(R)-2-[(2H-1, 3-benzodioxol-5-yl) methyl] pyrrolidine as well as preparation method, composition and application of (R)-2-[(2H-1, 3-benzodioxol-5-yl) methyl] pyrrolidine

Abstract

# imgabs0 # The present application includes enantiomerically pure compounds of formula (R)-I, or salts and / or solvates thereof. The present application also includes compositions of enantiomerically pure compounds of formula (R)-I and methods of using compounds of formula (R)-I or compositions thereof to treat diseases, disorders or conditions, e.g., that benefit from psychotherapy. The present application also includes compositions 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 (R)-I, or a salt and / or solvate thereof, is present in the composition in a greater amount in enantiomeric equivalents relative to (S)-I, or a salt and / or solvate thereof, and uses thereof. The present application also includes a method of preparing a compound of formula (R)-I or (S)-I.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to co-pending U.S. Provisional Patent Application No. 63 / 392,948, filed on July 28, 2022, the contents of which are incorporated herein by reference in their entirety.

[0003] field

[0004] The present application relates to enantiomerically pure (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine or its salts and / or solvates, and compositions and uses thereof. The present application also relates to compositions comprising non-racemic mixtures of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, and to methods of using these compositions in therapeutic treatments, for example, for the treatment of mental disorders. The present application also relates to methods for preparing 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine.

[0005] background

[0006] 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (E) or molly, is a psychoactive drug first developed by Merck in 1912. Currently, MDMA is often used recreationally. However, the original application of MDMA was as an adjunct to psychotherapy. Recently, MDMA has been studied in various clinical trials, for example, investigating MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), anxiety associated with terminal illness, and social anxiety in adults with autism. The U.S. Food and Drug Administration (FDA) has now granted Breakthrough Therapy designation for MDMA for the treatment of PTSD.

[0007] MDMA is usually obtained and consumed in the form of a racemate. The racemate of MDMA is also considered to have potential adverse effects, such as hyperthermia and neurotoxicity. However, studies have shown that there are qualitative differences in the effects of MDMA isomers. There is evidence that the R isomer of MDMA may provide an improved therapeutic index by maintaining some of the therapeutic effects of the MDMA racemate with reduced side effects (Pitts et al. Psychopharmacology 235, 377-392, 2018 and Curry et al. Neuropharmacology. 2018 Jan;128:196-206).

[0008] Analogs of MDMA are known, for example, N-methyl-1,3-benzodioxolylbutylamine (MBDB), commonly known as Eden or Methyl-J, is an analog of MDMA with an ethyl group attached to the alpha carbon next to the amine instead of a methyl group. Like MDMA, MBDB is also classified as an entactogen. MBDB is also commonly available and consumed in the form of a racemate.

[0009] Methods for the synthesis of the cyclic analogue of MDMA, 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine and its S enantiomer have been disclosed in Williams et al., Med. Chem. Commun., 2015, 6, 1054 and Dolby L.J. et al., J. Org. Chem., 37(23), 1972 p3691.

[0010] Further development of analogs of MDMA is needed, and further studies are also needed to determine the therapeutic potential of enantiomers of MDMA and its analogs.

[0011] Overview

[0012] The applicant has studied an analog of MDMA, namely (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, and provided enantiomerically pure (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, a preparation method, a composition and use thereof.

[0013] Applicants further investigated compositions 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 to develop a composition comprising a sufficient amount of the R enantiomer to achieve an improved toxicological profile, such as reduced cardiotoxicity, compared to a racemic mixture of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine. Applicants developed a composition comprising both enantiomers of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine in an optimal ratio range to provide the desired therapeutic effect while minimizing undesirable effects.

[0014] In the present application, applicants also describe novel therapeutic uses of enantiomerically pure (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine and compositions thereof, as well as compositions comprising non-racemic mixtures of enantiomers of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, including as treatments for autism spectrum disorders, clinical depression in palliative patients, and substance use disorders (e.g., opioid use disorder).

[0015] Therefore, the present application includes enantiomerically pure compounds of formula (R)-I or their salts and / or solvates

[0016]

[0017] The present application also includes compositions comprising an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof and a carrier.

[0018] The present application also includes methods of treating a disease, disorder or condition treatable by activating serotonin receptors, 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.

[0019] The present application also includes 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:

[0020]

[0021] wherein the compound of formula (R)-I or its salt and / or solvate is present in the composition in a greater amount on an enantiomeric equivalent basis relative to (S)-I or its salt and / or solvate.

[0022] The present application includes a method for activating 5-HT receptors in cells in a biological sample or a patient, which comprises administering a composition comprising a compound of formula (R)-I or a salt and / or solvate thereof and a non-racemic mixture of (S)-I or a salt and / or solvate thereof to an individual in need thereof.

[0023] The present application also includes a method of treating a disease, disorder or condition that can be treated by activating serotonin receptors, which comprises administering to a subject in need thereof a compound of formula (R)-I or a salt and / or solvate thereof and a non-racemic mixture of (S)-I or a salt and / or solvate thereof.

[0024] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a disease, disorder, or condition that benefits from treatment with racemic MDMA, a disease, disorder, or condition that benefits from treatment with racemic MBDB, any disease, disorder, or condition that benefits from psychotherapy, and any disease, disorder, or condition that benefits from treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), such as Parkinson's disease.

[0025] The present application includes methods for preparing compounds of formula (R)-I or (S)-I:

[0026]

[0027] The method comprises:

[0028] The compound of formula (R)-A or (S)-A

[0029]

[0030] Wherein L is selected from halogen and C(O)OR 2 ,

[0031] R 1 is unsubstituted or substituted benzyl; and

[0032] R 2 It is C 1-6 Alkyl, or

[0033] In the compound of formula (R)-A, R 2 yes Or in the compound of formula (S)-A, R 2 yes

[0034] In the presence of a Lewis acid, react with a compound of formula B

[0035]

[0036] to provide compounds of formula (R)-C and (S)-C, respectively; and

[0037]

[0038] Where R 1 is unsubstituted or substituted benzyl

[0039] Compounds of formula (R)-C and (S)-C are converted to compounds of formula (R)-I or (S)-I, respectively.

[0040] From the following detailed description, other features and advantages of the present application will become apparent. However, it should be understood that although the detailed description and specific examples show the embodiments of the present application, they are only given by way of illustration, and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the entirety of the specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The present application will be described in more detail with reference to the accompanying drawings and tables, in which:

[0043] Figure 1 Is displayed using Use of 5-HT 2A The cryoEM structure of 6WHA was obtained by combining the compound of formula (R)-I (upper panel) and the compound of formula (S)-I (lower panel) with 5-HT 2AImage of the receptor docking study results, with a resolution of 3.4A.

[0044] Figure 2 Is displayed using A picture of the docking study results of the compound of formula (R)-I (top) and the compound of formula (S)-I (bottom) with the 5-HT2B receptor using the 6DRZ cryoEM structure of 5-HT2B at a resolution of 3.1A.

[0045] Figure 3 is a graph showing the total number of entries into the test compartment during each phase of the social preference procedure by saline-injected C57 (solid bars) and BTBR (open bars) mice prior to novelty, sociability, and social novelty (Soc Nov) testing.

[0046] Figure 4 is a graph showing baseline strain differences in preference during each phase of the social preference procedure for C57 (solid bars) and BTBR (open bars) mice administered saline injection prior to testing. The bars represent group means, and the error bars represent standard error mean (SEM). Note that both strains showed considerable indifference during the novelty preference control test (upper panel), but consistent with their autism-like phenotype, BTBR mice showed social avoidance during the sociability (middle panel) and social novelty (lower panel) phases.

[0047] Figure 5 Graph showing the effects of 1 mg / kg saline (first bar from left), (R)-I (cross-hatched bars - second bar from left), (S)-I (horizontal lines - third bar from left), and racemic MDMA (diagonal lines - fourth bar from left) on the time spent by sham mice during the novelty preference test of C57 mice (left graph) and BTBR mice (right graph). Note that C57 and BTBR receiving saline showed essentially identical behavior in this test, showing little preference for the novel sham mice.

[0048] Figure 6 Graphs showing the effects of 1 mg / kg intraperitoneal injection of saline (first bar from the left), (R)-I (cross-hatched bars - second bar from the left), (S)-I (horizontal lines - third bar from the left), and racemic MDMA (diagonal lines - fourth bar from the left) on the time spent with an unfamiliar mouse during the sociability test in C57 mice (left) and BTBR mice (right).

[0049] Figure 7Graph showing the effects of 1 mg / kg saline (first bar from left), (R)-I (cross-hatched bars - second bar from left), (S)-I (horizontal lines - third bar from left), and racemic MDMA (diagonal lines - fourth bar from left) on time spent with unfamiliar mice during the social novelty preference test in C57 (left graph) and BTBR (right graph) mice. Note that BTBR receiving saline showed the expected autistic-like social avoidance in this test, showing avoidance of unfamiliar mice.

[0050] Figure 8 Graphs showing the effects of 1 mg / kg intraperitoneal injection of saline (first bar from the left), (R)-I (cross-hatched bars - second bar from the left), (S)-I (horizontal lines - third bar from the left), and racemic MDMA (diagonal lines - fourth bar from the left) on the number of compartment entries during the social novelty test in C57 mice (left) and BTBR mice (right).

[0051] Fig. 9 are graphs showing: A the effects of saline (first bar from the left) or various doses of (R)-I (second bar from the left), (S)-I (horizontal line - third group of bars from the left), (R / S)-I (fourth group of bars from the left), and racemic MDMA (fifth group of bars from the left) on the number of compartment entries during the social novelty test in C57 mice (left panel) and BTBR mice (right panel); and B the effects of saline (first bar from the left) or various doses of (R)-I (second bar from the left), (S)-I (horizontal line - third group of bars from the left), (R / S)-I (fourth group of bars from the left), and racemic MDMA (fifth group of bars from the left) on the time spent with an unfamiliar mouse during the social novelty preference test in C57 mice (left panel) and BTBR mice (right panel).

[0052] Fig.10 Graphs showing the effects of saline injection on core temperature (left graph) and locomotor activity (right graph) of C57 (filled circles) and BTBR mice (open circles). Symbols represent group means, and error bars represent SEM unless the SEM is smaller than the size of the symbol. The bar at the bottom of each graph indicates when the room light was on or off.

[0053] Fig.11 Graphs showing time activity curves of the effect of (R)-I on core body temperature of C57 (left graph) and BTBR mice (right graph). All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g.

[0054] Fig.12Figure 2 is a graph showing the dose effect curves for the maximum and minimum temperatures observed within 4 hours of injection of (R)-I in C57 (filled circles) and BTBR mice (open circles). All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g. (* = significantly different from strain appropriate saline value, # = significantly different between strains within dose (by one-way ANOVA and Tukey's HSD post hoc test).

[0055] Fig.13 Graphs showing time-activity curves of the effect of (R)-I on home cage locomotor activity in C57 (left graph) and BTBR (right graph) mice. All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g.

[0056] Fig.14 Graph showing dose-effect curves for total locomotor activity over 8 hours following injection of (R)-I in C57 (closed symbols) and BTBR mice (open symbols). All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g. (* = significantly different from strain appropriate saline value by one-way ANOVA with Tukey's HSD post hoc test).

[0057] Fig.15 Graphs showing time activity curves of the effect of (S)-I on core body temperature of C57 (left) and BTBR mice (right). All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g.

[0058] Fig.16 Graph showing dose-effect curves for maximum and minimum temperatures observed within 4 hours of injection of (S)-I in C57 (closed symbols) and BTBR mice (open symbols). All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g. (* = significantly different from strain appropriate saline value, # = significantly different between strains within dose (by one-way ANOVA and Tukey's HSD post hoc test).

[0059] Fig.17 Graphs showing time activity curves of the effect of (S)-I on locomotor activity in C57 (left) and BTBR (right). All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g.

[0060] Fig.18 is a graph showing dose-effect curves for total locomotor activity over 8 hours following injection of (S)-I in C57 (closed symbols) and BTBR mice (open symbols). All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g.

[0061] Fig.19Graph showing the effects of saline (hatched bars), (E)-I (solid bars), and (S)-I (open bars) on systolic (top), diastolic (middle), and mean arterial blood pressure (bottom) in C57 (upper graph) and BTBR (lower graph) mice. All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g.

[0062] Fig. 20 Is a graph showing the effects of saline (hatched bars), S-methamphetamine (solid bars) and racemic MDMA (open bars) on systolic (top) and diastolic (bottom) blood pressure in C57 (right) and BTBR (left) mice. All injections were administered intraperitoneally at a concentration of 0.1 cc / 10 g.

[0063] Fig.21 Graph showing the effects of saline or 3 mg / kg of MDMA (x3 pairs each) on place regulation at various enantiomeric ratios in C57 mice (black bars) and BTBR mice (open bars).

[0064] Fig. 22 is a graph showing the effects of saline, 1.0 or 3.0 mg / kg of S-METH (x3 pairs each) on place regulation in C57 mice (solid bars) and BTBR mice (open bars).

[0065] Fig.23 Graphs showing the effects of saline, 1.0 mg / kg (R)-I, or 1.0 mg / kg (S)-I (x3 pairs each) on place regulation in C57 mice (solid bars) and BTBR mice (open bars).

[0066] Specific description

[0067] I. Definitions

[0068] Unless otherwise stated, the definitions and embodiments described in this section and other sections are intended to apply to all embodiments and aspects of the application described herein, as those skilled in the art will understand that they apply to such embodiments and aspects.

[0069] In understanding the scope of the present application, the term "comprise" and its derivatives used herein are intended to be open terms, which specify the presence of features, elements, components, groups, wholes and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, wholes and / or steps. The above also applies to words with similar meanings, such as the terms "include", "have" and their derivatives.

[0070] The term "compound of the present application" or "compound of the application" etc. used herein refers to an enantiomerically pure compound of formula (R)-I, including a pharmaceutically acceptable salt or solvate thereof.

[0071] The term "composition of the present application" as used herein refers to any composition comprising an enantiomerically pure compound of formula (R)-I and / or its salt and / or solvate as described herein and / or its salt and / or solvate as well as any composition comprising a non-racemic mixture of a compound of formula (R)-I and (S)-I and / or its salt and / or solvate as described herein.

[0072] As used herein, the term "non-racemic" with respect to a mixture comprising two enantiomeric compounds means that the mixture comprises the two enantiomeric compounds in a ratio other than 1:1.

[0073] The term "racemic" as used herein with respect to a mixture comprising two enantiomeric compounds means that the mixture comprises the two enantiomeric compounds in a ratio of 1 : 1 or in equal amounts.

[0074] As used herein, the term "consisting of" and its derivatives are intended to be closed terms that specify the presence of features, elements, components, groups, integers and / or steps, but exclude the presence of other unrecited features, elements, components, groups, integers and / or steps.

[0075] As used herein, the term "consisting essentially of" is intended to specify the presence of features, elements, components, groups, integers and / or steps as well as those features, elements, components, groups, integers and / or steps that do not materially affect the basic and novel nature of the features, elements, components, groups, integers and / or steps.

[0076] The degree terms used herein such as "substantially", "about" and "approximately" refer to a reasonable amount of deviation of the modified term so that the end result is not significantly changed. These degree terms should be interpreted as including at least ± 5% deviation of the modified term, as long as the deviation does not negate the meaning of the word it modifies.

[0077] As used in this application, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise.

[0078] In embodiments including an "additional" or "second" component, the second component as used herein is chemically different from the other components or the first component. The "third" component is different from the other, first and second components, and further listed or "additional" components are similarly different.

[0079] The term "and / or" as used herein refers to the presence or use of the listed items alone or in combination. In fact, the term means the use or presence of "at least one" or "one or more" of the listed items.

[0080] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and appropriately refers to humans. Thus, the methods of the present application are suitable for both human therapy and veterinary applications.

[0081] The term "compound of formula (R / S)-I" as used herein refers to a compound having the chemical name (R / S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine or (R / S)-2-(benzo[d][1,3]dioxol-5-ylmethyl)pyrrolidine and having the following chemical structure:

[0082]

[0083] The term "compound of formula (R)-I" as used herein refers to a compound having the chemical name (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine or (R)-2-(benzo[d][1,3]dioxol-5-ylmethyl)pyrrolidine and having the following chemical structure:

[0084]

[0085] The term "compound of formula (S)-I" as used herein refers to a compound having the chemical name (S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine or (S)-2-(benzo[d][1,3]dioxol-5-ylmethyl)pyrrolidine and having the following chemical structure:

[0086]

[0087] As used herein, the term "MDMA" or "racemic MDMA" refers to a compound having the following 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:

[0088]

[0089] As used herein, the term "MBDB" refers to a compound having the following chemical name: 1-(1,3-benzodioxol-5-yl)-N-methylbutan-2-amine or N-methyl-1,3-benzodioxolylbutylamine, and having the chemical formula:

[0090]

[0091] As used herein, the term "reducing agent" refers to any compound or combination of compounds that reduces a desired functional group. Reducing agents result in the bulk addition of electrons, or in the case of organic chemistry, the addition of hydrogen atoms to a functional group.

[0092] As used herein, the term "inert solvent" means a solvent that does not interfere with or otherwise inhibit the reaction. Thus, the characteristics of the inert solvent will vary depending on the reaction being performed. The choice of an inert solvent is within the skill of those skilled in the art.

[0093] The term "solvent" includes a single solvent and a mixture comprising two or more solvents.

[0094] As used herein, the term "protecting group" or "PG" etc. refers to protecting or masking the reactive part of a molecule to prevent side reactions in those reactive parts of the molecule, while manipulating the different parts of the molecule or the chemical part that reacts the different parts of the molecule. After the operation or reaction is completed, the protecting group is removed under the conditions of the remainder of the molecule without degradation or decomposition. Those skilled in the art can select suitable protecting groups. Many conventional protecting groups are known in the art, such as in "Protective Groups in Organic Chemistry" McOmie, JFWEd., Plenum Press, 1973, in Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd edition, 1999 and in Kocienski, P. Protecting Groups, 3rd edition, 2003, described in GeorgThieme Verlag (The Americas).

[0095] As used herein, the term "enantiomerically pure" means one enantiomer of a compound that is substantially free of the opposite enantiomer of the compound.

[0096] The term "substantially" as used herein in reference to an enantiomerically pure compound should be interpreted to mean that the enantiomerically pure compound contains less than 1% of the opposite enantiomer of the compound.

[0097] The term "enantiomeric excess" or "ee" is the absolute difference between the mole fractions of each enantiomer of a racemic compound.

[0098] As used herein, the term "pharmaceutical composition" refers to a composition of matter intended for pharmaceutical use.

[0099] The term "for pharmaceutical use" means compatible with the treatment of an individual.

[0100] The term "pharmaceutically acceptable" means compatible with the treatment of the subject.

[0101] The term "pharmaceutically acceptable salt" refers to acid addition salts that are suitable or compatible with the treatment of the subject.

[0102] Acid addition salts which are suitable or compatible with the treatment of the subject are any non-toxic organic or inorganic acid addition salts of any basic compound.

[0103] As used herein, 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. Suitable solvents are physiologically tolerable at the administered doses.

[0104] As used herein, the term "administering" refers to administering the composition of the present application or the compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof to cells in cell culture or in an individual.

[0105] The term "treatment" as used herein and as fully understood in the art means a method for obtaining a beneficial or desired result (including a clinical result). Examples of beneficial or desired clinical results for any disease, disorder or condition include, but are not limited to, reduction in degree, stable (i.e., non-deterioration) state, prevention of spread, delay or slowing of progression, improvement or alleviation of state, and relief (partial or complete), whether detectable or undetectable. "To treat", "treating" and "treatment" may also refer to prolonged survival compared to expected survival without treatment.

[0106] "Mitigate" a disease, disorder or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder or condition are reduced and / or the time course of progression is slowed or prolonged, as compared to not treating the disease, disorder or condition.

[0107] As used herein, the terms "prevention" or "prophylaxis" or synonyms thereof refer to reducing the risk or likelihood that a patient will develop a disease, disorder or condition or will exhibit symptoms associated with a disease, disorder or condition.

[0108] As used herein, the term "treating a disease, disorder or condition treatable by activating serotonin receptors" means that the disease, disorder or condition to be treated is directly or indirectly affected, regulated and / or has some biological basis, which includes serotonergic activity, particularly an increase in serotonergic activity. When the serotonergic activity associated with the disease, disorder or condition is excited by one or more compounds or compositions of the present application, these diseases respond favorably.

[0109] As used herein, the term "activation" includes agonism, partial agonists, and positive allosteric modulation of serotonin receptors.

[0110] As used herein, the term "5-HT 2A ” refers to the 5-HT2 5-HT receptor 2A HT 2A Receptor subtype.

[0111] As used herein, the term "therapeutic agent" refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0112] As used herein, the term "ON-time" means the duration of the anti-Parkinson's disease effect of L-DOPA.

[0113] When used, for example, with respect to the methods of treatment, uses, compositions and / or kits of the present application, a subject (e.g., a "subject in need thereof") is a subject who has been diagnosed and / or treated for an inflammatory disease that can be induced by activation of serotonin receptors (e.g., 5-HT 2A ) is a subject suffering from a disease, disorder or condition to be treated.

