonin, such as MDMA, can be predicted to produce MDMA-like entactogenic effects. In contrast, psychostimulants such as methamphetamine or methylphenidate mainly enhance dopaminergic neurotransmission. Dopamine mediates the reinforcing and addictive properties of abused drugs. In contrast, an increase in the serotonergic properties of a substance is associated with a decrease in the potential for addiction. As a result, the in vitro dopaminergic versus serotonergic relative properties (dopamine / serotonin transporter inhibition ratio) of novel substances can be determined as a useful marker of their potential clinical psychotropic and acute toxic effects. Serotonin release, and typically a DAT / SERT inhibition ratio of 0.01 to 0.1, is predicted to produce subjective drug effects such as those of MDMA or other empathogens." (Liechti M. (2015). Swiss Medical Weekly, 145(0304), w14043.)

[0446] (R)-I, predicted IC for (S)-I 50 (Table 4) shows that R-I is predicted to exhibit behavior highly similar to R-MDMA. R-MDMA has a well-established lower potential toxicity than its S-enantiomer counterpart and racemic MDMA (Pitts et al., (2018) Psychopharmacology, 235(2), 377-392).

[0447] Example 7: Behavioral Experiment a. Social Interaction Test The social interaction test, which has been used to test the effects of MDMA, particularly its prosocial effects, is described in Morley and McGregnor Eur J Pharmacol. 2000;408:41-9 and is used to test the exemplary compositions and comparative compositions of the present application.

[0448] The social interaction test is performed twice to acclimate the test subjects (mice) to the test procedure and screen out aggressive test subjects. During the first session, the test subjects receive an injection of the exemplary composition, comparative composition, or saline of the present application, and the test subjects are isolated in a clean cage at 30-minute intervals. Then, each test subject is paired with an unfamiliar, weight-matched conspecific belonging to the same treatment group in a 30 x 18 cm transparent plexiglass test chamber for 10 minutes. To separate aggressive test subjects, an experimenter is present during the first day of testing. If a removed test subject is present, it is replaced with a new naive test subject so that each treatment condition has an equal number of non-aggressive test subjects.

[0449] A second test session is conducted 48 hours later using the same pairs, treatments, and procedures, except that the experimenter is not present in the room during the test. While in the test arena, the test individuals can move around freely and interact, allowing for a variety of observable behaviors. On the second day of the test, the social pairings are video-recorded, and the duration of social behavior is quantified by an observer blinded to the experimental conditions using JWatcher or BORIS (Friard and Gamba, Methods Ecol Evol. 2016;7(11)1325-1330). The duration of three behaviors is scored: anogenital exploration (sniffing the anogenital region of a conspecific), general exploration (sniffing areas other than the anogenital region, grooming, and following a conspecific), and lying side by side in proximity (lying in a “W” formation in contact or huddling). These behaviors are averaged for each pair and then summed to generate a total social interaction score, for which statistical analysis is performed.

[0450] b. Spontaneous locomotor behavior The effects of the exemplary compositions of the present application and comparative compositions on spontaneous locomotor activity are tested in an open field chamber measuring 45×39×37 cm, with a 16×16 photocell array placed 2.5 cm from the chamber. Immediately prior to placing the mice in the chamber for 1 hour, the mice are treated with the exemplary composition of the present application, a comparative composition, or saline (n = 13 / group). The test is conducted in a dark, enclosed space. The cumulative number of beam breaks in adjacent photocells is recorded as a measure of spontaneous locomotor activity. c. Fear conditioning and extinction Using an established protocol previously used to test racemic MDMA (Young et al., 2015, Transl Psychiatry. 5:1-8), the effects of the exemplary compositions of the present application and comparative compositions on conditioned freezing are evaluated. For consistency with this previous study, C57BL / 6 mice are used in this experiment. Briefly, the mice receive cue fear conditioning on day 1, fear extinction training on day 3, and an extinction test on day 4. Cue fear conditioning consists of a single pairing of a tone (80 dB, 4.5 kHz, 30 s), which is the conditioned stimulus (CS), and a foot shock (1 mA, 2 s), which is the unconditioned stimulus (US). Extinction training is performed 48 hours later in a new context different from the conditioning. R-MDMA, S-MDMA, or saline (n = 6-7 / group) is administered 30 minutes before training on day 3. Extinction training consists of a sub-optimal regimen of four re-exposures to the CS tone at 45-second intervals. The extinction test is performed 24 hours later to determine the lasting effect of the treatment on conditioned freezing. The extinction test is performed in the same context as the training and follows the same procedure except that no treatment is given. Throughout these experiments, the percentage of freezing (conditioned response) is estimated by scoring the presence or absence of movement other than breathing every 5 seconds.

[0451] d. Social preference and locomotor activity (LMA) tests in rodent models Introduction Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder defined by two major behavioral clusters. The first group of behaviors is defined by deficits in social communication and social interaction, and the second group of behaviors consists of repetitive and inflexible patterns of behavior, interests, and thoughts. In 2016, the Autism and Developmental Disabilities Monitoring Network estimated the prevalence of ASD to be 1 in 54 children and stated that the prevalence of ASD is 4.3 times higher in boys than in girls in adolescents. Over the past few decades, the reported incidence of ASD has been increasing in the United States, but the understanding of the etiology of ASD remains poor.

[0452] To better understand the neurological basis of ASD, rodent models of ASD have been developed for research. The BTBR T+Itpr3tf / J mouse (BTBR), originally bred for tests related to insulin resistance, diabetic nephropathy, and phenylketonuria, was identified approximately 10 years ago to exhibit strong and consistent autism-related behaviors. The identification of novel drugs that increase sociality and decrease repetitive behaviors in the autism-like BTBR mouse and C57BL / 6J (C57) background stock may be therapeutically useful for social anxiety, generalized anxiety, and / or ASD.

[0453] In the tests described in this disclosure, male BTBR and C57 mice were used to evaluate the effects of racemic 3,4-methylenedioxymethamphetamine (MDMA), (R / S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine ((R / S)-1), and its individual enantiomers ((R)-I and (S)-I) in social preference as an autism-related assay and in tests of the safety and abuse potential of these drugs.