[0114] As used herein, the term "enantiomeric equivalents" refers to the molar amount of the base compound of each enantiomer (i.e., the compound of formula (R)-I and the compound of formula (S)-I), regardless of whether the enantiomer exists as a salt and / or a solvate. Thus, the percentage of enantiomeric equivalents of each of (R)-I and (S)-I is defined as the molar amount of (R)-I or (S)-I divided by the total molar amount of both (R)-I and (S)-I. The amount of any anion-forming salt and / or solvate-forming solvent is excluded and is not calculated when determining the percentage of enantiomeric equivalents of each of (R)-I and (S)-I.

[0115] II. Compounds of the present application

[0116] The applicant has studied an analog of MDMA, namely (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine, and provided enantiomerically pure (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine and its compositions and uses.

[0117] The present application includes enantiomerically pure compounds of formula (R)-I or salts and / or solvates thereof.

[0118]

[0119] In some embodiments, the enantiomerically pure compound of Formula (R)-I or its salt and / or solvate contains about 99 weight % or more of the compound of Formula (R)-I and about 1 weight % or less of the compound of Formula (S)-I or its salt and / or solvate.

[0120]

[0121] In some embodiments, the enantiomerically pure compound of formula (R)-I, or its salt and / or solvate, comprises greater than 99% by weight of the compound of formula (R)-I, or its salt and / or solvate, and less than 1% by weight of the compound of formula (S)-I, or its salt and / or solvate. In some embodiments, the enantiomerically pure compound of formula (R)-I, or its salt and / or solvate, 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%, 99.99% or 1% by weight. 0.00% by weight of a compound of formula (R)-I or a salt and / or solvate thereof, and 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01% or 0% by weight of a compound of formula (S)-I or a salt and / or solvate thereof.

[0122] In some embodiments, the enantiomerically pure compound of formula (R)-I, or its salt and / or solvate, comprises an enantiomeric excess (ee) of 98% or more. In some embodiments, the enantiomerically pure compound of formula (R)-I, or its salt and / or solvate, comprises an enantiomeric excess (ee) of 98% to 100%. In some embodiments, the enantiomerically pure compound of formula (R)-I, or its salt and / or solvate, comprises 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%.

[0123] In some embodiments, the enantiomerically pure compound of Formula (R)-I is in the form of a free base. In some embodiments, the enantiomerically pure compound of Formula (R)-I is in the form of an acid salt or a solvate thereof.

[0124] In one embodiment, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.The selection of suitable salts can be made by one skilled in the art (see, for example, SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0125] Acid addition salts suitable for individual treatment or compatible with individual treatment are any nontoxic organic or inorganic acid addition salts of any basic compound. The basic compound forming the acid addition salt includes, for example, a compound comprising an amine group. Exemplary inorganic acids forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and acidic metal salts, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids forming 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-hydroxyethylsulfonic acid. In one embodiment, monoacid salts or diacid salts are formed, and such salts exist in hydrated, solvated or substantially anhydrous forms. Typically, acid addition salts are more soluble in water and various hydrophilic organic solvents, and typically exhibit higher fusing points compared to their free alkali forms. The selection criteria for suitable salts are well known to those skilled in the art. Other non-pharmaceutically acceptable salts can be used, such as, but not limited to, oxalates, such as for separating the compounds of the present application for laboratory use, or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0126] In some embodiments, the enantiomerically pure compound of formula (R)-I or its salt and / or solvate is an enantiomerically pure salt of a compound of formula (R)-I or its solvate. Therefore, the present application includes an enantiomerically pure salt of a compound of formula (R)-I or its solvate. In some embodiments, the enantiomerically pure salt of a compound of formula (R)-I is an HCl salt. Therefore, in some embodiments, the present application includes an enantiomerically pure HCl salt of a compound of formula (R)-I or its solvate.

[0127] In some embodiments, the enantiomerically pure compound of formula (R)-I or its salt is provided as a solvate. The solvates of the present application compound include, for example, those prepared with a pharmaceutically acceptable solvent. Examples of such solvents include water (the resulting solvate is referred to as a hydrate) and ethanol, etc. Suitable solvents are physiologically tolerable at the administered dose.

[0128] The compounds of the present application may further exist in different polymorphic forms or amorphous forms, and it is contemplated that any polymorphic or amorphous form, or mixtures thereof, is included within the scope of the present application.

[0129] In some embodiments, the enantiomerically pure compound of formula (R)-I or its salt and / or solvate is crystalline. In some embodiments, the enantiomerically pure crystalline compound of formula (R)-I is an enantiomerically pure crystalline salt of a compound of formula (R)-I or its solvate. In some embodiments, the enantiomerically pure crystalline salt of a compound of formula (R)-I is an enantiomerically pure crystalline HCl salt of a compound of formula (R)-I or its solvate.

[0130] In some embodiments, the enantiomerically pure compound of Formula (R)-I, or a salt and / or solvate thereof, is amorphous.

[0131] In some embodiments, the enantiomeric excess of an enantiomer is determined using a variety of analytical techniques known in the art, including NMR spectroscopy, chiral column chromatography, or polarimetry. In some embodiments, the enantiomeric excess of an enantiomer is determined using a polarimeter using methods known in the art.

[0132] III. Composition of the present application

[0133] (i) Compositions of enantiomerically pure compounds of formula (R)-I or their salts and / or solvates

[0134] The enantiomerically pure compound of formula (R)-I or its salt and / or solvate is suitably formulated into a composition using one or more carriers in a conventional manner. Therefore, the present application also includes a composition comprising an enantiomerically pure compound of formula (R)-I or its salt and / or solvate and a carrier.

[0135]

[0136] The enantiomerically pure compound of formula (R)-I or its salt and / or solvate is suitably formulated into a pharmaceutical composition for administration to an individual in a biocompatible form suitable for in vivo administration. Therefore, the present application also includes a pharmaceutical composition comprising an enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate and a pharmaceutically acceptable carrier. In an embodiment of the present application, the pharmaceutical composition is used to treat any disease, disorder or condition described herein.

[0137] 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 to treat any disease, disorder or condition described herein.

[0138] (ii) Composition of non-racemic mixture of compounds of formula (R)-I and (S)-I of the present application

[0139] The present application also includes 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:

[0140]

[0141] wherein the compound of formula (R)-I or its salt and / or solvate is present in the composition in a greater amount on an enantiomeric equivalent basis relative to (S)-I or its salt and / or solvate.

[0142] In some embodiments, the composition comprises greater than 50% of the compound of Formula (R)-I or a salt and / or solvate thereof on an enantiomeric equivalent basis.

[0143] In some embodiments, the composition comprises 51% to 99% of the compound of formula (R)-I, or its salt and / or solvate, by enantiomeric equivalents, and 1% to about 49% of the compound of formula (S)-I, or its salt and / or solvate, by enantiomeric equivalents. In some embodiments, the composition comprises 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 its salt and / or solvate, by enantiomeric equivalents, and 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 its salt and / or solvate, by enantiomeric equivalents.

[0144] In some embodiments, the composition comprises 51% to 99% of the compound of formula (R)-I, or its salt and / or solvate, by enantiomeric equivalents, and 1% to 49% of the compound of formula (S)-I, or its salt and / or solvate, by enantiomeric equivalents.

[0145] In some embodiments, the composition comprises about 60% to 99% of a compound of formula (R)-I, or a salt and / or solvate thereof, by enantiomeric equivalents, and about 1% to about 40% of a compound of formula (S)-I, or a salt and / or solvate thereof, by enantiomeric equivalents.

[0146] In some embodiments, the composition comprises from about 60% to about 69.9% of a compound of formula (R)-I, or a salt and / or solvate thereof, by enantiomeric equivalents, and from about 30.1% to about 40% of a compound of formula (S)-I, or a salt and / or solvate thereof, by enantiomeric equivalents.

[0147] In some embodiments, the composition comprises about 70% to 99% of a compound of formula (R)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis, and about 1% to about 30% of a compound of formula (S)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis.

[0148] In some embodiments, the composition comprises about 70% to about 79.9% of a compound of formula (R)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis, and about 20.1% to about 30% of a compound of formula (S)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis.

[0149] In some embodiments, the composition comprises from about 70% to about 75% of a compound of formula (R)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis, and from 25% to about 30% of a compound of formula (S)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis.

[0150] In some embodiments, the composition comprises from about 75% to about 79.9% of a compound of formula (R)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis, and from about 20.1% to about 25% of a compound of formula (S)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis.

[0151] In some embodiments, the composition comprises about 75% to about 85% of the compound of formula (R)-I, or its salt and / or solvate, on an enantiomeric equivalent basis, and about 15% to about 25% of the compound of formula (S)-I, or its salt and / or solvate, on an enantiomeric equivalent basis.

[0152] In some embodiments, the composition comprises from about 80% to about 89.9% of a compound of formula (R)-I, or a salt and / or solvate thereof, by enantiomeric equivalents, and from about 10.1% to about 20% of a compound of formula (S)-I, or a salt and / or solvate thereof, by enantiomeric equivalents.

[0153] In some embodiments, the composition comprises about 80% to about 85% of Formula (R)-I or its salt and / or solvate by enantiomeric equivalents, and about 15% to about 20% of Formula (S)-I or its salt and / or solvate by enantiomeric equivalents.

[0154] In some embodiments, the composition comprises about 80% by enantiomeric equivalent of Formula (R)-I or a salt and / or solvate thereof, and about 20% by enantiomeric equivalent of Formula (S)-I or a salt and / or solvate thereof.

[0155] In some embodiments, the composition comprises from about 85% to about 89.9% of a compound of formula (R)-I, or a salt and / or solvate thereof, by enantiomeric equivalents, and from about 10.1% to about 15% of a compound of formula (S)-I, or a salt and / or solvate thereof, by enantiomeric equivalents.

[0156] In some embodiments, the composition comprises about 90% to 99% of a compound of formula (R)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis, and 1% to about 10% of a compound of formula (S)-I, or a salt and / or solvate thereof, on an enantiomeric equivalent basis.

[0157] In some embodiments, the composition comprises about 90% to 95% of the compound of Formula (R)-I or its salt and / or solvate on an enantiomeric equivalent basis, and 5% to about 10% of the compound of Formula (S)-I or its salt and / or solvate on an enantiomeric equivalent basis.

[0158] In some embodiments, the composition comprises 95% to 99% by enantiomeric equivalent of a compound of formula (R)-I or a salt and / or solvate thereof, and 1% to 5% by enantiomeric equivalent of a compound of formula (S)-I or a salt and / or solvate thereof.

[0159] In some embodiments, the compounds of formula (R)-I and (S)-I or their salts and / or solvates in the composition of the non-racemic mixture of the compound of formula (R)-I or its salt and / or solvate and (S)-I or its salt and / or solvate of the present application are all in the form of free base. In some embodiments, the compounds of formula (R)-I and (S)-I, their salts and / or solvates are all in the form of acid salts or their solvates.

[0160] In some embodiments, the enantiomeric excess of an enantiomer is determined using a variety of analytical techniques known in the art, including NMR spectroscopy, chiral column chromatography, or polarimetry. In some embodiments, the enantiomeric excess of an enantiomer is determined using polarimetry using methods known in the art using a polarimeter.

[0161] (iii) Composition of the present application

[0162] In some embodiments, the compounds of formula (R)-I and / or (S)-I (including enantiomerically pure compounds of formula (R)-I) are provided in the form of salts. The selection of suitable salts can be made by one skilled in the art. Acids that are generally considered suitable for forming pharmaceutically acceptable salts from basic drug compounds are discussed. For example, 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 in The Orange Book (Food & Drug Administration, Washington, DC on its website).

[0163] In some embodiments, the acid addition salt that is suitable for or compatible with individual treatment is any nontoxic organic or inorganic acid addition salt. Exemplary inorganic acids forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid and acidic metal salts, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids forming 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-hydroxyethylsulfonic acid. In some embodiments, exemplary acid addition salts also include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthylsulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as toluenesulfonate (tosylate)), etc. In some embodiments, the salt is present in a hydrated, solvated or substantially anhydrous form. Typically, acid addition salts are more soluble in water and various hydrophilic organic solvents and typically exhibit a higher melting point than their free base forms.

[0164] Salts of compounds of formula (R)-I or (S)-I (including enantiomerically pure compounds of formula (R)-I) can be formed by methods known to those of ordinary skill in the art, for example, by reacting (R)-I or (S)-I (including enantiomerically pure compounds of formula (R)-I) with an amount (e.g., an equal amount) of an acid in a medium (e.g., a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization.

[0165] In some embodiments, solvates of compounds of formula (R)-I and / or (S)-I (including enantiomerically pure compounds of formula (R)-I) are provided. Solvates include, for example, those prepared with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are referred to as hydrates) and ethanol, etc. Suitable solvents are physiologically tolerable at the administered dose.

[0166] Typically, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. Solvates are typically dried or azeotroped under ambient conditions. The selection of suitable conditions for forming a particular solvate can be performed by those skilled in the art.

[0167] The compounds of formula (R)-I and (S)-I (including enantiomerically pure compounds of formula (R)-I) or pharmaceutically acceptable salts and / or solvates thereof may also exist in various polymorphic and amorphous forms, and any polymorphic or amorphous form or mixture thereof is contemplated, and its form is included within the scope of the present application. In some embodiments of the present application, the pharmaceutical composition of the present application is used to treat any disease, disorder or condition described herein.

[0168] The compounds of formula (R)-I and (S)-I (including enantiomerically pure compounds of formula (R)-I) and / or pharmaceutically acceptable salts and / or solvates thereof are suitably formulated into pharmaceutical compositions for administration to individuals in a biocompatible form suitable for in vivo administration. Therefore, in one embodiment, the composition of the present application is a pharmaceutical composition and further comprises one or more pharmaceutically acceptable carriers.

[0169] The pharmaceutical composition of the present application is applied to individuality in various forms, depending on the selected route of administration, as will be understood by those skilled in the art. For example, the composition of the present application is applied by oral, suction, parenteral, buccal, sublingual, nose, rectum, vagina, patch, pump, mini pump, topical or transdermal application, and the pharmaceutical composition is formulated accordingly. In some embodiments, it is applied by a pump for periodic or continuous delivery. For example, in Remington's Pharmaceutical Sciences, (2000-20 edition) and The United States Pharmacopeia: The National Formulary (USP 24NF19) published in 1999, conventional operations and compositions for selecting and preparing suitable compositions are described.

[0170] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, 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) administration. Parenteral administration can be performed by continuous infusion over a selected period of time.

[0171] In some embodiments, the composition of the present application is administered orally, for example, with an inert diluent or with an absorbable edible carrier, or it may be encapsulated in a hard or soft shell gelatin capsule, or it may be compressed into a tablet, or it may be directly incorporated into the food of the diet. For oral therapeutic administration, the composition may be mixed with an excipient and used in the form of an ingestible tablet, buccal tablet, lozenge, capsule, caplet, pill, granule, lozenge, chewing gum, powder, syrup, elixir, wafer, aqueous solution or suspension. In the case of tablets, the carrier used includes lactose, corn starch, sodium citrate and phosphate. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silicon dioxide); 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, pills or granules for oral administration, a pH-sensitive enteric coating such as Eudragits designed to control the release of the active ingredient is optionally used. TM Oral dosage forms also include modified release formulations, such as immediate release 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), for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., molecular sieve-type particles) or thin hollow permeable fiber bundles or short-cut hollow permeable fibers (agglomerated or maintained in fiber packages). Timed release compositions can be formulated in, for example, liposomes or those in which the composition is protected by differential degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed by a variety of phospholipids such as cholesterol, stearylamine or phosphatidylcholine. For oral administration in capsule form, useful carriers or diluents include lactose and dry corn starch.

[0172] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as dry products for reconstitution with water or other suitable vehicles before use. When aqueous suspensions and / or emulsions are administered orally, the composition of the present application is appropriately suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. If necessary, certain sweeteners and / or flavoring agents and / or coloring agents are added. In some embodiments, this liquid preparation for oral administration is prepared by conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters or ethanol); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0173] In some embodiments, the composition of the present application is formulated as a solid or semisolid composition. In some embodiments, the composition of the present application is formulated as a tablet, a buccal tablet, a lozenge, a capsule, a caplet, a pill, a granule, a lozenge, a chewing gum, a powder, a syrup, an elixir, a wafer, an aqueous solution or a suspension. In some embodiments, the composition of the present application is formulated as a tablet or a capsule. In some embodiments, the composition of the present application is formulated as a tablet.

[0174] The composition of the present application can also be lyophilized and the lyophilizate obtained can be used, for example, for the preparation of a product for injection.

[0175] In some embodiments, the composition of the present application is administered parenterally. For example, a solution of the composition of the present application is prepared in water appropriately mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO and mixtures thereof containing or not containing alcohol, and in oil. Under ordinary storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms. Those skilled in the art know how to prepare suitable preparations. For parenteral administration, sterile solutions of the compositions of the present application are usually prepared, and the pH of the solutions is appropriately adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the preparation isotonic. For ocular administration, ointments or drop-able liquids are delivered, for example, by ocular delivery systems known in the art such as applicators or eye drops. In some embodiments, such preparations contain mucus mimics (mucomimetics), such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol; preservatives such as sorbic acid, EDTA or benzyl chromium chloride; conventional amounts of diluents or carriers. For pulmonary administration, a suitable diluent or carrier is selected to form an aerosol.

[0176] In some embodiments, the composition of the present application is formulated for parenteral administration by injection, including the use of conventional catheter insertion techniques or infusions. Compositions for injection are, for example, present in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of preservatives. In some embodiments, the composition is formulated as a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and contains preparatons such as suspending agents, stabilizers and / or dispersants. In all cases, the form must be sterile and must be a fluid that is easy to inject. Alternatively, the composition of the present application is suitably in a sterile powder form, for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0177] In some embodiments, the compositions of the application are for intranasal administration.

[0178] Therefore, in some embodiments, the present application also includes an intranasal 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 also includes an intranasal 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.

[0179] In some embodiments, the present application also includes 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:

[0180] wherein the compound of formula (R)-I or its salt and / or solvate is present in the composition in a greater amount on an enantiomeric equivalent basis relative to (S)-I or its salt and / or solvate.

[0181] In some embodiments, the enantiomeric equivalents are as described under the "Composition of Non-racemic Mixtures of Compounds of Formula (R)-I and (S)-I" section of this application.

[0182] In embodiments of the present application, the intranasal compositions are used to treat any of the diseases, disorders, or conditions described herein.

[0183] In some embodiments, the composition for nasal administration is conveniently formulated as aerosol, drops, gel and powder. For intranasal administration or by inhalation administration, the composition of the present application is conveniently delivered from a pump spray container squeezed or pumped by an individual in the form of a solution, dry powder preparation or suspension, or presented as an aerosol spray and delivered from a pressurized container or atomizer. Aerosol compositions generally comprise a solution or fine suspension of the composition of the present application in a physiologically acceptable aqueous or non-aqueous solvent, and are generally present in a sealed container in a single dose or multiple doses in a sterile form, and sealed containers are for example taken in cartridges or refilled forms for use by atomizing devices. Alternatively, sealed containers are single dispensing devices, for example single dose nasal inhalers or aerosol dispensers equipped with metering valves, and metering valves are used to discard after use. When dosage form includes an aerosol dispenser, it can contain propellants, for example compressed gases such as compressed air or organic propellants such as fluorochlorohydrocarbons. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, sevoflurane, carbon dioxide or other suitable gases. In the case of pressurized aerosols, the dosage unit is appropriately determined by providing a valve to deliver a metered amount. In some embodiments, a pressurized container or sprayer contains a solution or suspension of the composition of the application. Capsules and cartridges (e.g., made of gelatin) for inhalers or insufflators are, for example, formulated into a powder mixture containing the composition of the application and a suitable powder base such as lactose or starch. Aerosol dosage forms can also take the form of a pump-sprayer.

[0184] In some embodiments, intranasal pharmaceutical compositions are formulated as an aerosol for use with a pump-nebulizer.

[0185] 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 pyrogen-free water.

[0186] In some embodiments, the powder is formulated for use or administration with an inhaler or insufflator. Thus, in some embodiments, the dry powder is formulated for use or administration as capsules and cartridges for use with an inhaler or insufflator.

[0187] In some embodiments, the dry powder further comprises a suitable powder base. In some embodiments, the suitable powder base comprises lactose or starch.

[0188] 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.

[0189] In some embodiments, the intranasal pharmaceutical composition is a solution, suspension, or emulsion. In some embodiments, the intranasal pharmaceutical composition is a solution.

[0190] In some embodiments, the aqueous intranasal pharmaceutical composition is formulated for administration into 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 presented as an aerosol spray delivered from a pressurized container or nebulizer. In some embodiments, the aqueous intranasal pharmaceutical composition is formulated as an aerosol for use with a pump-nebulizer.

[0191] In some embodiments, water is present in an amount of about 50% by weight to about 75% by weight, about 50% by weight to about 70% by weight, about 50% by weight to about 65% by weight, about 33% by weight to about 75% by weight, about 55% by weight to about 70% by weight, or about 55% by weight to about 65% by weight of the composition. In some embodiments, water is present in an amount of about 50% by weight, about 60% by weight, about 65% by weight, or about 70% by weight of the composition. In some embodiments, water is present in an amount of about 55% by weight to about 65% by weight of the composition. In some embodiments, water is about 60% by weight of the composition.

[0192] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the compositions of the present application are formulated with carriers such as sugar, 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.