[0454] In three-dimensional space, these enantiomers are distinguished from each other as non-superposable mirror images, like left and right hands, based on whether the groups attached to the chiral carbon project above or below the plane of the rest of the molecule. Pharmacologically, since the "fitting" of these two species into the binding pockets of the relevant receptors is different, enantiomers can have very different biological effects, including quantitative differences in potency and efficacy and qualitative differences in mechanism of action or internal receptor effects. In the case of methamphetamine, the S(+)-enantiomer is a misused psychostimulant with potent and long-lasting psychostimulant effects, while the R(-)-enantiomer has less than 1 / 100 the ability to induce any of these effects (because it "fits" into the relevant receptors in a manner like a left glove on a right hand). In the case of MDMA, both enantiomers are active at similar doses, but they induce different types of effects from each other. In a social preference test, based on the similar chemical structures of methamphetamine and MDMA, methamphetamine was selected as a positive control compound to compare the effects of MDMA. Both compounds were predicted to induce a locomotor-stimulating effect at high doses, but methamphetamine was not predicted to induce a prosocial effect.

[0455] General animal handling Adult male C57 mice and BTBR mice were transported to the University of Arkansas for Medical Sciences from Charles River Laboratories and Jackson Laboratory, respectively. After arrival, the mice were housed three per cage according to strain, and food and water were available ad libitum. Any experimental procedures were performed after the mice had been acclimated to the facilities at the University of Arkansas for Medical Sciences for more than 48 hours.

[0456] Drug administration All drugs were dissolved in 0.9% normal saline and administered at a fixed volume of 1 ml / 100 g body weight. Since all the drugs used in these tests were synthesized as hydrochloride (HCl) salts, they were weighed as salts before the preparation of all solutions. All drugs were readily soluble in aqueous solutions of normal pH at all concentrations. All drug injections were performed intraperitoneally (IP), which mimicked the pharmacokinetic parameters specific to oral administration without the behavioral impairment effects of forced administration stress.

[0457] Social preference test method This assay was performed on adult male C57 mice and BTBR mice (n = 6 / group) in a dedicated conditioning room where environmental light, sound, and human contact were strictly controlled.

[0458] The social preference chamber consisted of two polycarbonate boxes (width 13.5 cm × height 22.5 cm × depth 31.0 cm) lined with rough-textured black ABS plastic and connected to each other by 1.25-inch PVC T-joints. Infrared photobeam emitter / detector arrays were attached at each location where the T-joint intersected with each preference compartment, such that when a mouse crossed the device upon entering or exiting each preference compartment, the mouse would block the photobeam. Beam interruption started or stopped a counter on an interface-connected computer, enabling the automatic collection of the time spent in each compartment. At the end of each test, data were reported as the time (in seconds) spent in each compartment, the number of entries into each compartment, and the average time spent in each compartment after entry. The social preference test was performed repeatedly, and each test subject completed the four distinct phases described below. Between test sessions, the chamber was disinfected by wiping the interior with a disinfectant product provided by the Department of Laboratory Animal Medicine, Albert Einstein College of Medicine. At the end of the week (upon completion of all phases of the procedure), each device was disassembled and all components were disinfected. Food and water were not available during the social preference session but were made available in the home cage immediately afterwards.

[0459] Phase 1 - Acclimation

[0460] A single acclimation session was conducted prior to the preference test, and each compartment contained the same empty wire mesh pencil cup (9.0 cm in diameter × 10.5 cm in height). During this session, the mice were weighed, no injections were given, the test subjects were introduced to the T-junction, and allowed to explore both preference compartments for 30 minutes. This acclimation session was conducted as a procedural control to allow animals to become accustomed to the apparatus and to exclude animals that had a strong initial bias for one of the two compartments. Exclusion criteria were established in advance such that any test subject that spent more than 75% of the total time in a single preference compartment would be excluded from further testing, but none of the test subjects in these tests met this criterion for exclusion. The acclimation session was always conducted on a Monday or Tuesday so as not to conduct tests on weekends.

[0461] Phase 2 - Novelty preference

[0462] A single novelty preference session was conducted the day after the acclimation test. In the novelty preference session, one compartment contained an empty wire mesh cup, and the other compartment contained the same wire mesh cup with a novel dummy mouse inside. The position of the dummy mouse (left or right compartment) was balanced among the test subjects. The dummy mouse was constructed from a 2.5-inch long white 3 / 4-inch PVC pipe, with a zip tie attached to one end (to mimic a tail) and two red dots drawn on the other end (to mimic eyes). During this session, the mice were weighed, injected, and returned to their home cages for a 30-minute pretreatment period. Then, the mice were introduced to the T-junction and allowed to explore both preference compartments for 15 minutes. These tests were conducted as procedural controls to ensure that any observed drug effects were not simply due to an enhancement of the mice's innate novelty preference. The novelty preference session was always conducted on a Tuesday or Wednesday so as not to conduct tests on weekends.

[0463] Phase 3 - Sociality test

[0464] A single social session was conducted the day after the novelty preference test. In the social session, a wire mesh cup containing a dummy mouse was placed in one compartment, and a male naive NIH Swiss mouse, which had previously been in an empty cup, was placed in the other compartment (see Figure 4). The wire mesh cup allowed for visual, olfactory, auditory, and limited tactile contact while preventing aggressive behavior that could cause harm in the absence of the wire mesh cup. The position of the dummy mouse (left or right compartment) remained the same as during the novelty test the previous day for each test subject, thereby counterbalancing the position of the naive mouse between test subjects. The naive NIH Swiss mouse was similar in mass and appearance to the dummy PVC mouse and was housed in a colony facility separately from the experimental subjects (C57 mice and BTBR mice). The first encounter of the experimental subject with the naive mouse occurred when the experimental subject entered the compartment containing the naive mouse. During this session, the body weight of the mouse was measured, the same injection as the previous day was given, and the mouse was returned to its home cage for a 30-minute pretreatment period. The mouse was then introduced to the T-junction and allowed to explore both preference compartments for 15 minutes. The social test was always conducted on Wednesday or Thursday so as not to conduct tests on weekends.

[0465] Phase 4 - Social novelty preference

[0466] A single social novelty preference session was conducted the day after the social test. In one compartment, a wire mesh cup containing the same NIH Swiss mice (now called "familiar" mice) as the previous day was placed inside. In the other compartment, a new male unfamiliar NIH Swiss mouse was placed inside the cup that had previously contained dummy mice during the social test (see Figure 5). The wire mesh cup allowed for visual, olfactory, auditory, and limited tactile contact, while preventing aggressive behavior that could cause harm in the absence of the wire mesh cup. The position of the now familiar NIH Swiss mice (left or right compartment) remained the same as during the previous day's social test for each test subject, thereby counterbalancing the position of the new unfamiliar NIH Swiss mouse among the test subjects. As before, the new unfamiliar NIH Swiss mice were housed in a colony facility separately from the experimental subjects (C57 mice and BTBR mice), and the first encounter of the experimental subjects with the new unfamiliar NIH Swiss mice occurred when the experimental subjects entered the compartment containing the new unfamiliar NIH Swiss mice. During this session, the body weight of the mice was measured, the same injection as the previous day was given, and the mice were returned to their home cages for a 30-minute pretreatment period. The mice were then introduced to the T-junction and allowed to explore both preference compartments for 15 minutes. The social novelty test was always conducted on Thursday or Friday to avoid weekend testing.

[0467] Drug effects on spontaneous locomotor activity By quantifying the total number of entries into the preference zones, proxy measurements of the locomotor-stimulating effects of various doses of various test drugs are obtained. This establishes the limits of drug doses that can be tested in the social preference procedure, because the induction of the locomotor-stimulating effect intersects with the preference assessment (the mouse stops responding to social stimuli within each zone and instead spends its time in locomotor behavior). Locomotor activity varies between different phases of the social preference test, which is partly because the acclimation session is twice as long (30 minutes) as the novelty test, social test, and social novelty test (15 minutes each), and also because mice exhibit a high level of exploratory behavior in a novel environment. Therefore, the number of entries decreases as the mice become more accustomed to the test apparatus through successive exposures to the chamber.

[0468] Figure 3 shows this decreasing trend in the locomotor activity of C57 (black bars) and BTBR (white bars) in the absence of drug injection. It was also noted that a baseline difference in locomotor activity was observed between C57 and BTBR mice in the absence of drug injection, as BTBR test subjects always showed more entries in any phase of the social preference procedure.

[0469] Since the baseline activity of C57 and BTBR mice did not change between the social test and the social novelty test (the final test phase in which the mice are most accustomed to the apparatus), the locomotor-stimulating effects of various therapeutic drugs were determined by focusing on the drug effects during this phase. (The number of entries was collected for all tests, but it should be noted that the drug effects on entries in the initial phase may be less reliable due to the confounding effect of the change in acclimation to the apparatus between phases.)

[0470] In C57 mice (see Figure 4, black bars), approximately 20 entries were observed after saline administration.

[0471] C57 mice (see Figure 5, left panel) and BTBR mice (see Figure 5, right panel) did not show a strong preference for dummy mice over an empty cup as they spent approximately equal amounts of time in each compartment after saline administration.

[0472] (R)-I, (S)-I or racemic MDMA injections did not have a systematic effect on novelty preference at this dose. Since none of the test drugs increased novelty preference, if there was an enhancement of social preference in subsequent tests, that enhancement was unlikely to be confounded by novelty-related effects such as changes in the motivational properties of novel objects (without the above premise, such novelty-related effects could have been confused with prosocial effects).

[0473] Drug effects on sociality C57 mice spent slightly less time in the compartment containing unfamiliar mice than in the compartment containing the dummy after saline administration, thus slightly avoiding unfamiliar mice (see Figure 6, left panel). In BTBR mice (see Figure 6, right panel), a predicted autistic-like reduction in sociality was observed after saline administration, and the mice strongly avoided unfamiliar mice.

[0474] Injection of 1 mg / kg (R)-I or racemic MDMA had no effect on the sociality of C57 mice. However, injection of 1 mg / kg (S)-I caused a slight increase in the time spent with unfamiliar mice, resulting in a moderate preference for unfamiliar mice compared to the dummy.

[0475] In BTBR mice, (S)-I caused a strong response in sociality. However, for (R)-I and racemic MDMA, the increase in social response was slight.

[0476] Drug effects on social novelty preference After administration of saline, C57 mice spent slightly more time in the compartment housing novel unfamiliar mice than in the compartment housing now familiar mice, indicating a slight preference for novel unfamiliar mice (see left panel of Figure 7). In BTBR mice (see right panel of Figure 7), a predicted decrease in autistic-like sociality was observed after administration of saline, with mice showing a slight avoidance of unfamiliar mice.

[0477] Injection of 1 mg / kg of (R)-I and (S)-I into C57 mice increased only slightly the total number of entries during social novelty compared to saline, with no effect at this dose for racemic MDMA (see left panel of Figure 8). In BTBR mice, approximately 40 entries were observed after administration of saline, which was consistent with the previously described and increased baseline levels of the locomotor effect shown in Figure 3.

[0478] Injection of 1 mg / kg of (S)-I strongly stimulated BTBR mice compared to (R)-I, racemic MDMA, and saline (right panel, Figure 8). This stimulation appeared to increase with increasing dose in BTBR mice (see right panel of Figure 9A), but was reversed in C57 mice (see left panel of Figure 9A).

[0479] In BTBR mice (see right panel of Figure 9B), the prosocial response recorded with 1 mg / kg of (R)-I was similar to the prosocial response of 3 mg / kg of racemic MDMA. This demonstrates that (R)-I is a more potent drug than racemic MDMA when testing for social preference in BTBR mice.

[0480] Similarly, in C57 mice (see left panel of Figure 9), the prosocial response of mice at the time of injection of 1 mg / kg of (R)-I was similar to that recorded when mice were injected with 1.8 mg / kg of racemic MDMA. Interestingly, (R / S)-I had the strongest prosocial response at 1 mg / kg, with a decreased response at 1.8 mg / kg.