[0193] In some embodiments, the compositions of the application are for sublingual administration.

[0194] Therefore, in some embodiments, the present application also includes 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 also includes 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.

[0195] In some embodiments, the present application also includes 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:

[0196] wherein the compound of formula (R)-I or its salt and / or solvate is present in the composition in a greater amount on an enantiomeric equivalent basis relative to (S)-I or its salt and / or solvate.

[0197] In some embodiments, the enantiomeric equivalents are as described under the "Composition of Non-racemic Mixtures of Compounds of Formula (R)-I and (S)-I" section of this application.

[0198] In some embodiments, the sublingual dosage form is formulated as a tablet, drops, strips, spray, lozenge, or effervescent tablet.

[0199] In an embodiment of the present application, the sublingual composition is used to treat any disease, disorder or condition described herein.

[0200] In some embodiments, the intranasal and / or sublingual compositions provide a faster onset of activity, exhibit reduced neurotoxicity and / or exhibit reduced cardiotoxicity compared to oral compositions. In some embodiments, to achieve the same beneficial effects, the required dose of the compound of Formula (R)-I or the dose of the non-racemic combination of the compound of Formula (R)-I and the compound of Formula (S)-I in the intranasal and / or sublingual compositions is lower than the dose of the compound of Formula (R)-I or the dose of the non-racemic combination of the compound of Formula (R)-I and the compound of Formula (S)-I in the oral compositions.

[0201] The suppository form of the composition of the present application can be used for vaginal, urethral and rectal administration. Such suppositories are usually composed of a mixture of substances that are solid at room temperature but melt at body temperature. The materials commonly used to prepare such vehicles include, but are not limited to, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th edition, Mack Publishing, Easton, PA, 1980, pp.1530-1533 for further discussion of suppository dosage forms.

[0202] In some embodiments, the composition of the present application comprises about 40 mg to about 180 mg of a compound of formula (R)-I or both compounds of formula (R)-I and (S)-I, and / or a salt and / or solvate thereof. In some embodiments, the composition of the present application comprises 40 mg, 60 mg, 75 mg, 80 mg, 100 mg, 120 mg or 125 mg of a compound of formula (R)-I or both compounds of formula (R)-I and (S)-I, and / or a salt and / or solvate thereof. In some embodiments, depending on the mode of administration, the composition of the present application is a pharmaceutical composition comprising about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of a compound of formula (R)-I or both compounds of formula (R)-I and (S)-I and / or pharmaceutically acceptable salts and / or solvates thereof, and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of one or more pharmaceutically acceptable carriers, all weight percentages being based on the total composition.

[0203] In some embodiments, the enantiomerically pure compound of formula (R)-I and / or its salt and / or solvate, or both compounds of formula (R)-I and (S)-I and / or their salts and / or solvates are present in the composition in an amount effective, for example, to treat or prevent a disease that can be treated by activating 5-hydroxytryptamine receptors (particularly 5-HT 2A ) is an effective amount of a disease, disorder or condition to be treated.

[0204] In some embodiments, the composition of the present application is a pharmaceutical composition comprising an additional therapeutic agent and optionally one or more pharmaceutically acceptable carriers. In some embodiments, the additional therapeutic agent is a known agent that can be used to treat a disease, disorder or condition that benefits from treatment with racemic MDMA and / or a pharmaceutically acceptable salt and / or solvate thereof, or benefits from treatment with a combination of psychotherapy and racemic MDMA and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0205] IV. Methods and Uses of the Present Application

[0206] (i) Methods and uses of (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine

[0207] A three-dimensional model of all 5-hydroxytryptamine (5-HT) receptor subtypes has been constructed, and based on the 5-HT 1B / 5-HT 2B / 5-HT 2CThe existing crystal structure data of , was validated using homology modeling, and residues that contribute to the selectivity of each receptor have been identified (Wang, Yq et al., Acta Pharmacologica Sinica (2019) 40: 1138-1156). Using such a model, the applicant has performed molecular docking studies using the (R) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (compound of formula (R)-I). The applicant has 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) with a lower and more balanced affinity than its opposite enantiomer. 2B ) and 5-hydroxytryptamine 2A receptor (5-HT 2A ) binding, where the opposite enantiomer binds to the 5-hydroxytryptamine 2B receptor (5-HT 2B ) has a higher affinity.

[0208] 5-HT 2B Involved in mediating toxicities 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 5-HT 2B and 5-HT 2A Therefore, in 5-HT 2B and 5-HT 2A Compounds with more balanced affinities between the two would be advantageous.

[0209] Therefore, the (R) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine is expected to have an improved toxicological profile compared to its racemate (ie, the compound of formula (R / S)-I) while maintaining the therapeutic efficacy of the racemate.

[0210] In fact, the applicant has conducted studies in C57 mice (a general colony mouse model) and BTBR mice (a mouse model of autism spectrum disorder), and has shown that, unlike MDMA, the (R) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (a compound of formula (R)-I) did not cause a dose-dependent increase in core body temperature in either mouse model in core temperature and locomotor activity studies in both C57 mice and BTBR mice. Elevated body temperature, hyperthermia, is known to cause cell damage and neurotoxicity (Walter and Carraretto, Crit Care. 2016 Jul 14; 20(1): 199). In addition, while the compound of formula (R)-I did exhibit a dose-dependent lowering effect on body temperature, no decrease in core body temperature was observed at a dose of about 5.6 mg / kg (R)-I in either mouse strain. In contrast, the (S) enantiomer of 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (compound of formula (S)-I) was found to cause a significant decrease in temperature at a lower dose of about 5.6 mg / kg. Thus, Applicants have shown that at a dose of about 5.6 mg / kg, (R)-I does not cause an increase or decrease in core body temperature in the tested mouse strains.

[0211] These studies further demonstrated that neither (R)-I nor (S)-I induced significant dose-dependent locomotor stimulation.

[0212] In cardiovascular toxicity studies, the compound of formula (R)-I was shown to have significantly lower effects on cardiovascular effects as measured by systolic, diastolic and mean arterial pressure in C57 and BTBR mouse models compared to the compound of formula (S)-I, MDMA and S-methamphetamine. This is consistent with the above-mentioned predictive docking studies and further predictive IC 50 Studies are consistent, showing that (S)-I binds 5-HT more strongly than (R)-I 2B Receptor.

[0213] In social testing studies, (R)-I was shown to induce similar prosocial responses compared to MDMA in both C57 and BRTB mouse models, but at lower doses compared to MDMA, indicating that (R)-I is a more effective drug than MDMA in terms of prosocial responses. In addition, (R)-I showed social preference without motor stimulation in both C57 and BRTB mouse models.

[0214] Thus, Applicants have shown that (R)-I exhibits social preferences comparable to MDMA, but at lower doses, and advantageously with reduced side effects (as shown in core body temperature, locomotor activity, and cardiovascular studies), particularly at doses up to about 5.6 mg / kg in the mouse strains tested.

[0215] The compounds of formula (R)-I can be used to treat diseases that can activate 5-hydroxytryptamine receptors such as 5-HT 2A Diseases, disorders or conditions to be treated. Therefore, the compounds of the present application can be used as drugs. Therefore, the present application also includes compounds of the present application used as drugs.

[0216] Thus, the present application includes methods of treating a disease, disorder or condition treatable by activating serotonin receptors 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.

[0217] The present application also includes the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for treating a disease, disorder or condition that can be treated by activating 5-hydroxytryptamine receptors, and the use of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for preparing a medicament for treating a disease, disorder or condition that can be treated by activating 5-hydroxytryptamine receptors. The present application also includes an enantiomerically pure compound of formula (R)-I of the present application or a pharmaceutically acceptable salt and / or solvate thereof for treating a disease, disorder or condition that can be treated by activating 5-hydroxytryptamine receptors.

[0218] In some embodiments, the serotonin receptor is 5-HT 2A Thus, the present application includes methods for activating 5-hydroxytryptamine 2A receptors (5-HT 2A ) method, which comprises administering to cells an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof. The present application also includes a method for activating 5-HT in cells 2A The enantiomerically pure compound of formula (R)-I or its salt and / or solvate, and the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate in the preparation of a 5-HT 2A The present application also includes enantiomerically pure compounds of formula (R)-I or pharmaceutically acceptable salts and / or solvates thereof, which are used to activate 5-HT in cells 2A .

[0219] The present application also includes treatments that can activate 5-HT 2AA method for treating a disease, disorder or condition comprising administering an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof to an individual in need thereof. The present application also includes an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof for treating a disease, disorder or condition that can be treated by activating 5-HT 2A The invention relates to a method for treating a disease, disorder or condition, and a method for treating a disease, disorder or condition by activating 5-HT 2A The present application also includes enantiomerically pure compounds of formula (R)-I or their salts and / or solvates for use in treating diseases, disorders or conditions that can be treated by activating 5-HT 2A The disease, disorder or condition being treated.

[0220] In some embodiments, treatment with an enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof includes a reduced risk of adverse side effects compared to treatment with racemic 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (i.e., a compound of Formula (R / S)-I) or treatment with an enantiomerically pure compound of Formula (S)-I.

[0221] In some embodiments, treatment with an enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof includes a reduced risk of adverse side effects compared to treatment with racemic 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (i.e., a compound of Formula (R / S)-I).

[0222] In some embodiments, treatment with an enantiomerically pure compound of Formula (R)-I, or a pharmaceutically acceptable salt and / or solvate thereof, comprises a reduced risk of adverse side effects compared to treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA).

[0223] 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.

[0224] In some embodiments, the adverse side effect is hyperthermia or hypothermia. In some embodiments, the adverse side effect is hyperthermia. In some embodiments, the adverse side effect is hypothermia.

[0225] Reports indicate that long-term use of MDMA may lead to heart valve fibrosis and dysfunction, such as valvular heart disease (VHD) (Setola et al., Mol. Pharmacol. 63: 1223-1229, 2003). Therefore, in some embodiments, the adverse side effect is cardiotoxicity. In some embodiments, the cardiotoxicity is heart valve fibrosis and dysfunction. In some embodiments, the cardiotoxicity is valvular heart disease. Therefore, in some embodiments, the adverse side effect is valvular heart disease. In some embodiments, the cardiotoxicity is tachycardia or tremor.

[0226] In some embodiments, the risk of adverse side effects is reduced by combining 5-hydroxytryptamine 2A (5-HT 2A ) receptor, using an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof as compared to a compound of formula (R / S)-I or a salt and / or solvate thereof or as compared to an enantiomerically pure compound of formula (S)-I or a salt and / or solvate thereof, binds to the 5-hydroxytryptamine 2B receptor (5-HT 2B )combined.

[0227] In some embodiments, the reduced risk of adverse side effects is achieved by using an enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof in the presence of 5-hydroxytryptamine 2B (5-HT 2B ) receptors and 5-hydroxytryptamine 2A (5-HT 2A ) receptors to provide a more balanced binding.

[0228] In some embodiments, the disease, disorder or condition treatable by activation of serotonin receptors is a disease, disorder or condition that benefits from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof.

[0229] In some embodiments, the disease, disorder or condition treatable by activation of serotonin receptors is a disease, disorder or condition that would benefit from treatment with racemic MBDB or a pharmaceutically acceptable salt and / or solvate thereof.

[0230] In some embodiments, the disease, disorder, or condition treatable by activation of serotonin receptors is a disease, disorder, or condition that benefits from treatment with racemic MDMA, and the method includes a reduced risk of adverse side effects compared to treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA).

[0231] In some embodiments, the disease, disorder, or condition treatable by activation of serotonin receptors is any disease, disorder, or condition that benefits from psychotherapy, including but not limited to one or more of post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction, and eating disorders.

[0232] 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 to treat a disease, disorder or condition. In some embodiments, the compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of psychotherapy. In some embodiments, psychotherapy is used for mental disorders.

[0233] In some embodiments, the disease, disorder or condition treatable by activating serotonin receptors is one or more psychiatric disorders. In some embodiments, the one or more psychiatric 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.

[0234] 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.

[0235] In some embodiments, the mood disorder is selected from one or both of depression and bipolar disorder.

[0236] In some embodiments, the developmental disorder is selected from one or both of autism spectrum disorder (ASD) and Asperger's syndrome.

[0237] In some embodiments, the substance use disorder and addiction are selected from one or more of alcoholism, drug abuse, drug dependence, and compulsive gambling. In some embodiments, drug dependence is opioid dependence. In some embodiments, the substance use disorder is opioid use disorder.

[0238] In some embodiments, the eating disorder is selected from anorexia and bulimia.

[0239] In some embodiments, the personality disorder is selected from borderline personality disorder and dependent personality disorder.

[0240] In some embodiments, the psychiatric disorder is selected from schizophrenia and other disorders causing dissociation from reality.

[0241] In some embodiments, the one or more psychiatric disorders are selected from one or more of autism spectrum disorder (ASD), depression, and drug dependence. In some embodiments, the depression is clinical depression, for example, in a palliative care individual.

[0242] In some embodiments, the one or more psychiatric disorders are selected from post-traumatic stress disorder (PTSD), eating disorders, and alcoholism. In some embodiments, the one or more psychiatric disorders are post-traumatic stress disorder (PTSD).

[0243] In some embodiments, the one or more mental disorders are selected from autism spectrum disorder (ASD), depression, and drug dependence. In some embodiments, depression is clinical depression, e.g., in a palliative care individual. In some embodiments, the substance use disorder is an opioid use disorder.

[0244] In some embodiments, the disease, disorder, or condition treatable by activation of serotonin receptors is an autism spectrum disorder.

[0245] 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.

[0246] In some embodiments, an 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, an enantiomerically pure compound of formula (R)-I, or a pharmaceutically acceptable salt and / or solvate thereof, is administered during and / or after psychotherapy.

[0247] In some embodiments, the psychotherapy is selected from behavioral psychotherapy, exposure-based psychotherapy, cognitive psychotherapy, and psychodynamically oriented psychotherapy.

[0248] In some embodiments, a disease, disorder, or condition treatable by activation of serotonin receptors is any disease, disorder, or condition that would benefit from treatment with L-3,4-dihydroxyphenylalanine (L-DOPA).

[0249] In some embodiments, an 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 treat a disease, disorder, or condition that benefits from treatment with L-DOPA. In some embodiments, an enantiomerically pure compound of formula (R)-I, or a pharmaceutically acceptable salt and / or solvate thereof, improves the therapeutic effect of L-DOPA. In some embodiments, an 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 therapeutic effect of L-DOPA.

[0250] In some embodiments, the disease, disorder, or condition that benefits from treatment with L-DOPA is Parkinson's disease.

[0251] The present application also includes a method for treating Parkinson's disease, comprising administering an enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0252] The present application also includes 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 preparing 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 treating Parkinson's disease.

[0253] In some embodiments, an 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 treat Parkinson's disease. In some embodiments, an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the efficacy of L-DOPA in treating Parkinson's disease. In some embodiments, an 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 in treating Parkinson's disease.

[0254] In some embodiments, an enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the therapeutic efficacy of L-DOPA by reducing L-DOPA-induced dyskinesias.

[0255] Thus, in some embodiments, the disease, disorder or condition that benefits from treatment with racemic MDMA, or a pharmaceutically acceptable salt and / or solvate thereof, is a movement disorder. In some embodiments, the movement disorder is an L-DOPA-induced movement disorder.

[0256] In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the therapeutic effect of L-DOPA by increasing the duration of the anti-Parkinson's disease benefit of L-DOPA (e.g., duration (ON-time)). In some embodiments, the enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the therapeutic effect of L-DOPA by increasing the duration of the anti-Parkinson's disease benefit of L-DOPA without disabling dyskinesia.

[0257] In some embodiments, the enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof improves the therapeutic efficacy of L-DOPA by reducing L-DOPA-induced Parkinson's disease psychosis.

[0258] Thus, in some embodiments, the disease, disorder or condition that benefits from treatment with racemic MDMA, or a pharmaceutically acceptable salt and / or solvate thereof, is L-DOPA-induced Parkinson's disease psychosis.

[0259] "Reducing L-DOPA-induced dyskinesia" or "reducing L-DOPA-induced Parkinson's disease psychosis" refers to any reduction in the extent of dyskinesia, stabilization of the state (i.e., not worsening), delay or slowing of progression, improvement or alleviation and relief (whether partial or total), whether detectable or undetectable, in the presence of an enantiomerically pure compound of Formula (R)-I, or a pharmaceutically acceptable salt and / or solvate thereof, as compared to otherwise identical conditions except for the absence of an enantiomerically pure compound of Formula (R)-I, or a pharmaceutically acceptable salt and / or solvate thereof.

[0260] "Increasing the duration of the anti-Parkinson's disease benefit of L-DOPA" means any increase in the duration of the anti-Parkinson's disease benefit of L-DOPA compared to otherwise identical conditions except for the absence of enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0261] "Increasing the duration of the anti-Parkinson's disease benefit of L-DOPA without defeating dyskinesias" means any increase in the duration of the anti-Parkinson's disease benefit of L-DOPA without defeating dyskinesias compared to otherwise identical conditions except for the absence of enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0262] Those skilled in the art will appreciate that methods for assessing L-DOPA-induced dyskinesia and / or psychosis are well known in the art, such as those found in: 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.

[0263] The applicant has shown that the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate promotes prosocial behavior in vivo in C57 mice (general colony mouse model) and BRTB mice (mouse model of autism spectrum disorder). Compared with MDMA, (R)-I also shows that it causes prosocial effects at lower doses. It is further shown that in C57 and BRTB mouse models, the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate does not affect the motor activity in the mouse model. The applicant further shows that the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate does not cause a significant impact on core temperature. In addition, the applicant has shown that compared with the compound of formula (S)-I, (racemic) MDMA and methamphetamine, the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate has a lower impact on cardiovascular events.

[0264] Therefore, the present application also includes a method of treating one or more signs or symptoms of a disease, disorder or condition treatable by activating serotonin receptors, 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.

[0265] The present application also includes 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 condition that can be treated by activating 5-hydroxytryptamine receptors, 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 condition that can be treated by activating 5-hydroxytryptamine receptors, and 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 condition that can be treated by activating 5-hydroxytryptamine receptors.

[0266] In some embodiments, at least one sign or symptom of a disease, disorder, or condition treatable by activating serotonin receptors is alleviated following administration of an enantiomerically pure compound of Formula (R)-I, or a pharmaceutically acceptable salt and / or solvate thereof.

[0267] Thus, in some embodiments, the methods and uses provided herein reduce at least one sign or symptom of a disease, disorder or condition that can be treated by activating a serotonin receptor. In some embodiments, the methods and uses provided herein reduce at least one sign or symptom of a disease, disorder or condition that can be treated by activating a serotonin receptor by about 5% to about 100%, for example, 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 treatment without an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0268] In some embodiments, signs or symptoms of a disease, disorder, or condition treatable by activating serotonin receptors are reduced or eliminated in a subject within about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, or about 3 months after administration of an enantiomerically pure compound of Formula (R)-I, or a pharmaceutically acceptable salt and / or solvate thereof.

[0269] In some embodiments, signs or symptoms of a disease, disorder, or condition that can be treated by activating serotonin receptors are reduced or eliminated in an individual within 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.

[0270] "Alleviation of at least one sign or symptom of a disease, disorder or condition treatable by activation of serotonin receptors" refers to any reduction or alleviation of the signs or symptoms of the disease, disorder or condition compared to otherwise identical conditions except for the absence of enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof.

[0271] In some embodiments, signs or symptoms of a disease, disorder, or condition that can be treated by activating serotonin receptors are neurotoxicity, hyperthermia, hypothermia, cardiotoxicity, and substance use disorder.

[0272] In some embodiments, the disease, disorder or condition treatable by activating 5-HT receptors is autism spectrum disorder, and the present application also includes a method for treating one or more signs or symptoms of autism spectrum disorder, which comprises administering to an individual 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.

[0273] The present application also includes 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 disorders, 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 disorders, and 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 disorders.

[0274] In some embodiments, the one or more signs or symptoms of an autism spectrum disorder are selected from general anxiety, clinical anxiety, irritability, inappropriate speech, stereotypies, social withdrawal, repetitive behaviors, and hyperactivity.

[0275] In some embodiments, one or more signs or symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal. In some embodiments, one or more signs or symptoms of autism spectrum disorder are stereotypy. In some embodiments, one or more signs or symptoms of autism spectrum disorder are social withdrawal. Therefore, in some embodiments, enantiomerically pure compounds of formula (R)-I or pharmaceutically acceptable salts and / or solvates thereof are used to promote prosocial activities.

[0276] The present application also includes treating one or more symptoms of autism spectrum disorder while reducing the adverse side effects of treatment with racemic MDMA or (R / S)-I, which comprises administering or using an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof to an individual in need thereof.

[0277] In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal, and the adverse side effects are selected from hyperthermia, stereotypy and neurotoxicity. In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal, and the adverse side effects are selected from hyperthermia and neurotoxicity. In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal, and the adverse side effects are selected from hyperthermia and neurotoxicity.

[0278] In some embodiments, the autism spectrum disorder is as defined by DSM-IV, wherein 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.

[0279] In some embodiments, the one or more symptoms are selected from qualitative impairment in social interaction.