[0481] e. Drug effects on the conditioned place preference rodent model The same two-compartment chamber as described above in the social preference test was used for conditioned place preference. In these tests, the compartments were distinguished by floor texture (coarse black plastic vs. steel punch plate) and wall pattern (vertical stripes vs. horizontal stripes). An initial preference / acclimation test was first conducted, in which mice were able to freely cross the apparatus for 30 minutes. The next day, mice were assigned such that saline was administered in one compartment and drug was administered in the other compartment. Saline pairings were done in the morning and drug pairings were done in the afternoon, with an interval of more than 4 hours between these pairings, during which time the mice were returned to their home cages. Such pairings were done 3 times, where the mice were injected, returned to their home cages for a 15-minute pretreatment period, and then confined to the injection-appropriate compartment1 for 30 minutes. Half of the test individuals (within the strain) received drug pairings on the side with the plastic floor + vertical stripes, and the other half received drug pairings on the side with the punch plate floor + horizontal stripes. Counterbalancing was achieved by initially assigning the drug to the side not initially preferred by all mice that exhibited preference, and then filling the remaining slots with mice that did not exhibit preference in the initial test. The post-conditioning preference test was the same as the initial preference / acclimation session, in which mice were able to freely cross the apparatus for 30 minutes. The time spent in each compartment was recorded and expressed as a preference score for the side where the drug was paired (calculated as the time spent in that compartment in the post-test - the time spent there in the pre-test). Both the preference session and the conditioning session were conducted under the same low-light conditions as the social preference test.

[0482] Figure 21 shows the effects of saline or 3 mg / kg of MDMA at various enantiomeric ratios (pairings were ×3 each) on place conditioning in C57 mice (black bars) and BTBR mice (white bars). Saline administered in both compartments had a negligible effect on place conditioning, and 3 mg / kg of S-MDMA or racemic MDMA induced significant place preference in both C57 and BTBR mice. BTBR mice showed a higher place preference than C57 mice, suggesting greater sensitivity to the rewarding effects of racemic MDMA (note that no statistical comparison between strains was made). 3 mg / kg of R-MDMA was not tested because it did not produce a significant effect at 10 mg / kg in either strain (see Figure 22).

[0483] Figure 22: Effects of saline, 1.0 or 3.0 mg / kg of S-METH (pairings were ×3 each) on place conditioning in C57 mice (black bars) and BTBR mice (white bars). Saline administered in both compartments had a negligible effect on place conditioning, while 1.0 and 3.0 mg / kg of S-methamphetamine (METH) induced significant place preference only in C57 mice (see Figure 22). Thus, these results suggest that the apparent increased sensitivity to the rewarding effects of MDMA observed in BTBR mice is not simply due to a general increase in sensitivity to all drugs. The effect may be specific to MDMA-like compounds.

[0484] Figure 23 shows the effects of saline, 1.0 mg / kg of (R)-I or 1.0 mg / kg of (S)-I1 (each pairing was ×3) on place conditioning in C57 mice (black bars) and BTBR mice (white bars). Saline administered in both compartments had a negligible effect on place conditioning, and neither 1.0 mg / kg (R)-I nor 1.0 mg / kg (S)-I induced significant place preference in C57 mice. BTBR mice were not tested. Given the apparent increased sensitivity of the BTBR strain to the rewarding effects of MDMA-like drugs, this strain may show place preference at doses that are ineffective in C57 mice.

[0485] When 1 mg / kg of (R)-I and (S)-I in C57 mice were tested compared to S-methamphetamine (tested at the same dose), both enantiomers had a negligible effect on the mice (see Figure 23).

[0486] 3 mg / kg of racemic MDMA and S-MDMA induced significant place preference in C57 mice and BTBR mice (see Figure 22).

[0487] Example 8: Neurotoxicity Test a. Neurotoxic dosing and tissue collection In the modified dosing regimen from Itzhak et al., Psychopharmacol. 2003;166:241-248, test individuals receive a total of 4 injections over 2 consecutive days, at 2-hour intervals, of the exemplary composition, comparative composition, or saline of the present application. Test individuals are isolated during treatment and returned to their home cages 2 hours after the second of the 1-day doses. After treatment, the test individuals are divided into two groups. 48 hours after the final injection, the test individuals in Group 1 are anesthetized and perfused transcardially with 4% formaldehyde. Their brains are post-fixed overnight, then immersed in 15% sucrose for 48 hours, frozen in cooled methylbutane, sectioned at 35 μm, and stored at -20°C until analysis by immunohistochemistry. The test individuals in Group 2 are euthanized by cervical dislocation 14 days after the last injection. Their brains are removed, dissected rapidly into the prefrontal cortex, striatum, and hippocampus, and stored at -80°C for subsequent analysis by high-performance liquid chromatography (HPLC) or Western blot.

[0488] b. Body temperature monitoring The effects of the exemplary composition and comparative composition of the present application, administered twice at 2-hour intervals, on body temperature are monitored using a rectal thermometer (n = 5 / group). Measurements are taken every 30 minutes at an ambient room temperature of 22 ± 2°C. During monitoring, the mice are separated into individual holding cages.

[0489] c. Body temperature monitoring test in a rodent model of autism spectrum disorder

[0490] Radio-telemetry and locomotor activity test methods for deep body temperature Monoamine mimetic agents can affect body temperature regulation, especially in amphetamine derivatives such as MDMA, which are perhaps the most widely tested (Docherty & Green, (2010), British Journal of Pharmacology, 160(5), 1029 - 1044.; Freedman et al., (2005), Psychopharmacology, 183(2), 248 - 256; Kendrick et al., (1977), Annals of Internal Medicine, 86(4), 381; Parrott, (2012), Drug and Alcohol Dependence, 121(1 - 2), 1 - 9). Therefore, this study aimed to test the effect of the drug of interest on the core body temperature of C57 and BTBR mice.

[0491] A radiotelemetry assay was performed on adult male C57 and BTBR mice (n = 6 / group) in a dedicated test chamber where environmental light, sound, and human contact were tightly controlled.