[0280] In some embodiments, qualitative impairments in social interaction include one or more of the following: significant impairment in the use of a variety of nonverbal behaviors, including eye-to-eye gaze, facial expressions, body posture, and gestures to regulate social interactions; failure to develop peer relationships appropriate to the level of progress; lack of spontaneous seeking to share enjoyment, interests, or achievements with others (e.g., lack of showing, bringing, or pointing out objects of interest); and lack of social or emotional reciprocity.

[0281] In some embodiments, qualitative impairments in communication include one or more of: delay or complete lack of oral language development (without accompanying attempts to compensate through alternative modes of communication such as gestures or gesticulations); in individuals with adequate speech, marked impairment in the ability to initiate or maintain conversations with other individuals; stereotyped and repetitive use of speech or specialized language; and lack of varied, spontaneous belief play or social imitation play appropriate to developmental level.

[0282] In some embodiments, restricted, repetitive and stereotyped patterns of behavior, interests, and activities include one or more of the following: preoccupations including stereotyped and restricted patterns of preoccupation with one or more preoccupations that are abnormal in intensity or focus; marked inflexibility in adhering to specific, nonfunctional routines or rules; stereotyped and repetitive movement patterns (e.g., hand or finger flapping or twisting or complex whole-body movements); and persistent preoccupation with parts of objects.

[0283] In some embodiments, the disease, disorder or condition treatable by activating serotonin receptors is anxiety, and the application also includes a method of treating one or more signs or symptoms of anxiety, comprising administering to an individual 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.

[0284] The present application also includes the use of the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate for treating one or more signs or symptoms of anxiety, the use of the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate for preparing a medicament for treating one or more signs or symptoms of anxiety, and the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate for treating one or more signs or symptoms of anxiety.

[0285] In some embodiments, one or more signs or symptoms of an anxiety disorder are measured according to a diary assessment, a clinician or caregiver assessment, or a clinical scale.

[0286] In some embodiments, the one or more signs or symptoms of an anxiety disorder are phobias, including fear of social interactions or situations, avoidance of anxiety triggers, feelings of stress, irritability, catastrophizing, nervousness, tachycardia, palpitations, tremors, fatigue, worry, irritability, obsessions, compulsions, muscle tension, sweating, dizziness, shortness of breath, sleep disturbances, or a combination thereof.

[0287] Thus, in some embodiments, an enantiomerically pure compound of Formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof is used to promote prosocial activities in an individual suffering from an anxiety disorder.

[0288] 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.

[0289] In some embodiments, an 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 "add-on" therapy.

[0290] In some embodiments, the enantiomerically pure compound of formula (R)-I comprises greater 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%, 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%, 99.99% by weight. 9 wt % or 100 wt % of the compound of formula (R)-I and 0.9 wt %, 0.8 wt %, 0.7 wt %, 0.6 wt %, 0.5 wt %, 0.4 wt %, 0.3 wt %, 0.2 wt %, 0.1 wt %, 0.09 wt %, 0.08 wt %, 0.07 wt %, 0.06 wt %, 0.05 wt %, 0.04 wt %, 0.03 wt %, 0.02 wt %, 0.01 wt % or 0 wt % of the compound of formula (S)-I.

[0291] In some embodiments, the enantiomerically pure compound of formula (R)-I comprises an enantiomeric excess (ee) of 98% or more. In some embodiments, the enantiomerically pure compound of formula (R)-I comprises an enantiomeric excess (ee) of 98% to 100%. In some embodiments, the enantiomerically pure compound of formula (R)-I comprises 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%.

[0292] In some embodiments, the enantiomeric purity of a compound is determined by optical rotation.

[0293] In some embodiments, the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate is used or applied in an amount that, when applied to an individual, is sufficient to achieve a beneficial or desired result, including a clinical result, and therefore, the amount depends on the context of its application. Therefore, the amount applied or used is the amount of the compound sufficient to treat, prevent or inhibit a disease or condition. In some embodiments, the amount of the compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate applied will vary according to factors such as pharmaceutical preparations, routes of administration, conditions, types of diseases or illnesses, the identity of the individual being treated, but can still be routinely determined by those skilled in the art. In one embodiment, the amount applied or used is the amount that is manifested as an improvement or reduction in any disease, illness or condition symptoms after treatment with it, particularly compared to a disease, illness or condition symptom that is not treated.

[0294] In one embodiment, the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate, or its pharmaceutically acceptable salt and / or solvate is applied at least once a week. However, in another embodiment, the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate is applied to the individual about once every two weeks, three weeks or one month. In another embodiment, the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate is applied about once a week to about once a day. In another embodiment, the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate is applied 2, 3, 4, 5 or 6 times a day. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the individual, the concentration and / or activity of the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate, and / or a combination thereof. It should also be understood that the effective dose of the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate for treatment can be increased or decreased during a specific treatment regimen. The variation in dosage can be produced and become apparent by standard diagnostic assays known in the art. In some cases, long-term administration is required. For example, the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate is applied to an individual in an amount and duration sufficient to treat the individual.

[0295] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In one embodiment, the subject is a non-human animal. In one embodiment, the subject is a canine. In one embodiment, the subject is a feline. Thus, the methods and uses of the present application are directed to human and veterinary diseases, disorders and conditions.

[0296] 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 for treating diseases, disorders or conditions treatable by activating serotonin receptors.

[0297] In some embodiments, when used in combination with other agents that can be used to treat diseases, disorders or conditions that can be treated by activating serotonin receptors, the embodiment is to administer an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof simultaneously with those agents. As used herein, "simultaneous administration" of two substances to an individual means providing each of the two substances so that they are simultaneously active in the individual. The exact details of administration will 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, or even administering one substance within 24 hours of administering the other substance, if the pharmacokinetics are appropriate. The design of a suitable administration regimen is conventional for those skilled in the art. In a specific embodiment, the two substances will be administered substantially simultaneously, i.e., administered within a few minutes of each other, or administered in a single composition containing the two substances. Another embodiment of the present application is to administer a combination of agents to an individual in a non-simultaneous manner.

[0298] The dosage of the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate varies according to many factors, such as the pharmacodynamic properties of the compound, 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 of concurrent treatment (if any) and the clearance rate of the enantiomerically pure compound of formula (R)-I or its pharmaceutically acceptable salt and / or solvate in the individual to be treated. Those skilled in the art can determine the appropriate dosage based on the above factors.

[0299] As a representative example, the oral dosage of an enantiomerically pure compound of formula (R)-I or a pharmaceutically acceptable salt and / or solvate thereof will be between about 1 mg per day and about 50 mg per day for an adult, suitably about 1 mg per day to about 40 mg per day, more suitably about 2 mg per day to about 30 mg per day. In some embodiments, the individual body weight is 55 to 65 kg, suitably 60 kg. For oral administration, a representative amount is 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.

[0300] 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 to treat any disease, disorder or condition described herein as described below.

[0301] (ii) Methods and uses of the compositions of the present application

[0302] In some embodiments, the compositions (including pharmaceutical compositions) of the present application can be used to treat diseases that can be treated by activating 5-hydroxytryptamine receptors (such as 5-HT 2A ) is a disease, disorder or condition to be treated.

[0303] Thus, the present application includes methods of treating a disease, disorder, or condition treatable by activating serotonin receptors, comprising administering to an individual in need thereof a therapeutically effective amount of a composition of the present application.

[0304] The present application also includes the use of the composition of the present application for treating diseases, disorders or conditions that can be treated by activating 5-hydroxytryptamine receptors, and the use of the composition of the present application for preparing a medicament for treating diseases, disorders or conditions that can be treated by activating 5-hydroxytryptamine receptors. The present application also includes the composition of the present application for treating diseases, disorders or conditions that can be treated by activating 5-hydroxytryptamine receptors.

[0305] In some embodiments, the serotonin receptor is 5-HT 2A Thus, the present application includes methods for activating 5-hydroxytryptamine 2A receptors (5-HT 2A ) method, which comprises administering one or more compositions of the present application to an individual in need thereof.

[0306] The present application also includes one or more compositions of the present application for activating 5-HT in cells 2A Use of, and one or more compositions of the present application for preparing a method for activating 5-HT in cells 2A The present application also includes one or more compositions of the present application for activating 5-HT in cells. 2A .

[0307] The present application also includes treatments that can activate 5-HT 2A A method for treating a disease, disorder or condition comprising administering the composition of the present application to an individual in need thereof. The present application also includes the composition of the present application for treating a disease, disorder or condition that can be treated by activating 5-HT 2A The use of the composition of the present application for treating diseases, disorders or conditions that can be treated by activating 5-HT 2A The present application also includes the composition of the present application, which is used to treat diseases, disorders or conditions that can be treated by activating 5-HT 2A The disease, disorder or condition being treated.

[0308] In some embodiments, the 5-HT2A The disease, disorder or condition treated is any disease, disorder or condition that benefits from treatment with racemic MDMA.

[0309] In some embodiments, treatment with the compositions of the present application includes a reduced risk of adverse side effects compared to treatment with racemic methylenedioxyphenethylamine (MDMA).

[0310] In some embodiments, treatment with the compositions of the present application includes a reduced risk of adverse side effects compared to treatment with racemic 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (ie, a compound of formula (R / S)-I).

[0311] In some embodiments, treatment with the compositions of the present application includes a reduced risk of adverse side effects compared to treatment with racemic 2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine (i.e., a compound of formula (R / S)-I) or treatment with an enantiomerically pure compound of formula (S)-I.

[0312] 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.

[0313] In some embodiments, the adverse side effect is hyperthermia or hypothermia. In some embodiments, the adverse side effect is hyperthermia. In some embodiments, the adverse side effect is hypothermia.

[0314] Reports indicate that long-term use of MDMA may lead to heart valve fibrosis and dysfunction, such as valvular heart disease (VHD) (Setola et al., Mol. Pharmacol. 63: 1223-1229, 2003). Therefore, in some embodiments, the adverse side effect is cardiotoxicity. In some embodiments, the cardiotoxicity is heart valve fibrosis and dysfunction. In some embodiments, the cardiotoxicity is valvular heart disease. Therefore, in some embodiments, the adverse side effect is valvular heart disease. In some embodiments, the cardiotoxicity is tachycardia or tremor.

[0315] In some embodiments, the reduced risk of adverse side effects is achieved by using the compositions of the present application to react with 5-hydroxytryptamine 2A (5-HT 2A) receptors with lower affinity than 5-hydroxytryptamine 2B (5-HT 2B ) receptor binding.

[0316] In some embodiments, the reduced risk of adverse side effects is achieved by using the compositions of the present application in the presence of 5-hydroxytryptamine 2B (5-HT 2B ) receptors and 5-hydroxytryptamine 2A (5-HT 2A ) receptors to provide a more balanced binding.

[0317] In some embodiments, the disease, disorder or condition treatable by activation of serotonin receptors is a disease, disorder or condition that benefits from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof.

[0318] In some embodiments, the disease, disorder or condition treatable by activation of serotonin receptors is a disease, disorder or condition that would benefit from treatment with racemic MBDB or a pharmaceutically acceptable salt and / or solvate thereof.

[0319] In some embodiments, the disease, disorder, or condition treatable by activation of serotonin receptors is a disease, disorder, or condition that benefits from treatment with racemic MDMA, and the method includes a reduced risk of adverse side effects compared to treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA).

[0320] In some embodiments, the disease, disorder, or condition treatable by activation of serotonin receptors is any disease, disorder, or condition that benefits from psychotherapy including, but not limited to, one or more of post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction, and eating disorders.

[0321] In some embodiments, one or more compositions are administered or used in combination with psychotherapy to treat a disease, disorder, or condition. In some embodiments, one or more compositions improve the efficacy of psychotherapy. In some embodiments, psychotherapy is used for mental disorders.

[0322] In some embodiments, the disease, disorder or condition treatable by activating serotonin receptors is one or more psychiatric disorders. In some embodiments, the one or more psychiatric 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.

[0323] 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.

[0324] In some embodiments, the mood disorder is selected from one or both of depression and bipolar disorder.

[0325] In some embodiments, the developmental disorder is selected from one or both of autism spectrum disorder (ASD) and Asperger's syndrome.

[0326] In some embodiments, the substance use disorder and addiction are selected from one or more of alcoholism, drug abuse, drug dependence, and compulsive gambling. In some embodiments, drug dependence is opioid dependence. In some embodiments, the substance use disorder is opioid use disorder.

[0327] In some embodiments, the eating disorder is selected from anorexia and bulimia.

[0328] In some embodiments, the personality disorder is selected from borderline personality disorder and dependent personality disorder.

[0329] In some embodiments, the psychiatric disorder is selected from schizophrenia and other disorders causing dissociation from reality.

[0330] In some embodiments, the one or more mental disorders are selected from one or more of autism spectrum disorder (ASD), depression, and drug dependence. In some embodiments, depression is clinical depression, e.g., in a palliative care individual. In some embodiments, the substance use disorder is an opioid use disorder.

[0331] In some embodiments, the 5-HT 2A The disease, disorder or condition treated is autism spectrum disorder.

[0332] 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.

[0333] In some embodiments, the one or more psychiatric disorders are selected from post-traumatic stress disorder (PTSD), eating disorders, and alcoholism. In some embodiments, the one or more psychiatric disorders are post-traumatic stress disorder (PTSD).

[0334] In some embodiments, the one or more mental disorders are selected from autism spectrum disorder (ASD), depression, and substance use disorder. In some embodiments, depression is clinical depression, e.g., in a palliative care individual. In some embodiments, the substance use disorder is opioid use disorder.

[0335] 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.

[0336] In some embodiments, the psychotherapy is selected from behavioral psychotherapy, exposure-based psychotherapy, cognitive psychotherapy, and psychodynamically oriented psychotherapy.

[0337] In some embodiments, a disease, disorder, or condition treatable by activation of serotonin receptors is any disease, disorder, or condition that would benefit from treatment with L-3,4-dihydroxyphenylalanine (L-DOPA).

[0338] In some embodiments, the composition is administered or used in combination with L-DOPA to treat a disease, disorder, or condition that benefits from treatment with L-DOPA. In some embodiments, the composition improves the therapeutic effect of L-DOPA. In some embodiments, the composition is administered or used in combination with L-DOPA to improve the therapeutic effect of L-DOPA.

[0339] In some embodiments, the disease, disorder, or condition that benefits from treatment with L-DOPA is Parkinson's disease.

[0340] The present application also includes a method for treating Parkinson's disease, comprising administering one or more compositions of the present application to an individual in need thereof.

[0341] The present application also includes the use of one or more compositions of the present application for treating Parkinson's disease, the use of one or more compositions of the present application for preparing drugs for treating Parkinson's disease, and one or more compositions of the present application for treating Parkinson's disease.

[0342] In some embodiments, one or more compositions are administered or used in combination with L-DOPA to treat Parkinson's disease. In some embodiments, one or more compositions improve the efficacy of L-DOPA in treating Parkinson's disease. In some embodiments, one or more compositions are administered or used in combination with L-DOPA to improve the efficacy of L-DOPA in treating Parkinson's disease.

[0343] In some embodiments, one or more compositions improve the therapeutic efficacy of L-DOPA by reducing L-DOPA-induced dyskinesias.

[0344] Thus, in some embodiments, the disease, disorder or condition that benefits from treatment with racemic MDMA is a movement disorder. In some embodiments, the movement disorder is an L-DOPA-induced movement disorder.

[0345] In some embodiments, one or more compositions improve the efficacy of L-DOPA by increasing the duration (e.g., duration) of the anti-Parkinson's disease benefit of L-DOPA. In some embodiments, one or more compositions improve the efficacy of L-DOPA by increasing the duration of the anti-Parkinson's disease benefit of L-DOPA without disabling dyskinesia.

[0346] In some embodiments, one or more compositions improve the efficacy of L-DOPA by reducing L-DOPA-induced Parkinson's disease psychosis.

[0347] Thus, in some embodiments, the disease, disorder, or condition that benefits from treatment with one or more compositions of the present application is L-DOPA-induced Parkinson's disease psychosis.

[0348] "Reducing L-DOPA-induced dyskinesia" or "reducing L-DOPA-induced Parkinson's disease psychosis" means any reduction in the extent of dyskinesia, stabilization of the state (i.e., not worsening), delay or slowing of progression, improvement or alleviation, and relief (whether partial or total), whether detectable or undetectable, in the presence of one or more compositions of the present application, as compared to otherwise identical conditions except in the absence of one or more compositions of the present application.

[0349] "Increasing the duration of the anti-Parkinson's disease benefit of L-DOPA" means any increase in the duration of the anti-Parkinson's disease benefit of L-DOPA compared to otherwise identical conditions except for the absence of one or more compositions of the present application.

[0350] "Increasing the duration of the anti-Parkinson's benefit of L-DOPA without disabling dyskinesias" means any increase in the duration of the anti-Parkinson's benefit of L-DOPA without disabling dyskinesias compared to otherwise identical conditions except for the absence of one or more compositions of the present application.

[0351] Those skilled in the art will appreciate that methods for assessing L-DOPA-induced dyskinesia and / or psychosis are well known in the art, such as those found in: 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.

[0352] The applicant has shown that the composition of the present application promotes prosocial behavior in the in vivo mouse model of autism spectrum disorder. It is further shown that the composition of the present application does not affect the motor activity in the mouse model of autism spectrum disorder. The applicant further shows that the composition of the present application will not cause a significant impact on core temperature. In addition, the applicant has shown that compared with the compound of formula (S)-I, MDMA and methamphetamine, the composition of the present application has a lower impact on cardiovascular events.

[0353] Thus, the present application also includes methods of treating one or more signs or symptoms of a disease, disorder, or condition treatable by activating serotonin receptors, comprising administering a composition of the present application to an individual in need thereof.

[0354] The present application also includes the use of the composition of the present application for treating one or more signs or symptoms of a disease, disorder or condition that can be treated by activating 5-hydroxytryptamine receptors, the use of the composition of the present application for preparing a medicament for treating one or more signs or symptoms of a disease, disorder or condition that can be treated by activating 5-hydroxytryptamine receptors, and the above-mentioned composition of the present application, which is used to treat one or more signs or symptoms of a disease, disorder or condition that can be treated by activating 5-hydroxytryptamine receptors.

[0355] In some embodiments, at least one sign or symptom of a disease, disorder, or condition treatable by activating a serotonin receptor is reduced following administration of a composition of the present application.

[0356] In some embodiments, the methods and uses provided herein reduce at least one sign or symptom of a disease, disorder or condition that can be treated by activating 5-hydroxytryptamine receptors. In some embodiments, the methods and uses provided herein reduce at least one sign or symptom of a disease, disorder or condition that can be treated by activating 5-hydroxytryptamine receptors by about 5% to about 100%, for example, 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 treatment without the composition of the present application.

[0357] In some embodiments, signs or symptoms of a disease, disorder, or condition that can be treated by activating serotonin receptors are reduced or eliminated in an individual within about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, or about 3 months after administration of a composition of the present application.

[0358] In some embodiments, signs or symptoms of a disease, disorder, or condition that can be treated by activating serotonin receptors are reduced or eliminated in an individual within 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 a composition of the present application.

[0359] "Reducing at least one sign or symptom of a disease, disorder, or condition treatable by activating serotonin receptors" refers to any reduction or alleviation of a sign or symptom of a disease, disorder, or condition compared to otherwise identical conditions except for the absence of the composition of the present application.

[0360] In some embodiments, signs or symptoms of a disease, disorder, or condition that can be treated by activating serotonin receptors are neurotoxicity, hyperthermia, hypothermia, cardiotoxicity, and substance use disorder.

[0361] In some embodiments, the disease, disorder or condition treatable by activating serotonin receptors is autism spectrum disorder, and the present application also includes a method of treating one or more signs or symptoms of autism spectrum disorder, which comprises administering a therapeutically effective amount of a composition of the present application to an individual in need thereof.

[0362] The present application also includes the use of the composition of the present application for treating one or more signs or symptoms of autism spectrum disorders, the use of the composition of the present application for preparing a medicament for treating one or more signs or symptoms of autism spectrum disorders, and the above-mentioned composition of the present application, which is used to treat one or more signs or symptoms of autism spectrum disorders.

[0363] In some embodiments, the one or more signs or symptoms of an autism spectrum disorder are selected from general anxiety, clinical anxiety, irritability, inappropriate speech, stereotypies, social withdrawal, repetitive behaviors, and hyperactivity.

[0364] In some embodiments, one or more signs or symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal. In some embodiments, one or more signs or symptoms of autism spectrum disorder are stereotypy. In some embodiments, one or more signs or symptoms of autism spectrum disorder are social withdrawal. Therefore, in some embodiments, the compositions of the present application are used to promote prosocial activities.

[0365] The present application also includes methods or uses of treating one or more symptoms of autism spectrum disorder while reducing adverse side effects of treatment with racemic MDMA or (R / S)-I.

[0366] In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal, and the adverse side effects are selected from hyperthermia, stereotypy and neurotoxicity. In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal, and the adverse side effects are selected from hyperthermia and neurotoxicity. In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal, and the adverse side effects are selected from hyperthermia and neurotoxicity.

[0367] In some embodiments, the autism spectrum disorder is as defined by DSM-IV, wherein 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.

[0368] In some embodiments, the one or more symptoms is a qualitative impairment in social interaction.

[0369] In some embodiments, qualitative impairments in social interaction include one or more of the following: significant impairment in the use of a variety of nonverbal behaviors, including eye-to-eye gaze, facial expressions, body posture, and gestures to regulate social interactions; failure to develop peer relationships appropriate to the level of progress; lack of spontaneous seeking to share enjoyment, interests, or achievements with others (e.g., lack of showing, bringing, or pointing out objects of interest); and lack of social or emotional reciprocity.