[0492] Before surgical implantation of the radio - telemetry probe, mice were administered meloxicam (3 mg / kg) intraperitoneally (IP). Anesthesia was induced with 4% inhaled isoflurane and maintained with 1 - 3% isoflurane at a flow rate of 1.5 liters / min throughout the procedure (as needed). The abdominal area of each animal was treated with depilatory cream and then disinfected by alternating rubbing washes three times with iodine and alcohol. A rostro - caudal incision approximately 1.5 cm in length was made with sterile surgical scissors to gain access to the peritoneal cavity. Then, a cylindrical glass - encapsulated radio - telemetry probe (Model ER - 4000 E - Mitter, Mini Mitter, Bend, OR, USA) was inserted. These probes are 15.5 mm × 6.5 mm in size and weigh approximately 1 gram. The incision was closed using a reverse - cutting needle 5 - 0 Vicryl absorbable suture for the muscle layer and a 5 - 0 nylon suture material for the skin layer (separately for the skin and muscle layers). Surgery was performed at least 7 days before the start of the experimental conditions, thus allowing time for the incision to heal and the animals to regain normal body weight. After surgery, all implanted mice were individually housed in plexiglass cages in a telemetry room for the duration of the entire experiment. The implanted transmitter generates activity - modulated and body - temperature - modulated signals that are transmitted to a receiver (Model ER - 4000 Receiver, Mini Mitter Co., Inc.) located under each cage. After use, the telemetry probe was removed from the carcass, wiped with an alcohol swab, and stored in a disinfectant solution until reuse.

[0493] At least 7 days after surgical implantation of the radio telemetry probe, mice in individual home cages are placed on a telemetry energizer / receiver, which powers the probe and transmits their data to a computer with an interface connection. When an experimental session begins, the computer collects two data updates from the probe at 5-minute intervals: deep body temperature (°C) on one channel and spontaneous movement count (in arbitrary units, depending on the relative position of the probe on the receiver) on the other channel. After at least 60 minutes of baseline data collection, the mice are removed from the cage, injected with saline or a given dose of a specific drug, and then returned to the home cage for 24 hours of data collection.

[0494] In the home cages, food and water were always freely available. Mice were injected with incremental doses of a given drug, with an interval of at least 48 hours between administrations. Since there has been little research on the drug effects in BTBR mice, the first drug dose tested could induce an unexpectedly large spontaneous movement effect in these animals. In these cases, a lower drug dose was then tested after at least a one-day drug-free period.

[0495] Results - Deep body temperature and spontaneous locomotor activity

[0496] Effect of saline injection on deep body temperature and (spontaneous locomotor activity) LMA in C57 and BTBR mice [Establishment of baseline and characterization of mouse strains]

[0497] Both strains showed a transiently elevated deep body temperature and increased activity levels for approximately 30 minutes after saline administration (Figure 10). Also, in both strains, activity followed a normal circadian pattern. More locomotor activity was recorded during the subjective dark period. Interestingly, BTBR mice showed more activity than C57, along with an elevated deep body temperature that seems to be due to this higher activity (Figure 10).

[0498] Effect of (R)-I injection on deep body temperature and (locomotor activity) LMA in C57 and BTBR mice

[0499] Intraperitoneal injection of (R)-I produced a more acute response in C57 mice compared to BTBR mice (Figure 11). Unlike MDMA, (R)-I did not produce an increase in deep body temperature at any dose tested in either strain. However, both strains showed a dose-dependent decrease in body temperature after injection. These effects were greater in C57 mice after doses of 10, 18, 30, and 56 mg / kg (Figure 12). It was noted that at 5.6 mg / kg, (R)-I did not cause an increase or decrease in deep body temperature in either mouse strain.

[0500] Intraperitoneal injection of various doses of (R)-I in C57 and BTBR had no significant stimulatory effect on locomotor activity, even at the high dose of 30 mg / kg (Figure 13). At 56 mg / kg intraperitoneal injection, (Figure 14) BTBR mice induced a stronger locomotor effect than C57 mice at the same dose, and this was also significantly different from saline.

[0501] Combined with the data shown in Figures 12 and 13, it can be seen that (R)-I has a large safety margin, especially at doses up to 5.6 mg / kg in BTBR and C57 mice. At doses above 10 mg / kg, a decrease in body temperature was observed in both strains.

[0502] Effect of (S)-I injection on deep body temperature and (locomotor activity) LMA in C57 and BTBR mice

[0503] Intraperitoneal injection of (S)-I had a more acute response in C57 mice compared to BTBR mice.

[0504] However, (S)-I was more potent, and in C57 mice, (S)-I produced a significant decrease in body temperature at a lower dose (5.6 mg / kg) compared to the same doses tested with (R)-I (see Figures 15 - 18). It was noted that neither strain showed a locomotor stimulation effect at any of the tested doses. However, since the home cage activity during the light period when the injection was administered was extremely low, it is possible that the procedure used here did not detect a locomotor inhibitory effect. To determine whether S-PharmAla1 reduces locomotor activity, mice may be placed in a new cage with a new bedding and nesting material immediately after injection (to stimulate exploration and nest building in the saline control), or an open field photobeam box without habituation may be used.

[0505] Example 9: Cardiotoxicity Test The cardiotoxicity of drugs is mainly related to the ability of drugs to inhibit the human ether-a-go-go related gene (hERG) cardiac potassium channel. Inhibition of the cardiac hERG channel by drugs is known to be potentially associated with lethal arrhythmias. Therefore, the drug interaction with hERG is commonly investigated to avoid the risk of cardiac side effects. Thus, numerous in-silico, in-vitro and in-vivo assays using hERG have been reported, including in-vitro model systems (hERG is typically expressed in HEK cells or CHO cells) (Gintant G, Pharmacol Ther. 2011 Feb;129(2):109-19; Garrido et al. Eur J Med Chem. 2020 Jun 1;195:112290.).

[0506] hERG inhibition tests are performed using the compounds of formula (R)-I and (S)-I, as well as the exemplary and comparative compositions of the present application. Cardiotoxicity Test in a Rodent Model of Autism Spectrum Disorder

[0507] To monitor the blood pressure of C57 and BTBR mice, an 8-channel CODA™ non-invasive blood pressure system was set up. Mice were acclimated to restraint, saline injection (intraperitoneal injection (IP)), and tail cuff blood pressure monitoring for at least 3 days before drug administration. Over several days, groups of acclimated mice were injected intraperitoneally with escalating doses of the test drugs, in this case (R)-I, (S)-I, and (R / S)-I, and then returned to their home cages for 30 minutes. Next, in a session lasting approximately 30 minutes, the effects on systolic pressure, diastolic pressure, and mean arterial pressure of restrained C57 and BTBR mice were determined by tail cuff blood pressure monitoring.