[0370] In some embodiments, qualitative impairments in communication include one or more of: delay or complete lack of oral language development (without accompanying attempts to compensate through alternative modes of communication such as gestures or gesticulations); in individuals with adequate speech, marked impairment in the ability to initiate or maintain conversations with other individuals; stereotyped and repetitive use of speech or specialized language; and lack of varied, spontaneous belief play or social imitation play appropriate to developmental level.

[0371] In some embodiments, restricted, repetitive and stereotyped patterns of behavior, interests, and activities include one or more of the following: preoccupations including stereotyped and restricted patterns of preoccupation with one or more preoccupations that are abnormal in intensity or focus; marked inflexibility in adhering to specific, nonfunctional routines or rules; stereotyped and repetitive movement patterns (e.g., hand or finger flapping or twisting or complex whole-body movements); and persistent preoccupation with parts of objects.

[0372] In some embodiments, the disease, disorder or condition treatable by activating serotonin receptors is anxiety, and the application also includes a method of treating one or more signs or symptoms of anxiety comprising administering to an individual in need thereof a therapeutically effective amount of a composition of the application.

[0373] The present application also includes the use of the composition of the present application for treating one or more signs or symptoms of anxiety, the use of the composition of the present application for preparing a medicament for treating one or more signs or symptoms of anxiety, and the composition of the present application for treating one or more signs or symptoms of anxiety.

[0374] In some embodiments, one or more signs or symptoms of an anxiety disorder are measured according to a diary assessment, a clinician or caregiver assessment, or a clinical scale.

[0375] In some embodiments, the one or more signs or symptoms of an anxiety disorder are phobias, including fear of social interactions or situations, avoidance of anxiety triggers, feelings of stress, irritability, catastrophizing, nervousness, tachycardia, palpitations, tremors, fatigue, worry, irritability, obsessions, compulsions, muscle tension, sweating, dizziness, shortness of breath, sleep disturbances, or a combination thereof.

[0376] Thus, in some embodiments, the compositions of the present application are used to promote prosocial activities in individuals suffering from anxiety disorders.

[0377] 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.

[0378] In some embodiments, the compositions of the present application are administered or used as a second agent or "add-on" therapy.

[0379] In some embodiments, the composition of the present application is used or applied in a certain amount, and when applied to an individual, the amount is enough to achieve beneficial or desired results, including clinical results, and therefore, the amount depends on the background of its application. Therefore, the amount used or used is enough to treat, prevent or suppress the amount of the composition of a disease or condition. In some embodiments, the amount of a given composition used or used will vary according to factors such as a given composition, pharmaceutical preparation, route of administration, type of disease, disease or condition, the identity of the individual treated, but can still be routinely determined by those skilled in the art. In one embodiment, the amount used or used is to show the improvement or reduction of any disease, disease or condition symptom after treatment with it, particularly compared with the disease, disease or condition symptom without treatment.

[0380] In some embodiments, the composition of the present application is applied at least once a week. In some embodiments, the composition of the present application is applied about once every two weeks, three weeks or a month. In some embodiments, the composition of the present application is applied about once a week to about once a day. In some embodiments, the composition of the present application is applied 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, illness or condition, the age of the individual, the concentration and / or activity of the composition of the present application, and / or a combination thereof.

[0381] It should also be understood that the effective dose of the composition for treatment can be increased or decreased over the course of a particular treatment regimen. Changes in dosage can be produced and made apparent by standard diagnostic assays known in the art. In some cases, long-term administration is required. For example, the composition is administered to an individual in an amount and duration sufficient to treat the individual.

[0382] 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 canine. In some embodiments, the subject is a feline. Therefore, the compositions, methods, and uses of the present application are directed to human and veterinary diseases, disorders, and conditions. In some embodiments, an "individual in need thereof" is an individual suffering from a disease, disorder, or condition to be treated.

[0383] The composition of the present application can be used alone or in combination with other known agents that can be used to treat diseases, disorders or conditions that can be treated by activating 5-hydroxytryptamine receptors. When used in combination with other agents that can be used to treat diseases, disorders or conditions that can be treated by activating 5-hydroxytryptamine receptors, one embodiment is that the composition of the present application is used simultaneously with those agents. As used herein, "simultaneous administration" of two substances to an individual means providing each of the two substances so that they are active in the individual at the same time. The exact details of administration will 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, or if the pharmacokinetics are suitable, even administering a substance within 24 hours of administering another substance. The design of a suitable administration regimen is conventional for those skilled in the art. In a specific embodiment, the substances will be administered substantially simultaneously, i.e., administered within a few minutes of each other, or administered in a single composition containing all substances. Another embodiment of the present application is a combination of administering agents to an individual in a non-simultaneous manner.

[0384] The dosage of the composition of the present application varies according to many factors, such as the pharmacodynamic properties of the compound, 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 simultaneous treatment (if any), and the clearance rate of the compound in the individual to be treated. Those skilled in the art can determine the appropriate dosage based on the above factors. In some embodiments, the composition of the present application is initially administered with a suitable dosage adjusted as needed according to the clinical response.

[0385] As a representative example, for adults, the oral dosage of one or more compositions of the present application will be in the range of about 1 mg per day to about 50 mg per day, suitably about 1 mg per day to about 40 mg per day, more suitably about 2 mg per day to about 30 mg per day. In some embodiments, the individual body weight is 55 to 65 kg, suitably 60 kg. For oral administration, a representative amount is 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.

[0386] V. Methods of the present application

[0387] The present application includes novel methods 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 method for preparing compounds of (R)-I or (S)-I using an aryl acylation reaction followed by a carbonyl reduction.

[0388] Therefore, the present application includes a method for preparing a compound of formula (R)-I or (S)-I:

[0389]

[0390] The method comprises:

[0391] The compound of formula (R)-A or (S)-A

[0392]

[0393] Wherein L is selected from halogen and C(O)OR 2 ,

[0394] R 1 is unsubstituted or substituted benzyl; and

[0395] R 2 It is C 1-6 Alkyl, or

[0396] In the compound of formula (R)-A, R 2 yes Or in the compound of formula (S)-A, R 2 yes

[0397] In the presence of a Lewis acid, react with a compound of formula B

[0398]

[0399] to provide compounds of formula (R)-C and (S)-C, respectively; and

[0400]

[0401] Where R 1 is unsubstituted or substituted benzyl

[0402] Compounds of formula (R)-C and (S)-C are converted to compounds of formula (R)-I or (S)-I, respectively.

[0403] In some embodiments, L is a halogen. 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 acid chloride.

[0404] In some embodiments, L is C(O)OR 2 In some embodiments, R 2 It is C 1-4 In some embodiments, R 2is CH3. In some embodiments, in the compound of formula (R)-A, R 2 yes Or in the compound of formula (S)-A, R 2 yes Thus, in some embodiments, the compound of formula (R)-A or (S)-A is an anhydride.

[0405] In some embodiments, R 1 is an unsubstituted benzyl group, and the compound of formula (R)-A or (S)-A is a benzyloxycarbonyl-protected compound.

[0406] In some embodiments, R 1 In some embodiments, the substituted benzyl group is replaced by one or more selected from NO2, halogen, C 1-4 Alkyl and C 1-4 In some embodiments, R 1 is one or more selected from NO2, Br, Cl, C 1-4 Alkyl and C 1-4 In some embodiments, R 1 is benzyl substituted with NO2. In some embodiments, R 1 is p-nitrobenzyl or o-nitrobenzyl. 1 In some embodiments, R 1 is benzyl substituted with one or more of Cl or Br. In some embodiments, R 1 is 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2-bromobenzyl or 4-bromobenzyl. 1 is one or more C 1-4 In some embodiments, R 1 is benzyl substituted with one or more OCH3. 1 is 3,4-dimethoxybenzyl or p-methoxybenzyl. In some embodiments, R 1 is benzyl substituted with one or more CH3 and C(CH3)3. In some embodiments, R 1 It is 3,5-di-tert-butylbenzyl.

[0407] In some embodiments, the Lewis acid is any Lewis acid suitable for Friedel-Crafts acylation reaction. In some embodiments, the Lewis acid is selected from BF3, AlCl3, SbCl5, SbF5, InCl3, GaCl3, BCl3, FeCl3, SnCl4, TiCl4, Mo2Cl10 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.

[0408] 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 provide compounds of formula (R)-C and (S)-C, respectively, is carried out in a suitable solvent. In some embodiments, the suitable solvent is selected from dichloromethane, carbon disulfide, 1,2-dichloroethane, tetrachloroethane, 1,1,2,2-tetrachloroethane, and mixtures thereof. In some embodiments, the suitable solvent is dichloromethane.

[0409] In some embodiments, a compound of formula (R)-A or (S)-A is reacted with a compound of formula B in the presence of an excess (e.g., about 1.2 to about 4, about 1.5 to about 2.5, about 1.2 to about 2, about 1.2 to about 1.5 molar equivalents) of a Lewis acid to provide compounds of formula (R)-C and (S)-C, respectively.

[0410] As a representative, non-limiting example, the temperature at which a compound of formula (R)-A or (S)-A is reacted with a compound of formula B in the presence of a Lewis acid to provide compounds of formula (R)-C and (S)-C, respectively, is about -18°C to about 25°C, about -10°C to about 25°C, about -5°C to about 10°C, about 0°C to about 10°C, about 0°C to about 20°C, about 0°C to about 5°C, or 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, a compound of formula (R)-A or (S)-A is combined with a compound of formula B in the presence of a Lewis acid at about -5°C to about 10°C or about 0°C to about 10°C and then allowed to warm to room temperature or about 18°C ​​to about 25°C.

[0411] In some embodiments, any suitable conditions known in the art for acylation of a compound of formula (R)-A or (S)-A with a compound of formula B in the presence of a Lewis acid to provide compounds of formula (R)-C and (S)-C, respectively, are used, for example, using the synthetic procedures found in Ookawa and Soai J. Chem. Soc., Perkin Trans. 1, 1987, 1465-1471 to prepare compounds of formula (R)-C or (S)-C.

[0412] In some embodiments, compounds of formula (R)-A or (S)-A are commercially available or can be prepared using methods known in the art or are readily prepared from available precursors using methods known in the art.

[0413] For example, in some embodiments, when L is Cl, the compound of formula (R)-A or (S)-A is prepared by reacting benzyloxycarbonyl protected D-proline or L-proline, respectively, in the presence of a suitable chlorinating agent in a suitable solvent. In some embodiments, when L is Cl, the compound of formula (R)-A or (S)-A is prepared by reacting benzyloxycarbonyl protected D-proline or L-proline, respectively, in the presence of an excess (e.g., about 1.2 to about 2, about 1.2 to about 1.5, or about 1.5 molar equivalents) of a suitable chlorinating agent in a suitable solvent. In some embodiments, the suitable chlorinating agent is selected from thionyl chloride (SOCl2), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), or oxalyl chloride [(COCl)2]. In some embodiments, the suitable chlorinating agent is oxalyl chloride. In some embodiments, the suitable solvent is an inert solvent such as dichloromethane, carbon disulfide, 1,2-dichloroethane, tetrachloroethane, 1,1,2,2-tetrachloroethane, and mixtures thereof. In some embodiments, the suitable solvent is dichloromethane.

[0414] In some embodiments, benzyloxycarbonyl protected D-proline or L-proline is commercially available or can be prepared using methods known in the art. For example, in some embodiments, benzyloxycarbonyl protected D-proline (i.e., N-Cbz-D-proline) and benzyloxycarbonyl protected L-proline (i.e., N-Cbz-L-proline) can be obtained from Millipore-Sigma (Burlington, Massachusetts).

[0415] In some embodiments, when L is Cl, the compound of formula (R)-A or (S)-A is prepared in situ. Thus, in some embodiments, the method comprises reacting a benzyloxycarbonyl protected D-proline or a benzyloxycarbonyl protected L-proline in the presence of a suitable chlorinating agent in a suitable solvent to provide a compound of formula (R)-A or (S)-A, respectively, wherein L is Cl, and further reacting the compound of formula (R)-A or (S)-A, wherein L is Cl, with a compound of formula B in the presence of a Lewis acid without separation to provide a compound of formula (R)-C or (S)-C, respectively, wherein L is Cl.

[0416] In some embodiments, a suitable solvent for reacting benzyloxycarbonyl-protected D-proline or benzyloxycarbonyl-protected L-proline in the presence of a suitable chlorinating agent to provide a compound of formula (R)-A or (S)-A (wherein L is Cl), respectively, and further reacting the compound of formula (R)-A or (S)-A (wherein L is Cl) with a compound of formula B in the presence of a Lewis acid to provide a compound of formula (R)-C or (S)-C (wherein L is Cl), respectively, without isolation, is dichloromethane.

[0417] In some embodiments, the compound of formula B (1,3-benzodioxole) is commercially available or can be prepared using methods known in the art. For example, in some embodiments, the compound of formula B (1,3-benzodioxole) can be obtained from Millipore-Sigma (Burlington, Massachusetts).

[0418] In some embodiments, compounds of Formula (R)-C and (S)-C are converted to compounds of Formula (R)-I or (S)-I using a one-step process or a two-step process, respectively.

[0419] In some embodiments, a one-step process is used to convert compounds of formula (R)-C and (S)-C to compounds of formula (R)-I or (S)-I, respectively. In some embodiments, a one-step process is used to convert compounds of formula (R)-C and (S)-C to compounds of formula (R)-I or (S)-I, respectively, in the presence of H2 and a catalyst. Thus, in some embodiments, the method comprises converting compounds of formula (R)-C and (S)-C to compounds of formula (R)-I or (S)-I, respectively, in the presence of H2 and a catalyst.

[0420] In some embodiments, the catalyst is a nickel, palladium or 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 on carbon (Pd(OAc)2). In some embodiments, the palladium catalyst is palladium on carbon (Pd / C). In some embodiments, palladium on carbon (Pd / C) is about 5% to about 10% palladium on carbon (Pd / C). In some embodiments, palladium on carbon (Pd / C) is about 10% palladium on carbon (Pd / C).

[0421] Those skilled in the art will understand that in the step of converting the compounds of formula (R)-C and (S)-C into compounds of formula (R)-I or (S)-I, respectively, a hydrogenolysis reaction for removing the benzyloxycarbonyl protecting group from the compounds of formula (R)-C and (S)-C and a hydrogenation reaction for reducing the aryl carbonyl group in the compounds of formula (R)-C and (S)-C occur simultaneously in the presence of H2 and a catalyst.

[0422] In some embodiments, the step of converting the compounds of formula (R)-C and (S)-C to provide the compounds of formula (R)-I or (S)-I, respectively, can be performed in two steps.

[0423] In some embodiments, a two-step process is used to convert compounds of formula (R)-C and (S)-C, respectively, into compounds of formula (R)-I or (S)-I. Thus, in some embodiments, the method comprises converting compounds of formula (R)-C and (S)-C, respectively, into compounds of formula (R)-I or (S)-I, wherein the conversion comprises

[0424] Reducing compounds of formula (R)-C and (S)-C with a suitable reducing agent to provide compounds of formula (R)-D and (S)-D, respectively, and

[0425]

[0426] Where R 1 is unsubstituted or substituted benzyl

[0427] Compounds of (R)-D and (S)-D are deprotected to provide compounds of formula (R)-I or (S)-I, respectively.

[0428] In some embodiments, the reducing agent that provides 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 ketones of the compounds of (R)-C and (S)-C to alkylene groups. In some embodiments, the compounds of formula (R)-C and (S)-C are reduced with a suitable reducing agent under Clemmensen reduction conditions to provide the compounds of (R)-D and (S)-D. In some embodiments, a 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.

[0429] In some embodiments, deprotecting (R)-D and (S)-D compounds to provide 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, palladium or 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 on carbon (Pd(OAc)2). In some embodiments, the palladium catalyst is palladium on carbon (Pd / C). In some embodiments, palladium on carbon (Pd / C) is about 5% to about 10% palladium on carbon (Pd / C). In some embodiments, palladium on carbon (Pd / C) is about 10% palladium on carbon (Pd / C).

[0430] In some embodiments, the step of deprotecting (R)-D and (S)-D compounds to provide compounds of formula (R)-I or (S)-I, respectively, is performed in the presence of a Lewis acid and an acid. In some embodiments, the acid is hydrobromic acid.

[0431] In some embodiments, the methods provide a compound of Formula (R)-I or (S)-I, respectively, as the major isomer. In some embodiments, the methods provide a compound of Formula (R)-I with greater than 60%ee, 65%ee, 70%ee, 75%ee, 80%ee, 85%ee, 90%ee, 95%ee, 98%ee, or 99%ee. In some embodiments, the methods provide a compound of Formula (S)-I with greater than 60%ee, 65%ee, 70%ee, 75%ee, 80%ee, 85%ee, 90%ee, 95%ee, 98%ee, or 99%ee.

[0432] In some embodiments, the enantiomeric excess of an enantiomer is determined using a variety of analytical techniques known in the art, including NMR spectroscopy, chiral column chromatography, or polarimetry. In some embodiments, the enantiomeric excess of an enantiomer is determined using a polarimeter using methods known in the art.

[0433] In some embodiments, the method provides a compound of formula (R)-I. Therefore, the present application includes a method for preparing a compound of formula (R)-I:

[0434]

[0435] The method comprises:

[0436] The compound of formula (R)-A

[0437]

[0438] Wherein L is selected from halogen and C(O)OR 2,

[0439] R 1 is unsubstituted or substituted benzyl; and

[0440] R 2 Yes-C 1-6 Alkyl or

[0441] In the presence of a Lewis acid, react with a compound of formula B

[0442]

[0443] To provide a compound of formula (R)-C; and

[0444]

[0445] Where R 1 is unsubstituted or substituted benzyl

[0446] The compound of formula (R)-C is converted to the compound of formula (R)-I.

[0447] In some embodiments, the method provides a compound of formula (S)-I. Therefore, the present application includes a method for preparing a compound of formula (S)-I:

[0448]

[0449] The method comprises:

[0450] The compound of formula (S)-A

[0451]

[0452] Wherein L is selected from halogen and C(O)OR 2 ,

[0453] R 1 is unsubstituted or substituted benzyl; and

[0454] R 2 Yes-C 1-6 Alkyl or

[0455] In the presence of a Lewis acid, react with a compound of formula B

[0456]

[0457] To provide a compound of formula (S)-C; and

[0458]

[0459] Where R 1is unsubstituted or substituted benzyl

[0460] The compound of formula (S)-C is converted to the compound of formula (S)-I.

[0461] In an exemplary embodiment of the method of the present application, the present application includes a method for preparing a compound of formula (R)-I or (S)-I:

[0462]

[0463] The method comprises:

[0464] The compound of formula (R)-A or (S)-A

[0465]

[0466] wherein L is a halogen; and

[0467] R 1 is unsubstituted or substituted benzyl;

[0468] In the presence of a Lewis acid, react with a compound of formula B

[0469]

[0470] to provide compounds of formula (R)-C and (S)-C, respectively; and

[0471]

[0472] Where R 1 is unsubstituted or substituted benzyl

[0473] In the presence of H2 and a catalyst, the compounds of formula (R)-C and (S)-C are converted into compounds of formula (R)-I or (S)-I, respectively. In an exemplary embodiment of the method of the present application, the present application includes a method for preparing a compound of formula (R)-I:

[0474]

[0475] The method comprises:

[0476] The compound of formula (R)-A

[0477]

[0478] wherein L is a halogen; and

[0479] R 1 is unsubstituted or substituted benzyl;

[0480] In the presence of a Lewis acid, react with a compound of formula B

[0481]

[0482] To provide a compound of formula (R)-C; and

[0483]

[0484] Where R 1 is unsubstituted or substituted benzyl

[0485] The compound of formula (R)-C is converted to the compound of formula (R)-I in the presence of H2 and a catalyst.

[0486] In an exemplary embodiment of the method of the present application, the present application includes a method for preparing a compound of formula (S)-I:

[0487]

[0488] The method comprises:

[0489] The compound of formula (S)-A

[0490]

[0491] wherein L is a halogen; and

[0492] R 1 is unsubstituted or substituted benzyl;

[0493] In the presence of a Lewis acid, react with a compound of formula B

[0494]

[0495] To provide a compound of formula (S)-C; and

[0496]

[0497] Where R 1 is unsubstituted or substituted benzyl

[0498] The compound of formula (S)-C is converted to the compound of formula (S)-I in the presence of H2 and a catalyst.

[0499] In an exemplary embodiment, R 1 is an unsubstituted benzyl group.

[0500] In some embodiments, the compound of formula (R)-I or (S)-I prepared by the method of the present application: is further converted into a salt, solvate and / or prodrug thereof, such as a pharmaceutically acceptable salt, solvate and / or prodrug thereof. In some embodiments, the compound of formula (R)-I prepared by the method of the present application is further converted into a salt, solvate and / or prodrug thereof, such as a pharmaceutically acceptable salt, solvate and / or prodrug thereof. In some embodiments, the compound of formula (S)-I prepared by the method of the present application is further converted into a salt, solvate and / or prodrug thereof, such as a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0501] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt, and the selection of suitable salts can be made by one skilled in the art (see, eg, SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0502] Pharmaceutically acceptable, suitable for individual treatment or compatible with individual treatment acid addition salt is any nontoxic organic or inorganic acid addition salt of any basic compound. The basic compound forming the acid addition salt includes, for example, a compound comprising an amine group. Exemplary inorganic acids forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and acidic metal salts, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids forming 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-hydroxyethylsulfonic acid. In one embodiment, monoacid salts or diacid salts are formed, and such salts exist in hydrated, solvated or substantially anhydrous forms. Typically, acid addition salts are more soluble in water and various hydrophilic organic solvents, and typically exhibit higher fusing points compared to their free alkali forms. The selection criteria for suitable salts are well known to those skilled in the art. Other non-pharmaceutically acceptable salts can be used, such as, but not limited to, oxalates, such as for separating the compounds of the present application for laboratory use, or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0503] In some embodiments, the compound of formula (R)-I or (S)-I is reacted with hydrochloric acid to provide the hydrochloride salt of the compound of formula (R)-I or (S)-I. In some embodiments, the compound of formula (R)-I is reacted with hydrochloric acid to provide the hydrochloride salt of the compound of formula (R)-I. In some embodiments, the compound of formula (S)-I is reacted with hydrochloric acid to provide the hydrochloride salt of the compound of formula (S)-I. Solvates of compounds of formula (R)-I or (S)-I include, for example, those prepared with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is referred to as a hydrate) and ethanol, etc. Suitable solvents are physiologically tolerable at the administered dose.

[0504] Formation of salts of the desired compounds is achieved using standard techniques, for example, by treating the neutral compound with an acid in a suitable solvent and isolating the salt formed by filtration, extraction or any other suitable method.

[0505] The formation of solvates will vary according to the compound and the solvate. Typically, solvates are formed by dissolving the compound in an appropriate solvent and separating the solvate by cooling or using an anti-solvent. Solvates are typically dried or azeotropic under ambient conditions. Those skilled in the art can select suitable conditions for forming a specific solvate.

[0506] Prodrugs of compounds of formula (R)-I or (S)-I can be, for example, conventional esters formed with available amino groups. Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C1-C 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0507] Examples of inert solvents include, but are not limited to, benzene, toluene, tetrahydrofuran, diethyl ether, ethyl acetate, dimethylformamide (DMF), acetonitrile, C 1-6 Alkyl 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). Other examples may include aqueous solutions, such as water and dilute acids and bases, and ionic liquids, provided that such solvents do not interfere with the reaction.

[0508] VI. Methods and preparations of the present application

[0509] The compounds of formula (R)-I can also be prepared by a variety of synthetic methods known in the art. The selection of a particular method is within the capabilities of those skilled in the art. Some raw materials are available from commercial chemical sources. Other raw materials are easily prepared from available precursors using direct conversions well known in the art.

[0510] Compounds of formula (R)-I can generally be prepared according to the methods shown in the following routes. Those skilled in the art will appreciate that many of the reactions depicted in the following routes will be sensitive to oxygen and water, and will know to react under an anhydrous inert atmosphere if desired. Reaction temperatures and times are presented for illustrative purposes only, and may vary to optimize yields, as those skilled in the art will appreciate.

[0511] Thus, in some embodiments, compounds of Formula (R)-I are prepared as shown in Scheme 1. Thus, in some embodiments, (R)-prolinol ((R)-2-(hydroxymethyl)pyrrolidine) is reacted with a sulfonyl 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 provide a sulfamate intermediate of Formula A. The sulfamate intermediate of Formula A is then reacted with a compound of Formula B (wherein X is a leaving group) in the presence of an organolithium reagent such as n-butyllithium, followed by acidic hydrolysis of the resulting sulfamate in the presence of a suitable acid such as HCl and a suitable solvent such as ethanol at a suitable temperature such as about 70°C to about 95°C to provide a compound of Formula (R)-I.

[0512]

[0513] Route 1

[0514] In some embodiments, the compound of formula (R)-I is prepared as shown in Scheme 2. Thus, in some embodiments, an N,N-dimethylpiperonylamide compound of formula C and pyrrole are condensed in the presence of a coupling agent such as phosphorus oxychloride to provide 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 provides a compound of formula E. Hydrogenation of the pyrrole ring in the compound of formula E provides a racemic compound of formula (R / S)-I. The racemic compound of formula (R / S)-I can be resolved into the individual R and S enantiomers of formula (R)-I and (S)-I by methods known in the art.

[0515]

[0516] Route 2

[0517] Those skilled in the art will appreciate that the compounds of formula (S)-I and formula (R / S)-I can be prepared using raw materials or racemic raw materials with corresponding (S) enantiomeric configurations according to the methods described in the above routes. 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 Williams et al., Med.Chem.Commun., 2015, 6, 1054 and Dolby LJ et al., J.Org.Chem., 37 (23), 1972 p3691 disclosed methods.

[0518] The racemic MDMA compounds of interest can be prepared by a variety of synthetic methods. The choice of a particular method is within the capabilities of one skilled in the art. For example, by Dunlap et al., (2018), ACS Chem Neurosci; 9(10): 2408-2427; Llabrés 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 disclosed methods.

[0519] Nucleophilic displacement reaction conditions include any known method for the reaction of nucleophiles to displace leaving groups to form bonds that are compatible with the intermediates and products shown in the above schemes or that can be used to prepare compounds of the present application. In some embodiments, such conditions include combining reactants in a suitable solvent in the presence of a base.

[0520] Throughout the methods described herein, it will be understood that, where appropriate, suitable protecting groups will be added to various reactants and intermediates in a manner readily understood by those skilled in the art, and subsequently removed from various reactants and intermediates. Conventional procedures using such protecting groups and examples of suitable protecting groups are described in, for example, "Protective Groups in Organic Synthesis", TW Green, PGM Wuts, Wiley-Interscience, New York, (1999).

[0521] It should also be understood that by chemical manipulation, a group or substituent is converted into another group or substituent and can be carried out on the synthetic path towards the final product to any intermediate or final product, wherein the possible conversion type is only subject to the inherent incompatibility of other functional groups carried by the molecule at this stage with the conditions or reagents used in the conversion. Those skilled in the art will easily understand this inherent incompatibility and the way to circumvent them by carrying out appropriate conversion and synthesis steps in a suitable order. This paper provides the example of conversion, and it should be understood that the described conversion is not limited to the universal group or substituent of illustrating the conversion. The references and descriptions of other suitable conversions are provided in " Comprehensive Organic Transformations-A Guide to Functional Group Preparations " RC Larock, VHC Publishers, Inc. (1989). The references and descriptions of other suitable reactions are described in organic chemistry textbooks, such as " Advanced Organic Chemistry ", March, the 4th edition. McGraw Hill (1992) or " Organic Synthesis ", Smith, McGraw Hill, (1994).

[0522] Techniques for purification of intermediates and final products include, for example, straight and reverse phase chromatography on columns or spinning plates, recrystallization, distillation and liquid-liquid or solid-liquid extraction, and will be readily understood by those skilled in the art.

[0523] The products of the methods of the present application can be isolated according to known methods, for example, the compounds can be isolated by evaporating the solvent, by filtration, centrifugation, chromatography or other suitable methods.

[0524] Typically, the above reaction can be carried out in a suitable inert organic solvent at a temperature and time that will 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, dichloromethane, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0525] Formation of salts of the desired compounds is achieved using standard techniques, for example, by treating the neutral compound with an acid or base in a suitable solvent and isolating the salt formed by filtration, extraction or any other suitable method.

[0526] The formation of the solvate of the present application's compound can vary according to the compound and the solvate. Typically, the solvate is formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. The solvate is typically dried or azeotropic under ambient conditions. Those skilled in the art can select the appropriate conditions for forming a specific solvate.

[0527] Prodrugs of the compounds of the present invention may be conventional esters formed, for example, with available hydroxyl, thiol, amino or carboxyl groups. For example, available hydroxyl or amino groups may be acylated in the presence of a base and optionally in an inert solvent (e.g., an acyl chloride in pyridine) using an activated acid.

[0528] Those skilled in the art will recognize that while the reaction steps of the present application are carried out in various solvents or solvent systems, the reaction steps can also be carried out in mixtures of suitable solvents or solvent systems. Example

[0529] The following non-limiting examples illustrate the present application:

[0530] Example 1: Exemplary Preparation of (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine-A

[0531] (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine can be prepared using the method described in Williams et al., Med. Chem. Commun., 2015, 6, 1054 for the preparation of (S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine.

[0532] (R)-Tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide

[0533] Under argon, a solution of sulfonyl chloride (8mL, 99mmol) in DCM (40mL) was added dropwise to a well-stirred (R)-2-(hydroxymethyl)pyrrolidine (10g, 99mmol) and pyridine (16mL, 20mmol) in -78°C of DCM (60mL) in 1.5 hours. After 3 hours, the cooling bath was removed and the mixture was brought to 0°C. The reaction mixture was quenched in ice water and transferred to a separatory funnel. Each layer was separated, and the aqueous layer was extracted with DCM (2x). The combined organic extracts were washed with 1M HCl aqueous solution, water and brine. The organic layer was dried with Na2SO4, filtered, and evaporated in vacuo to obtain a yellow solid. It was then redissolved in THF (50mL), filtered through a sintering funnel to remove residual pyridine.HCl and concentrated in vacuo to obtain the title compound, which was a light yellow solid (8.8g, 55%).

[0534] (R)-2-(Benzo[d][1,3]dioxol-5-ylmethyl)pyrrolidine

[0535] Under argon, a 1.6M hexane solution of n-BuLi was added to a THF solution of 4-bromo-1,2-(methylenedioxy)benzene (1.8 mL, 15 mmol) at a rate that kept the internal temperature below -70 °C. After a few minutes, the mixture became cloudy and formed a suspension. After 30 minutes, a THF solution of (R)-tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (2.0 g, 12 mmol) was added, keeping the internal temperature below -70 °C. The cooling bath was removed and the mixture was slowly returned to room temperature (RT), where all solids returned to the solution. The solution was stirred at room temperature for 1 hour, and the volatiles were removed in vacuo. The residue was dissolved in a 1:1 2M aqueous HCl solution and ethanol and heated to 95 °C for 40 h. The reaction mixture was cooled to room temperature, diluted with H2O, and the mixture was washed with TBME (1x). The extracts were discarded and the aqueous phase was basified with 5M aqueous NaOH and re-extracted with TBME (3 x 60 mL).The combined organic extracts were dried over Na2SO4, filtered, and evaporated in vacuo to give the title compound.

[0536] Example 2: Exemplary Preparation of (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine-B

[0537] (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine can be prepared using the method described in Dolby LJ et al., J. Org. Chem., 37(23), 1972 p3691 for the preparation of (R / S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine.

[0538] N,N-Dimethylpiperamide

[0539] Piperonyl acid (63.8 g, 0.384 mol) was added to thionyl chloride (270 mL) in portions under stirring over 20 minutes. The slurry was heated to reflux for 1 hour, during which the acid gradually dissolved. Excess thionyl chloride was removed under reduced pressure, and the residue was evaporated with dry benzene. Under stirring and cooling, the crude acid chloride was added to a 40% aqueous dimethylamine solution in portions over 15 minutes. The mixture was stirred at room temperature for 2 hours, then made strongly alkaline with 4N sodium hydroxide and saturated with sodium chloride. The aqueous solution was extracted with dichloromethane, and the organic phase was filtered through paper and concentrated under reduced pressure to obtain a crude amide (57.1 g, 77%), which was a dark oil. Distillation gave the amide as a hygroscopic viscous liquid (53 g, 71%):

[0540] 2-(3,4-Methylenedioxybenzoyl)pyrrole

[0541] To a cooled solution of N,N-dimethylpiperonylamide (58.5 g, 0.303 mol) in dichloroethane (60 mL) was added freshly distilled phosphorus oxychloride (46.5 g, 0.303 mol) dropwise under stirring over 15 minutes. The mixture was stirred for 10 minutes under cooling and then stirred at room temperature for 1.5 hours. Additional dichloroethane (60 mL) was added and then a solution of freshly distilled pyrrole (20.3 g, 0.303 mol) in dichloroethane (60 mL) was added over 10 minutes. The mixture was stirred at room temperature for 10 minutes and then refluxed for 1 hour. The dark red mixture was cooled and water (600 mL) containing sodium acetate trihydrate (300 g) was first added slowly and then as quickly as possible under vigorous stirring. The mixture was refluxed for about 15 minutes and then the phases were separated while still warm. The aqueous phase was extracted with chloroform and the combined organic solution was washed with brine, dried and concentrated under reduced pressure. The dark solid residue was washed with a small amount of cold methanol, then with diethyl ether, and dried to give the acylpyrrole (51.7 g, 80%) as a yellow solid.

[0542] 2-(3,4-Methylenedioxybenzyl)pyrrole

[0543] 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) was refluxed under nitrogen for 4 hours. The solution was concentrated under reduced pressure, diluted with water (500 mL), and extracted with ether-dichloromethane (2:1, 300 mL). The organic solution was washed with water, dried, and concentrated under reduced pressure to give a dark viscous oil. Benzylpyrrole was distilled under reduced pressure as a colorless liquid (20.8 g, 59%) with a boiling point of 125-130° (0.03 mm).

[0544] 2-(3,4-Methylenedioxybenzyl)pyrrolidine

[0545] A solution of 2-(3,4-methylenedioxybenzyl)pyrrole (28.9 g, 0.144 mol) in glacial acetic acid (100 mL) was hydrogenated over 5% rhodium on alumina (3 g) in a Parr apparatus at an initial pressure of 50 psi for 8 hours. The catalyst was filtered and the filtrate was diluted to 500 mL with water. The aqueous solution was extracted with ether, then made strongly alkaline with 50% sodium hydroxide and extracted with dichloromethane. The organic solution was dried, concentrated under reduced pressure, and the dark oil was distilled under reduced pressure to give benzylpyrrolidine. The hydrochloride was prepared by adding saturated ethanolic hydrochloride to a solution of pyrrolidine in ether.

[0546] (R)-2-(3,4-methylenedioxybenzyl)pyrrolidine

[0547] (R)-2-(3,4-methylenedioxybenzyl)pyrrolidine (compound of formula (R)-1) is resolved using enantiomeric separation methods known in the art, for example, using chromatography such as chiral chromatography, crystallization, synthetic methods such as by introducing suitable asymmetric groups at the N-atom to form diastereomers that can be resolved using chromatography, or using other such methods to obtain compounds of formula (R)-1 from racemic mixtures, for example, as described in Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, 1962). The method disclosed in Dame, IN, 1972 and Thompson, Wayne J. et al.: Journal of Medicinal Chemistry, 33(2), 789-808; 1990.

[0548] Example 3: Exemplary Preparation of (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine using the method of the present application*

[0549] (R)-2-(Chlorocarbonyl)pyrrolidine-1-carboxylic acid benzyl ester (Cbz-(D)-Pro-OH)a (2.0 g, 8.0 mmol) was dissolved in DCM (10 mL), oxalyl chloride (6 mL of a 2M solution, 12.0 mmol) was added, and then DMF (2 drops) was added. The mixture was stirred at room temperature for 30 min. The solution was concentrated to give (R)-2-(Chlorocarbonyl)pyrrolidine-1-carboxylic acid benzyl ester. The acyl chloride was mixed with DCM (10 mL) containing aluminum chloride (1.03 g, 8.4 mmol) and stirred under a cooling water bath until the aluminum chloride was completely dissolved. Then 2H-1,3-benzodioxole (1.074 g, 8.8 mmol) was added dropwise and stirred at room temperature. The reaction mixture was poured into water and ice. The organic layer was extracted with DCM and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give *CBz protected (R)-benzo[d][1,3]dioxol-5-yl(pyrrolidin-2-yl)methanone.

[0550] A suspension of about 100 g of CBz-protected (R)-benzo[d][1,3]dioxol-5-yl(pyrrolidin-2-yl)methanone in about 1000 mL of methanol and 10% Pd / C (about 1.0-5 g) was hydrogenated at about 45-50 psi. After the reaction was complete, the catalyst was filtered and the solvent was removed by distillation under vacuum to obtain the title compound. *(S)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine was prepared in the same manner as (R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine. CBz protected (S)-benzo[d][1,3]dioxol-5-yl(pyrrolidin-2-yl)methanone was prepared in the same manner starting from (S)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate from (Cbz-(L)-Pro-OH).

[0551] 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

[0552] Step 1: Preparation of (S)-tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide

[0553]

[0554] 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.

[0555] After 4 hours, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight.

[0556] The reaction mixture was filtered through a short plug of silica to remove the precipitated imidazolium salt and washed with water (1X).

[0557] The aqueous layer was back extracted with DCM (x3) and the organic layers were combined. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a light yellow oil.

[0558] The product was crystallized from ethanol / ether to give a white solid. (4.22 g, 52%). The spectral data matched those reported in the literature (Ferrari et al., (2022), Org. Process Res. Dev. 26, 9, 2614-2623).

[0559] The above procedure was modified to prepare the R-enantiomer (4.46 g, 55%) by starting from (R)-(-)-prolinol.

[0560] Step 2: Preparation of (S)-2-(Benzo[d][1,3]dioxol-5-ylmethyl)pyrrolidine ((S)-I)

[0561]

[0562] nBuLi (2.5 M in hexanes, 5.88 mL, 14.7 mmol) was added to a solution of 4-bromo-1,2-methylenedioxybenzene (2.95 g, 14.7 mmol) in THF (40 mL) under nitrogen at such a rate that the internal temperature remained below -70 °C.

[0563] A cloudy white suspension formed in the solution. The suspension was stirred at -78°C for about 90 minutes, then sulfamate (in THF) (2.0 g, 12.25 mmol) was added dropwise at -78°C over 1 hour. It was slowly warmed to room temperature overnight and then concentrated in vacuo.

[0564] The residue was dissolved in 2M aqueous HCl (25 mL) and ethanol (25 mL) and heated at reflux for 2 days. The reaction mixture was cooled to room temperature, concentrated in vacuo to remove ethanol, and diluted with H2O.

[0565] The aqueous layer was extracted with ether and the ether layer was discarded. The aqueous solution was basified with 5N NaOH and extracted with DCM (5x).

[0566] The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow oil (1.1 g).

[0567] The oil was dissolved in EtOH and 2N HCl in ether was added to give the hydrochloride salt as an off-white solid ((S)-I. hydrochloride) (525 mg, 27%).

[0568] The same procedure was performed to give the hydrochloride salt of (R)-I. hydrochloride (610 mg, 31%) as an off-white solid.

[0569] 1 H NMR*(CD3OD)δ:1.70-1.76(m,1H),1.99-2.17(m,3H),2.92-2.96(m,2H),3.24-3. 35(m,3H),3.69-3.73(pent,1H,J=8Hz,15.2Hz),5.93(s,2H),6.75-6.81(m,3H). 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

[0570] *HCl salt

[0571] Final yield: (S)-I hydrochloride: 27%; (R)-I hydrochloride: 31%

[0572] Example 5: Exemplary compositions of the present application

[0573] Exemplary Composition 1: Enantiomerically pure compound of formula (R)-I (>99% R enantiomer)

[0574] Exemplary composition 2: 90-99% compound of formula (R)-I, 1-10% compound of formula (S)-I

[0575] Exemplary composition 3: 80-89.9% compound of formula (R)-I, 10.1%-20% compound of formula (S)-I

[0576] Exemplary Composition 4: 70-79.9% compound of formula (R)-I, 20.1-30% compound of formula (S)-I

[0577] Exemplary composition 5: 60-69.9% compound of formula (R)-I, 30.1-40% compound of formula (S)-I

[0578] Exemplary Composition 6: 51-59.9% compound of formula (R)-I, 40.1-40% compound of formula (S)-I

[0579] Comparative composition 1: racemic compound of formula (R / S)-I

[0580] Comparative composition 2: racemic MDMA

[0581] Comparative composition 2: racemic MBDB

[0582] Biological data

[0583] Example 6: Computational study

[0584] a. Docking study

[0585] Compounds of formula (R)-I and (S)-I are used to treat 5-HT 2A Receptor docking studies were performed using A ligand docking program (e.g., Halgren TA et al., J. Med. Chem. 2004, 47, 1750-1759) was used, using the 6WHA cryoEM structure of 5-HT2A, solved at 3.4 Å ( Figure 1 ).like Figure 1 As shown, the basic alkylamine forms a salt bridge with the highly conserved D155 side chain in TM3. Aromatic residue clusters F243, W336, F339 and F340 are present.

[0586] The compounds of formula (R)-I and (S)-I were used to perform docking studies with the 5-HT2B receptor. The ligand docking program was used with the 6DRZ cryoEM structure of 5-HT2B, solved at 3.1A ( Figure 2 ).like Figure 2 As shown, the basic alkylamine forms a salt bridge with the highly conserved D135 side chain in TM3. Aromatic and aliphatic residue clusters V136, I186, F340, F341, V366 are present.

[0587] Similar docking studies were performed using the (R)- and (S)-enantiomers of MDMA.

[0588] 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 5-HT are provided in Table 1. 2A The docking score of the receptor.

[0589] When combined with 5-HT 2B The docking scores for compounds of formula (R)-I and (S)-I and the (R)- and (S)-enantiomers of MDMA upon receptor docking are provided in Table 2.

[0590] Table 1

[0591]

[0592] *Glide evdw stands for van der Waals energy.