[0508] In tail cuff blood pressure monitoring, an occluding tail cuff was inflated to impede blood flow to the tail. The cuff was slowly deflated, and a second tail cuff incorporating a VPR sensor was used to measure the physiological characteristics of the returning blood flow. As blood returned to the tail, the VPR sensor cuff measured the tail swelling resulting from arterial blood flow pulsations. Systolic blood pressure was automatically measured at the first appearance of tail swelling. Diastolic blood pressure was automatically measured when the rate of increase in swelling in the tail ceased. Effects of (R)-I and (S)-I on cardiovascular effects in C57 and BTBR mice

[0509] In both C57 and BTBR mice, hypothermic effects of both (R)-I and (S)-I were observed at 10 mg / kg. Therefore, in this study, the effects of the drug on systolic pressure, diastolic pressure, and mean arterial pressure were evaluated at 10 mg / kg and 30 mg / kg.

[0510] Based on the data shown in Figure 14, it was clear that at 10 mg / kg and 30 mg / kg of (R)-I, there was less impact on cardiovascular effects than with (S)-I. This is consistent with the above docking data predicting that (S)-I binds more strongly to the 5HT2b receptor than (R)-I. Compared to racemic MDMA and S-methamphetamine (see Figure 20), the blood pressure increase in both strains by (R)-I (see Figure 19) was significantly lower.

[0511] Abstract: In the docking test, the binding affinity of (S)-I for the 5HT2b receptor was predicted to be stronger and to cause an increase in blood pressure. At a dose of 10 mg / kg intraperitoneally administered (Figure 19), (S)-I was actually found to result in higher systolic and diastolic blood pressures than (R)-I. Compared with racemic MDMA (Figure 20), both enantiomers, (R)-I and (S)-I, are significantly less toxic.

[0512] Although the present application has been described with reference to examples, it should be understood that the claims should not be limited by the embodiments described in the examples, but should be given the broadest interpretation consistent with the entire specification.

[0513] All publications, patents, and patent applications are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. If terms of this application are found to be defined differently in a document incorporated by reference into this disclosure, the definitions provided in this disclosure shall control.

Claims

1. An enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof. 【Chemical Formula 1】

2. The enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof, comprising about 99% by weight or more of the compound of formula (R)-I or a salt and / or solvate thereof and about 1% by weight or less of the compound of formula (S)-I [Chemical Formula 2] or a salt and / or solvate thereof, the compound according to claim 1.

3. The enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof, being 99.1% by weight, 99.2% by weight, 99.3% by weight, 99.4% by weight, 99.5% by weight, 99.6% by weight, 99.7% by weight, 99.8% by weight, 99.9% by weight, 99.91% by weight, 99.92% by weight, 99.93% by weight, 99.94% by weight, 99.95% by weight, 99.96% by weight, 99.97% by weight, 99.98% by weight, 99.9% by weight or 100% by weight of the compound of formula (R)-I, and 0.9% by weight or less, 0.8% by weight or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, 0.1% by weight or less, 0.09% by weight or less, 0.08% by weight or less, 0.07% by weight or less, 0.06% by weight or less, 0.05% by weight or less, 0.04% by weight or less, 0.03% by weight or less, 0.02% by weight or less, 0.01% by weight or less or 0% by weight or less of the compound of formula (S)-I or a salt and / or solvate thereof, the compound according to claim 1.

4. The enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof, having an enantiomeric excess (ee) of 98% or more, the compound according to claim 1.

5. The enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof, being in acid salt form or a solvate thereof, the compound according to any one of claims 1 to 4.

6. A pharmaceutical composition comprising the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 5, and a pharmaceutically acceptable carrier.

7. A composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof, [Chemical Formula 3] The composition wherein the compound of formula (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount, in terms of enantiomeric equivalents, than the (S)-I or a salt and / or solvate thereof.

8. The composition according to claim 7, comprising a compound of formula (R)-I or a salt and / or solvate thereof in an enantiomeric equivalent amount of about 70% to about 79.9%, and a compound of formula (S)-I or a salt and / or solvate thereof in an enantiomeric equivalent amount of about 20.1% to about 30%.

9. The composition according to claim 7, comprising a compound of formula (R)-I or a salt and / or solvate thereof in an enantiomeric equivalent amount of about 80% to about 89.9%, and a compound of formula (S)-I or a salt and / or solvate thereof in an enantiomeric equivalent amount of about 10.1% to about 20%.

10. The composition according to claim 7, comprising a compound of formula (R)-I or a salt and / or solvate thereof in an enantiomeric equivalent amount of about 90% to 95%, and a compound of formula (S)-I or a salt and / or solvate thereof in an enantiomeric equivalent amount of 5% to about 10%.

11. A method of treating a disease, disorder or medical condition treatable by activation of a serotonin receptor, the method comprising administering to a subject in need thereof an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 5.

12. The serotonin receptor is 5-HT ２Ａ The method according to claim 11, wherein the method is such that

13. The method according to claim 11 or claim 12, wherein treatment with the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof results in a reduced risk of adverse side effects compared to treatment with the racemate 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine.

14. The method according to claim 11 or claim 12, wherein treatment with the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof results in a reduced risk of adverse side effects compared to treatment with the racemate 3,4-methylenedioxymethamphetamine (MDMA).

15. The method according to claim 13 or claim 14, wherein the adverse side effect is selected from one or more of neurotoxicity, hyperthermia, hypothermia, cardiotoxicity and substance use disorder.

16. The method according to claim 15, wherein the harmful side effect is hyperthermia or hypothermia.

17. The method according to claim 15, wherein the harmful side effect is cardiotoxicity.

18. The reduced risk of adverse side effects is due to the use of the enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof, compared to the compound of formula (R / S)-I or a salt and / or solvate thereof, or compared to the enantiomerically pure compound of formula (S)-I or a salt and / or solvate thereof, to bind to the 5-hydroxytryptamine 2B receptor (5-HT ２Ａ ) with a lower affinity compared to the 5-hydroxytryptamine 2A (5-HT ２Ｂ ) receptor. The method according to claim 14.

19. The method according to any one of claims 11 to 18, wherein the disease, disorder or condition treatable by activation of a serotonin receptor is a disease, disorder or condition in which treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof is beneficial.

20. The method according to any one of claims 11 to 19, wherein the disease, disorder or condition treatable by activation of a serotonin receptor is any disease, disorder or condition in which psychotherapy is beneficial.

21. The method according to claim 20, wherein the disease, disorder or condition in which psychotherapy is beneficial is selected from post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction and eating disorders.

22. The method according to claim 20 or claim 21, wherein the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with psychotherapy for treating the disease, disorder or condition.

23. The method according to any one of claims 11 to 19, wherein the disease, disorder or condition treatable by activation of a serotonin receptor is one or more mental disorders.

24. The method according to claim 23, wherein the one or more mental disorders are selected from one or more of anxiety disorders, mood disorders, developmental disorders, substance use disorders and addictions, eating disorders, personality disorders and psychotic disorders.

25. The method according to claim 24, wherein the anxiety disorder is selected from one or more of obsessive-compulsive disorder (OCD), social anxiety disorder, phobia, panic disorder and post-traumatic stress disorder (PTSD).

26. The method according to claim 24, wherein the mood disorder is selected from one or both of depression and bipolar disorder.

27. The method according to claim 24, wherein the developmental disorder is selected from one or both of autism spectrum disorder (ASD) and Asperger's syndrome.

28. The method according to claim 24, wherein the substance use disorder and addiction are selected from one or more of alcohol dependence, drug abuse, drug dependence and compulsive gambling.

29. The method according to claim 24, wherein the eating disorder is selected from anorexia and bulimia nervosa.

30. The method according to claim 24, wherein the personality disorder is selected from borderline personality disorder and dependent personality disorder.

31. The method according to claim 24, wherein the psychotic disorder is selected from schizophrenia and other disorders that cause detachment from reality.

32. The method according to claim 24, wherein the one or more mental disorders are selected from one or more of autism spectrum disorder (ASD), depression, and drug dependence.

33. The method according to claim 24, wherein the disease, disorder, or condition treatable by activation of a serotonin receptor is autism spectrum disorder.

34. The method according to claim 11, wherein the disease, disorder, or condition treatable by activation of a serotonin receptor is any disease, disorder, or condition in which treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is beneficial.

35. The method according to claim 34, wherein the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered or used in combination with L-DOPA for treating the disease, disorder, or condition in which treatment with L-DOPA is beneficial.

36. The method according to claim 34, wherein the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of L-DOPA or is administered in combination with L-DOPA to improve the efficacy of L-DOPA.

37. The method according to claim 34, wherein the disease, disorder, or condition in which treatment with L-DOPA is beneficial is Parkinson's disease.

38. A method for treating Parkinson's disease, comprising administering to a subject in need thereof the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 5.

39. The method according to any one of claims 11 to 34, wherein after administering an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 5 to a subject in need thereof, at least one sign or symptom of the disease, disorder or condition treatable by activation of a serotonin receptor is treated.

40. The method according to claim 39, wherein the disease, disorder or condition treatable by activation of a serotonin receptor is an anxiety disorder, and the method treats at least one sign or symptom of the anxiety disorder.

41. The method according to claim 38, wherein the disease, disorder or condition treatable by activation of a serotonin receptor is an autism spectrum disorder, and the method treats at least one sign or symptom of the autism spectrum disorder.

42. A method of treating a disease, disorder or condition treatable by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a composition according to any one of claims 6 to 10.

43. The serotonin receptor is 5-HT ２Ａ The method according to claim 42, wherein the method is as described above. ２Ａ

44. The method according to claim 42 or claim 43, wherein treatment with the composition results in a reduced risk of adverse side effects compared to treatment with the racemate 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine.

45. The method according to claim 42 or claim 43, wherein treatment with the composition results in a reduced risk of adverse side effects compared to treatment with the racemate 3,4-methylenedioxymethamphetamine (MDMA).

46. The method according to claim 44 or claim 45, wherein the adverse side effect is selected from one or more of neurotoxicity, hyperthermia, hypothermia, cardiotoxicity and substance use disorder.

47. The method according to claim 46, wherein the adverse side effect is hyperthermia or hypothermia.

48. The method according to claim 46, wherein the adverse side effect is cardiotoxicity.

49. The reduced risk of adverse side effects is due to binding to the 5-hydroxytryptamine 2B receptor (5-HT ２Ｂ ) with a lower affinity compared to the 5-hydroxytryptamine 2A (5-HT ２Ａ ) receptor, by using the composition according to any one of claims 12 to 30, as compared to a composition comprising a racemic compound of formula (R / S)-I. ２Ａ ), as compared to the 5-hydroxytryptamine 2A (5-HT ２Ａ ) receptor, by binding to the 5-hydroxytryptamine 2B receptor (5-HT ２Ｂ ) with a lower affinity. ２Ｂ The method according to claim 45.

50. The method according to any one of claims 42 to 49, wherein the disease, disorder or condition treatable by activation of a serotonin receptor is a disease, disorder or condition in which treatment with the racemate MDMA or a pharmaceutically acceptable salt and / or solvate thereof is beneficial.

51. The method according to any one of claims 42 to 49, wherein the disease, disorder or medical condition treatable by activation of a serotonin receptor is any disease, disorder or medical condition for which psychotherapy is beneficial.

52. The method according to claim 51, wherein the disease, disorder or medical condition for which psychotherapy is beneficial is selected from post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction and eating disorder.

53. The method according to claim 51 or claim 52, wherein the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with psychotherapy for treating the disease, disorder or medical condition.

54. The method according to any one of claims 42 to 49, wherein the disease, disorder or medical condition treatable by activation of a serotonin receptor is one or more mental disorders.

55. The method according to claim 54, wherein the one or more mental disorders are selected from one or more of anxiety disorders, mood disorders, developmental disorders, substance use disorders and addictions, eating disorders, personality disorders and psychotic disorders.

56. The method according to claim 54, wherein the anxiety disorder is selected from one or more of obsessive-compulsive disorder (OCD), social anxiety disorder, phobia, panic disorder and post-traumatic stress disorder (PTSD).

57. The method according to claim 54, wherein the mood disorder is selected from one or both of depression and bipolar disorder.

58. The method according to claim 54, wherein the developmental disorder is selected from one or both of autism spectrum disorder (ASD) and Asperger's syndrome.

59. The method according to claim 54, wherein the substance use disorder and addiction are selected from one or more of alcohol dependence, drug abuse, drug dependence and compulsive gambling.