[0593] **Glide ecoul stands for Coulomb energy.

[0594] All items are included in the Glide gscore algorithm

[0595] Table 2

[0596]

[0597] *Glide evdw stands for van der Waals energy.

[0598] **Glide ecoul stands for Coulomb energy.

[0599] All items are included in the Glide gscore algorithm.

[0600] As can be seen from the docking scores in Tables 1 and 2, in a manner similar to S-MDMA, the compound of formula (S)-I binds 5HT with a stronger affinity than its corresponding R enantiomer. 2B .

[0601] b. Predict IC 50

[0602] In silico studies (QSAR and docking) are useful tools to understand the mechanism of drugs and they are relatively cheaper and faster than experiments. QSAR models were created for each monoamine transporter. In addition, the docking properties of phenethylamine were studied.

[0603] QSAR: DAT, SERT and NET IC of 73 phenylethylamines collected from literature 50 Three different softwares were used for descriptor calculation and nearly 2000 descriptors were calculated. Highly correlated descriptors were removed before multiple linear regression (MLR) analysis. All descriptors were merged with the experimental inhibition values ​​in the QSARiNS software. The QSARiNS multi-criteria decision tool was used to select the optimal model.

[0604] Docking: The selected compounds were built by MOE with +1 charge (extra hydrogen is always on the amine). The energy minimization tool of MOE was used to optimize the molecular geometry. The transporter and receptor 3D structures were downloaded from the Protein Data Bank (PDB) website as shown in Table 3. Unnecessary components in the PDB file were removed. The energy minimization tool was used to optimize the 3D structure of the protein.

[0605] Table 3: Protein structures of transporters and receptors selected for QSAR modeling

[0606]

[0607]

[0608] Predicted ICs of test molecules generated based on the QSAR developed as described above 50 The (mM) values ​​are presented in Table 4.

[0609] Table 4: Predicted ICs of test molecules based on in-house developed QSAR models 50 (μM) value

[0610]

[0611] *DAT / SERT ratio = 1 / DAT IC50: 1 / SERT IC50

[0612] As stated in Liechti 2015: "Many new psychoactive substances interact with biogenic amine neurotransmitter transporters. Amphetamines (including methamphetamine and MDMA) inhibit dopamine, serotonin, and norepinephrine (noradrenaline) transporters (DAT, SERT, NET, respectively) and release these monoamines through the corresponding transporters. Meth increases primarily dopamine and norepinephrine. MDMA increases primarily serotonin and norepinephrine. It is generally believed that the endogenous effects of MDMA depend on its serotonergic effects. Therefore, substances that primarily release serotonin, such as MDMA, can be expected to produce MDMA-like endogenous effects." . In contrast, psychostimulants such as methamphetamine or methylphenidate primarily enhance dopaminergic neurotransmission. Dopamine mediates the reinforcing and addictive properties of drugs of abuse. In contrast, an increase in the serotonergic properties of a substance is associated with a decrease in its addictive potential. Therefore, the relative in vitro dopaminergic and serotonergic properties of a new substance (dopamine / serotonin transporter inhibition ratio) can be determined as a useful marker for its potential clinical psychiatric and acute toxic effects. Serotonin release and a DAT / SERT inhibition ratio of typically 0.01-0.1 are expected to produce subjective pharmacodynamics, such as those of MDMA or other empathetic drugs. (Liechti M. (2015). Swiss Medical Weekly, 145(0304), w14043.)

[0613] Predicted IC of (R)-I and (S)-I 50 (Table 4) shows that the RI is expected to behave much like R-MDMA. R-MDMA has a well-established lower toxicity potential than its S-enantiomer counterpart and racemic MDMA (Pitts et al., (2018) Psychopharmacology, 235(2), 377-392).

[0614] Example 7: Behavioral Experiment

[0615] a. Social interaction test

[0616] A social interaction test that has been used to test the effects of MDMA, particularly the prosocial effects of MDMA, is described in Morley and McGregnor Eur J Pharmacol. 2000; 408: 41-9 and was used to test the exemplary and comparative compositions of the present application.

[0617] In order to make the individual (mice) familiar with the test procedure and screen for aggressive individuals, two social interaction tests were performed. In the first stage, the individual received the injection of the exemplary composition of the application, the comparison composition or saline, and was isolated in a clean cage for 30 minutes. Then in a 30 × 18 cm transparent Plexiglas test chamber, each individual was paired with an unfamiliar weight-matched same-species animal from the same treatment group for 10 minutes. During the first test day, there was an experimenter to separate the aggressive individuals. Any individual taken out was replaced with a new original individual so that each treatment condition had the same number of non-aggressive individuals.

[0618] The second test phase was performed 48 hours later using the same pairing, treatment and procedure, except that there was no experimenter in the room during the test. When in the test field, individuals moved around freely and interacted, allowing observable behaviors of different ranges. On the second test day, social pairs were recorded, and the duration of social behavior was quantified using JWatcher or BORIS (Friard and Gamba, Methods Ecol Evol. 2016; 7 (11) 1325-1330) by observers who did not understand the experimental conditions. The duration of 3 behaviors was scored: anal investigation (sniffing the anal genital area of ​​the same species), general investigation (non-anal sniffing, combing and following the same species) and adjacent lying (side by side contact or gathering). These behaviors of each pair were averaged and then summed to produce a total social interaction score, which was statistically analyzed based on the total social interaction score.

[0619] b. Movement behavior

[0620] The effects of the exemplary compositions and comparative compositions of the present application on motor activity were tested in a 45×39×37 cm open field chamber, wherein a 16×16 photocell was located 2.5 cm from the chamber. Mice were treated with the exemplary compositions of the present application, comparative compositions, or saline (n=13 / group) 1 hour before being placed in the chamber. The test was conducted in a dark enclosed space. The cumulative beam interruptions of adjacent photocells were recorded as a measure of motor activity.

[0621] c. Fear conditioning and extinction

[0622] The effects of the exemplary compositions and comparative compositions of the present application on conditioned freezing were evaluated using an established protocol previously used to test racemic MDMA (Young et al., 2015, Transl Psychiatry. 5: 1-8). In order to be consistent with previous studies, C57BL / 6 mice were used in this experiment. In brief, mice were exposed to conditioned fear on the 1st day, fear extinction training on the 3rd day, and extinction test on the 4th day. The conditioned fear suggested consisted of a single pair of conditioned stimulus (CS) tone (80dB, 4.5kHz, 30s) and unconditioned stimulus (US) foot shock (1mA, 2s). Extinction training was performed in a new environment 48 hours after the start of conditioning. R-MDMA, S-MDMA or saline (n=6-7 / group) was administered 30 minutes before training on the 3rd day. Extinction training consisted of a suboptimal protocol of 4CS-tone re-exposure at intervals of 45 seconds. Extinction test was performed 24 hours later to determine the lasting effect of treatment on conditioned freezing. Extinction testing was performed in the same environment as training and followed the same procedure, except that no treatment was administered. In these experiments, the percentage of freezing (conditioned response) was estimated by scoring the presence or absence of non-respiratory movements every 5 seconds.

[0623] d. Social preference and locomotor activity (LMA) studies in rodent models

[0624] introduce

[0625] Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder defined by two major behavioral clusters. The first cluster of behaviors is defined by deficits in social communication and social interaction, while the second cluster consists of repetitive and inflexible patterns of behavior, interests, and thoughts. In 2016, the Autism and DevelopmentalDisabilities Monitoring Network estimated that 1 in 54 children has ASD and noted that the prevalence of ASD in boys is 4.3 times higher than in girls. The reported incidence of ASD in the United States has increased over the past few decades, but the causes of ASD remain poorly understood.

[0626] To better understand the neurological basis of ASD, rodent models of ASD have been developed for research. BTBR T+Itpr3tf / J mice (BTBR), originally used for the study of insulin resistance, diabetes-induced nephropathy, and phenylketonuria, were identified about a decade ago as displaying strong and consistent autism-related behaviors. Identifying new drugs that improve sociability and reduce repetitive behaviors in the autism-like BTBR mouse and C57BL / 6J (C57) background library may be useful in the treatment of social anxiety disorder, general anxiety, and / or ASD.

[0627] The studies described here used male BTBR and C57 mice 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 autism-relevant assays of social preference, as well as in studies of the safety and abuse liability of these drugs.

[0628] In three-dimensional space, based on whether the group bonded to the chiral carbon is protruding above or below the plane of the rest of the molecule, these enantiomers are distinguished from each other as non-overlapping mirror images (such as left and right hands). Pharmacologically, enantiomers can have very different biological effects, including the quantitative differences in effectiveness and effectiveness and the qualitative differences in the mechanism of action or interoceptive effects, because the binding pockets of the two substances "match" the relevant receptors differently. With regard to methamphetamine, the S (+)-enantiomer is a psychostimulant of abuse, with effective and lasting psychoactive effects, and the R (-)-enantiomer induces any one of these effects with more than 100 times lower effectiveness (because it "matches" the relevant receptors in the left glove, as the right hand). With regard to MDMA, both enantiomers are active at similar doses, although they cause different effects of each other. Based on their similar chemical structures, methamphetamine is selected as a positive control compound, compared with the effect of MDMA in the social preference test. It is expected that both compounds cause motor excitement at high doses, but methamphetamine is not expected to cause any prosocial effects.

[0629] General Animal Handling

[0630] Adult male C57 and BTBR mice were shipped to the University of Arkansas for Medical Sciences from Charles River Laboratories and The Jackson Laboratory, respectively. Upon arrival, mice were housed three per cage according to strain and had access to food and water ad libitum. Mice were acclimated to the UAMS facility for at least 48 h prior to any experimental manipulation.

[0631] Drug administration

[0632] All drugs were dissolved in 0.9% saline and administered at a constant volume of 1 ml / 100 g body weight. Because all drugs used in these studies were synthesized as hydrochlorides (HCl), they were weighed as salts before preparing all solutions. All drugs at all concentrations were readily soluble in aqueous solutions at normal pH. Injections of all drugs were administered intraperitoneally (IP) to simulate typical pharmacokinetic parameters of oral administration without the behavioral impairment effects of gavage stress.

[0633] Social Preference Test Method

[0634] Assays were performed in adult male C57 and BTBR mice (n=6 per group) in dedicated conditioning rooms where ambient light, sound, and human contact were strictly controlled.

[0635] The social preference chamber consisted of two polycarbonate boxes (13.5 cm wide x 22.5 cm high x 31.0 cm deep) with a floor made of rough textured black ABS plastic and connected to each other by 1.25" PVC T-joints. An infrared beam emitter / detector array was mounted at each intersection of the T-joints and each preference compartment, and as the mouse traversed the apparatus, it would break the beam upon entering or leaving each preference compartment. The beam break started or stopped a counter on the interface computer, allowing for the automatic collection of the time spent in each compartment. At the end of each test, data were reported as the time spent in each compartment (in seconds), the number of entries into each compartment, and the average time spent in each compartment after an entry. The social preference test was performed in an iterative manner, with each test individual completing four different phases as follows. During the test, the chambers were disinfected by wiping the interior with a disinfectant product provided by the UAMS Department of Laboratory Animal Medicine. At the end of the week (when all phases of the procedure were completed), each apparatus was disassembled and all components disinfected. No food or water was available during the social preference experiment, but was available in the home cage immediately afterwards.

[0636] Stage 1 – Habitualization

[0637] A single habituation phase was performed prior to preference testing, in which each compartment contained an identical empty wire mesh pencil cup (9.0 cm diameter x 10.5 cm high). During this phase, mice were weighed, no injections were given, and individuals were introduced to the T-junction and allowed to explore both preference compartments for 30 minutes. This habituation phase was performed as a procedural control to accustom the animals to the apparatus and to screen out any animals with a strong initial bias for one of the two compartments. An a priori exclusion criterion was established so that any individual who spent more than 75% of the total time in a single preference compartment was excluded from further studies, but no individuals in these studies met this exclusion criterion. The habituation phase always occurred on Mondays or Tuesdays to prevent any weekend testing.

[0638] Stage 2 – Novelty Preference

[0639] A single novelty preference phase occurred one day after the habituation test, with one compartment containing an empty wire mesh cup and the other compartment containing the same wire mesh cup with a novel sham mouse inside. The location of the sham mouse (left or right compartment) was counterbalanced between individuals. The sham mouse consisted of a 2.5" long white 3 / 4" PVC tube with a zipper tape attached to one end (to mimic a tail) and two red dots painted on the other end (to mimic eyes). During this phase, mice were weighed, injected, and returned to their home cages for a 30-minute pretreatment. The mice were then introduced into a T-junction and allowed to explore the two preference compartments for 15 minutes. These experiments were performed as procedural controls to ensure that any observed drug effects were not simply due to an enhancement of the mice's inherent novelty preference. The novelty preference phase always occurred on Tuesdays or Wednesdays to prevent any weekend testing.

[0640] Stage 3 - Social Testing

[0641] A socialization session was conducted on the day following the novelty preference test, in which one compartment contained a wire mesh cup with a sham mouse inside and the other compartment contained a male NIH Swiss stranger mouse (see Figure 4). The wire mesh cup allows visual, olfactory, auditory and limited tactile contact, but prevents aggressive behavior that may cause damage. For each individual, the position of the sham mouse (left or right compartment) remains the same as during the novelty test of the previous day, thereby balancing the position of the strange mouse between individuals. NIH Swiss strange mice are similar to sham PVC mice in weight and appearance, and are housed separately from experimental individuals (C57 and BTBR mice) in a group facility. The first time the experimental individuals encounter strange mice is when they enter the compartment that houses them. During this stage, the mice are weighed, the same injection as the previous day is administered, and they are returned to their breeding cages for a 30-minute pretreatment. The mice are then introduced into the T-connection and allowed to explore the two preference compartments for 15 minutes. Sociability testing usually occurs on Wednesdays or Thursdays to prevent any weekend testing.

[0642] Stage 4 – Social Novelty Preference

[0643] The single social novelty preference phase occurred on the day after the sociability test, with one compartment containing a wire mesh cup with the same NIH Swiss mouse from the previous day (now referred to as the “familiar” mouse) inside, and the other compartment containing a new male NIH Swiss stranger mouse inside the cup that had previously contained a sham mouse during the sociability test (see Figure 5 ). The wire mesh cup allows visual, olfactory, auditory and limited tactile contact, but prevents aggressive behavior that may cause damage. The position of the now familiar NIH Swiss mouse (left or right compartment) remains the same for each individual as during the sociability test on the previous day, thereby balancing the position of the new NIH Swiss stranger mouse between individuals. As previously described, the new NIH Swiss stranger mice are housed separately from the experimental individuals (C57 and BTBR mice) in a group facility, and the first time the experimental individuals encounter them is when they enter the compartment that houses them. During this stage, the mice are weighed, the same injection as the previous day is administered, and they are returned to their breeding cages for a 30-minute pretreatment. The mice are then introduced into a T-connection and allowed to explore the two preference compartments for 15 minutes. Social novelty testing always occurs on Thursdays or Fridays to prevent any weekend testing.

[0644] Effects of Drugs on Motor Activity

[0645] Quantification of the total number of entries into the preference compartment provides an alternative measurement of the motor stimulant effect of various test drugs of various doses. This determines the limitation of the drug dosage that can be tested in the social preference program, because the induction of the motor stimulant effect confuses the preference assessment (because mice stop participating in the social stimulation in each compartment, but spend the time they participate in motor behavior). Motor activity changes in the different stages of the social preference test, partly because the habituation stage is twice as long (30 minutes) as the novelty, sociability and social novelty test (15 minutes each time), and also because mice send out high-level exploratory behavior in a new environment. Therefore, as the familiarity to the test device increases with the continuous exposure to the chamber, the number of entries decreases.

[0646] Figure 3 This decreasing trend in locomotor activity in C57 (solid bars) and BTBR (open bars) is illustrated in the absence of any drug injection. Note that baseline differences in locomotor activity were also observed between C57 and BTBR mice in the absence of drug injection, with BTBR individuals consistently exhibiting more entries during each phase of the social preference procedure.

[0647] Because baseline activity of C57 and BTBR mice did not change from the sociability to the social novelty test (the final test phase, when mice are most familiar with the apparatus), we focused on drug effects during this phase to determine the locomotor stimulating effects of various treatments. (Note that the number of entries was collected for each test, but drug effects on the number of entries during earlier phases may be less reliable due to the confounding effects of changes in familiarity with the apparatus across phases.)

[0648] In C57 mice (see Figure 4 , solid bars), approximately 20 entries were observed after saline administration.

[0649] C57 mice (see Figure 5 , left) and BTBR mice (see Figure 5 , right panel ) did not show a strong preference for the sham mice over the empty cup, as approximately equal amounts of time were spent in each compartment following saline administration.

[0650] Injections of (R)-I, (S)-I, or racemic MDMA had no systematic effects on novelty preference at this dose. Because none of the tested drugs increased novelty preference, any enhancement of social preference in subsequent tests is unlikely to be confounded by novelty-related effects, such as changes in the motivational properties of novel objects, which could otherwise be confounded as effects on prosociality.

[0651] Effects of drugs on sociability

[0652] C57 mice mildly avoided the stranger mouse, as they spent slightly less time in the compartment containing the stranger mouse than in the compartment containing the sham mouse after saline administration (see Figure 6 , left). In BTBR mice (see Figure 6 , right), the expected autism-like reduction in sociability was observed after saline administration, with mice showing strong avoidance of unfamiliar mice.

[0653] Injection of 1 mg / kg (R)-I, racemic MDMA, had no effect on the sociability of C57 mice. However, injection of 1 mg / kg (S)-I caused a slight increase in the time spent with the stranger mouse, producing a modest preference for the stranger mouse over the sham mouse.

[0654] In BTBR mice, (S)-I induced a strong social response. However, (R)-I and racemic MDMA had a smaller increase in social responding.

[0655] Effects of drugs on social novelty preference

[0656] C57 mice showed a small preference for the new stranger mouse, as after saline administration, they spent slightly more time in the compartment containing the new stranger mouse than in the compartment containing the now familiar mouse (see Figure 7 , left). In BTBR mice (see Figure 7 , right), the expected autism-like reduction in sociability was observed after saline administration, with mice showing mild avoidance of unfamiliar mice.

[0657] Injections of (R)-I and (S)-I at 1 mg / kg in C57 mice only slightly increased the total number of entries during social novelty relative to saline, whereas racemic MDMA had no effect at this dose (see Figure 8 , left panel). In BTBR mice, approximately 40 entries were observed after saline administration, consistent with previous descriptions and Figure 3 This is consistent with the larger baseline levels of their motor effects shown in .

[0658] Compared with (R)-I, racemic MDMA, and saline, injection of 1 mg / kg (S)-I significantly stimulated BTBR mice (right panel, Figure 8 In BTBR mice, this stimulation appeared to increase with increasing doses ( Fig. 9 A, right), but was reversed in C57 mice (see Fig. 9 A, left).

[0659] In BTBR mice ( Fig. 9B, right), the prosocial responses recorded by 1 mg / kg (R)-I were similar to those recorded by 3 mg / kg racemic MDMA, thereby demonstrating that (R)-I is a more effective drug when testing social preference in BTBR mice.

[0660] Similarly, in C57 mice ( Fig. 9 , left), the prosocial responses of mice after injection of 1 mg / kg (R)-I were similar to those recorded when mice were injected with 1.8 mg / kg racemic MDMA. Interestingly, (R / S)-I had the strongest prosocial response at 1 mg / kg, and the response decreased at 1.8 mg / kg.

[0661] e. Effects of drugs on rodent models of conditioned place preference

[0662] The same 2-compartment chamber as described above in the social preference research of conditional position preference.For these studies, the compartment is distinguished by floor texture (rough black plastic is relative to steel punching plate) and wall pattern (vertical stripes are relative to horizontal stripes).First, the initial preference / habit test is carried out, wherein mice can freely pass through the equipment for 30 minutes.On the second day, mice are assigned to receive saline in a compartment, and receive medicine in another compartment.Saline pairing occurs in the morning, and drug pairing occurs in the afternoon, and is at least 4 hours apart, during which mice return to their feeding cage.Carry out such pairing three times, wherein mice are injected, return to the pretreatment period of 15 minutes in the feeding cage, and then be restricted in the compartment that injection is suitable for 30 minutes.Half of individuals (in strain) receive drug pairing on plastic base plate+vertical stripe side, and the other half receive drug pairing on punching plate base plate+horizontal stripe side.By distributing drugs to the initial non-preferred side of all mice expressing preference, then fill the remaining groove with the mice that do not express preference in the initial test to realize balance. The post-conditioning preference test was identical to the initial preference / habituation phase, in which mice were able to freely traverse the apparatus for 30 minutes. The time spent in each compartment was recorded and expressed as a preference score for the drug-paired side (calculated as the time spent in that compartment during the post-test period - the time spent in that compartment during the pre-test period). All preference and conditioning phases were conducted under the same low light conditions as in the social preference test.

[0663] Fig.21Shown are the effects of saline or 3 mg / kg of MDMA (each x3 pairing) on ​​place conditioning at various enantiomer ratios in C57 mice (solid bars) and BTBR mice (open bars). Saline administered in both compartments had a negligible effect on place conditioning, and 3 mg / kg S-MDMA or racemic MDMA induced significant place preference in C57 and BTBR mice. BTBR mice exhibited a greater place preference than C57 mice, indicating an increased sensitivity to the rewarding effects of racemic MDMA (but note that no statistical comparisons between strains were performed). 3 mg / kg R-MDMA was not tested because it had no significant effect in either strain at 10 mg / kg (see Fig. 22 ).

[0664] Fig. 22 : Effects of saline, 1.0 or 3.0 mg / kg S-METH (each x3 pairing) on ​​place regulation in C57 mice (solid bars) and BTBR mice (open bars). Saline administered in both compartments had a negligible effect on place regulation, but 1.0 and 3.0 mg / kg S-methamphetamine (METH) only induced significant place preference in C57 mice (see Fig. 22 ). Thus, these results suggest that the apparent increased sensitivity to the rewarding effects of MDMA observed in BTBR mice is not simply a generalized increase in sensitivity to all drugs. The effect may be specific to MDMA-like compounds.

[0665] Fig.23 Effects of saline, 1.0 mg / kg (R)-I or 1.0 mg / kg (S)-I1 (each x3 pairing) on ​​place regulation in C57 mice (solid bars) and BTBR mice (open bars) are shown. Saline administered in both compartments had a negligible effect on place regulation, 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 to the rewarding effects of MDMA-like drugs in BTBR mice, this strain may display place preference at doses that are ineffective in C57 mice.

[0666] When 1 mg / kg of (R)-I and (S)-I were tested in C57 mice relative to S-methamphetamine (tested at the same dose), both enantiomers had negligible effects on the mice (see Fig.23 ).

[0667] 3 mg / kg of racemic MDMA and S-MDMA induced significant place preference in C57 and BTBR mice (see Fig. 22 ).

[0668] Example 8: Neurotoxicity Study

[0669] a. Neurotoxicity Dose and Tissue Collection

[0670] Itzhak et al., Psychopharmacol. 2003; 166: 241-248 in a modified administration scheme, individuals received a total of four injections of the exemplary composition of the present application, the comparative composition or saline twice, two hours apart for two consecutive days. Individuals were isolated during treatment and returned to their cages 2 hours after the second daily dose. After treatment, individuals were divided into two groups. 48 hours after the last injection, individuals from Group 1 were anesthetized and perfused transcardially with 4% formaldehyde. Their brains were post-fixed overnight, then immersed in 15% sucrose for 48 hours, frozen in frozen methylbutane, sliced ​​at 35 μm, and stored at -20°C until analyzed by immunohistochemistry. Individuals in Group 2 were euthanized by cervical dislocation 14 days after the last injection. Their brains were removed, and the prefrontal cortex, striatum, and hippocampus were quickly dissected and stored at -80°C for subsequent analysis by high performance liquid chromatography (HPLC) or Western blot.

[0671] b. Temperature monitoring

[0672] The effects of the exemplary compositions and comparative compositions of the present application on body temperature were monitored using a rectal thermometer (n=5 / group) (twice at 2-hour intervals). Measurements were made every 30 minutes at an ambient room temperature of 22±2°C. During the monitoring process, mice were divided into individual cages.

[0673] c. Temperature Monitoring in Rodent Models of Autism Spectrum Disorder

[0674] Radiotelemetry of core temperature and locomotor activity testing methods

[0675] Monoamine mimetics can affect temperature control, particularly amphetamine derivatives such as MDMA, which have probably been most extensively studied (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 investigate the effects of target drugs on core body temperature in C57 and BTBR mice.

[0676] Radiotelemetry measurements were performed on adult male C57 and BTBR mice (n=6 per group) in a dedicated testing room where environmental light, sound, and human contact were carefully controlled.

[0677] Prior to surgical implantation of the radiotelemetry probe, mice received 3 mg / kg meloxicam (IP), anesthesia was induced with 4% inhaled isoflurane, and maintained with 1-3% isoflurane (as needed) at a flow rate of 1.5 liters / minute throughout the procedure. The abdominal area of ​​each animal was treated with depilatory cream and then disinfected with 3 alternating scrubs of iodine and alcohol. A head-to-tail incision of approximately 1.5 cm in length was made with sterile skin scissors to provide access to the intraperitoneal cavity. A cylindrical glass-encapsulated radiotelemetry probe (model ER-4000E-Mitter, Mini Mitter, Bend, OR, USA) was then inserted. These probes measured 15.5 mm×6.5 mm and weighed approximately 1 g. The incision was sutured using reverse-cut 5-0 Vicryl absorbable sutures (muscle layer) and 5-0 nylon suture material (skin layer) (skin layer and muscle layer were sutured separately). Surgery was performed at least 7 days before the start of experimental conditions to provide time for the incision to heal and for the animals to return to normal weight. After surgery, all implanted mice were housed individually in Plexiglas cages in a telemetry room during all experiments. The implanted transmitters produced activity and temperature modulated signals that were sent to a receiver (model ER-4000 receiver, Mini Mitter Co., Inc.) located below each cage. After use, the telemetry probes were removed from the carcass, wiped with alcohol cotton, and stored in a disinfectant solution until reused.

[0678] At least 7 days after surgical implantation of the radiotelemetry probe, mice in their individual home cages were placed atop a telemetry stimulator / receiver, which powered the probe and transmitted its data to an interface computer. At the beginning of the experimental period, the computer collected two data updates from the probe at 5-minute intervals: core temperature (in °C) on one channel, and movement counts (in arbitrary units, depending on the relative position of the probe atop the receiver) on the other channel. After at least 60 minutes of baseline data collection, mice were removed from their cages, injected with saline or a given dose of a specific drug, and then returned to their home cages for 24 hours of data collection.

[0679] Food and water were always freely available in the home cage. Mice were injected with increasing doses of a given drug at intervals of at least 48 hours. Because few studies of drug effects have been conducted in BTBR mice, the first drug dose tested occasionally causes unexpectedly large motor effects in these animals. In these cases, after a washout period of at least one full day, smaller drug doses were then tested.

[0680] Results - Core Body Temperature and Motor Activity

[0681] Effects of saline injection on core temperature and (locomotor activity) LMA in C57 and BTBR mice [Establishing baselines and characteristics of mouse species]

[0682] Both strains showed transient increases in core temperature and higher activity levels approximately 30 minutes after saline administration ( Fig.10 ). Activity of both strains also followed a normal circadian rhythm. More locomotor activity was recorded during the subjective dark phase, but interestingly, BTBR mice showed more activity than C57 mice, as well as elevated core temperatures (which may be due to this higher activity) ( Fig.10 ).

[0683] Effects of (R)-I injection on core temperature and (locomotor activity) LMA in C57 and BTBR mice

[0684] Intraperitoneal injection of (R)-I resulted in a more acute response in C57 mice compared with BTBR mice ( Fig.11 Unlike MDMA, (R)-I did not cause an increase in core body temperature in either strain at any dose tested. However, both strains showed a dose-dependent hypothermic effect following injection. These effects were greater in C57 mice following doses of 10, 18, 30, and 56 mg / kg ( Fig.12 ). Note that at 5.6 mg / kg, (R)-I did not cause an increase or decrease in core body temperature in either mouse strain.

[0685] Intraperitoneal injection of different doses of (R)-I did not have a significant locomotor stimulatory effect in C57 and BTBR, even at doses as high as 30 mg / kg ( Fig.13 ). Under 56mg / kg intraperitoneal injection, ( Fig.14 ) BTBR mice elicited stronger locomotor effects than C57 mice at the same dose, which was also significantly different from saline.

[0686] and Fig.12 and Fig.13 Together with the data presented in , it can be seen that (R)-I has a wide safety margin, especially at doses up to 5.6 mg / kg in BTBR and C57 mice. At 10 mg / kg and above, a hypothermic effect was noted in both strains.

[0687] Effects of (S)-I injection on core temperature and (locomotor activity) LMA in C57 and BTBR mice

[0688] Intraperitoneal injection of (S)-I resulted in a more acute response in C57 mice compared to BTBR mice.

[0689] However, in C57 mice, (S)-I was more effective and caused a significant decrease in body temperature at a lower dose (5.6 mg / kg) compared to the same dose of (R)-I tested (see Figures 15 to 18 ).

[0690] It is noted that neither strain exhibited locomotor stimulation at any dose tested. However, the procedure used here may not have detected locomotor inhibition because home cage activity was very low during the light phase when the injections were administered. To determine whether S-PharmAla1 reduces locomotor activity, mice can be placed in a new cage with fresh bedding and nesting material immediately after injection (to stimulate exploratory and nesting activity in saline controls), or an open field beam box without habituation can be used.

[0691] Example 9: Cardiotoxicity Study

[0692] The cardiotoxicity of drugs is largely related to the ability of drugs to inhibit the human ether-à-go-go-related gene (hERG) cardiac potassium channel. Drug inhibition of cardiac hERG channels is known to be associated with potentially fatal arrhythmias. Therefore, drug interactions with hERG are routinely studied to avoid the risk of cardiac side effects. Therefore, a large number of computer simulations, in vitro and in vivo assays using hERG have been reported, including in vitro model systems (hERG is usually expressed in HEK 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.)

[0693] hERG inhibition studies were performed using compounds of Formula (R)-I and (S)-I, as well as exemplary and comparative compositions of the present application.

[0694] Cardiotoxicity in rodent models of autism spectrum disorder

[0695] Set up 8-chamber CODA TMNon-invasive blood pressure system to monitor blood pressure of C57 and BTBR mice. Before drug administration, mice were habituated to restraint, saline injection (IP) and tail cuff pressure monitoring for at least three days. Over several days, groups of habituated mice were injected intraperitoneally with increasing doses of test drugs (in this case (R)-I, (S)-I and (R / S)-I) and then returned to the breeding cage for 30 minutes. Then, tail cuff pressure monitoring was used to determine the effects on systolic, diastolic and mean arterial pressure in restrained C57 and BTBR mice over a period of about 30 minutes.

[0696] In tail cuff pressure monitoring, an occlusive tail cuff is inflated to block blood flow to the tail. The cuff is slowly deflated, and a second tail cuff containing a VPR sensor measures the physiological characteristics of the returning blood flow. As blood returns to the tail, the VPR sensing cuff measures the swelling of the tail caused by the pulsation of arterial blood flow. Systolic pressure is automatically measured at the first onset of tail swelling. Diastolic pressure is automatically measured when the rate of increase in tail swelling stops.

[0697] Effects of (R)-I and (S)-I on cardiovascular function in C57 and BTBR mice

[0698] In C57 and BTBR mice, hypothermic effects of (R)-I and (S)-I were observed at 10 mg / kg. Therefore, the effects of 10 mg / kg and 30 mg / kg of the drug on systolic, diastolic, and mean arterial pressure were evaluated in this study.

[0699] based on Fig.14 From the data presented in Figure 1, it is clear that 10 mg / kg and 30 mg / kg of (R)-I have less effect on cardiovascular effects than (S)-I. This is consistent with the docking data above, where (S)-I is predicted to bind more strongly to the 5HT2b receptor than (R)-I. Fig. 20 ), due to (R)-I (see Fig.19 ), the blood pressure increase was significantly lower in both strains.

[0700] Summary: Docking studies predict that (S)-I binds to the 5HT2b receptor with greater affinity, which would lead to increased blood pressure. Fig.19 )10mg / kg ip, it can be seen that (S)-I indeed causes higher systolic and diastolic blood pressure than (R)-I. Relative to racemic MDMA (Figure), both enantiomers (R)-I and (S)-I have significantly reduced toxicity.

[0701] Although the present application has been described with reference to examples, it should be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the specification as a whole.

[0702] All publications, patents, and patent applications are incorporated herein 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. When a term in this application is found to be defined differently in a document incorporated herein by reference, the definition provided herein serves as the definition for that term.

Claims

1. An enantiomerically pure compound of formula (R)-I or a salt and / or solvate thereof 2. The compound according to claim 1, wherein the enantiomerically pure compound of formula (R)-I or its salt and / or solvate comprises about 99 wt % or more of the compound of formula (R)-I or its salt and / or solvate and about 1 wt % or less of the compound of formula (S)-I or its salt and / or solvate 3. The compound according to claim 1, wherein the enantiomerically pure compound of formula (R)-I or its salt and / or solvate comprises 99.1 wt%, 99.2 wt%, 99.3 wt%, 99.4 wt%, 99.5 wt%, 99.6 wt%, 99.7 wt%, 99.8 wt%, 99.9 wt%, 99.91 wt%, 99.92 wt%, 99.93 wt%, 99.94 wt%, 99.95 wt%, 99.96 wt%, 99.97 wt%, 99.98 wt%, respectively. %, 99.9% by weight or 100% by weight of the compound of formula (R)-I and 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01% or 0% by weight of the compound of formula (S)-I or its salt and / or solvate.

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

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

6. A pharmaceutical composition comprising 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 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: wherein the compound of formula (R)-I or its salt and / or solvate is present in the composition in a larger amount in terms of enantiomeric equivalent relative to (S)-I or its salt and / or solvate.

8. A composition according to claim 7, wherein the composition comprises about 70% to about 79.9% of the compound of formula (R)-I or its salt and / or solvate, calculated on an enantiomeric equivalent basis, and about 20.1% to about 30% of the compound of formula (S)-I or its salt and / or solvate, calculated on an enantiomeric equivalent basis.

9. A composition according to claim 7, wherein the composition comprises about 80% to about 89.9% of the compound of formula (R)-I or its salt and / or solvate, calculated on an enantiomeric equivalent basis, and about 10.1% to about 20% of the compound of formula (S)-I or its salt and / or solvate, calculated on an enantiomeric equivalent basis.

10. The composition of claim 7, wherein the composition comprises about 90% to 95% of the compound of formula (R)-I or its salt and / or solvate, calculated on an enantiomeric equivalent basis, and 5% to about 10% of the compound of formula (S)-I or its salt and / or solvate, calculated on an enantiomeric equivalent basis.

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

12. The method of claim 11, wherein the serotonin receptor is 5-HT 2A .

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

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

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

16. The method of claim 15, wherein the adverse side effect is hyperthermia or hypothermia.

17. The method of claim 15, wherein the adverse side effect is cardiotoxicity.

18. The method of claim 14, wherein the reduced risk of adverse side effects is achieved by interacting with 5-hydroxytryptamine 2A (5-HT 2A ) receptor, using the enantiomerically pure compound of formula (R)-I or its salt and / or solvate as compared to the compound of formula (R / S)-I or its salt and / or solvate or compared to the enantiomerically pure compound of formula (S)-I or its salt and / or solvate to bind to the 5-hydroxytryptamine 2B receptor (5-HT 2B )combined.

19. A method according to any one of claims 11 to 18, wherein the disease, disorder or condition treatable by activation of serotonin receptors is a disease, disorder or condition that benefits from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof.

20. The method of any one of claims 11 to 19, wherein the disease, disorder or condition treatable by activation of serotonin receptors is any disease, disorder or condition that benefits from psychological treatment.

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

22. The method of claim 20 or 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 to treat the disease, disorder or condition.

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

24. The method of claim 23, wherein the one or more psychiatric 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 of 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 of claim 24, wherein the mood disorder is selected from one or both of depression and bipolar disorder.

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

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

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

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

31. The method of claim 24, wherein the psychiatric disorder is selected from schizophrenia and other disorders causing dissociation from reality.

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

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

34. The method of claim 11, wherein the disease, disorder, or condition treatable by activation of serotonin receptors is any disease, disorder, or condition that benefits from treatment with L-3,4-dihydroxyphenylalanine (L-DOPA).

35. The method of 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 to treat a disease, disorder or condition that benefits from treatment with L-DOPA.

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

37. The method of claim 34, wherein the disease, disorder or condition that benefits from treatment with L-DOPA is Parkinson's disease.

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

39. The method of any one of claims 11 to 34, wherein the method treats at least one sign or symptom of a disease, disorder or condition that can be treated by activating serotonin receptors following administration of an enantiomerically pure compound of formula (R)-I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt and / or solvate thereof, to a subject in need thereof.

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

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

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

43. The method of claim 42, wherein the serotonin receptor is 5-HT 2A .

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

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

46. ​​The method of claim 44 or claim 45, wherein the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, hypothermia, cardiotoxicity, and substance use disorder.

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

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

49. The method of claim 45, wherein the reduced risk of adverse side effects is achieved by interacting with 5-hydroxytryptamine 2A (5-HT 2A ) receptor, the use of a composition according to any one of claims 12 to 30 binds to the 5-hydroxytryptamine 2B receptor (5-HT 2B) with lower affinity than a composition comprising a racemic compound of formula (R / S)-I 2B )combined.

50. A method according to any one of claims 42 to 49, wherein the disease, disorder or condition treatable by activation of serotonin receptors is a disease, disorder or condition that benefits from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof.

51. The method of any one of claims 42 to 49, wherein the disease, disorder or condition treatable by activation of serotonin receptors is any disease, disorder or condition that benefits from psychotherapy.

52. The method of claim 51, wherein the disease, disorder or condition that benefits from psychotherapy is selected from post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction and eating disorders.

53. The method of claim 51 or 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 to treat the disease, disorder or condition.

54. The method of any one of claims 42 to 49, wherein the disease, disorder or condition treatable by activation of serotonin receptors is one or more psychiatric disorders.

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

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

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

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

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

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

62. The method of claim 54, wherein the psychiatric disorder is selected from schizophrenia and other disorders causing dissociation from reality.

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

64. The method of claim 63, wherein the disease, disorder or condition treatable by activation of serotonin receptors is an autism spectrum disorder.

65. The method of claim 42, wherein the disease, disorder, or condition treatable by activation of serotonin receptors is any disease, disorder, or condition that benefits from treatment with L-3,4-dihydroxyphenylalanine (L-DOPA).

66. The method of claim 65, wherein the composition is administered in combination with L-DOPA to treat a disease, disorder or condition that benefits from treatment with L-DOPA.

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

68. The method of claim 65, wherein the disease, disorder or condition that benefits from treatment with L-DOPA is Parkinson's disease.

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

70. The method of any one of claims 42 to 65, wherein the method treats at least one sign or symptom of a disease, disorder, or condition that can be treated by activating serotonin receptors following administration of a composition according to any one of claims 6 to 10 to an individual in need thereof.

71. The method of claim 70, wherein the disease, disorder or condition treatable by activation of serotonin receptors is anxiety disorder and the method treats at least one sign or symptom of the anxiety disorder.

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

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

74. A method for preparing a compound of formula (R)-I or (S)-I: The method comprises: The compound of formula (R)-A or (S)-A Wherein L is selected from halogen and C(O)OR 2 , R 1 is unsubstituted or substituted benzyl; and R 2 It is C 1-6 Alkyl, or In the compound of formula (R)-A, R 2 yes Or in the compound of formula (S)-A, R 2 yes reacting with a compound of formula B in the presence of a Lewis acid, to provide compounds of formula (R)-C and (S)-C, respectively; and Where R 1 is unsubstituted or substituted benzyl; The compounds of formula (R)-C and (S)-C are converted into compounds of formula (R)-I or (S)-I, respectively.

75. The method of claim 74, wherein L is a halogen selected from Cl, Br and I.

76. The method of claim 75, wherein L is Cl.

77. The method of claim 74, wherein L is C(O)OR 2 .

78. The method of claim 77, wherein R 2 It is C 1-4 alkyl.

79. The method of claim 77, wherein in the compound of formula (R)-A, R 2 yes Or in the compound of formula (S)-A, R 2 yes 80. The method of any one of claims 74 to 79, wherein R 1 It is an unsubstituted benzyl group.

81. The method of any one of claims 74 to 79, wherein R 1 is one or more selected from NO2, Br, Cl, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted benzyl.

82. The method of any one of claims 74 to 81, wherein the Lewis acid is selected from BF3, AlCl3, SbCl5, SbF5, InCl3, GaCl3, BCl3, FeCl3, SnCl4, TiCl4, Mo2Cl 10 and AlBr3 and combinations thereof.

83. The method of claim 83, wherein the Lewis acid is AlCl3.

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

85. The method of claim 84, wherein the solvent is dichloromethane.

86. The method of claim 74, wherein the compounds of formula (R)-C and (S)-C are converted into the compounds of formula (R)-I or (S)-I, respectively, using a one-step process in the presence of H2 and a catalyst.

87. The method of claim 86, wherein the catalyst is a nickel, palladium or platinum catalyst.

88. The method of claim 97, wherein the catalyst is a palladium catalyst.

89. The method of claim 88, wherein the palladium catalyst is palladium on carbon (Pd / C).

90. The method of claim 74, wherein the compounds of formula (R)-C and (S)-C are converted to the compounds of formula (R)-I or (S)-I, respectively, using a two-step process comprising: Reducing said compounds of formula (R)-C and (S)-C with a suitable reducing agent to provide compounds of formula (R)-D and (S)-D, respectively, and Where R 1 is unsubstituted or substituted benzyl, The (R)-D and (S)-D compounds are deprotected to provide the compounds of formula (R)-I or (S)-I, respectively.

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

92. A method according to claim 90 or claim 91, wherein deprotecting the compounds of (R)-D and (S)-D to provide the compounds of formula (R)-I or (S)-I, respectively, is carried out in the presence of H2 and a catalyst.

93. The method of any one of claims 74 to 92, wherein the method provides the compound of formula (R)-I or (S)-I, respectively, as the major isomer.

94. The composition of any one of claims 6 to 10, wherein the composition is an intranasal composition.

95. A composition according to any one of claims 6 to 10, wherein the composition is a sublingual composition.

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