60. The method according to claim 54, wherein the eating disorder is selected from anorexia and bulimia.

61. The method according to claim 54, wherein the personality disorder is selected from borderline personality disorder and dependent personality disorder.

62. The method according to claim 54, wherein the psychotic disorder is selected from schizophrenia and other disorders that cause detachment from reality.

63. The method according to claim 54, wherein the one or more mental disorders are selected from one or more of autism spectrum disorder (ASD), depression and drug dependence.

64. The method according to claim 63, wherein the disease, disorder or medical condition treatable by activation of a serotonin receptor is an autism spectrum disorder.

65. The method according to claim 42, wherein the disease, disorder or medical condition treatable by activation of a serotonin receptor is any disease, disorder or medical condition for which treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is beneficial.

66. The method according to claim 65, wherein the composition is administered in combination with L-DOPA for treating the disease, disorder or medical condition for which treatment with L-DOPA is beneficial.

67. The method according to claim 65, wherein the composition improves the efficacy of L-DOPA or is administered in combination with L-DOPA to improve the efficacy of L-DOPA.

68. The method according to claim 65, wherein the disease, disorder or medical condition for which treatment with L-DOPA is beneficial is Parkinson's disease.

69. A method for treating Parkinson's disease, the method comprising administering to a subject in need thereof a composition according to any one of claims 6 to 10.

70. The method according to any one of claims 42 to 65, wherein the method comprises treating at least one sign or symptom of the disease, disorder or medical condition treatable by activation of a serotonin receptor after administering to a subject in need thereof a composition according to any one of claims 6 to 10.

71. The method according to claim 70, wherein the disease, disorder or medical condition treatable by activation of a serotonin receptor is an anxiety disorder and the method treats at least one sign or symptom of the anxiety disorder.

72. The method according to claim 70, wherein the disease, disorder or medical condition treatable by activation of a serotonin receptor is an autism spectrum disorder and the method treats at least one sign or symptom of the autism spectrum disorder.

73. A composition according to any one of claims 6 to 10, used in combination with another known agent useful for treating a disease, disorder or medical condition treatable by activation of a serotonin receptor.

74. A process for preparing a compound of formula (R)-I or (S)-I: 【Chemical Formula 4】 comprising reacting a compound of formula (R)-A or (S)-A which is) with a compound of formula B in the presence of a Lewis acid 【Chemical Formula 5】 (wherein L is selected from halo and C(O)OR ２ and is selected from R １ is an unsubstituted benzyl group or a substituted benzyl group, R ２ is C １～６ alkyl, or R ２ in the compound of formula (R)-A 【Chemical Formula 6】 or R ２ in the compound of formula (S)-A 【Chemical Formula 7】 to give compounds of formula (R)-C and (S)-C respectively 【Chemical 8】 ​ 【Chemical Formula 9】 (wherein R １ is an unsubstituted benzyl group or a substituted benzyl group), and Converting the compounds of formula (R)-C and (S)-C into the compounds of formula (R)-I or (S)-I, respectively, A process comprising.

75. The process according to claim 74, wherein L is a halo selected from Cl, Br and I.

76. The process according to claim 75, wherein L is Cl.

77. wherein L is C(O)OR ２ The process according to claim 74, wherein

78. R ２ is C １～４ alkyl, the process according to claim 77.

79. R ２ in the compound of formula (R)-A 【Chemical 10】 or R ２ in the compound of formula (S)-A 【Chemical 11】 The process according to claim 77, wherein.

80. R １ The process according to any one of claims 74 to 79, wherein R is an unsubstituted benzyl group.

81. R １ is NO ２ , Br, Cl, C １～４ alkyl and C １～４ a benzyl group substituted by one or more substituents selected from alkoxy, the process according to any one of claims 74 to 79.

82. wherein the Lewis acid is BF ３ , AlCl ３ , SbCl ５ , SbF ５ , InCl ３ , GaCl ３ , BCl ３ , FeCl ３ , SnCl ４ , TiCl ４ , Mo ２ Cl １０ and AlBr ３ , and combinations thereof, a process according to any one of claims 74 to 81.

83. wherein the Lewis acid is AlCl ３ The process according to claim 83, wherein the Lewis acid is AlCl

84. The step of reacting the compound of formula (R)-A or (S)-A with the compound of formula B in the presence of a Lewis acid to give the compounds of formula (R)-C and (S)-C, respectively, is carried out in a solvent selected from methylene dichloride, carbon disulfide, 1,2-dichloroethane, tetrachloroethane, 1,1,2,2-tetrachloroethane, and mixtures thereof. The process according to any one of claims 74 to 83.

85. The process according to claim 84, wherein the solvent is methylene dichloride.

86. The compounds of formula (R)-C and (S)-C are H ２ The process according to claim 74, wherein the compounds of formula (R)-C and (S)-C are each converted to a compound of formula (R)-I or (S)-I using a one-step method in the presence of H and a catalyst.

87. The process according to claim 86, wherein the catalyst is a nickel catalyst, a palladium catalyst or a platinum catalyst.

88. The process according to claim 97, wherein the catalyst is a palladium catalyst.

89. The process according to claim 88, wherein the palladium catalyst is palladium on carbon (Pd / C).

90. Reducing the compounds of formula (R)-C and (S)-C with a suitable reducing agent to give (R)-D and (S)-D, respectively 【Chemical Formula 12】 (wherein R １ is an unsubstituted benzyl group or a substituted benzyl group), and Deprotecting the compounds of (R)-D and (S)-D to give the compounds of formula (R)-I or (S)-I, respectively Using a two-step method comprising, the compounds of formula (R)-C and (S)-C are converted into the compounds of formula (R)-I or (S)-I, respectively. The process according to claim 74.

91. The process according to claim 90, wherein the suitable reducing agent for reacting with the compounds of (R)-C and (S)-C is zinc amalgam (Zn-Hg) in the presence of an acid.

92. It is possible to deprotect the compounds of (R)-D and (S)-D to give the compounds of formula (R)-I or (S)-I, respectively, in the presence of H ２ and a catalyst, the process according to claim 90 or claim 91.

93. The process according to any one of claims 74 to 92, giving the compounds of formula (R)-I or (S)-I as the main isomers, respectively.

94. The composition according to any one of claims 6 to 10, which is a nasal composition.

95. The composition according to any one of claims 6 to 10, which is a sublingual composition.

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